ORCID Profile
0000-0001-7171-2935
Current Organisations
Universidad Autónoma Metropolitana Iztapalapa
,
University of Adelaide
,
SA Pathology
,
South Australian Health and Medical Research Institute
,
Flinders University School of Medicine
,
Centre for Cancer Biology
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 4 Research Topics
ANZSRC Field of Research (FoR)
Manufacturing Engineering | Manufacturing Processes and Technologies (excl. Textiles) | Microtechnology
ANZSRC Socio-Economic Objective (SEO)
Related Links
Publications
Association of TIM-3 checkpoint receptor expression on T cells with treatment-free remission in chronic myeloid leukemia
Publisher: American Society of Hematology
Date: 25-05-2023
DOI: 10.1182/BLOODADVANCES.2022008854
Abstract: Dysregulation of immune-checkpoint receptors has been reported at diagnosis of chronic myeloid leukemia (CML), however, their role in the maintenance of remission after tyrosine kinase inhibitor (TKI) cessation is unclear. We assessed programmed cell death-1 (PD-1), T-cell immunoglobulin, and mucin-domain containing protein-3 (TIM-3), cytotoxic T-lymphocyte–associated protein-4 (CTLA-4), lymphocyte-activation gene-3 (LAG-3), and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) expression on T-cell subsets, regulatory T cells (T-regs), and natural killer (NK) cells at the time of TKI cessation in 44 patients (22 patients sustained treatment-free remission [TFR] and 22 experienced molecular relapse [MolR]). We confirmed our previous finding that absolute numbers of T-regs are increased in patients who experienced MolR compared with those who sustained TFR. The immune-checkpoint receptors PD-1, CTLA-4, LAG-3, and TIGIT on T or NK cells were not differentially expressed between the MolR and TFR groups. However, TIM-3 was consistently upregulated on bulk T cells (CD3+) and T-cell subsets including, CD4+ T cells, CD8+ T cells, and T-regs, in patients who relapsed in comparison with those who maintained TFR after discontinuation. Furthermore, gene expression analysis from publicly available data sets showed increased TIM-3 expression on CML stem cells compared with normal hematopoietic stem cells. These findings suggest that among the targetable immune-checkpoint molecules, TIM-3 blockade may potentially improve effector immune response in patients with CML stopping TKI, while concomitantly targeting leukemic stem cells and could be a promising therapeutic strategy for preventing relapse after cessation of TKI in patients with CML.
Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML
Publisher: American Society of Hematology
Date: 09-05-2013
DOI: 10.1182/BLOOD-2012-10-462291
Abstract: Independent predictors of stable, undetectable BCR-ABL1 during first-line imatinib therapy were female sex and the BCR-ABL1 value at 3 months. Time to achieve an MMR influenced time to stable, undetectable BCR-ABL1, suggesting slower dynamics of BCR-ABL1 decline with delayed MMR.
Sudden onset vision loss: an atypical presentation of giant cell arteritis and myeloproliferative neoplasm.
Publisher: AMPCo
Date: 08-12-2020
DOI: 10.5694/MJA2.50888
Myeloid somatic mutation panel testing in myeloproliferative neoplasms
Publisher: Elsevier BV
Date: 04-2021
Distribution of genomic breakpoints in chronic myeloid leukemia: analysis of 308 patients
Publisher: Springer Science and Business Media LLC
Date: 16-04-2013
DOI: 10.1038/LEU.2013.116
A DNA Real-Time Quantitative PCR Method Suitable for Routine Monitoring of Low Levels of Minimal Residual Disease in Chronic Myeloid Leukemia
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.JMOLDX.2014.10.002
Abstract: The BCR-ABL1 sequence has advantages over the BCR-ABL1 transcript as a molecular marker in chronic myeloid leukemia and has been used in research studies. We developed a DNA real-time quantitative PCR (qPCR) method for quantification of BCR-ABL1 sequences, which is also potentially suitable for routine use. The BCR-ABL1 breakpoint was sequenced after isolation by nested short-range PCR of DNA from blood, marrow, and cells on slides, obtained either at diagnosis or during treatment, or from artificial mixtures. PCR primers were chosen from a library of presynthesized and pretested BCR (n = 19) and ABL1 (n = 568) primers. BCR-ABL1 sequences were quantified relative to BCR sequences in 521 assays on 266 s les from 92 patients. For minimal residual disease detectable by DNA qPCR and RT-qPCR, DNA qPCR gave similar minimal residual disease results as RT-qPCR but had better precision at low minimal residual disease levels. The limit of detection of DNA qPCR depended on the amount of DNA assayed, being 10(-5.8) when 5 μg was assayed and 10(-7.0) when 80 μg was assayed. DNA qPCR may be useful and practical for monitoring the increasing number of patients with minimal residual disease around or below the limit of detection of RT-qPCR as the assay itself is simple and the up-front costs will be amortized if sequential assays are performed.
