ORCID Profile
0000-0002-7514-3298
Current Organisations
Walter and Eliza Hall Institute of Medical Research
,
Peter MacCallum Cancer Centre
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Publisher: Springer Science and Business Media LLC
Date: 29-03-2019
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618428
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641326
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618425
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641323
Abstract: Table S11
Publisher: Wiley
Date: 11-05-2022
DOI: 10.1111/BJH.18240
Abstract: Hypomethylating agents remain the current standard of care for patients with higher‐risk myelodysplastic syndromes. Adès et al. report outcomes from a randomised ‘pick‐a‐winner’ study design that examined the addition of either lenalidomide, valproic acid or idarubicin in combination with azacitidine, compared to azacitidine alone. Commentary on: Adès et al. A randomised phase II study of azacitidine (AZA) alone or with lenalidomide (LEN), valproic acid (VPA) or idarubicin (IDA) in higher‐risk MDS: GFM’s ‘pick a winner’ trial, with the impact of somatic mutations. Br J Haematol 2022 :535‐544.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618422
Abstract: Table S9: CEBPA_UP signature
Publisher: Wiley
Date: 02-2008
Publisher: Springer Science and Business Media LLC
Date: 10-07-2020
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532751
Abstract: AbstractPurpose: To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and i TP53 /i sup mut /sup or i TP53 /i sup wt /sup . Patients and Methods: We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1–28) + azacitidine (75 mg/m sup /sup days 1–7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. i TP53 /i status was analyzed centrally cytogenetic studies were performed locally. Results: Patients ( i n /i = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine ( i TP53 /i sup wt /sup = 50 i TP53 /i sup mut /sup = 54) were compared with patients with poor-risk cytogenetics ( i n /i = 56) receiving azacitidine alone ( i TP53 /i sup wt /sup = 22 i TP53 /i sup mut /sup = 18). For poor-risk cytogenetics + i TP53 /i sup wt /sup patients, venetoclax + azacitidine versus azacitidine alone resulted in composite remission rates (CRc) of 70% versus 23%, median duration of remission (DoR) of 18.4 versus 8.5 months, and median overall survival (OS) of 23.4 versus 11.3 months, respectively. Outcomes with venetoclax + azacitidine were comparable with similarly treated patients with intermediate-risk cytogenetics and i TP53 /i sup wt /sup . For poor-risk cytogenetics + i TP53 /i sup mut /sup patients, venetoclax + azacitidine versus azacitidine alone resulted in CRc of 41% versus 17%, median DoR of 6.5 versus 6.7 months, and median OS of 5.2 versus 4.9 months, respectively. For poor-risk cytogenetics + i TP53 /i sup mut /sup patients, predominant grade ≥3 adverse events (AE) for venetoclax + azacitidine versus azacitidine were febrile neutropenia (55%/39%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/6%), and pneumonia (28%/33%). AEs were comparable between i TP53 /i sup mut /sup and i TP53 /i sup wt /sup patients. Conclusions: In poor-risk cytogenetics + i TP53 /i sup mut /sup patients, venetoclax + azacitidine improved remission rates but not DoR or OS compared with azacitidine alone. However, in poor-risk cytogenetics + i TP53 /i sup wt /sup patients, venetoclax + azacitidine resulted in higher remission rates and longer DoR and OS than azacitidine alone, with outcomes comparable with similarly treated patients with intermediate-risk cytogenetics. Toxicities were similar in i TP53 /i sup mut /sup and i TP53 /i sup wt /sup patients. i a href="lincancerres/article/doi/10.1158/1078-0432.CCR-22-2664" target="_blank" See related commentary by Green and Zeidner, p. 5235 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641329
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541170.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: Informa UK Limited
Date: 2008
Publisher: Wiley
Date: 27-05-2022
DOI: 10.1002/AJH.26589
Abstract: Therapy‐related myeloid neoplasms (t‐MN) are aggressive malignancies in need of effective therapies. The BCL‐2 inhibitor venetoclax represents a paradigm shift in the treatment of acute myeloid leukemia. However, the effectiveness of venetoclax has not been studied in a large cohort of t‐MN. We retrospectively analyzed 378 t‐MN patients, of which 96 (25.4%, 47 therapy‐related acute myeloid leukemia, 1 therapy‐related chronic myelomonocytic leukemia, 48 therapy‐related myelodysplastic syndrome) received venetoclax. Median interval from t‐MN to venetoclax initiation was 2.9 (Interquartile range [IQR] 0.7–12) months, and patients received a median of 3 (IQR 1–4) cycles. The composite complete remission (CRc) rate, median progression‐free survival (PFS), and overall survival (OS) were 39.1%, 4.9 months, and 7 months, respectively. The upfront use of venetoclax and achieving CRc were associated with improved survival, whereas the presence of Chromosome 7 abnormalities was associated with an inferior survival. Neither the TP53‐status nor the percent bone marrow blast predicted the likelihood of CRc or survival. Paired genetic analysis performed at venetoclax initiation and failure did not show the evidence of the selection of the TP53 ‐mutated clone. In a propensity‐matched analysis, the use of venetoclax‐based regimen as the first‐line therapy was associated with a superior survival compared to hypomethylating agent (HMA)‐based first‐line therapy (9.4 vs. 6.1 months, p = .01). We conclude that the upfront use of venetoclax with HMA improved survival, though PFS and OS remain poor. As the phenotype at diagnosis or the percent blasts did not predict outcomes, venetoclax should be studied in all t‐MN phenotypes.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541182
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541188
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: Informa UK Limited
Date: 21-11-2020
DOI: 10.1080/10428194.2019.1691192
Abstract: Recent regulatory approval of midostaurin, a FLT3 targeting small molecular inhibitor, will likely lead to increased use of midostaurin in combination with intensive chemotherapy for patients with
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.CCELL.2018.11.004
Abstract: Defects in apoptotic cell death can promote cancer and impair responses of malignant cells to anti-cancer therapy. Pro-survival BCL-2 proteins prevent apoptosis by keeping the cell death effectors, BAX and BAK, in check. The BH3-only proteins initiate apoptosis by neutralizing the pro-survival BCL-2 proteins. Structural analysis and medicinal chemistry led to the development of small-molecule drugs that mimic the function of the BH3-only proteins to kill cancer cells. The BCL-2 inhibitor venetoclax has been approved for treatment of refractory chronic lymphocytic leukemia and this drug and inhibitors of pro-survival MCL-1 and BCL-XL are being tested in erse malignancies.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541185
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641320
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579598.V1
Abstract: Table S9: CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641320.V1
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: Massachusetts Medical Society
Date: 24-12-2020
Publisher: American Society of Hematology
Date: 07-12-2017
DOI: 10.1182/BLOOD-2017-08-784066
Abstract: In 2017, 4 drugs received US Food and Drug Administration marketing approval for acute myeloid leukemia (AML) treatment: targeted therapies for mutant FLT3 and IDH2, a liposomal cytarabine-daunorubicin formulation for therapy-related AML and AML with myelodysplasia-related changes, and resurgence of an antibody-drug conjugate designed to target CD33. Promising results also emerged for the BCL-2 inhibitor venetoclax combined with low-intensity therapy in older patients unfit for intensive chemotherapy. This quintet of new drugs is likely to reshape the therapeutic landscape of AML.
Publisher: American Society of Hematology
Date: 04-2021
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579643
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: Informa UK Limited
Date: 05-04-2019
DOI: 10.1080/10428194.2019.1576872
Abstract: Outcomes for adults with relapsed/refractory acute lymphoblastic leukemia (ALL) are poor with chemotherapy, particularly in later salvage. The TOWER study examined survival, remission, bridge to allogeneic hematopoietic stem cell transplantation (HSCT), and safety with blinatumomab versus chemotherapy. This report examined outcomes separately for study treatment as first or later salvage. Adults with Philadelphia chromosome-negative B-cell precursor ALL relapsed/refractory to chemotherapy were randomly assigned 2:1 to receive blinatumomab by continuous infusion for 4 weeks in 6-week cycles, or standard salvage chemotherapy. Overall survival for blinatumomab versus chemotherapy was higher both in first salvage and in later salvage. Safety was similar between patients in first salvage and those in later salvage. Blinatumomab as later salvage was associated with higher complete remission rates and served as a bridge to allogeneic HSCT, supporting the use of blinatumomab in both settings. This study is registered at www.clinicaltrials.gov as #NCT02013167.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641317
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641314.V1
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-03-2017
Publisher: Elsevier BV
Date: 08-2020
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641314
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579640
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618437
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Society of Hematology
Date: 30-03-2023
Publisher: American Society of Hematology
Date: 09-02-2023
Abstract: Randomized trials in acute myeloid leukemia (AML) have demonstrated improved survival by the BCL-2 inhibitor venetoclax combined with azacitidine in older patients, and clinical trials are actively exploring the role of venetoclax in combination with intensive chemotherapy in fitter patients with AML. As most patients still develop recurrent disease, improved understanding of relapse mechanisms is needed. We find that 17% of patients relapsing after venetoclax-based therapy for AML have acquired inactivating missense or frameshift/nonsense mutations in the apoptosis effector gene BAX. In contrast, such variants were rare after genotoxic chemotherapy. BAX variants arose within either leukemic or preleukemic compartments, with multiple mutations observed in some patients. In vitro, AML cells with mutated BAX were competitively selected during prolonged exposure to BCL-2 antagonists. In model systems, AML cells rendered deficient for BAX, but not its close relative BAK, displayed resistance to BCL-2 targeting, whereas sensitivity to conventional chemotherapy was variable. Acquired mutations in BAX during venetoclax-based therapy represent a novel mechanism of resistance to BH3-mimetics and a potential barrier to the long-term efficacy of drugs targeting BCL-2 in AML.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618434
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641311
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Association for Cancer Research (AACR)
Date: 21-01-2022
DOI: 10.1158/1078-0432.CCR-21-3405
Abstract: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with FLT3-mutant acute myeloid leukemia. Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1–28) and azacitidine (75 mg/m2 days 1–7/28-day cycle). FLT3 mutation was analyzed centrally on pretreatment bone marrow aspirates. In the biomarker evaluable population, FLT3 mutation was detected in 42 (15%) and 22 (19%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc complete remission (CR) + CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) for FLT3-mutant patients were 67%/36%, median duration of remission (DoR) was 17.3/5.0 months, and median OS was 12.5/8.6 months. The CRc rates among FLT3 wild-type patients were 67%/25%, median DoR 18.4/13.4 months, and median OS 14.7/10.1 months. In patients treated with venetoclax + azacitidine, CRc in patients with FLT3-ITD and FLT3-TKD was 63% and 77% and median OS was 9.9 and 19.2 months, and in comutated FLT3-ITD + NPM1 patients, CRc was 70%, median DoR was not reached, and median OS was 9.1 months. There were no unexpected toxicities in the venetoclax + azacitidine group. When treated with venetoclax + azacitidine, patients with FLT3 mutations and FLT3 wild-type had similar outcomes. Future analyses in larger patient populations may further define the impact of venetoclax + azacitidine in patients harboring FLT3-ITD. See related commentary by Perl and Vyas, p. 2719
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618431
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541194
Abstract: Supplementary Figure from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: Research Square Platform LLC
Date: 12-2021
DOI: 10.21203/RS.3.RS-1083624/V1
Abstract: The enhancer of zeste homolog 2 (EZH2) oncogene is a histone methyltransferase that functions canonically as a catalytic subunit of the polycomb repressive complex 2 (PRC2) to tri-methylate histone H3 at Lys 27 (H3K27me3). Although targeting of EZH2 methyltransferase is a promising therapeutic strategy against cancer, methyltransferase-independent oncogenic functions of EZH2 are also described. Moreover, pharmacological EZH2 methyltransferase inhibition was only variably effective in pre-clinical and clinical studies, suggesting that targeting EZH2 methyltransferase alone may be insufficient. Here, we demonstrate a non-canonical mechanism of EZH2’s oncogenic activity through interactions with inosine monophosphate dehydrogenase 2 (IMPDH2) and downstream promotion of guanosine-5'-triphosphate (GTP) production. Liquid Chromatography-Mass Spectrometry (LC-MS) of EZH2 immunoprecipitates from melanoma cell lines and human patient-derived xenografts (PDXs) revealed EZH2-IMPDH2 interactions that were verified to occur between the N-terminal EED-binding domain of cytosolic EZH2 and the CBS domain of IMPDH2 in a PRC2- and methylation-independent manner. EZH2 silencing reduced cellular GTP, ribosome biogenesis, RhoA-mediated actomyosin contractility and melanoma cell proliferation and invasion by impeding the activity and cytosolic localization of IMPDH2. Guanosine, which replenishes GTP, reversed these effects and thereby promoted invasive and clonogenic cell states even in EZH2 silenced cells. IMPDH2 silencing antagonized the proliferative and invasive effects of EZH2, also in a guanosine-reversible manner. In human melanomas, high cytosolic EZH2 and IMPDH2 expression were associated with nucleolar enlargement, a marker for ribosome biogenesis. We also identified EZH2-IMPDH2 complexes in a range of cancers in which Sappanone A (SA), which inhibits EZH2-IMPDH2 interactions and thereby IMPDH2 tetramerization, was anti-tumorigenic, although notably non-toxic in normal human melanocytes and bone marrow derived blood progenitor cells that lacked observable EZH2-IMPDH2 interactions. These findings illuminate a previously unrecognized, non-canonical, methyltransferase-independent, but GTP-dependent mechanism by which EZH2 regulates tumorigenicity in melanoma and other cancers, opening new avenues for development of anti-EZH2 therapeutics.
Publisher: Public Library of Science (PLoS)
Date: 23-12-2010
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579637.V1
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618464.V1
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.BMC.2015.08.035
Abstract: The serine-threonine kinase CDK9 is a target of emerging interest for the development of anti-cancer drugs. There are multiple lines of evidence linking CDK9 activity to cancer, including the essential role this kinase plays in transcriptional regulation through phosphorylation of the C-terminal domain (CTD) of RNA polymerase II. Indeed, inhibition of CDK9 has been shown to result in a reduction of short-lived proteins such as the pro-survival protein Mcl-1 in malignant cells leading to the induction of apoptosis. In this work we report our initial studies towards the discovery of selective CDK9 inhibitors, starting from the known multi-kinase inhibitor PIK-75 which possesses potent CDK9 activity. Our series is based on a pyrazolo[1,5-a]pyrimidine nucleus and, importantly, the resultant lead compound 18b is devoid of the structural liabilities present in PIK-75 and possesses greater selectivity.
Publisher: Springer Science and Business Media LLC
Date: 09-2008
DOI: 10.1038/NM0908-917
Publisher: Wiley
Date: 08-10-2015
DOI: 10.1002/AJH.24179
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579643.V1
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641308.V1
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: Elsevier BV
Date: 2018
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579649
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: American Society of Hematology
Date: 05-07-2022
DOI: 10.1182/BLOODADVANCES.2022007083
Abstract: The clinical benefit of adding venetoclax (VEN) to hypomethylating agents or low-dose cytarabine in older and/or unfit patients with newly diagnosed acute myeloid leukemia (AML) has been confirmed in phase 3 studies. With the increased uptake of VEN-based therapies for patients with AML, a pertinent question is whether treatment can be safely ceased among patients who have achieved sustained remission. We hypothesized that a proportion of patients opting to cease therapy may benefit from a treatment-free remission (TFR) period without indefinite treatment. We report the retrospective outcomes of 29 patients in remission for a minimum of 12 months on VEN-based therapy, with 55% continuing therapy until disease progression and 45% electively ceasing treatment (STOP). With follow-up exceeding 5 years, we observed a median TFR lasting 45.8 months among the STOP cohort, with & % of patients still in sustained remission at the data cutoff. The risk of relapse and duration of relapse-free and overall survival were similar between the 2 cohorts. Factors favoring sustained TFR within the cohort included NPM1 and/or IDH2 mutation at diagnosis, complete remission without measurable residual disease, and at least 12 months of VEN-based combination therapy prior to treatment cessation.