Use of romiplostim in pregnancy for refractory idiopathic thrombocytopenic purpura: Two case reports with maternal and fetal outcomes and literature review
Publisher: SAGE Publications
Date: 29-05-2018
Abstract: Idiopathic thrombocytopenic purpura is a relatively rare complication occurring in pregnancy, with the potential for serious maternal and fetal outcomes. Rarely, the poor response to established first-line therapies results in consideration of second-line therapies, which may have poorly understood risks to the fetus. We report two women with severe idiopathic thrombocytopenic purpura during pregnancy unresponsive to corticosteroids and intravenous immunoglobulin who were treated with romiplostim, a thrombopoietin receptor agonist. One woman with chronic idiopathic thrombocytopenic purpura had a partial response to romiplostim and suffered a post-partum haemorrhage related to uterine atony. The second woman developed severe idiopathic thrombocytopenic purpura in pregnancy and initially responded well to romiplostim. However, a lower segment Caesarean section was performed at 37 weeks for pre-ecl sia. The newborn suffered from severe idiopathic thrombocytopenic purpura and a grade 1 cerebral haemorrhage requiring intravenous immunoglobulin and platelet transfusions. Romiplostim might be a useful therapy for severe idiopathic thrombocytopenic purpura in pregnancy but requires further study.
Single cells tell multiple tales in CML
Publisher: American Society of Hematology
Date: 06-2023
The effect of tyrosine kinase inhibitor interruption and interferon use on pregnancy outcomes and long-term disease control in chronic myeloid leukemia
Publisher: Informa UK Limited
Date: 11-01-2019
DOI: 10.1080/10428194.2018.1551533
Abstract: The management of CML in pregnancy is challenging with the need to balance disease control against potential teratogenic effects of TKI therapy. In this multi-center case-cohort study of 16 women in chronic phase, CML ceased TKI treatment pre- or post-conception during their first pregnancy. Thirteen patients were on imatinib 9 ceased their TKI prior to conception and 7 ceased at pregnancy confirmation. Twelve patients had achieved either MMR or better at time of TKI cessation. Eleven women lost MMR during pregnancy and two patients lost CHR. Fourteen women reestablished MMR on TKI recommenced. The depth molecular response prior to conception appeared to correlate well with restoration of disease control on TKI recommencement though duration of MMR did not appear to be as important. While interruption of TKI treatment for pregnancy usually leads to loss of molecular response, loss of hematological response is uncommon and disease control is reestablished with resumption of therapy in the majority of women.