Publisher: Future Medicine Ltd
Date: 05-2020
Abstract: Patients with refractory or relapsed acute myeloid leukemia (R/R AML) have a poor prognosis, with a high unmet medical need. Idasanutlin is a small-molecule inhibitor of MDM2, a negative regulator of tumor suppressor p53. By preventing the p53–MDM2 interaction, idasanutlin allows for p53 activation, particularly in patients with TP53 wild-type (WT) status. MIRROS (NCT02545283) is a randomized Phase III trial evaluating idasanutlin + cytarabine versus placebo + cytarabine in R/R AML. The primary end point is overall survival in the TP53-WT population. Secondary end points include complete remission rate (cycle 1), overall remission rate (cycle 1) and event-free survival in the TP53-WT population. MIRROS has an innovative design that integrates a stringent interim analysis for futility continuation criteria were met in mid-2017 and accrual is ongoing. Trial registration number: NCT02545283
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541191
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579646
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541164.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-10-2020
DOI: 10.1200/JCO.20.00572
Abstract: The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax has an emerging role in acute myeloid leukemia (AML), with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients. The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown. Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). Venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose r -up (days −6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m 2 on days 1-5 and idarubicin 12 mg/m 2 intravenously on days 2-3 (ie, 5 + 2). Consolidation (4 cycles) included 14 days of venetoclax (days −6 to 7) combined with cytarabine (days 1-2) and idarubicin (day 1). Maintenance venetoclax was permitted (7 cycles). The primary objective was to assess the optimal dose schedule of venetoclax with 5 + 2. Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72% it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in NPM1-, IDH2-, and SRSF2-mutant AML. Venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618449
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579625.V1
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579631.V1
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618446
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618443
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: American Society of Hematology
Date: 02-2023
Abstract: Myelodysplastic syndromes/neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. While the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS and in their ability to fully capture clinical benefits of novel investigational drugs or to serve as valid surrogates for longer-term clinical endpoints (e.g., overall survival). Further, issues related to ambiguity and practicality of some criteria lead to variability in interpretation and inter-observer inconsistency in reporting results from the same sets of data. Thus, we convened an international panel of 36 MDS experts and used an established modified Delphi process to develop consensus recommendations for updated response criteria that would be more reflective of patient-centered and clinically relevant outcomes in higher-risk MDS. Among others, the IWG 2023 criteria include changes in the hemoglobin threshold for complete remission (CR), the introduction of CR with limited count recovery (CRL) and CR with partial hematologic recovery (CRh) as provisional response criteria, elimination of marrow CR, and specific recommendations for standardization of time-to-event endpoints and the derivation and reporting of responses. The updated criteria should lead to better correlation between patient-centered outcomes and clinical trial results in an era of multiple emerging new agents with novel mechanisms of action.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618440
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618470.V1
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: Springer Science and Business Media LLC
Date: 21-08-2013
DOI: 10.1007/S00520-013-1938-9
Abstract: Patients having undergone allogeneic stem cell transplantation (SCT) require complex medication regimens. To ensure the safe and effective management of this patient group, specialised care in a centre with a dedicated and experienced healthcare team is essential. The aim of this study was to evaluate the effectiveness of a specialty clinical pharmacist working in an ambulatory SCT clinic. A prospective cohort study was conducted on patients post SCT and discharged to the ambulatory setting. Patients were reviewed by a clinical pharmacist weekly for six visits. At these visits a medication review was undertaken. Interventions from these reviews were recorded. Interventions were then assigned a risk rating by a multidisciplinary panel. Adherence was also assessed by a Morisky questionnaire and review of dose administration aids. Comparison of data over the six-visit period was undertaken. In total 23 patients were enrolled in the study. All six visits were completed in 17 patients and 161 interventions were recorded at an average of 1.4 interventions per patient visit. The panel rated 40 % of interventions as high risk, 46 % as medium risk and 14 % as low risk. At all visit points high- and medium-risk interventions constituted >80 % of the total. Morisky scores improved by an average of 1.53 (p < 0.0001) between visits 1 and 6. All patients were scored as highly adherent by visit 6. A specialist clinical pharmacist in the SCT outpatient clinic resulted in regular and effective intervention contributing to improved medication management and adherence.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2011
DOI: 10.1038/LEU.2011.201
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541194.V1
Abstract: Supplementary Figure from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: Wiley
Date: 06-2010
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641332.V1
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641326.V1
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Society of Hematology
Date: 20-10-2020
DOI: 10.1182/BLOODADVANCES.2020001576
Abstract: The specific targeting of inhibitor of apoptosis (IAP) proteins by Smac-mimetic (SM) drugs, such as birinapant, has been tested in clinical trials of acute myeloid leukemia (AML) and certain solid cancers. Despite their promising safety profile, SMs have had variable and limited success. Using a library of more than 5700 bioactive compounds, we screened for approaches that could sensitize AML cells to birinapant and identified multidrug resistance protein 1 inhibitors (MDR1i) as a class of clinically approved drugs that can enhance the efficacy of SM therapy. Genetic or pharmacological inhibition of MDR1 increased intracellular levels of birinapant and sensitized AML cells from leukemia murine models, human leukemia cell lines, and primary AML s les to killing by birinapant. The combination of clinical MDR1 and IAP inhibitors was well tolerated in vivo and more effective against leukemic cells, compared with normal hematopoietic progenitors. Importantly, birinapant combined with third-generation MDR1i effectively killed murine leukemic stem cells (LSCs) and prolonged survival of AML-burdened mice, suggesting a therapeutic opportunity for AML. This study identified a drug combination strategy that, by efficiently killing LSCs, may have the potential to improve outcomes in patients with AML.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532317.V1
Abstract: AbstractPurpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with i FLT3 /i -mutant acute myeloid leukemia. Patients and Methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1–28) and azacitidine (75 mg/m sup /sup days 1–7/28-day cycle). i FLT3 /i mutation was analyzed centrally on pretreatment bone marrow aspirates. Results: In the biomarker evaluable population, i FLT3 /i mutation was detected in 42 (15%) and 22 (19%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc complete remission (CR) + CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) for i FLT3 /i -mutant patients were 67%/36%, median duration of remission (DoR) was 17.3/5.0 months, and median OS was 12.5/8.6 months. The CRc rates among i FLT3 /i wild-type patients were 67%/25%, median DoR 18.4/13.4 months, and median OS 14.7/10.1 months. In patients treated with venetoclax + azacitidine, CRc in patients with i FLT3-ITD /i and i FLT3-TKD /i was 63% and 77% and median OS was 9.9 and 19.2 months, and in comutated i FLT3-ITD /i + i NPM1 /i patients, CRc was 70%, median DoR was not reached, and median OS was 9.1 months. There were no unexpected toxicities in the venetoclax + azacitidine group. Conclusions: When treated with venetoclax + azacitidine, patients with i FLT3 /i mutations and i FLT3 /i wild-type had similar outcomes. Future analyses in larger patient populations may further define the impact of venetoclax + azacitidine in patients harboring i FLT3-ITD. /i i a href="lincancerres/article/doi/10.1158/1078-0432.CCR-22-0279" target="_blank" See related commentary by Perl and Vyas, p. 2719 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541188.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641338
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: American Society of Hematology
Date: 30-09-2021
Abstract: BCL2 and MCL1 are commonly expressed prosurvival (antiapoptotic) proteins in hematologic cancers and play important roles in their biology either through dysregulation or by virtue of intrinsic importance to the cell-of-origin of the malignancy. A new class of small-molecule anticancer drugs, BH3 mimetics, now enable specific targeting of these proteins in patients. BH3 mimetics act by inhibiting the prosurvival BCL2 proteins to enable the activation of BAX and BAK, apoptosis effectors that permeabilize the outer mitochondrial membrane, triggering apoptosis directly in many cells and sensitizing others to cell death when combined with other antineoplastic drugs. Venetoclax, a specific inhibitor of BCL2, is the first approved in class, demonstrating striking single agent activity in chronic lymphocytic leukemia and in other lymphoid neoplasms, as well as activity against acute myeloid leukemia (AML), especially when used in combination. Key insights from the venetoclax experience include that responses occur rapidly, with major activity as monotherapy proving to be the best indicator for success in combination regimens. This emphasizes the importance of adequate single-agent studies for drugs in this class. Furthermore, secondary resistance is common with long-term exposure and often mediated by genetic or adaptive changes in the apoptotic pathway, suggesting that BH3 mimetics are better suited to limited duration, rather than continuous, therapy. The success of venetoclax has inspired development of BH3 mimetics targeting MCL1. Despite promising preclinical activity against MYC-driven lymphomas, myeloma, and AML, their success may particularly depend on their tolerability profile given physiological roles for MCL1 in several nonhematologic tissues.
Publisher: American Society of Hematology
Date: 25-05-2017
DOI: 10.1182/BLOOD-2016-05-718171
Abstract: Inhibition of RNA Pol I by CX-5461 treats aggressive AML and outperforms standard chemotherapy regimens. CX-5461 induces p53-dependent apoptosis, p53-independent cell-cycle defects and differentiation, and reduces LICs.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618458
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549562
Abstract: Abstract Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies. Significance: We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition. i This article is highlighted in the In This Issue feature, p. 1397 /i /
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488524.V1
Abstract: Supplementary Figure from Outcomes in Patients with Poor-Risk Cytogenetics with or without i TP53 /i Mutations Treated with Venetoclax and Azacitidine
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641332
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488518.V1
Abstract: Supplementary Table from Outcomes in Patients with Poor-Risk Cytogenetics with or without i TP53 /i Mutations Treated with Venetoclax and Azacitidine
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618455
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: American Society of Hematology
Date: 28-03-2019
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618431.V1
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618452
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: Informa UK Limited
Date: 2007
Publisher: American Society of Hematology
Date: 14-06-2023
Publisher: Springer Science and Business Media LLC
Date: 10-09-2019
Publisher: Elsevier BV
Date: 08-2017
Publisher: American Association for Cancer Research (AACR)
Date: 21-03-2022
DOI: 10.1158/2159-8290.CD-20-1145
Abstract: We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition. This article is highlighted in the In This Issue feature, p. 1397
Publisher: Cold Spring Harbor Laboratory
Date: 18-05-2005
DOI: 10.1101/GAD.1304105
Abstract: Commitment of cells to apoptosis is governed largely by the interaction between members of the Bcl-2 protein family. Its three subfamilies have distinct roles: The BH3-only proteins trigger apoptosis by binding via their BH3 domain to prosurvival relatives, while the proapoptotic Bax and Bak have an essential downstream role involving permeabilization of organellar membranes and induction of caspase activation. We have investigated the regulation of Bak and find that, in healthy cells, Bak associates with Mcl-1 and Bcl-x L but surprisingly not Bcl-2, Bcl-w, or A1. These interactions require the Bak BH3 domain, which is also necessary for Bak dimerization and killing activity. When cytotoxic signals activate BH3-only proteins that can engage both Mcl-1 and Bcl-x L (such as Noxa plus Bad), Bak is displaced and induces cell death. Accordingly, the BH3-only protein Noxa could bind to Mcl-1, displace Bak, and promote Mcl-1 degradation, but Bak-mediated cell death also required neutralization of Bcl-x L by other BH3-only proteins. The results indicate that Bak is held in check solely by Mcl-1 and Bcl-x L and induces apoptosis only if freed from both. The finding that different prosurvival proteins have selective roles has notable implications for the design of anti-cancer drugs that target the Bcl-2 family.
Publisher: Springer Science and Business Media LLC
Date: 18-03-2014
DOI: 10.1038/LEU.2014.105
Publisher: Proceedings of the National Academy of Sciences
Date: 16-07-2019
Abstract: It is believed that the Bcl-2 family protein Bok has a redundant role similar to Bax and Bak in regulating apoptosis. We report that this protein interacts with the key enzyme involved in uridine biosynthesis, uridine monophosphate synthetase, and positively regulates uridine biosynthesis and chemoconversion of 5-fluorouracil (5-FU). Bok-deficient cell lines are resistant to 5-FU. Bok down-regulation is a key feature of cell lines and primary colorectal tumor tissues that are resistant to 5-FU. Our data also show that through its impact on nucleotide metabolism, Bok regulates p53 level and cellular proliferation. Our results have implications for developing Bok as a biomarker for 5-FU resistance and for the development of BOK mimetics for sensitizing 5-FU-resistant cancers.
Publisher: Wiley
Date: 16-05-2014
DOI: 10.1002/AJH.23746
Abstract: A major limitation to improved outcomes in acute myelogenous leukemia (AML) is relapse resulting from leukemic cells that persist at clinical remission. Regulatory T cells (Tregs), which are increased in AML patients, can contribute to immune evasion by residual leukemic cells. Tumor necrosis factor (TNF), a pro-inflammatory cytokine present at high levels within patients, can induce TNF receptor-2 (TNFR2) expression on Tregs. We hypothesized that since TNFR2 is required for Treg stabilization and TNFR2+ Tregs are potent suppressors, targeting TNFR2+ Tregs may restore the effectiveness of immune-surveillance mechanisms. In this pilot study, we report AML patients in clinical remission have substantially increased levels of TNFR2+ T cells, including TNFR2+ Tregs and impaired effector CD4 T cell function with reduced IL-2 and IFNγ production. The immunomodulatory drug, lenalidomide, and the demethylating agent, azacitidine have been moderately successful in treating AML patients, but their combined effects on TNFR2+ T cells, including Tregs are currently unknown. Our data indicates that although treatment with lenalidomide and azacitidine increased cytokine production by effector T cells in all patients, durable clinical remissions may be observed in patients with a concomitant reduction in TNFR2+ T cells and TNFR2+ Tregs. In vitro studies further demonstrated that lenalidomide can reduce TNFR2 expression and can augment effector cytokine production by T cells, which can be further enhanced by azacitidine. These results indicate that reduction of TNFR2+ T cells in AML postremission phase may result from combined azacitidine/lenalidomide therapy and may contribute to an improved clinical outcome.
Publisher: Wiley
Date: 26-05-2020
DOI: 10.1111/BJH.16722
Publisher: American Society of Hematology
Date: 26-01-2023
Abstract: Mutations in the nucleophosmin 1 gene (NPM1) occur frequently in acute myeloid leukemia (AML) and are associated with a favorable prognosis. Applying the new 2022 European LeukemiaNet (ELN) classifier, Angenendt et al tested the prognostic significance of the copresence of NPM1 mutations and adverse-risk cytogenetics among 2426 patients. The authors demonstrate that outcomes for cytogenetic adverse-risk AML are not modulated by the presence or absence of NPM1 mutations, thereby clarifying management for patients.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641338.V1
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: Wiley
Date: 08-2014
DOI: 10.1111/IMJ.12478
Abstract: Induction chemotherapy for acute myeloid leukaemia (AML) is one of the most resource-intensive cancer therapies delivered in hospitals. To assess the health resource impact of different chemotherapy approaches for AML commonly used in Australia. A retrospective analysis was undertaken in 63 patients aged 18-55 years with AML given induction with either 7 + 3 (cytarabine 100 mg/m(2) days 1-7 and idarubicin 12 mg/m(2) days 1-3) or HiDAC-3 (high-dose cytarabine 3 g/m(2) twice daily days 1, 3, 5 and 7 and idarubicin 12 mg/m(2) days 1-3) chemotherapy. Average costs of hospitalisation, pathology, radiology, chemotherapy and ancillary drugs were calculated and compared with current Victorian casemix funding. Two consolidation approaches, HiDAC (cytarabine 3 g/m(2) twice daily days 1, 3, 5 and 7) × either three or four cycles (following 7 + 3) and IcE (idarubicin 12,mg/m(2) days 1-2, cytarabine 100 mg/m(2) × 5 days and etoposide 75 mg/m(2) × 5 days) × 2 cycles (following HiDAC-3) were modelled, using a policy of discharge following completion of chemotherapy with outpatient monitoring. The cost (in AUD) of induction was similar between 7 + 3 ($58,037) and HiDAC-3 ($56,902), with bed day costs accounting for 61-62% of the total expense. Blood bank costs ranked second, accounting for 15%. Accumulated costs for HiDAC consolidation were $44,289 for a three-cycle protocol and $59,052 for four cycles ($14,763 per cycle) versus $31,456 for two cycles of IcE consolidation ($15,728 per cycle). Overall, the classical 7 + 3 → HiDAC approach ($102,326/$117,089 for three or four consolidation cycles) incurs a greater cost than a HiDAC-3 → IcE × 2 approach ($88,358). For patients requiring complete hospitalisation until neutrophil recovery, the estimated costs of treatment will be even higher, ranging between $122,282 for HiDAC-3 → IcE × 2, $153,212 for 7 + 3 → HiDAC × 3 and $184,937 for 7 + 3 → HiDAC × 4. State-based casemix funding for non-complicated AML therapy is currently $74,013 for 7 + 3 → HiDAC × 4, $64,177 for 7 + 3 → HiDAC × 3 and $54,340 for HiDAC-3 → IcE × 2 based on outpatient recovery after consolidation chemotherapy. These calculations do not take into account additional resource implications associated with complications of consolidation chemotherapy or reinduction for treatment failure. Regimens minimising the total number of chemotherapy cycles may represent the most efficient use of limited health resources for the treatment of AML.
Publisher: Springer Science and Business Media LLC
Date: 28-11-2012
DOI: 10.1038/LEU.2012.346
Publisher: BMJ
Date: 06-2003
DOI: 10.1136/JCP.56.6.406
Abstract: The application of immunohistology to the spectrum of plasma cell disorders has yet to be incorporated widely into routine haematology practice. This technique enables the direct visualisation of specific surface and cytoplasmic antigens in the context of the in idual cell and the surrounding anatomical neighbourhood. This review outlines the role of bone marrow immunohistology in the laboratory evaluation of patients with suspected and established plasma cell neoplasms and its emerging role in understanding myeloma biology for possible future therapeutic application.
Publisher: Informa UK Limited
Date: 08-10-2009
DOI: 10.3109/10428190903288456
Abstract: Neurologic relapse of systemic diffuse large B-cell lymphoma (DLBCL) is associated with poor outcome. The existing literature about this specific entity is very limited. We present a retrospective analysis of patients with neurological relapse of DLBCL and correlate the outcome according to the disease stage at autologous stem cell transplantation (ASCT) and the cell of origin phenotype. Totally, 11 patients with neurologic relapse of DLBCL underwent ASCT, seven in complete remission (CR) and four with active disease. The conditioning regimens included LACE (six), BEAM (two), and Bu/Mel (three). Ten patients relapsed after ASCT. All patients with CNS relapse died of progressive disease. Patients with systemic relapse were salvaged by further treatment. The median disease free survival (DFS) and overall survival (OS) for patients in CR at ASCT is far superior than those with active disease at ASCT (24 and 33 months versus 3 and 5 months, respectively). For patients undergoing ASCT in CR, the germinal centre (GC) phenotype is associated with a superior DFS and OS as compared to non GC phenotype (36 and 40 months versus 3.5 months and 5 months, respectively). Patients with neurological relapse of DLBCL have a poor outcome after ASCT the outcome is worse for patients with non-GC phenotype irrespective of the disease stage at ASCT.
Publisher: Springer Science and Business Media LLC
Date: 28-02-2019
DOI: 10.1038/S41408-019-0190-Z
Abstract: Since the publication of the original article the authors noticed the the affiliation details for Paresh Vyas are incorrect. The correct affiliation details for this author are given below:
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641296.V1
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486449.V1
Abstract: Supplementary Table from Impact of i F /i i LT3 /i Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618434.V1
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579613.V1
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Society of Hematology
Date: 22-12-2022
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532317
Abstract: AbstractPurpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with i FLT3 /i -mutant acute myeloid leukemia. Patients and Methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1–28) and azacitidine (75 mg/m sup /sup days 1–7/28-day cycle). i FLT3 /i mutation was analyzed centrally on pretreatment bone marrow aspirates. Results: In the biomarker evaluable population, i FLT3 /i mutation was detected in 42 (15%) and 22 (19%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc complete remission (CR) + CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) for i FLT3 /i -mutant patients were 67%/36%, median duration of remission (DoR) was 17.3/5.0 months, and median OS was 12.5/8.6 months. The CRc rates among i FLT3 /i wild-type patients were 67%/25%, median DoR 18.4/13.4 months, and median OS 14.7/10.1 months. In patients treated with venetoclax + azacitidine, CRc in patients with i FLT3-ITD /i and i FLT3-TKD /i was 63% and 77% and median OS was 9.9 and 19.2 months, and in comutated i FLT3-ITD /i + i NPM1 /i patients, CRc was 70%, median DoR was not reached, and median OS was 9.1 months. There were no unexpected toxicities in the venetoclax + azacitidine group. Conclusions: When treated with venetoclax + azacitidine, patients with i FLT3 /i mutations and i FLT3 /i wild-type had similar outcomes. Future analyses in larger patient populations may further define the impact of venetoclax + azacitidine in patients harboring i FLT3-ITD. /i i a href="lincancerres/article/doi/10.1158/1078-0432.CCR-22-0279" target="_blank" See related commentary by Perl and Vyas, p. 2719 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486455.V1
Abstract: Supplementary Table from Impact of i F /i i LT3 /i Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Publisher: Springer Science and Business Media LLC
Date: 16-03-2020
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618440.V1
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: American Society of Hematology
Date: 03-01-2019
DOI: 10.1182/BLOOD-2018-08-868752
Abstract: Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (& %) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773).
Publisher: American Society of Hematology
Date: 13-10-2022
Abstract: The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial (ClinicalTrials.gov identifier: NCT01757535) evaluated oral azacitidine (Oral-AZA) in patients with acute myeloid leukemia (AML) in first remission after intensive chemotherapy (IC) who were not candidates for hematopoietic stem cell transplantation. Eligible patients were randomized 1:1 to Oral-AZA 300 mg or placebo for 14 days per 28-day cycle. We evaluated relapse-free survival (RFS) and overall survival (OS) in patient subgroups defined by NPM1 and FLT3 mutational status at AML diagnosis and whether survival outcomes in these subgroups were influenced by presence of post-IC measurable residual disease (MRD). Gene mutations at diagnosis were collected from patient case report forms MRD was determined centrally by multiparameter flow cytometry. Overall, 469 of 472 randomized patients (99.4%) had available mutational data 137 patients (29.2%) had NPM1 mutations (NPM1mut), 66 patients (14.1%) had FLT3 mutations (FLT3mut with internal tandem duplications [ITD], tyrosine kinase domain mutations [TKDmut], or both), and 30 patients (6.4%) had NPM1mut and FLT3-ITD at diagnosis. Among patients with NPM1mut, OS and RFS were improved with Oral-AZA by 37% (hazard ratio [HR], 0.63 95% confidence interval [CI], 0.41-0.98) and 45% (HR, 0.55 95% CI, 0.35-0.84), respectively, vs placebo. Median OS was improved numerically with Oral-AZA among patients with NPM1mut whether without MRD (48.6 months vs 31.4 months with placebo) or with MRD (46.1 months vs 10.0 months with placebo) post-IC. Among patients with FLT3mut, Oral-AZA improved OS and RFS by 37% (HR, 0.63 95% CI, 0.35-1.12) and 49% (HR, 0.51 95% CI, 0.27-0.95), respectively, vs placebo. Median OS with Oral-AZA vs placebo was 28.2 months vs 16.2 months, respectively, for patients with FLT3mut and without MRD and 24.0 months vs 8.0 months for patients with FLT3mut and MRD. In multivariate analyses, Oral-AZA significantly improved survival independent of NPM1 or FLT3 mutational status, cytogenetic risk, or post-IC MRD status.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618425.V1
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.BLRE.2018.03.006
Abstract: The International Working Group (IWG) response criteria for acute myeloid leukemia, published in 2003, have remained the standard by which the efficacy of new drugs is measured in clinical trials. Over the last decade, concepts related to treatment response have been challenged by several factors for ex le, the dissociation between early clinical response and survival outcome in older patients, the recognition that epigenetic and newer differentiating-agent therapies may produce delayed responses and also hematologic improvement/transfusion independence without a morphologic response, and evidence that remissions without minimal (or measurable) residual disease (MRD) may result in outcomes superior to those of morphologic remissions with persistent MRD. The evolving role of MRD status as a potential surrogate for predicting long-term survival has enhanced the clinical need to standardize and incorporate emerging technologies that enable deeper responses beyond those recognized by the IWG, and to pre-emptively identify patients at risk of early relapse. The potential for therapeutic interventions to erase MRD and alter the natural history represents an important and open research question. Reviewed here are some of the implications and challenges associated with establishing and incorporating new treatment response criteria, initially into clinical research, and eventually into real-world practice.
Publisher: Wiley
Date: 06-06-2018
DOI: 10.1111/EJH.13089
Abstract: Core-binding factor acute myeloid leukaemia (CBF AML) defined by t(8 )(q22 q22) or inv(16)(p13q22)/t(16 )(p13 q22) has a favourable prognosis however, 30%-40% of patients still relapse after chemotherapy. We sought to evaluate the risk factors for relapse in a de novo CBF AML cohort. A retrospective review of patients from four Australian tertiary centres from 2001 to 2012, comprising 40 t(8 ) and 30 inv(16) AMLs. Multivariate analysis identified age (P = .032) and white cell count (WCC)>40 (P = .025) as significant predictors for inferior OS and relapse, respectively. Relapse risk was higher in the inv(16) group vs the t(8 ) group (57% vs 18%, HR 4.31, 95% CI: 1.78-10.42, P = .001). Induction therapy had no bearing on OS or relapse-free survival (RFS) however, consolidation treatment with >3 cycles of intermediate-/high-dose cytarabine improved OS (P = .035) and RFS (P = .063). Five patients demonstrated post-treatment stable q PCR positivity without relapse. >3 consolidation cycles of intermediate-/high-dose cytarabine improves patient outcomes Age and inv(16) CBF AML subtype are predictors of inferior OS and RFS, respectively. Stable low-level MRD by qPCR does not predict relapse Similar OS in the inv(16) cohort compared to the t(8 ) cohort, despite a higher relapse rate, confirms salvageability of relapsed disease.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618446.V1
Abstract: Table S15: Relative quantification by lipid class
Publisher: American Society of Hematology
Date: 02-03-2022
Publisher: Springer Science and Business Media LLC
Date: 11-11-2021
DOI: 10.1038/S43018-021-00264-Y
Abstract: Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a 'MitoScore' signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with cytarabine (AraC) resistance and a high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) + AraC (but not to VEN + azacytidine). Single-cell transcriptomics of VEN + AraC-residual cell populations revealed adaptive resistance associated with changes in oxidative phosphorylation, electron transport chain complex and the TP53 pathway. Accordingly, treatment of VEN + AraC-resistant AML cells with electron transport chain complex inhibitors, pyruvate dehydrogenase inhibitors or mitochondrial ClpP protease agonists substantially delayed relapse following VEN + AraC. These findings highlight the central role of mitochondrial adaptation during AML therapy and provide a scientific rationale for alternating VEN + azacytidine with VEN + AraC in patients with a high MitoScore and to target mitochondrial metabolism to enhance the sensitivity of AML cells to currently approved therapies.
Publisher: American Society of Hematology
Date: 26-01-2017
DOI: 10.1182/BLOOD-2016-08-733196
Abstract: The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for ex le, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease.
Publisher: Wiley
Date: 09-10-2008
Publisher: Informa UK Limited
Date: 08-06-2017
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-07-2019
DOI: 10.1200/JCO.19.00400
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579601.V1
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 30-06-2015
Publisher: Wiley
Date: 10-11-2020
DOI: 10.1002/AJH.26039
Abstract: This analysis represents the longest‐term follow‐up for patients with acute myeloid leukemia (AML) treated with 400 mg of venetoclax plus azacitidine or decitabine. Adults with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in an open‐label, non‐randomized, multicenter phase 1b trial of venetoclax with azacitidine (AZA 75 mg/m 2 days 1‐7) or decitabine (DEC 20 mg/m 2 days 1‐5). Endpoints included safety, response rates (complete remission [CR], CR with incomplete blood count recovery [CRi]), response duration and overall survival (OS). The median follow‐up time was 29 and 40 months for patients treated with venetoclax plus AZA and DEC combinations, respectively. Key Grade ≥ 3 AEs (AZA and DEC) were febrile neutropenia (39% and 65%), anemia (30% and 26%), thrombocytopenia (25% and 23%), and neutropenia (20% and 10%). The CR/CRi rate was 71% for venetoclax plus AZA and 74% for venetoclax plus DEC. The median duration of CR/CRi was 21.9 months and 15.0 months, and the median OS was 16.4 months and 16.2 months, for venetoclax plus AZA and DEC, respectively. These results support venetoclax plus hypomethylating agents as highly effective frontline AML therapies for patients unfit for intensive chemotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/2159-8290.CD-22-0411
Abstract: FLT3 mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. This article is highlighted in the In This Issue feature, p. 1501
Publisher: Elsevier BV
Date: 10-2011
Publisher: Public Library of Science (PLoS)
Date: 07-05-2013
Publisher: Springer Science and Business Media LLC
Date: 10-2021
DOI: 10.1038/S41408-021-00555-8
Abstract: VIALE-C compared the safety and efficacy of venetoclax or placebo plus low-dose cytarabine (+LDAC) in patients with untreated AML ineligible for intensive chemotherapy. Overall, 211 patients were enrolled ( n = 143, venetoclax n = 68, placebo). At the primary analysis, the study did not meet its primary endpoint of a statistically significant improvement in overall survival (OS), however, ~60% of patients had been on study for ≤6-months. Here, we present an additional 6-months of follow-up of VIALE-C (median follow-up 17.5 months range 0.1–23.5). Median OS was (venetoclax +LDAC vs. placebo +LDAC) 8.4 vs. 4.1 months (HR = 0.70, 95% CI 0.50,0.99 P = 0.040) a 30% reduction in the risk of death with venetoclax. Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 48.3% vs. 13.2%. Transfusion independence rates (RBC) were 43% vs.19% and median event-free survival was 4.9 vs. 2.1 months (HR = 0.61 95% CI 0.44,0.84 P = 0.002). These results represent improved efficacy over the primary analysis. Incidence of grade ≥3 adverse events were similar between study arms and overall safety profiles were comparable to the primary analysis. These data support venetoclax +LDAC as a frontline treatment option for patients with AML ineligible for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.