How I determine if and when to recommend stopping tyrosine kinase inhibitor treatment for chronic myeloid leukaemia
Publisher: Wiley
Date: 23-04-2014
DOI: 10.1111/BJH.12892
Abstract: Treatment-free remission (TFR) has recently emerged as a goal of treatment in chronic myeloid leukaemia (CML). Molecular remission is sustained in around 30% of imatinib-treated patients who stop treatment after ≥2 years with undetectable minimal residual disease (UMRD) by conventional real-time reverse transcription polymerase chain reaction. An additional 20-30% of patients will lose UMRD, but remain in stable major molecular remission off treatment. Most patients with molecular recurrence have a significant increase in BCR-ABL1 within the first 6 months off treatment, but there are also rare late relapses. As re-treatment with imatinib restores control, a trial of TFR is safe so long as careful molecular monitoring is provided to enable prompt re-treatment. The minimum eligibility criteria for a trial of TFR are not yet defined, but the available data support a MRD level of around a molecular response of 4.5 log for at least 2 years. Factors associated with a higher probability of TFR include low risk Sokal score, prior interferon treatment, longer total duration of imatinib treatment and higher numbers of natural killer cells at the time of imatinib discontinuation. Preliminary data suggest that the rate of TFR in patients treated with more potent tyrosine kinase inhibitors will probably be higher. The biology that underlies TFR is an area of active investigation.
Sensitive detection and quantification of minimal residual disease in chronic myeloid leukaemia using nested quantitative PCR for BCR-ABL DNA.
Publisher: Wiley
Date: 26-10-2010
Genomic translocation breakpoint sequences are conserved in BCR-ABL1 cell lines despite the presence of amplification.
Publisher: Elsevier BV
Date: 03-2009
Reply to 'What do we mean by sensitivity when we talk about detecting minimal residual disease?' by Steinbach and Debatin.
Publisher: Springer Science and Business Media LLC
Date: 20-11-2009
DOI: 10.1038/LEU.2008.330
Spatial disparities in the reported incidence and survival of myeloproliferative neoplasms in Australia
Publisher: Elsevier BV
Date: 04-2022
Vosaroxin is a novel topoisomerase-II inhibitor with efficacy in relapsed and refractory acute myeloid leukaemia
Publisher: Informa Healthcare
Date: 10-05-2015
DOI: 10.1517/14656566.2015.1044437
Abstract: Vosaroxin is a first-in-class anti-cancer quinolone that inhibits topoisomerase-II leading to cell cycle arrest and apoptosis. It has shown efficacy in a range of solid organ and haematopoietic tumours in vitro, and several clinical trials are underway or completed in the field of Acute Myeloid Leukaemia (AML). The treatment of relapsed and refractory AML is a clinical challenge, where long-term survival is rare without allogeneic haematopoietic stem cell transplantation. We review the data from the published clinical trials of vosaroxin, including the recently presented Phase III VALOR study. In combination with intermediate dose cytarabine, vosaroxin almost doubled complete response (CR) rates in relapsed and refractory AML compared with cytarabine alone, and prolonged median survival by 1.4 months. Vosaroxin is a promising new agent in the treatment of AML, with the potential to improve CR rates in a high-risk group of patients with relapsed and refractory AML. However, higher CR rates have been associated with higher rates of treatment-related morbidity and mortality, especially in elderly/unfit patients. Maximising the potential of vosaroxin will therefore require the identification of patients most likely to benefit from vosaroxin-containing combination regimens.
Long-term treatment-free remission of chronic myeloid leukemia with falling levels of residual leukemic cells
Publisher: Springer Science and Business Media LLC
Date: 12-10-2018
DOI: 10.1038/S41375-018-0264-0
Abstract: Following the achievement of deep molecular response on tyrosine kinase inhibitors (TKIs), approximately half of patients with chronic myeloid leukemia (CML) can discontinue TKI and remain in treatment-free remission (TFR). The ALLG CML8 study enrolled 40 imatinib-treated patients with undetectable BCR-ABL1 mRNA (approximately MR
Treatment-free remission following frontline nilotinib in patients with chronic phase chronic myeloid leukemia: 5-year update of the ENESTfreedom trial
Publisher: Springer Science and Business Media LLC
Date: 11-03-2021
DOI: 10.1038/S41375-021-01205-5
Abstract: The ENESTfreedom trial assessed the feasibility of treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) following frontline nilotinib treatment. Results for long-term outcomes after a 5-year follow-up are presented herein. Patients who had received ≥2 years of frontline nilotinib therapy and achieved MR 4.5 underwent a 1-year nilotinib treatment consolidation phase before attempting TFR. At the 5-year data cut-off, 81/190 patients entering the TFR phase (42.6%) were still in TFR, with 76 (40.0%) in MR 4.5 . Patients who lost major molecular response (MMR) entered a treatment re-initiation phase 90/91 patients entering this phase (98.9%) regained MMR and 84/91 patients (92.3%) regained MR 4.5 . The Kaplan–Meier estimated treatment-free survival rate at 5 years was 48.2%. No disease progression or CML-related deaths were reported. Whereas the incidence of adverse events (AEs) declined from 96 weeks following the start of TFR, an increase in AE frequency was observed for patients in the treatment re-initiation phase. Low Sokal risk score, BCR-ABL1 IS levels at 48 weeks of TFR and stable MR 4.5 response for the first year of TFR were associated with higher TFR rates. Overall, these results support the efficacy and safety of attempting TFR following upfront nilotinib therapy of years in patients with CML-CP.
Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure.
Publisher: Massachusetts Medical Society
Date: 12-12-2019
Supplementary Figure S1 from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792318.V1
Abstract: Figure showing X-ray crystal structure of pseudokinase domain inhibitor
Masked polycythaemia vera is genetically intermediate between JAK2V617F mutated essential thrombocythaemia and overt polycythaemia vera
Publisher: Springer Science and Business Media LLC
Date: 19-08-2016
DOI: 10.1038/BCJ.2016.70
Lenalidomide maintenance treatment after imatinib discontinuation: results of a phase 1 clinical trial in chronic myeloid leukaemia
Publisher: Wiley
Date: 27-03-2019
DOI: 10.1111/BJH.15894
TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets
Publisher: American Society of Hematology
Date: 05-02-2015
DOI: 10.1182/BLOOD-2014-07-590315
Abstract: Using imatinib to treat CML first-line, with selective nilotinib switching, leads to excellent molecular response and survival. This strategy may be preferable to universal first-line use of more potent agents, considering efficacy, toxicity, and economic factors.
How complete is complete molecular response in imatinib-treated chronic myeloid leukemia?
Publisher: Informa UK Limited
Date: 2008
Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia
Publisher: American Society of Hematology
Date: 30-06-2022
Abstract: Inducing cell death by the sphingolipid ceramide is a potential anticancer strategy, but the underlying mechanisms remain poorly defined. In this study, triggering an accumulation of ceramide in acute myeloid leukemia (AML) cells by inhibition of sphingosine kinase induced an apoptotic integrated stress response (ISR) through protein kinase R–mediated activation of the master transcription factor ATF4. This effect led to transcription of the BH3-only protein Noxa and degradation of the prosurvival Mcl-1 protein on which AML cells are highly dependent for survival. Targeting this novel ISR pathway, in combination with the Bcl-2 inhibitor venetoclax, synergistically killed primary AML blasts, including those with venetoclax-resistant mutations, as well as immunophenotypic leukemic stem cells, and reduced leukemic engraftment in patient-derived AML xenografts. Collectively, these findings provide mechanistic insight into the anticancer effects of ceramide and preclinical evidence for new approaches to augment Bcl-2 inhibition in the therapy of AML and other cancers with high Mcl-1 dependency.
Moving treatment-free remission into mainstream clinical practice in CML
Publisher: American Society of Hematology
Date: 07-07-2016
DOI: 10.1182/BLOOD-2016-01-694265
Abstract: The dramatic success of tyrosine kinase inhibitors (TKIs) has led to the widespread perception that chronic myeloid leukemia (CML) has become another chronic disease, where lifelong commitment to pharmacologic control is the paradigm. Recent trials demonstrate that some CML patients who have achieved stable deep molecular response can safely cease their therapy without relapsing (treatment free remission [TFR]). Furthermore, those who are unsuccessful in their cessation attempt can safely re-establish remission after restarting their TKI therapy. Based on the accumulated data on TFR, we propose that it is now time to change our approach for the many CML patients who have achieved a stable deep molecular response on long-term TKI therapy. Perhaps half of these patients could successfully achieve TFR if offered the opportunity. For many of these patients ongoing therapy is impairing quality of life and imposing a heavy financial burden while arguably achieving nothing. This recommendation is based on the evident safety of cessation attempts and TFR in the clinical trial setting. We acknowledge that there are potential risks associated with cessation attempts in wider clinical practice, but this should not deter us. Instead we need to establish criteria for safe and appropriate TKI cessation. Clinical trials will enable us to define the best strategies to achieve TFR, but clinicians need guidance today about how to approach this issue with their patients. We outline circumstances in which it would be in the patient's best interest to continue TKI, as well as criteria for a safe TFR attempt.