Publisher: American Chemical Society (ACS)
Date: 26-06-2013
DOI: 10.1021/JM400556W
Abstract: Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-XL inhibitors originating from a high-throughput screening c aign. Small structural changes to the hit compound increased binding affinity more than 300-fold (to IC50 < 20 nM). This molecular series exhibits drug-like characteristics, low molecular weights (Mw < 450), and unprecedented selectivity for Bcl-XL. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-XL. Biological experiments using engineered Mcl-1 deficient mouse embryonic fibroblasts (MEFs, reliant only on Bcl-XL for survival) and Bax/Bak deficient MEFs (insensitive to selective activation of Bcl-2-driven apoptosis) support a mechanism-based induction of apoptosis. This manuscript describes the first series of selective small-molecule inhibitors of Bcl-XL and provides promising leads for the development of efficacious therapeutics against solid tumors and chemoresistant cancer cell lines.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641305
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579598
Abstract: Table S9: CEBPA_UP signature
Publisher: Wiley
Date: 15-05-2020
DOI: 10.1111/EJH.13431
Publisher: Informa UK Limited
Date: 21-06-2022
Publisher: Informa UK Limited
Date: 08-09-2012
DOI: 10.3109/10428194.2012.713479
Abstract: Improved therapeutic options for relapsing patients with acute myeloid leukemia (AML) are urgently needed. Poor outcomes following salvage therapy have been reported in those with short initial remission duration, adverse risk karyotype, prior allograft, older age, FLT3-internal tandem duplication (ITD) AML and prior high-dose cytarabine (HiDAC) induction therapy. We present a cohort of 58 patients (aged 18-70) treated with fludarabine, cytarabine, granulocyte-colony stimulating factor (G-CSF) and amsacrine (FLAG-amsacrine) as salvage chemotherapy for AML at first relapse. 83% had received prior HiDAC-based therapy. The overall complete remission (CR/CR with incomplete blood count recovery [CRi]) rate was 59%, with median event-free survival (EFS) and overall survival (OS) of 6.9 and 10.6 months, respectively. FLAG-amsacrine was an effective bridge to allogeneic transplant with 38% successfully transplanted with excellent outcomes (median OS not reached). FLAG-amsacrine was also effective in elderly patients (≥ 60 years), with 61% achieving second remission. The regimen was well tolerated, with 30- and 42-day treatment-related mortality of 3.4% and 13.8%, respectively. Outcomes remained poor in those with short initial remission duration (<6 months). We conclude that FLAG-amsacrine is a useful salvage option for AML at first relapse.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641302
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: Wiley
Date: 31-03-2017
DOI: 10.1111/BJH.14063
Publisher: Springer Science and Business Media LLC
Date: 09-11-2009
DOI: 10.1038/BMT.2009.322
Abstract: The long-term outcome of patients with haematological malignancies treated with reduced-intensity conditioned allogeneic peripheral blood stem cell transplantation is not known. We report the outcome of 79 patients with poor-risk myeloid and lymphoid malignancies transplanted with reduced-intensity conditioning (RIC) regimens. The diagnoses include AML/myelodysplastic syndrome (n=43), non Hodgkin's lymphoma (n=30), Hodgkin's lymphoma (n=3), ALL (n=2) and CML (n=1). For the entire cohort, the disease-free survival (DFS) and OS were 61.2 and 35.7%, respectively. Twenty patients relapsed, 18 within the first three years, and 14 patients succumbed to progressive disease. Overall, 31 patients died from transplant-related complications within the first three years. Day 100 non-relapse mortality correlated with a higher total nucleated cell dose in the graft (odds ratio: 3.9). For those in CR at 3 years, the DFS and OS were 84.2 and 81.1%, respectively. Furthermore, of 43 patients with active disease at the time of transplantation, 16 remained in CR after 3 years. The majority of the long-term survivors were functioning independently. One patient died from a second malignancy. No post-transplant lymphoproliferative disorder was seen. In conclusion, durable disease control was achieved after RIC allogeneic stem cell transplantation for patients with advanced myeloid and lymphoid malignancies.
Publisher: American Society of Hematology
Date: 30-01-2020
Abstract: Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P & .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.
Publisher: Springer Science and Business Media LLC
Date: 03-07-2016
DOI: 10.1038/LEU.2015.174
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486449
Abstract: Supplementary Table from Impact of i F /i i LT3 /i Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-0001
DOI: 10.1158/2159-8290.23641308
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.MOLCEL.2004.12.030
Abstract: Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. Strikingly, Noxa bound only Mcl-1 and A1. In accord with their complementary binding, Bad and Noxa cooperated to induce potent killing. The results suggest that apoptosis relies on selective interactions between particular subsets of these proteins and that it should be feasible to discover BH3-mimetic drugs that inactivate specific prosurvival targets.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486455
Abstract: Supplementary Table from Impact of i F /i i LT3 /i Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Publisher: American Society of Hematology
Date: 22-09-2022
Abstract: The 2010 and 2017 editions of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults are widely recognized among physicians and investigators. There have been major advances in our understanding of AML, including new knowledge about the molecular pathogenesis of AML, leading to an update of the disease classification, technological progress in genomic diagnostics and assessment of measurable residual disease, and the successful development of new therapeutic agents, such as FLT3, IDH1, IDH2, and BCL2 inhibitors. These advances have prompted this update that includes a revised ELN genetic risk classification, revised response criteria, and treatment recommendations.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486452
Abstract: Supplementary Table from Impact of i F /i i LT3 /i Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618458.V1
Abstract: Table S11
Publisher: American Association for Cancer Research (AACR)
Date: 25-08-2022
DOI: 10.1158/1078-0432.CCR-22-1183
Abstract: To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and TP53mut or TP53wt. We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1–28) + azacitidine (75 mg/m2 days 1–7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally cytogenetic studies were performed locally. Patients (n = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine (TP53wt = 50 TP53mut = 54) were compared with patients with poor-risk cytogenetics (n = 56) receiving azacitidine alone (TP53wt = 22 TP53mut = 18). For poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine versus azacitidine alone resulted in composite remission rates (CRc) of 70% versus 23%, median duration of remission (DoR) of 18.4 versus 8.5 months, and median overall survival (OS) of 23.4 versus 11.3 months, respectively. Outcomes with venetoclax + azacitidine were comparable with similarly treated patients with intermediate-risk cytogenetics and TP53wt. For poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine versus azacitidine alone resulted in CRc of 41% versus 17%, median DoR of 6.5 versus 6.7 months, and median OS of 5.2 versus 4.9 months, respectively. For poor-risk cytogenetics + TP53mut patients, predominant grade ≥3 adverse events (AE) for venetoclax + azacitidine versus azacitidine were febrile neutropenia (55%/39%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/6%), and pneumonia (28%/33%). AEs were comparable between TP53mut and TP53wt patients. In poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine improved remission rates but not DoR or OS compared with azacitidine alone. However, in poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine resulted in higher remission rates and longer DoR and OS than azacitidine alone, with outcomes comparable with similarly treated patients with intermediate-risk cytogenetics. Toxicities were similar in TP53mut and TP53wt patients. See related commentary by Green and Zeidner, p. 5235
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641284.V1
Abstract: Table S9: CEBPA_UP signature
Publisher: Oxford University Press (OUP)
Date: 08-03-2021
DOI: 10.1093/OFID/OFAB113
Abstract: Patients unable to take azoles are a neglected group lacking a standardized approach to antifungal prophylaxis. We evaluated the effectiveness and safety of intermittent liposomal hotericin B (L-AMB) prophylaxis in a heterogenous group of hematology patients. A retrospective cohort of all hematology patients who received a course of intravenous L-AMB, defined as 1 mg/kg thrice weekly from July 1, 2013 to June 30, 2018, were identified from pharmacy records. Outcomes included breakthrough-invasive fungal disease (BIFD), reasons for premature discontinuation, and acute kidney injury. There were 198 patients who received 273 courses of L-AMB prophylaxis. Using a conservative definition, the BIFD rate was 9.6% (n = 19 of 198) occurring either during L-AMB prophylaxis or up to 7 days from cessation in patients who received a course. Probable roven BIFD occurred in 13 patients (6.6%, 13 of 198), including molds in 54% (n = 7) and non-albicans Candidemia in 46% (n = 6). Cumulative incidence of BIFD was highest in patients with acute myeloid leukemia (6.8%) followed by acute lymphoblastic leukemia (2.7%) and allogeneic stem cell transplantation (2.5%). The most common indication for L-AMB was chemotherapy, or anticancer drug-azole interactions (75% of courses) dominated by vincristine, or acute myeloid leukemia clinical trials, followed by gut absorption concerns (13%) and liver function abnormalities (8.8%). Acute kidney injury, using a modified international definition, complicated 27% of courses but was not clinically significant, accounting for only 3.3% (9 of 273) of discontinuations. Our findings demonstrate a high rate of BIFD among patients receiving L-AMB prophylaxis. Pragmatic trials will help researchers find the optimal regimen of L-AMB prophylaxis for the many clinical scenarios in which azoles are unsuitable, especially as targeted anticancer drugs increase in use.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541182.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: Springer Science and Business Media LLC
Date: 17-04-2015
Publisher: Cold Spring Harbor Laboratory
Date: 15-01-2012
Abstract: Acute myeloid leukemia (AML) frequently relapses after initial treatment. Drug resistance in AML has been attributed to high levels of the anti-apoptotic Bcl-2 family members Bcl-x L and Mcl-1. Here we report that removal of Mcl-1, but not loss or pharmacological blockade of Bcl-x L , Bcl-2, or Bcl-w, caused the death of transformed AML and could cure disease in AML-afflicted mice. Enforced expression of selective inhibitors of prosurvival Bcl-2 family members revealed that Mcl-1 is critical for survival of human AML cells. Thus, targeting of Mcl-1 or regulators of its expression may be a useful strategy for the treatment of AML.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579607.V1
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: Public Library of Science (PLoS)
Date: 19-03-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 18-11-2008
Abstract: Deregulated Myc expression drives many human cancers, including Burkitt's lymphoma and a highly aggressive subset of diffuse large cell lymphomas. Myc-driven tumors often display resistance to chemotherapeutics because of acquisition of mutations that impair the apoptosis pathway regulated by the Bcl-2 protein family. Given the need to identify new therapies for such lymphomas, we have evaluated the efficacy of ABT-737, a small molecule that mimics the action of the BH3-only proteins, natural antagonists of the prosurvival Bcl-2 proteins. ABT-737 selectively targets certain prosurvival proteins (Bcl-2, Bcl-x L , and Bcl-w) but not others (Mcl-1 and A1). We treated mice transplanted with lymphomas derived either from Eμ- myc transgenic mice or Eμ- myc mice that also expressed an Eμ- bcl -2 transgene. As a single agent, ABT-737 significantly prolonged the survival of mice transplanted with the myc / bcl -2 lymphomas but was ineffective for the myc lymphomas, probably because of the relatively higher Mcl-1 levels found in the latter. Strikingly, when combined with low-dose cyclophosphamide, ABT-737 produced sustained disease-free survival of all animals transplanted with two of three myc / bcl -2 lymphomas tested. The combination therapy was also more effective against some myc lymphomas than treatment with either agent alone. Our data suggest that antagonism of Bcl-2 with small organic compounds is an attractive approach to enhance the efficacy of conventional therapy for the treatment of Myc-driven lymphomas that over-express this prosurvival molecule.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541176.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618452.V1
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641290.V1
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Society of Hematology
Date: 09-01-2020
Abstract: The acute myeloid leukemia (AML) treatment landscape has changed substantially since 2017. New targeted drugs have emerged, including venetoclax to target B-cell lymphoma 2, midostaurin and gilteritinib to target FLT3, and ivosidenib and enasidenib to target mutant isocitrate dehydrogenase 1 and 2, respectively. Other additions include reapproval of gemtuzumab ozogomycin to target CD33, glasdegib to target the hedgehog pathway, and a liposomal formulation of daunorubicin and cytarabine (CPX-351). Genomically heterogeneous AML has a tendency to evolve, particularly under selective treatment pressure. For decades, treatment decisions have largely centered around chemotherapy drug intensity. Physicians now have access to an increasing number of drugs with novel mechanisms of action and distinctive side-effect profiles. Key issues faced by hematologists in this era of new drugs include (1) the timely identification of actionable mutations at diagnosis and at relapse (2) deciding which drug to use among several therapeutic options and (3) increasing awareness of how to anticipate, mitigate, and manage common complications associated with these new agents. This article will use 3 case presentations to discuss some of the new treatment challenges encountered in AML management, with the goal of providing practical guidance to aid the practicing physician.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486446
Abstract: Supplementary Table from Impact of i F /i i LT3 /i Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Publisher: Springer Science and Business Media LLC
Date: 22-08-2018
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486443
Abstract: Supplementary Table from Impact of i F /i i LT3 /i Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486461.V1
Abstract: Supplementary Data from Impact of i F /i i LT3 /i Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Publisher: American Society of Hematology
Date: 12-01-2023
Abstract: This open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 (isocitrate dehydrogenase 2) inhibitor, with conventional care regimens (CCRs) in patients aged ≥60 years with late-stage, mutant-IDH2 acute myeloid leukemia (AML) relapsed/refractory (R/R) to 2 or 3 prior AML-directed therapies. Patients were first preselected to a CCR (azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or supportive care) and then randomized (1:1) to enasidenib 100 mg per day or CCR. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), time to treatment failure (TTF), overall response rate (ORR), hematologic improvement (HI), and transfusion independence (TI). Overall, 319 patients were randomized to enasidenib (n = 158) or CCR (n = 161). The median age was 71 years, median (range) enasidenib exposure was 142 days (3 to 1270), and CCR was 36 days (1 to 1166). One enasidenib (0.6%) and 20 CCR (12%) patients received no randomized treatment, and 30% and 43%, respectively, received subsequent AML-directed therapies during follow-up. The median OS with enasidenib vs CCR was 6.5 vs 6.2 months (HR [hazard ratio], 0.86 P = .23) 1-year survival was 37.5% vs 26.1%. Enasidenib meaningfully improved EFS (median, 4.9 vs 2.6 months with CCR HR, 0.68 P = .008), TTF (median, 4.9 vs 1.9 months HR, 0.53 P & .001), ORR (40.5% vs 9.9% P & .001), HI (42.4% vs 11.2%), and red blood cell (RBC)-TI (31.7% vs 9.3%). Enasidenib safety was consistent with prior reports. The primary study endpoint was not met, but OS was confounded by early dropout and subsequent AML-directed therapies. Enasidenib provided meaningful benefits in EFS, TTF, ORR, HI, and RBC-TI in this heavily pretreated older mutant-IDH2 R/R AML population.
Publisher: American Society of Hematology
Date: 12-04-2022
DOI: 10.1182/BLOODADVANCES.2021006303
Abstract: The phase III MIRROS trial (NCT02545283) evaluated the efficacy and safety of the small-molecule MDM2 antagonist idasanutlin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Adults (N=447) with R/R AML whose disease relapsed or was refractory after ≤2 prior induction regimens as initial treatment or following salvage chemotherapy regimen, with Eastern Cooperative Oncology Group performance status ≤2 were enrolled regardless of TP53 mutation status and randomly assigned 2:1 to idasanutlin 300 mg or placebo orally twice daily plus cytarabine 1 g/m2 intravenously on days 1 to 5 of 28-day cycles. At primary analysis (cutoff, November 2019), 436 patients were enrolled, including 355 in the TP53 wild-type intention-to-treat (TP53WT-ITT) population. The primary endpoint, overall survival in the TP53WT-ITT population, was not met (median, 8.3 vs 9.1 months with idasanutlin-cytarabine vs placebo-cytarabine stratified hazard ratio, 1.08 95% CI, 0.81-1.45 p = .58). The complete remission (CR) rate, a key secondary endpoint, was 20.3% vs 17.1% (odds ratio [OR], 1.23 95% CI, 0.70-2.18). The overall response rate (ORR) was 38.8% vs 22.0% (OR, 2.25 95% CI, 1.36-3.72). Common any-grade adverse events (≥10% incidence in any arm) were diarrhea (87.0% vs 32.9%), febrile neutropenia (52.8% vs 49.3%), and nausea (52.5% vs 31.5%). In summary, despite improved ORR, adding idasanutlin to cytarabine did not improve overall survival or CR rates in patients with R/R AML.
Publisher: American Society of Hematology
Date: 06-12-2021
DOI: 10.1182/BLOODADVANCES.2021005455
Abstract: Monitoring of NPM1 mutant (NPM1mut) measurable residual disease (MRD) in acute myeloid leukemia (AML) has an established role in patients who are treated with intensive chemotherapy. The European LeukemiaNet has defined molecular persistence at low copy number (MP-LCN) as an MRD transcript level & % to 2% with a & -log change between any 2 positive s les collected after the end of treatment (EOT). Because the clinical impact of MP-LCN is unknown, we sought to characterize outcomes in patients with persistent NPM1mut MRD after EOT and identify factors associated with disease progression. Consecutive patients with newly diagnosed NPM1mut AML who received ≥2 cycles of intensive chemotherapy were included if bone marrow was NPM1mut MRD positive at the EOT, and they were not transplanted in first complete remission. One hundred patients were followed for a median of 23.5 months 42% remained free of progression at 1 year, either spontaneously achieving complete molecular remission (CRMRD− 30%) or retaining a low-level NPM1mut transcript (12% for ≥12 months and 9% at last follow-up). Forty percent met the criteria for MP-LCN. Preemptive salvage therapy significantly prolonged relapse-free survival. Risk factors associated with disease progression were concurrent FLT3-internal tandem duplication at diagnosis and suboptimal MRD response (NPM1mut reduction & .4-log) at EOT.
Publisher: American Society of Hematology
Date: 20-12-2021
DOI: 10.1182/BLOODADVANCES.2021005576
Abstract: Pediatric regimens have improved outcomes in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL). However, results remain inferior to children with ALL. The Australasian Leukaemia and Lymphoma Group (ALLG) ALL06 study (anzctr.org.au/ACTRN12611000814976) was designed to assess whether a pediatric ALL regimen (Australian and New Zealand Children’s Haematology and Oncology Group [ANZCHOG] Study 8) could be administered to patients aged 15 to 39 years in a comparable time frame to children as assessed by the proportion of patients completing induction/consolidation and commencing the next phase of therapy (protocol M or high-risk [HR] treatment) by day 94. Minimal residual disease (MRD) response stratified patients to HR treatment and transplantation. From 2012 to 2018, a total of 86 patients were enrolled 82 were eligible. Median age was 22 years (range, 16-38 years). Induction/consolidation was equally deliverable in ALL06 as in Study 8. In ALL06, 41.5% (95% confidence interval [CI], 30.7-52.9) commenced protocol M or HR therapy by day 94 vs 39.3% in Study 8 (P = .77). Median time to protocol M/HR treatment was 96 days (interquartile range, 87.5-103 days) in ALL06 vs 98 days in Study 8 (P = .80). Induction mortality was 3.6%. With a median follow-up of 44 months (1-96 months), estimated 3-year disease-free survival was 72.8% (95% CI, 62.8-82.7), and estimated 3-year overall survival was 74.9% (95% CI, 65.3-84.5). End induction/consolidation MRD negativity rate was 58.6%. Body mass index ≥30 kg/m2 and day 79 MRD positivity were associated with poorer disease-free survival and overall survival. Pediatric therapy was safe and as deliverable in AYA patients as in children with ALL. Intolerance of pediatric ALL induction/consolidation is not a major contributor to inferior outcomes in AYA ALL.
Publisher: Wiley
Date: 27-02-2013
DOI: 10.1111/J.1445-5994.2012.02868.X
Abstract: Although induction chemotherapy comprising high-dose cytarabine (HiDAC) in combination with idarubicin and etoposide or 'ICE' for adult acute myeloid leukaemia (AML) produces a complete remission rate of nearly 80%, gastrointestinal toxicity is significant. Omission of etoposide may produce similar clinical outcomes with potentially less gastrointestinal toxicity. Fifty-three consecutive patients aged 15-60 with newly diagnosed AML, receiving high-dose cytarabine induction at the Alfred Hospital, Melbourne, were retrospectively analysed. Regimens included HiDAC-3 (idarubicin 12 mg/m(2) day 1-3, cytarabine 3 gm/m(2) bd day 1,3,5,7) or ICE (idarubicin 9 mg/m(2) day 1-3, cytarabine 3 g/m(2) bd day 1,3,5,7, etoposide 75 mg/m(2) day 1-7). Toxicity was assessed using Common Terminology Criteria for Adverse Events version 4.03. Thirty-one patients received HIDAC-3 and 22 patients received ICE induction. HiDAC-3 was better tolerated than ICE in terms of lower frequency of grade 3-4 nausea (0% vs 41% P < 0.01), grade 3-4 diarrhoea (26% vs 55% P = 0.05), lower rates of radiologically evident enterocolitis (6% vs 32% P = 0.03) and less cumulative days of total parenteral nutrition use (1.2 vs 7.3 days P < 0.01). Times to haematological recovery were similar between the two regimens. Thirty-day mortality was 0% for HiDAC-3 and 9% for ICE. Eighty-four per cent of HiDAC-3-treated patients achieved complete remission after the first cycle of therapy, compared with 77% with ICE. No differences in survival were evident between the two regimens. HiDAC-3 is a clinically effective induction regimen for adult AML, producing a high rate of first-cycle complete remission with less treatment-related gastrointestinal toxicity than ICE.
Publisher: American Society of Hematology
Date: 05-06-2023
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641311.V1
Abstract: Table S15: Relative quantification by lipid class
Publisher: Wiley
Date: 07-07-2007
Publisher: Springer Science and Business Media LLC
Date: 28-07-2017
DOI: 10.1038/LEU.2017.243
Abstract: Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the B-cell lymphoma 2 (BCL-2) family of proteins is an attractive option to combat chemoresistance in leukemia. Preclinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (for ex le, venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase antileukemic efficacy in a TP53-dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53. Consistent with an MCL1-specific effect, cell death from high-dose idarubicin was dependent on pro-apoptotic Bak. Combining higher-dose idarubicin with venetoclax was able to partially overcome resistance in Bak-deficient cells. Using inducible vectors and venetoclax to differentially target anti-apoptotic BCL-2 family members, BCL-2 and MCL1 emerged as critical and complementary proteins regulating cell survival in acute myeloid leukemia. Dual targeting of BCL-2 and MCL1, but not either alone, prolonged survival of leukemia-bearing mice. In conclusion, our findings support the further investigation of venetoclax in combination with standard chemotherapy, including intensified doses of idarubicin. Venetoclax should also be investigated in combination with direct inhibitors of MCL1 as a chemotherapy-free approach in the future.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541173.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: Informa UK Limited
Date: 19-12-2021
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488527
Abstract: Supplementary Figure from Outcomes in Patients with Poor-Risk Cytogenetics with or without i TP53 /i Mutations Treated with Venetoclax and Azacitidine
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641305.V1
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: American Association for Cancer Research (AACR)
Date: 12-2018
DOI: 10.1158/2159-8290.CD-18-0387
Abstract: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers. See related commentary by Leber et al., p. 1511. This article is highlighted in the In This Issue feature, p. 1494
Publisher: Informa UK Limited
Date: 04-10-2012
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618467.V1
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579646.V1
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641287
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641284
Abstract: Table S9: CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541167.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: Elsevier BV
Date: 03-2011
Publisher: American Society of Hematology
Date: 30-06-2023
DOI: 10.1182/BLOODADVANCES.2022009411
Abstract: Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Overall, 153 IDH1 inhibitor–naive patients with mIDH1R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) received olutasidenib monotherapy 150 mg twice daily in the pivotal cohort of this study. The median age of participants was 71 years (range, 32-87 years) and the median number of prior regimens received by patients was 2 (1-7). The rate of complete remission (CR) plus CR with partial hematologic recovery (CRh) was 35%, and the overall response rate was 48%. Response rates were similar in patients who had, and who had not, received prior venetoclax. With 55% of patients censored at the time of data cut-off, the median duration of CR/CRh was 25.9 months. The median duration of overall response was 11.7 months, and the median overall survival was 11.6 months. Of 86 patients who were transfusion dependent at baseline, a 56-day transfusion independence was achieved in 29 (34%), which included patients in all response groups. Grade 3 or 4 treatment-emergent adverse events (≥10%) were febrile neutropenia and anemia (n = 31 20% each), thrombocytopenia (n = 25 16%), and neutropenia (n = 20 13%). Differentiation syndrome adverse events of special interest occurred in 22 (14%) patients, with 14 (9%) grade ≥3 and 1 fatal case reported. Overall, olutasidenib induced durable remissions and transfusion independence with a well-characterized and manageable side effect profile. The observed efficacy represents a therapeutic advance in this molecularly defined, poor-prognostic population of patients with mIDH1 R/R AML. This trial was registered at www.clinicaltrials.gov as #NCT02719574.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.C.6713553.V3
Abstract: Abstract Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism i in vivo /i and in patients with i FLT3 /i -mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through i SCD /i downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of i FLT3 /i -mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of i FLT3 /i -mutant AML to ferroptosis with promising therapeutic application. Significance: i FLT3 /i mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-13-7-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 1501 /a /i /
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.LEUKRES.2016.09.012
Abstract: EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.C.6713553.V1
Abstract: Abstract Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism i in vivo /i and in patients with i FLT3 /i -mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through i SCD /i downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of i FLT3 /i -mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of i FLT3 /i -mutant AML to ferroptosis with promising therapeutic application. Significance: i FLT3 /i mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.C.6713553.V2
Abstract: Abstract Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism i in vivo /i and in patients with i FLT3 /i -mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through i SCD /i downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of i FLT3 /i -mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of i FLT3 /i -mutant AML to ferroptosis with promising therapeutic application. Significance: i FLT3 /i mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. /
Publisher: Elsevier BV
Date: 11-2020
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488521
Abstract: Supplementary Table from Outcomes in Patients with Poor-Risk Cytogenetics with or without i TP53 /i Mutations Treated with Venetoclax and Azacitidine
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488524
Abstract: Supplementary Figure from Outcomes in Patients with Poor-Risk Cytogenetics with or without i TP53 /i Mutations Treated with Venetoclax and Azacitidine
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486458
Abstract: Supplementary Table from Impact of i F /i i LT3 /i Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Publisher: Wiley
Date: 10-01-2013
Publisher: Wiley
Date: 19-04-2013
DOI: 10.1002/CNCR.28113
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488518
Abstract: Supplementary Table from Outcomes in Patients with Poor-Risk Cytogenetics with or without i TP53 /i Mutations Treated with Venetoclax and Azacitidine
Publisher: Wiley
Date: 2011
DOI: 10.1111/J.1445-5994.2010.02339.X
Abstract: Utilization of risk-stratification tools in the setting of neutropenic fever is currently limited by inadequate knowledge and lack of awareness. Within this context, the approach to management of low-risk patients with neutropenic fever is inconsistent with the available evidence across many Australian treating centres. These clinical guidelines define and clarify an accepted standard of care for this patient group given the current evidence base. The Multinational Association for Supportive Care in Cancer risk index is presented as the preferred risk assessment tool for determining patient risk. Suitability of ambulatory care within specific patient populations is discussed, with defined eligibility criteria provided to guide clinical decision-making. Detailed recommendations for implementing appropriate ambulatory strategies, such as early discharge and outpatient antibiotic therapy, are also provided. Due consideration is given to infrastructural requirements and other supportive measures at a resourcing and operational level. An analysis of the relevant health economics is also presented.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.CCELL.2016.01.006
Abstract: Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486461
Abstract: Supplementary Data from Impact of i F /i i LT3 /i Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Publisher: American Association for Cancer Research (AACR)
Date: 11-10-2022
DOI: 10.1158/2159-8290.CD-22-0332
Abstract: Emerging data on the impact of cytogenetic aberrations, TP53 allelic burden, immunobiology, and tumor microenvironment of TP53-mutated MDS and AML are further unraveling the complexity of this disease. An improved understanding of the functional consequences of TP53 mutations and immune dysregulation in TP53-mutated AML/MDS coupled with dismal outcomes has resulted in a shift from the use of cytotoxic and hypomethylating agent–based therapies to novel immune and nonimmune strategies for the treatment of this entity. It is hoped that these novel, rationally designed combinations will improve outcomes in this area of significant unmet need.
Publisher: Elsevier BV
Date: 06-2021
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2021
DOI: 10.1200/OP.20.00904
Abstract: Acute myeloid leukemia (AML) is a rare hematologic malignancy accounting for 0.8% of new cancer diagnoses in Australia. High mortality and morbidity affect work productivity through workforce dropout and premature death. This study sought to estimate the productivity loss attributable to AML in the Australian population over 10 years and to estimate the costs of this productivity loss. Productivity was measured using productivity-adjusted life years (PALYs), a similar concept to quality-adjusted life years, but adjusts for the productivity loss attributable to disease, rather than impaired health. Dynamic life tables modeled the Australian working population (age 15-65 years) between 2020 and 2029. The model population had two cohorts: those with and without AML. Differences in life years, PALYs, and costs represented the health and productivity impact of AML. Secondary analyses evaluated the impact of different scenarios. Over the next 10 years, there will be 7,600 years of life lost and 7,337 PALYs lost because of AML, amounting to Australian dollars (AU$) 1.43 billion in lost gross domestic product ($971 million in US dollars). Secondary analyses highlight potential savings of approximately AU$52 million if survival rates were improved by 20% and almost AU$118 million in savings if the return-to-work rates increased by 20% on the current estimates. Our study demonstrates that even in low-incidence cancer, high mortality and morbidity translate to profound impacts on years of life, productivity, and the broader economy. Better treatment strategies are likely to result in significant economic gains. This highlights the value of investing in research for improved therapies.
Publisher: American Society of Hematology
Date: 30-08-2023
Abstract: This study reports 1) frequency of TP53 co-mutation within each component of the ELN 2022 AML risk classification, 2) relevance of TP53 mut VAF& %, 3) prognostic impact of -7, -5/del(5q), -17/abn(17p), CK/MK or myelodysplasia related gene mutations with/without mutated TP53.
Publisher: Cold Spring Harbor Laboratory
Date: 2005
Abstract: The Bcl-2 protein family, which largely determines commitment to apoptosis, has central roles in tumorigenesis and chemoresistance. Its three factions of interacting proteins include the BH3-only proteins (e.g., Bim, Puma, Bad, Noxa), which transduce erse cytotoxic signals to the mammalian pro-survival proteins (Bcl-2, Bcl-x(L), Bcl-w, Mcl-1, A-1), whereas Bax and Bak, when freed from pro-survival constraint, provoke the mitochondrial permeabilization that triggers apoptosis. We have discovered unexpected specificity in their interactions. Only Bim and Puma, which mediate multiple cytotoxic signals, engage all the pro-survival proteins. Noxa and Bad instead bind subsets and cooperate in killing, indicating that apoptosis requires neutralization of different pro-survival subsets. Furthermore, Mcl-1 and Bcl-x(L), but not Bcl-2, directly sequester Bak in healthy cells, and Bak is freed only when BH3-only proteins neutralize both its guards. BH3-only proteins such as Bim are tumor suppressors and mediate many of the cytotoxic signals from anticancer agents. Hence, compounds mimicking them may prove valuable for therapy. Indeed, the recently described ABT-737 is a promising "BH3 mimetic" of Bad. We find that, like Bad, ABT-737 kills cells efficiently only if Mcl-1 is absent or down-regulated. Thus, manipulation of apoptosis by targeting the Bcl-2 family has exciting potential for cancer treatment.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488521.V1
Abstract: Supplementary Table from Outcomes in Patients with Poor-Risk Cytogenetics with or without i TP53 /i Mutations Treated with Venetoclax and Azacitidine
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641317.V1
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541191.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486443.V1
Abstract: Supplementary Table from Impact of i F /i i LT3 /i Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Publisher: American Society of Hematology
Date: 12-03-2020
Abstract: The BCL-2 inhibitor venetoclax combined with hypomethylating agents or low-dose cytarabine represents an important new therapy for older or unfit patients with acute myeloid leukemia (AML). We analyzed 81 patients receiving these venetoclax-based combinations to identify molecular correlates of durable remission, response followed by relapse (adaptive resistance), or refractory disease (primary resistance). High response rates and durable remissions were typically associated with NPM1 or IDH2 mutations, with prolonged molecular remissions prevalent for NPM1 mutations. Primary and adaptive resistance to venetoclax-based combinations was most commonly characterized by acquisition or enrichment of clones activating signaling pathways such as FLT3 or RAS or biallelically perturbing TP53. Single-cell studies highlighted the polyclonal nature of intratumoral resistance mechanisms in some cases. Among cases that were primary refractory, we identified heterogeneous and sometimes ergent interval changes in leukemic clones within a single cycle of therapy, highlighting the dynamic and rapid occurrence of therapeutic selection in AML. In functional studies, FLT3 internal tandem duplication gain or TP53 loss conferred cross-resistance to both venetoclax and cytotoxic-based therapies. Collectively, we highlight molecular determinants of outcome with clinical relevance to patients with AML receiving venetoclax-based combination therapies.
Publisher: Wiley
Date: 11-2021
DOI: 10.1111/IMJ.15564
Abstract: The benefits of non‐myeloablative stem cell transplant in older patients with acute myeloid leukaemia are unclear. We compare the long‐term outcomes of this regimen in those aged 55–65 years in first remission with a chemotherapy only cohort that achieved durable morphologic remission. Five‐year overall survival was similar (32% vs 33%, P = 0.90), as was relapse‐free survival (23% vs 20%, P = 0.37). There was a trend for decreased relapse that was balanced against increased non‐relapse mortality with transplantation.
Publisher: Wiley
Date: 10-06-2022
DOI: 10.1002/AJH.26600
Publisher: Springer Science and Business Media LLC
Date: 26-10-2021
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579640.V1
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Society of Hematology
Date: 15-09-2022
Abstract: The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2020
DOI: 10.1038/S41408-020-00376-1
Abstract: Conventional therapy for acute myeloid leukemia is composed of remission induction with cytarabine- and anthracycline-containing regimens, followed by consolidation therapy, including allogeneic stem cell transplantation, to prolong remission. In recent years, there has been a significant shift toward the use of novel and effective, target-directed therapies, including inhibitors of mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase (IDH), the B-cell lymphoma 2 inhibitor venetoclax, and the hedgehog pathway inhibitor glasdegib. In older patients the combination of a hypomethylating agent or low-dose cytarabine, venetoclax achieved composite response rates that approximate those seen with standard induction regimens in similar populations, but with potentially less toxicity and early mortality. Preclinical data suggest synergy between venetoclax and FLT3- and IDH-targeted therapies, and doublets of venetoclax with inhibitors targeting these mutations have shown promising clinical activity in early stage trials. Triplet regimens involving the hypomethylating agent and venetoclax with FLT3 or IDH1/2 inhibitor, the TP53-modulating agent APR-246 and magrolimab, myeloid cell leukemia-1 inhibitors, or immune therapies such as CD123 antibody-drug conjugates and programmed cell death protein 1 inhibitors are currently being evaluated. It is hoped that such triplets, when applied in appropriate patient subsets, will further enhance remission rates, and more importantly remission durations and survival.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.BEHA.2019.02.007
Abstract: Therapy-related myeloid neoplasm (t-MN) is a rare but devastating consequence of chemotherapy and/or radiotherapy used for the treatment of solid cancers and various hematologic malignancies. Our current understanding of the etiology is that hematopoietic clones that are contemporaneous with the primary cancer and resistant to the cytotoxic exposure have the potential to undergo selective expansion and transformation to t-MN. Consequently, a large proportion of cases are associated with adverse risk factors, resulting in limited effective treatment options. Despite the emergence of some therapies with promising activity in t-MN, most effects are short-lived and allogeneic stem cell transplantation remains the only curative option for eligible patients. This review summarizes the current literature on t-AML and t-MDS, with the aim of providing practical recommendations on the clinical evaluation and management of these conditions.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2019
DOI: 10.1158/2159-8290.CD-19-0575
Abstract: In this issue, McMahon and colleagues demonstrate that secondary clinical resistance to the FLT3 inhibitor gilteritinib in relapsed acute myeloid leukemia is often polyclonal and commonly mediated by heterogeneous mutations that activate downstream RAS–MAPK pathways. These findings and recent data from others indicate that emergence of multiple clones, each with distinct mechanisms of resistance, is a common finding at secondary failure of single-agent–targeted therapies for relapsed leukemias. See related article by McMahon et al., p. 1050.
Publisher: Wiley
Date: 06-02-2023
DOI: 10.1002/AJH.26847
Publisher: Springer Science and Business Media LLC
Date: 02-03-2021
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579628.V1
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2014
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2019
DOI: 10.1200/JCO.18.01600
Abstract: Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. An international phase Ib/II study evaluated the safety and preliminary efficacy of venetoclax, a selective B-cell leukemia/lymphoma-2 inhibitor, together with low-dose cytarabine (LDAC) in older adults with AML. Adults 60 years or older with previously untreated AML ineligible for intensive chemotherapy were enrolled. Prior treatment of myelodysplastic syndrome, including hypomethylating agents (HMA), was permitted. Eighty-two patients were treated at the recommended phase II dose: venetoclax 600 mg per day orally in 28-day cycles, with LDAC (20 mg/m 2 per day) administered subcutaneously on days 1 to 10. Key end points were tolerability, safety, response rates, duration of response (DOR), and overall survival (OS). Median age was 74 years (range, 63 to 90 years), 49% had secondary AML, 29% had prior HMA treatment, and 32% had poor-risk cytogenetic features. Common grade 3 or greater adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and WBC count decreased (34%). Early (30-day) mortality was 6%. Fifty-four percent achieved complete remission (CR)/CR with incomplete blood count recovery (median time to first response, 1.4 months). The median OS was 10.1 months (95% CI, 5.7 to 14.2), and median DOR was 8.1 months (95% CI, 5.3 to 14.9 months). Among patients without prior HMA exposure, CR/CR with incomplete blood count recovery was achieved in 62%, median DOR was 14.8 months (95% CI, 5.5 months to not reached), and median OS was 13.5 months (95% CI, 7.0 to 18.4 months). Venetoclax plus LDAC has a manageable safety profile, producing rapid and durable remissions in older adults with AML ineligible for intensive chemotherapy. High remission rate and low early mortality combined with rapid and durable remission make venetoclax and LDAC an attractive and novel treatment for older adults not suitable for intensive chemotherapy.
Publisher: American Society of Hematology
Date: 15-06-2023
DOI: 10.1182/BLOODADVANCES.2022008221
Abstract: Venetoclax is an effective treatment for certain blood cancers, such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, most patients relapse while on venetoclax and further treatment options are limited. Combining venetoclax with immunotherapies is an attractive approach however, a detailed understanding of how venetoclax treatment impacts normal immune cells in patients is lacking. In this study, we performed deep profiling of peripheral blood (PB) cells from patients with CLL and AML before and after short-term treatment with venetoclax using mass cytometry (cytometry by time of flight) and found no impact on the concentrations of key T-cell subsets or their expression of checkpoint molecules. We also analyzed PB from patients with breast cancer receiving venetoclax long-term using a single-cell multiomics approach (cellular indexing of transcriptomes and epitopes by sequencing) and functional assays. We found significant depletion of B-cell populations with low expression of MCL-1 relative to other immune cells, attended by extensive transcriptomic changes. By contrast, there was less impact on circulating T cells and natural killer (NK) cells, with no changes in their subset composition, transcriptome, or function following venetoclax treatment. Our data indicate that venetoclax has minimal impact on circulating T or NK cells, supporting the rationale of combining this BH3 mimetic drug with cancer immunotherapies for more durable antitumor responses.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 18-05-2016
DOI: 10.1126/SCITRANSLMED.AAD3099
Abstract: The combination of a SMAC mimetic and a caspase inhibitor kills AML cells by inducing necroptosis.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641299
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Society of Hematology
Date: 09-02-2017
DOI: 10.1182/BLOOD-2016-06-720433
Abstract: Inhibition of SPHK1 in human AML cells induces MCL1 degradation and caspase-dependent cell death. SPHK1 inhibitors reduce leukemic burden and prolong survival in orthotopic patient-derived xenografts of AML.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579634.V1
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: Springer Science and Business Media LLC
Date: 08-01-2016
DOI: 10.1038/CDD.2015.159
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.MOLMED.2017.01.005
Abstract: Malignant cells must circumvent endogenous cell death pathways to survive and develop into cancers. Acquired cell death resistance also sets up malignant cells to survive anticancer therapies. Acute Myeloid Leukemia (AML) is an aggressive blood cancer characterized by high relapse rate and resistance to cytotoxic therapies. Recent collaborative profiling projects have led to a greater understanding of the 'fearful symmetry' of the genomic landscape of AML, and point to the development of novel potential therapies that can overcome factors linked to chemoresistance. We review here the most recent research in the genetics of AML and how these discoveries have led, or might lead, to therapies that specifically activate cell death pathways to substantially challenge this 'fearful' disease.
Publisher: Proceedings of the National Academy of Sciences
Date: 08-05-2007
Abstract: Histone deacetylase inhibitors (HDACi) can elicit a range of biological responses that affect tumor growth and survival, including inhibition of cell cycle progression, induction of tumor cell-selective apoptosis, suppression of angiogenesis, and modulation of immune responses, and show promising activity against hematological malignancies in clinical trials. Using the Eμ-myc model of B cell lymphoma, we screened tumors with defined genetic alterations in apoptotic pathways for therapeutic responsiveness to the HDACi vorinostat. We demonstrated a direct correlation between induction of tumor cell apoptosis in vivo and therapeutic efficacy. Vorinostat did not require p53 activity or a functional death receptor pathway to kill Eμ-myc lymphomas and mediate a therapeutic response but depended on activation of the intrinsic apoptotic pathway with the proapoptotic BH3-only proteins Bid and Bim playing an important role. Our studies provide important information regarding the mechanisms of action of HDACi that have broad implications regarding stratification of patients receiving HDACi therapy alone or in combination with other anticancer agents.
Publisher: Massachusetts Medical Society
Date: 02-03-2017
Publisher: Elsevier BV
Date: 03-2021
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641290
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: Elsevier BV
Date: 11-2006
Publisher: Elsevier BV
Date: 07-2017
Publisher: Elsevier BV
Date: 03-2016
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641323.V1
Abstract: Table S11
Publisher: Informa UK Limited
Date: 15-07-2015
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618428.V1
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641296
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: Informa UK Limited
Date: 28-04-2010
Publisher: American Society of Hematology
Date: 22-06-2020
DOI: 10.1182/BLOODADVANCES.2019001416
Abstract: Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) remains a clinical challenge. Relapsed disease has a poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and chimeric antigen receptor T cells. Targeting aberrant cell survival pathways with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option. We report that combined targeting of BCL-2 and MCL1 is synergistic in B-ALL in vitro. The combination demonstrated greater efficacy than standard chemotherapeutics and TKIs in primary s les from adult B-ALL with Ph+ ALL, Ph-like ALL, and other B-ALL. Moreover, combined BCL-2 or MCL1 inhibition with dasatinib showed potent killing in primary Ph+ B-ALL cases, but the BH3-mimetic combination appeared superior in vitro in a variety of Ph-like ALL s les. In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph− and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3-mimetic approach is highly effective in erse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions.
Publisher: American Society of Hematology
Date: 15-06-2001
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579604.V1
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579610
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.C.6713553
Abstract: Abstract Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism i in vivo /i and in patients with i FLT3 /i -mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through i SCD /i downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of i FLT3 /i -mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of i FLT3 /i -mutant AML to ferroptosis with promising therapeutic application. Significance: i FLT3 /i mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-13-7-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 1501 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 04-0019
DOI: 10.1158/1078-0432.C.6532751.V1
Abstract: AbstractPurpose: To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and i TP53 /i sup mut /sup or i TP53 /i sup wt /sup . Patients and Methods: We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1–28) + azacitidine (75 mg/m sup /sup days 1–7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. i TP53 /i status was analyzed centrally cytogenetic studies were performed locally. Results: Patients ( i n /i = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine ( i TP53 /i sup wt /sup = 50 i TP53 /i sup mut /sup = 54) were compared with patients with poor-risk cytogenetics ( i n /i = 56) receiving azacitidine alone ( i TP53 /i sup wt /sup = 22 i TP53 /i sup mut /sup = 18). For poor-risk cytogenetics + i TP53 /i sup wt /sup patients, venetoclax + azacitidine versus azacitidine alone resulted in composite remission rates (CRc) of 70% versus 23%, median duration of remission (DoR) of 18.4 versus 8.5 months, and median overall survival (OS) of 23.4 versus 11.3 months, respectively. Outcomes with venetoclax + azacitidine were comparable with similarly treated patients with intermediate-risk cytogenetics and i TP53 /i sup wt /sup . For poor-risk cytogenetics + i TP53 /i sup mut /sup patients, venetoclax + azacitidine versus azacitidine alone resulted in CRc of 41% versus 17%, median DoR of 6.5 versus 6.7 months, and median OS of 5.2 versus 4.9 months, respectively. For poor-risk cytogenetics + i TP53 /i sup mut /sup patients, predominant grade ≥3 adverse events (AE) for venetoclax + azacitidine versus azacitidine were febrile neutropenia (55%/39%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/6%), and pneumonia (28%/33%). AEs were comparable between i TP53 /i sup mut /sup and i TP53 /i sup wt /sup patients. Conclusions: In poor-risk cytogenetics + i TP53 /i sup mut /sup patients, venetoclax + azacitidine improved remission rates but not DoR or OS compared with azacitidine alone. However, in poor-risk cytogenetics + i TP53 /i sup wt /sup patients, venetoclax + azacitidine resulted in higher remission rates and longer DoR and OS than azacitidine alone, with outcomes comparable with similarly treated patients with intermediate-risk cytogenetics. Toxicities were similar in i TP53 /i sup mut /sup and i TP53 /i sup wt /sup patients. i a href="lincancerres/article/doi/10.1158/1078-0432.CCR-22-2664" target="_blank" See related commentary by Green and Zeidner, p. 5235 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488527.V1
Abstract: Supplementary Figure from Outcomes in Patients with Poor-Risk Cytogenetics with or without i TP53 /i Mutations Treated with Venetoclax and Azacitidine
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618467
Abstract: Supplementary materials and methods
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618464
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: American Society of Clinical Oncology (ASCO)
Date: 09-2021
DOI: 10.1200/JCO.21.00080
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618461
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: Wiley
Date: 14-07-2015
DOI: 10.1111/TRF.13233
Abstract: Nivestim is a biosimilar approved for the same indications as Neupogen including the mobilization of autologous peripheral blood stem cells (PBSCs). The clinical efficacy and safety of Nivestim for this use have not been formally assessed in clinical trials. In our retrospective single-center study we compared variables of PBSC mobilization and engraftment of 60 patients mobilized with Nivestim to that of 38 patients mobilized with Neupogen. We found no difference between Nivestim and Neupogen in peripheral blood CD34+ at first leukapheresis (47 × 10(6) cells/L vs. 60 × 10(6) cells/L, p = 0.48) nor the total CD34+ collected (5.37 × 10(6)/kg vs. 4.59 × 10(6) /kg, p = 0.22). However, a difference in the median number of leukapheresis procedures (one vs. two, p = 0.0007) was observed. Eighty-one patients (51 Nivestim and 30 Neupogen mobilized) went on to transplantation. Median time to neutrophil engraftment (15 days vs. 13.5 days, p = 0.09) and platelet (PLT) engraftment (20 days vs. 18 days, p = 0.01) was longer in the Nivestim group. The significant delay in PLT engraftment did not, however, translate to increased PLT transfusions (two vs. three, p = 0.2) or impact significantly on hospitalization time for admissions within 30 days posttransplant (20 days vs. 18 days, p = .17). Nivestim is as effective as Neupogen for PBSC mobilization however, its use was associated with a delay in PLT recovery. A prospective study should be conducted to confirm our findings.
Publisher: Springer Science and Business Media LLC
Date: 04-02-2021
DOI: 10.1038/S41375-020-01089-X
Abstract: This study aimed to identify biomarkers for clinical outcomes in a phase 3 clinical study of blinatumomab or chemotherapy in adults with Philadelphia chromosome-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Patients were randomized 2:1 to receive blinatumomab, a BiTE ® therapy, for 4 weeks (9 μg/day cycle 1 week 1, 28 μg/day thereafter) every 6 weeks, or chemotherapy. Baseline blood s les were evaluated to identify biomarkers prognostic (both treatment groups) or predictive (either treatment groups) for overall survival, event-free survival, hematologic remission, minimal residual disease (MRD) response, duration of response, or adverse events. Baseline values were balanced between treatment groups. Prognostic biomarkers were platelets, tumor burden, and percentage of T cells: each 1-log increase in platelets at baseline was prognostic for improved 6-month survival lower tumor burden was prognostic for hematologic remission and a higher percentage of CD3 + T-cells was prognostic for MRD response. Consistent with the BiTE mechanism of action, higher percentage of CD45 + CD3 + CD8 + T cells was associated with hematologic remission following blinatumomab. No examined biomarkers were significant for the risk of grade ≥3 adverse events. Incorporating baseline biomarkers into future studies may help to identify subgroups most likely to benefit from blinatumomab.
Publisher: Springer Science and Business Media LLC
Date: 10-2016
DOI: 10.1038/NATURE19830
Abstract: Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618437.V1
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549562.V1
Abstract: Abstract Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies. Significance: We demonstrate that HDACis induce terminal differentiation of AML through epigenetic remodeling of pDCs, resulting in production of type I IFN that is important for the therapeutic effects of HDACis. The study demonstrates the important functional interplay between the immune system and leukemias in response to HDAC inhibition. i This article is highlighted in the In This Issue feature, p. 1397 /i /
Publisher: American Society of Hematology
Date: 07-04-2022
Abstract: Measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy is predictive of early relapse and poor survival. Postremission maintenance therapy that prolongs MRD negativity or converts MRD+ patients to MRD− status may delay or prevent relapse and improve overall survival (OS). In the phase 3 QUAZAR AML-001 trial, oral azacitidine (oral-AZA formerly CC-486), a hypomethylating agent, significantly prolonged OS and relapse-free survival (RFS) compared with placebo in patients aged ≥55 years with AML in first remission after intensive chemotherapy who were not candidates for hematopoietic stem cell transplantation. In this trial, MRD (≥0.1% leukemic cells in bone marrow) was assessed by multiparameter flow cytometry in serial s les collected at baseline and on day 1 of every 3 cycles. As expected, baseline MRD status was significantly associated with both OS and RFS. Multivariate analyses showed oral-AZA significantly improved OS and RFS vs placebo independent of baseline MRD status. Oral-AZA treatment also extended the duration of MRD negativity by 6 months vs placebo and resulted in a higher rate of conversion from MRD+ at baseline to MRD− during treatment: 37% vs 19%, respectively. In the oral-AZA arm, 24% of MRD responders achieved MRD negativity & months after treatment initiation. Although presence or absence of MRD was a strong prognostic indicator of OS and RFS, there were added survival benefits with oral-AZA maintenance therapy compared with placebo, independent of patients’ MRD status at baseline. Registered at clinicaltrials.gov as #NCT01757535.
Publisher: American Society of Hematology
Date: 12-2022
Publisher: American Society of Hematology
Date: 20-05-2021
Abstract: Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across erse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or MCL-1 was sublethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study revealed the key role of TP-53 in shaping long-term responses to BH3-mimetic drugs and reconciled the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia or acute myeloid leukemia. In contrast to BH3-mimetics targeting just BCL-2 or MCL-1 at doses that are in idually sublethal, a combined BH3-mimetic approach targeting both prosurvival proteins enhanced lethality and durably suppressed the leukemia burden, regardless of TP53 mutation status. Our findings highlight the importance of using sufficiently lethal treatment strategies to maximize outcomes of patients with TP53-mutant disease. In addition, our findings caution against use of sublethal BH3-mimetic drug regimens that may enhance the risk of disease progression driven by emergent TP53-mutant clones.
Publisher: Wiley
Date: 24-12-2012
DOI: 10.1111/BJH.12178
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579616
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: Elsevier BV
Date: 02-2018
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579613
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Society of Hematology
Date: 30-08-2023
Abstract: Assessment of measurable residual disease (MRD) by RT-qPCR is strongly prognostic in patients with NPM1-mutated AML treated with intensive chemotherapy, however there are no data regarding its utility in venetoclax-based non-intensive therapy, despite high efficacy in this genotype. We analysed the prognostic impact of NPM1 MRD in an international real-world cohort of 76 previously untreated patients with NPM1-mutated AML who achieved CR/CRi following treatment with venetoclax and hypomethylating agents (HMA) or low dose cytarabine (LDAC). 44 patients (58%) achieved bone marrow (BM) MRD negativity and a further 14 (18%) a reduction of ≥4 log10 from baseline as their best response, with no difference between HMA and LDAC. The cumulative rate of BM MRD negativity by the end of cycles 2, 4 and 6 was 25%, 47% and 50%. Patients achieving BM MRD negativity by the end of cycle 4 had 2-year overall (OS) of 84% compared to 46% if MRD positive. On multivariable analyses MRD negativity was the strongest prognostic factor. 22 patients electively stopped therapy in BM MRD negative remission after a median of 8 cycles with 2-year treatment-free remission of 88%. In patients with NPM1-mutated AML attaining remission with venetoclax combination therapies, NPM1 MRD provides valuable prognostic information.
Publisher: Wiley
Date: 02-02-2015
DOI: 10.1111/BJH.13281
Abstract: In this Phase 1b study, the safety and tolerability of maintenance therapy, comprising lenalidomide (0-25 mg, days 5-25) in combination with azacitidine (50-75 mg/m(2) , days 1-5) every 28 d, was explored in 40 patients with acute myeloid leukaemia (AML) in complete remission after chemotherapy. Eligibility included AML in first complete remission (CR1) with adverse risk karyotype (n = 8), fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) (n = 5), age ≥60 years (n = 31) or AML in second remission (CR2) (n = 14). Dose-limiting toxicity was not reached. Common toxicities were haematological, infection, injection pain, constipation, fatigue and diarrhoea. In CR1, median relapse-free (RFS) and overall survival (OS) was 12 and 20 months, respectively. In CR2, median RFS was 11 months, with median OS not yet reached. Among 29 patients with intermediate cytogenetic risk, RFS was 50% at 24 months. There were five patients with concomitant FLT3-ITD and nucleophosmin (NPM1) mutation none have relapsed and all are still alive after 17-39 months. Maintenance lenalidomide/azacitidine augmented the function of cytotoxic T lymphocytes, particularly in patients with NPM1 mutation. The lenalidomide/azacitidine maintenance combination was effective in suppressing residual DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A)-positive disease, resulting in sustained remission in patients with concurrent NPM1 mutation. Azacitidine/lenalidomide as maintenance therapy for high-risk AML warrants further exploration.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486446.V1
Abstract: Supplementary Table from Impact of i F /i i LT3 /i Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Publisher: Elsevier BV
Date: 02-2023
DOI: 10.1016/J.CLML.2022.11.002
Abstract: The global incidence of myelodysplastic syndromes (MDS) has been estimated as 0.06 to 0.26/100,000. Since their introduction, hypomethylating agents have played a central role in the treatment of MDS, with heterogeneous real-world outcomes. We assessed and synthesized clinical outcomes of azacitidine (AZA) monotherapy in treatment-naïve patients with higher-risk MDS. A systematic literature review was conducted by searching MEDLINE, Embase, and CENTRAL to identify randomized clinical trials (RCTs) and observational studies, both prospective and retrospective, reporting complete remission (CR), partial remission (PR), overall survival (OS), duration of response (DOR), time-to-response (TTR), and myelosuppressive adverse events (AEs) for patients treated with AZA monotherapy. Noncomparative meta-analyses were used to summarize effects. The search identified 3250 abstracts, of which 34 publications describing 16 studies (5 RCTs, 3 prospective, and 8 retrospective observational) were included. Across all studies, pooled CR was 16% PR was 6% Median OS was 16.4 months median DOR was 10.1 months median TTR was 4.6 months. Proportions of grade 3/4 anemia and thrombocytopenia AEs were 10% and 30%. The effectiveness and efficacy of AZA monotherapy-as measured by CR and median OS-was limited. These findings highlight a significant unmet medical need for effective treatments for patients with higher-risk MDS.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579622.V1
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641299.V1
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618470
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2017
Publisher: American Society of Hematology
Date: 24-03-2020
DOI: 10.1182/BLOODADVANCES.2019000901
Abstract: First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579616.V1
Abstract: Table S3: Clinical characteristics of s les from patients with AML used in PDX assays
Publisher: Informa UK Limited
Date: 13-01-2012
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.STEM.2019.07.001
Abstract: Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states.
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641329.V1
Abstract: Table S1: Transcriptome analysis of FLT3-ITD cell lines after FLT3 inhbition
Publisher: Springer Science and Business Media LLC
Date: 19-07-2018
DOI: 10.1038/S41408-018-0103-6
Abstract: In acute myeloid leukemia (AML), risk stratification based on cytogenetics and mutation profiling is essential but remains insufficient to select the optimal therapy. Accurate biomarkers are needed to improve prognostic assessment. We analyzed RNA sequencing and survival data of 430 AML patients and identified HMGA2 as a novel prognostic marker. We validated a quantitative PCR test to study the association of HMGA2 expression with clinical outcomes in 358 AML s les. In this training cohort, HMGA2 was highly expressed in 22.3% of AML, mostly in patients with intermediate or adverse cytogenetics. High expression levels of HMGA2 ( H + ) were associated with a lower frequency of complete remission (58.8% vs 83.4%, P 0.001), worse 3-year overall survival (OS, 13.2% vs 43.5%, P 0.001) and relapse-free survival (RFS, 10.8% vs 44.2%, P 0.001). A positive HMGA2 test also identified a subgroup of patients unresponsive to standard treatments. Multivariable analyses showed that H + was independently associated with significantly worse OS and RFS, including in the intermediate cytogenetic risk category. These associations were confirmed in a validation cohort of 260 patient s les from the UK NCRI AML17 trial. The HMGA2 test could be implemented in clinical trials developing novel therapeutic strategies for high-risk AML.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579607
Abstract: Table S6: Proteomic analysis of FLT3-ITD AML cell lines treated with vehicle or QUIZ
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618443.V1
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Publisher: Wiley
Date: 07-2018
DOI: 10.1111/IMJ.13714
Abstract: The burden of therapy-related acute myeloid leukaemia (tAML)/therapy-related myelodysplastic syndrome (tMDS) in Australia has not been characterised. To provide insights into the incidence, associated cancers, latency and survival outcomes of patients with tAML/tMDS in Victoria, Australia, based on a state-wide cancer registry and to assess if these features are different in tAML/tMDS compared with de novo AML/MDS. We analysed adults aged ≥20 years at diagnosis of AML/MDS reported to the Victorian Cancer Registry (VCR) between 2003 and 2014. In total, 73 of 3120 (2.3%) AML cases were classified tAML. tAML patients were younger than non-tAML patients at diagnosis (median age 66 vs 71 years, P = 0.000). Median overall survival was similar (6 months). Median latency to tAML was 82 months, with two incidence peaks at 1-4 and 7-8 years. In total, 59 of 73 patients had recorded cancers, the most frequent being non-Hodgkin lymphoma (NHL, 32.2%) and breast cancer (16.9%). In total, 532 of 3120 (14.1%) additional AML cases had ≥1 prior cancer (confirmation of chemoradiotherapy unavailable). tAML incidence increased (0.0/100 000 persons in 2003, 0.5/100 000 persons in 2014), as did the incidence of non-tAML with previous cancer (0.8/100 000 persons in 2003, 1.1/100 000 persons in 2014). In total, 101 of 4435 (2.3%) MDS cases were classified tMDS. Although tMDS incidence fluctuated (range 0-0.4/100 000 persons/year), the incidence of non-tMDS with prior cancer rose (1.4/100 000 persons in 2003, 1.9/100 000 persons in 2014). Compared to tAML, the tMDS cohort was older (median age 70 vs 66 years, P = 0.007). Median latency to tMDS was 42.5 months. NHL was also the most common cancer preceding tMDS, but the second most common cancer was myeloma (17.8%). In total, 1287 of 5061 (20.3%) non-tMDS patients had a prior cancer. The burden of tAML/tMDS in Victoria is likely to be underestimated. Linkage between VCR and clinical registries is needed to provide more accurate insights.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486452.V1
Abstract: Supplementary Table from Impact of i F /i i LT3 /i Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579604
Abstract: Table S7: Transcriptomics analysis of shCEBPA#2 versus shCTL
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579601
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618422.V1
Abstract: Table S9: CEBPA_UP signature
Publisher: American Association for Cancer Research (AACR)
Date: 02-2013
DOI: 10.1158/1078-0432.CCR-13-1576
Abstract: Purpose: Acute myeloid leukemia (AML) provides an environment that enables immune suppression, resulting in functionally defective effector T cells regulatory T cells (Treg) are significant contributors to the impaired antitumor immune response. As TNF is present at high levels in AML and TNF receptor-2 (TNFR2)–expressing Tregs identify highly functional Tregs, we examine the hypothesis that TNFR2+ Tregs are a relevant Treg subset in this cancer. We also determine the effect of the novel combinatorial therapy of the demethylating agent, azacitidine with the histone deacetylase inhibitor, panobinostat on Tregs, particularly TNFR2+ Tregs. Experimental Design: Thirty healthy donors and 14 patients with AML were enrolled in this study. Patients were treated with azacitidine and panobinostat for 28-day cycles. The frequency and functional relevance of TNFR2+ Tregs were analyzed subsequently. Results: We report that TNFR2+ Tregs are increased in AML and have a high migration potential toward the bone marrow. Furthermore, we demonstrate that the level of TNFR2+ Tregs in the peripheral blood and the bone marrow of patients are decreased in vivo after exposure to panobinostat and azacitidine. Reductions in TNFR2+ Tregs were associated with increases in Interferon (IFN)-γ and interleukin (IL)-2 production by effector T cells within the bone marrow and beneficial clinical responses. In vitro mechanistic studies indicated panobinostat as the primary driver for the reduction of Tregs. Conclusions: Our study provides for the first time, in vivo validation of the ability of panobinostat in combination with azacitidine to suppress prevalent TNFR2+ Tregs, resulting in clinical benefits within patients with AML. Clin Cancer Res 20(3) 724–35. ©2013 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579631
Abstract: Table S13: lipidomic results by lipid species in dox-inducible and constitutives shRNAs and siRNA CTL/CEBPA, empty vector/CEBPA-OE and vehicle/QUIZ conditions in MOLM-14 cells
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618449.V1
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541185.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: Massachusetts Medical Society
Date: 13-08-2020
Publisher: American Society of Hematology
Date: 13-10-2020
DOI: 10.1182/BLOODADVANCES.2020002904
Abstract: The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261 CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)–mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1% P = .044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4% P = .089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)–rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2017
Abstract: Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m 2 daily for 5 days, etoposide 75 mg/m 2 daily for 5 days, and idarubicin 9 mg/m 2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%] P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups. An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618455.V1
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: Wiley
Date: 11-04-2019
DOI: 10.1002/GCC.22750
Abstract: The therapeutic landscape is rapidly changing, with eight new drugs approved by the Food and Drug Administration within the last 2 years, including midostaurin and gilteritinib for FLT3 mutant newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML), respectively CPX-351 (liposomal cytarabine and daunorubicin) for therapy-related AML and AML with myelodysplasia-related changes gemtuzumab ozogamicin (anti-CD33 monoclonal antibody conjugated with calicheamicin) for newly diagnosed and R/R CD33-positive AML enasidenib and ivosidenib for IDH2 and IDH1 mutant R/R AML, respectively. Novel therapies have also emerged for newly diagnosed AML in adults who are age 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy. These include venetoclax (BCL-2 inhibitor) in combination with hypomethylating agents (azacitidine or decitabine) or low-dose cytarabine (LDAC), and glasdegib (sonic hedgehog pathway inhibitor) in combination with LDAC. This flurry of new drug approvals has markedly altered the treatment landscape in AML and provided new opportunities, as well as new challenges for treating clinicians. This review will focus on how these drugs might shape clinical practice and the hurdles likely to be faced by new therapies seeking entry into this dynamic and rapidly changing therapeutic landscape.
Publisher: Elsevier BV
Date: 09-2016
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541179.V1
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541167
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Society of Hematology
Date: 11-06-2020
Abstract: Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international phase 3 randomized double-blind placebo-controlled trial. Patients (N = 211) were randomized 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1 to 10. Primary end point was overall survival (OS) secondary end points included response rate, transfusion independence, and event-free survival. Median age was 76 years (range, 36-93 years), 38% had secondary AML, and 20% had received prior hypomethylating agent treatment. Planned primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs LDAC alone (hazard ratio [HR], 0.75 95% confidence interval [CI], 0.52-1.07 P = .11), although not statistically significant median OS was 7.2 vs 4.1 months, respectively. Unplanned analysis with additional 6-month follow-up demonstrated median OS of 8.4 months for the venetoclax arm (HR, 0.70 95% CI, 0.50-0.98 P = .04). Complete remission (CR) plus CR with incomplete blood count recovery rates were 48% and 13% for venetoclax plus LDAC and LDAC alone, respectively. Key grade ≥3 adverse events (venetoclax vs LDAC alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), and thrombocytopenia (45% vs 37%). Venetoclax plus LDAC demonstrates clinically meaningful improvement in remission rate and OS vs LDAC alone, with a manageable safety profile. Results confirm venetoclax plus LDAC as an important frontline treatment for AML patients unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.
Publisher: American Association for Cancer Research (AACR)
Date: 03-07-2023
DOI: 10.1158/2159-8290.23618461.V1
Abstract: Table S10: EnrichR analysis of CEBPA_UP signature
Publisher: American Society of Hematology
Date: 30-04-2015
DOI: 10.1182/BLOOD-2014-09-603555
Abstract: INPP4B promotes chemoresistance in AML independent of phosphoinositide phosphatase function.
Publisher: Wiley
Date: 27-10-2009
DOI: 10.1111/J.1365-2141.2009.07819.X
Abstract: Considerable progress has been made over the last two decades in delineating the key molecular events regulating the haemostatic function of platelets. Much of this new insight has been derived from the study of mouse models, in which the expression or structure of one or more platelet proteins has been genetically altered. Despite these advances on the research front, clinical progress in diagnosing patients with unexplained surgical bleeding or recurrent haemorrhage from mucocutaneous sites has been comparatively limited. There is a dearth of literature available to help physicians integrate and apply the burgeoning knowledge on platelet biology to diagnosing patients with atypical or unexplained platelet dysfunction. The purpose of this review is to summarise the major primary platelet disorders relevant to pathological bleeding in humans (excluding those primarily due to thrombocytopenia or acquired functional disorders), with a focus on lesions identified in mouse models that could represent candidate molecules for study in patients with impaired platelet function.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541164
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Society of Hematology
Date: 12-10-2023
DOI: 10.1182/BLOODADVANCES.2023010045
Abstract: In iduals with germline variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of pre-malignant states in HHMs have h ered efforts to design effective clinical surveillance programs, provide personalized pre-emptive treatments and inform appropriate counselling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies ("carriers-without HM"). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second-hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For ex le, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germline variants for the acquisition of somatic variants in BCOR, PHF6, TET2, and second hits in RUNX1 are warranted.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579637
Abstract: Table S11
Publisher: Wiley
Date: 2011
DOI: 10.1111/J.1445-5994.2010.02341.X
Abstract: The use of oral prophylactic antibiotics in patients with neutropenia is controversial and not recommended by this group because of a lack of evidence showing a reduction in mortality and concerns that such practice promotes antimicrobial resistance. Recent evidence has demonstrated non-significant but consistent, improvement in all-cause mortality when fluoroquinolones (FQs) are used as primary prophylaxis. However, the consensus was that this evidence was not strong enough to recommend prophylaxis. The evidence base for FQ prophylaxis is presented alongside current consensus opinion to guide the appropriate and judicious use of these agents. Due consideration is given to patient risk, as it pertains to specific patient populations, as well as the net effect on selective pressure from antibiotics if FQ prophylaxis is routinely used in a target population. The potential costs and consequences of emerging FQ resistance, particularly among Escherichia coli, Clostridium difficile and Gram-positive organisms, are considered. As FQ prophylaxis has been advocated in some chemotherapy protocols, specific regard is given to whether FQ prophylaxis should be used to support these regimens. The group also provides recommendations for monitoring and surveillance of emerging resistance in those centres that have adopted FQ prophylaxis.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579634
Abstract: Table S12: gene signatures used to analyze RNA-seq data from patients with AML before/after GILT
Publisher: Massachusetts Medical Society
Date: 03-08-2017
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579649.V1
Abstract: Supplemental figures S1-S22: Supplementary Figure S1 shows lipid metabolism dependency in FLT3-mutant AML, Supplementary Figure S2 shows anti-leukemic activity of GILT across a panel of AML PDX, Supplementary Figure S3 shows mechanisms of post-translational regulation of C/EBPα expression, Supplementary Figure S4 shows inhibition of C/EBPα phosphorylation and protein expression by FLT3i, Supplementary Figure S5 shows the implication of Ser-21 phosphorylation in post-translational regulation of C/EBPα expression, Supplementary Figure S6 shows that FLT3-ITD regulates the expression of C/EBPα and of proteins related to lipid biosynthesis in AML cell lines, Supplementary Figure S7 shows that FLT3-ITD regulates the expression of genes related to lipid biosynthesis in AML cell lines, Supplementary Figure S8 shows that C/EBPα directly regulates the transcription of lipid biosynthesis genes in AML, Supplementary Figure S9 shows the correlation between CEBPA mRNA expression and FLT3-ITD mutations, Supplementary Figure S10 shows scRNA-seq analysis from PDXTUH84, Supplementary Figure S11 shows scRNA-seq analysis from PDXTUH110, Supplementary Figure S12 shows the evolution of CEBPA_UP and FLT3-ITD_UP signatures in patients with AML treated with GILT, Supplementary Figure S13 shows that C/EBPα regulates rate-limiting lipid biosynthetic enzymes downstream of FLT3-ITD, Supplementary Figure S14 shows that C/EBPα controls lipid amount in FLT3-ITD cell lines, Supplementary Figure S15 shows that FLT3 inhibitors induce a lipid switch increasing neutral lipids dependent on C/EBPα, Supplementary Figure S16 shows that FLT3 inhibitor inhibits fatty acid synthesis fueled by glucose and glutamine, Supplementary Figure S17 shows that FLT3 inhibition decreases monounsaturated fatty acid dependent on C/EBPα, Supplementary Figure S18 shows that FLT3 inhibition increases PUFA/MUFA ratio dependent on C/EBPα, Supplementary Figure S19 shows that ferroptotic cell death induced by FLT3i is mediated by inhibition of SCD-dependent mono-unsaturated FA synthesis, Supplementary Figure S20 shows that FLT3 inhibitors unmask a vulnerability of FLT3-mutant leukemic cells to ferroptosis, Supplementary Figure S21 shows that lipid redox stress induction by GPX4 inhibition primed FLT3i activity in FLT3-ITD AML cells and Supplementary Figure S22 shows combined treatment with GILT and APR-246 in preclinical AML models in vivo.
Publisher: Wiley
Date: 25-03-2013
DOI: 10.1111/BJH.12295
Publisher: Elsevier BV
Date: 09-2015
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541179
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: Informa UK Limited
Date: 13-10-2020
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541173
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22486458.V1
Abstract: Supplementary Table from Impact of i F /i i LT3 /i Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641302.V1
Abstract: Table S4: GSEA results in FLT3-ITD PDX AML cells ex vivo-treated with QUIZ or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541170
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541176
Abstract: Supplementary Table from Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
Publisher: Springer Science and Business Media LLC
Date: 10-01-2014
DOI: 10.1038/BCJ.2013.68
Abstract: Therapeutic options are limited for elderly patients with acute myeloid leukemia (AML). A phase Ib/II study was undertaken to evaluate the maximum-tolerated dose (MTD) and preliminary efficacy of the pan-histone deacetylase inhibitor panobinostat (LBH589) in combination with azacitidine in patients with AML or high-risk myelodysplastic syndrome (MDS) naïve to intensive chemotherapy. Thirty-nine patients (AML=29, MDS=10) received azacitidine 75 mg/m 2 subcutaneously (days 1–5) and oral panobinostat (starting on day 5, thrice weekly for seven doses) in 28-day cycles until toxicity or disease progression. Dose-limiting toxicities during the phase Ib stage were observed in 0/4 patients receiving 10 mg panobinostat, in 1/7 patients (fatigue) receiving 20 mg, in 1/6 patients (fatigue) receiving 30 mg and in 4/5 patients (fatigue, syncope, hyponatremia and somnolence) receiving 40 mg. In phase II, an additional 17 patients received panobinostat at a MTD of 30 mg. The overall response rate (ORR=CR+CRi+PR) in patients with AML was 31% (9/29) and that in patients with MDS was 50% (5/10). After a median follow-up of 13 months, the median overall survival was 8 and 16 months in patients with AML and MDS, respectively. Increased histone H3 and H4 acetylation was a useful early biomarker of clinical response. Combining panobinostat with azacitidine was tolerable and clinically active in high-risk MDS/AML patients, warranting further exploration.
Publisher: Springer Science and Business Media LLC
Date: 09-05-2014
DOI: 10.1038/BCJ.2014.33
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.BEHA.2014.04.003
Abstract: Until recently, the standard of care in the treatment of APL has involved the combination of all-trans retinoic acid with anthracycline-based chemotherapy during both induction and consolidation. Additionally, the intensity of consolidation chemotherapy has evolved according to a universally accepted relapse-risk stratification algorithm based on the white cell and platelet counts at presentation. That standard of care is being challenged by the increasing incorporation of arsenic trioxide into front-line treatment protocols, based on two complementary observations. The first is the undoubted anti-leukaemic activity of arsenic trioxide as shown in the relapsed and refractory setting, and in the initial management of low- and intermediate-risk patients. The second is an improved understanding of the action of both all-trans retinoic acid and arsenic trioxide in mediating APL cell eradication, with increasing recognition that PML-RARA fusion protein degradation rather than direct induction of terminal differentiation is the primary mechanism for their ability to eliminate leukaemia initiating cells. As a result, we believe the standard of care for initial therapy in APL is shifting towards an all-trans retinoic acid plus arsenic trioxide-based approach, with additional chemotherapy reserved for patients with high-risk disease.
Publisher: Elsevier BV
Date: 10-2013
Publisher: Cold Spring Harbor Laboratory
Date: 27-05-2020
DOI: 10.1101/2020.05.26.116392
Abstract: Activating FMS-like tyrosine kinase 3 ( FLT3 ) mutations occur in approximately 30% of all acute myeloid leukaemias (AMLs) and are associated with poor prognosis. The limited clinical efficacy of FLT3 inhibitor monotherapy has highlighted the need for alternative therapeutic targets and treatments for FLT3-mutant AML. Using human and murine models of MLL-rearranged AML harbouring FLT3 internal tandem duplication (FLT3-ITD) and primary patient s les, we have demonstrated that FLT3-ITD promotes serine uptake and serine synthesis via transcriptional regulation of neutral amino acid transporters ( SLC1A4 and SLC1A5 ) and genes in the de novo serine synthesis pathway ( PHGDH and PSAT1 ). Mechanistically, dysregulation of serine metabolism in FLT3-mutant AML is dependent on the mTORC1-ATF4 axis, that drives RNA-Pol II occupancy at PHGDH, PSAT1, SLC1A4 and SLC1A5 . Genetic or pharmacological inhibition of the de novo serine synthesis pathway selectively inhibited the proliferation of FLT3-ITD AML cells, and this was potentiated by withdrawal of exogenous serine. Purine supplementation effectively rescued the antiproliferative effect of inhibiting de novo serine synthesis, consistent with the idea that serine fuels purine nucleotide synthesis in FLT3-mutant AML. Pharmacological inhibition of the de novo serine synthesis pathway, using the PHGDH inhibitor WQ-2101, sensitises FLT3-mutant AML cells to the standard of care chemotherapy agent cytarabine via exacerbation of DNA damage. Collectively, these data reveal new insights as to how FLT3 mutations reprogram metabolism in AML, and reveal a combination therapy strategy to improve the treatment of FLT3-mutant AML. FLT3 mutations are common in AML and are associated with poor prognosis. We show that FLT3-ITD stimulates serine metabolism, thereby rendering FLT3-ITD leukemias dependent on serine for proliferation and survival. This metabolic dependency can be exploited pharmacologically to sensitize FLT3-mutant AML to chemotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579628
Abstract: Table S14: PUFA/MUFA ratios in phospholipids
Publisher: American Association for Cancer Research (AACR)
Date: 07-07-2023
DOI: 10.1158/2159-8290.23641287.V1
Abstract: Table S8: Multimodal analysis of shCEBPA versus shCTL MOLM14 cell line
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579610.V1
Abstract: Table S5: GSEA results in FLT3-ITD PDX AML cells in vivo-treated with GILT or Veh.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579625
Abstract: Table S15: Relative quantification by lipid class
Publisher: Future Medicine Ltd
Date: 02-2016
DOI: 10.2217/FON.15.326
Abstract: Older patients with acute myeloid leukemia (AML) have worse rates of complete remission and shorter overall survival than younger patients. The epigenetic modifier CC-486 is an oral formulation of azacitidine with promising clinical activity in patients with AML in Phase I studies. The Phase III, randomized, double-blind, placebo-controlled QUAZAR AML Maintenance trial (CC-486-AML-001) examines CC-486 maintenance therapy (300 mg/day for 14 days of 28-day treatment cycles) for patients aged ≥55 years with AML in first complete remission. The primary end point is overall survival. Secondary end points include relapse-free survival, safety, health-related quality of life and healthcare resource utilization. This trial will investigate whether CC-486 maintenance can prolong remission and improve survival for older patients with AML.
Publisher: American Association for Cancer Research (AACR)
Date: 26-06-2023
DOI: 10.1158/2159-8290.23579622
Abstract: Table S2: EnrichR analysis of FLT3 gene signatures
Location: Australia
No related grants have been discovered for Andrew Wei.