Dielectric enhanced nanoparticles for three-dimensional optical manipulation
Publisher: SPIE
Date: 20-08-2009
DOI: 10.1117/12.825456
Minimal residual disease and discontinuation of therapy in chronic myeloid leukemia: can we aim at a cure?
Publisher: American Society of Hematology
Date: 10-12-2011
DOI: 10.1182/ASHEDUCATION-2011.1.136
Abstract: Patients with chronic myeloid leukemia (CML) who have achieved a complete molecular response (CMR) defined by no detectable BCR-ABL mRNA on imatinib (IM) treatment often ask whether it is necessary for treatment to continue. We now know that approximately 40% of patients with a stable CMR for at least 2 years are able to stop IM treatment and remain in molecular remission for at least 2 years. This exciting observation has raised hopes that many patients can be cured of CML without the need for transplantation and its attendant risks. One might argue that for many patients maintenance therapy with IM or an alternative kinase inhibitor is so well tolerated that there is no imperative to stop treatment however, chronic medical therapy may be associated with impaired quality of life and reduced compliance. Inferences about the biology of CML in patients responding to kinase inhibitors can be drawn from clinical experience, molecular monitoring data, and experimental observations. We summarize this information herein, and propose 3 possible pathways to “cure” of CML by kinase inhibitors: stem-cell depletion, stem-cell exhaustion, and immunological control.
Clonal and lineage analysis of somatic DNMT3A and JAK2 mutations in a chronic phase polycythemia vera patient.
Publisher: Wiley
Date: 22-08-2011
Practical management of patients with myelofibrosis receiving ruxolitinib
Publisher: Informa UK Limited
Date: 10-2013
Responses to pomalidomide and placebo in myelofibrosis-related anaemia
Publisher: Springer Science and Business Media LLC
Date: 09-12-2016
DOI: 10.1038/LEU.2016.348
Successful treatment-free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells.
Publisher: Wiley
Date: 30-04-2020
DOI: 10.1111/BJH.16718
Abstract: There is currently no biomarker that reliably predicts treatment‐free remission (TFR) in chronic myeloid leukaemia (CML). We characterised effector and suppressor immune responses at the time of tyrosine kinase inhibitor (TKI) cessation in patients from the CML8 and CML10 clinical studies. Natural killer (NK) cells with increased expression of activating NK receptors were higher in patients who achieved TFR. There was no difference in the proportion of CD4 + or CD8 + T cells. Furthermore, we found that FoxP3 + regulatory T cells (T reg) and monocytic myeloid‐derived suppressor cells (Mo‐MDSCs) were concomitantly decreased in TFR patients, suggesting that the effector and suppressor arms of the immune system work in concert to mediate TFR. A discovery cohort (CML10) was used to generate a predictive model, using logistic regression. Patients classified into the high‐risk group were more likely to relapse when compared with the low‐risk group (HR 7·4, 95% CI 2·9‐19·1). The model was successfully validated on the independent CML8 cohort (HR 8·3, 95% CI 2·2–31·3). Effective prediction of TFR success may be obtained with an effector‐suppressor score, calculated using absolute NK cell, T reg, and Mo‐MDSC counts, at TKI cessation, reflecting the contribution of both immune suppressors and effectors in the immunobiology underlying successful TFR.
Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study
Publisher: Springer Science and Business Media LLC
Date: 22-02-2018
The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1
Publisher: Springer Science and Business Media LLC
Date: 03-2017
DOI: 10.1038/NATURE21702
Abstract: Chronic myeloid leukaemia (CML) is driven by the activity of the BCR-ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years. Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR-ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment. Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph
Genomic profiling for clinical decision making in myeloid neoplasms and acute leukemia.
Publisher: American Society of Hematology
Date: 24-11-2022
Abstract: Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome sequencing, whole-genome sequencing, and whole-transcriptome sequencing or RNA sequencing. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are used not only for detecting somatically acquired gene mutations but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification of myeloid neoplasms and acute leukemias makes extensive use of genomic data. The aim of this report is to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with hematologic neoplasms.
Modeling the safe minimum frequency of molecular monitoring for CML patients attempting treatment-free remission.
Publisher: American Society of Hematology
Date: 04-07-2019
Personalized risk model for predicting risk of acute coronary syndrome in patients with myelodysplastic syndromes
Publisher: American Society of Hematology
Date: 30-06-2023
Do we have to kill the last CML cell?
Publisher: Springer Science and Business Media LLC
Date: 16-09-2010
DOI: 10.1038/LEU.2010.197
Abstract: Previous experience in the treatment of chronic myeloid leukaemia (CML) has shown that the achievement of clinical, morphological and cytogenetic remission does not indicate eradication of the disease. A complete molecular response (CMR no detectable BCR-ABL mRNA) represents a deeper level of response, but even CMR is not a guarantee of elimination of the leukaemia, because the significance of CMR is determined by the detection limit of the assay that is used. Two studies of imatinib cessation in CMR are underway, cumulatively involving over 100 patients. The current estimated rate of stable CMR after stopping imatinib is approximately 40%, but the duration of follow-up is relatively short. The factors that determine relapse risk are yet to be identified. The intrinsic capacity of any residual leukaemia [corrected] cells to proliferate following the withdrawal of treatment may be important, but there may also be a role for immunological suppression of the leukaemia [corrected] clone. No currently available test can formally prove that the leukaemic clone is eradicated. Here we discuss the sensitive measurement of minimal residual disease, and speculate on the biology of BCR-ABL-positive cells that may persist after effective therapy of CML.
A Personalized Risk Model for Azacitidine Outcome in Myelodysplastic Syndrome and Other Myeloid Neoplasms Identified by Machine Learning Model Utilizing Real-World Data
Publisher: MDPI AG
Date: 08-08-2023
Abstract: Azacitidine is an approved therapy for higher-risk myelodysplastic syndrome (MDS). However, only 30–40% patients respond to azacitidine, and the responses may take up to six cycles to become evident. Delayed responses and the myelosuppressive effects of azacitidine make it challenging to predict which patients will benefit. This is further compounded by a lack of uniform prognostic tools to identify patients at risk of early treatment failure. Hence, we performed a retrospective analysis of 273 consecutive azacytidine-treated patients. The median overall survival was 16.25 months with only 9% alive at 5 years. By using pre-treatment variables incorporated into a random forest machine learning model, we successfully identified those patients unlikely to benefit from azacytidine upfront (7.99 vs. 22.8 months, p 0.0001). This model also identified those who required significantly more hospitalizations and transfusion support. Notably, it accurately predicted survival outcomes, outperforming the existing prognostic scoring system. By integrating somatic mutations, we further refined the model and identified three distinct risk groups with significant differences in survival (5.6 vs. 10.5 vs. 43.5 months, p 0.0001). These real-world findings emphasize the urgent need for personalized prediction tools tailored to hypomethylating agents, reducing unnecessary complications and resource utilization in MDS treatment.
BCR-ABL1 doubling times more reliably assess the dynamics of CML relapse compared with the BCR-ABL1 fold rise: implications for monitoring and management
Publisher: American Society of Hematology
Date: 03-05-2012
DOI: 10.1182/BLOOD-2011-11-393041
Abstract: Rising BCR-ABL1 transcripts indicate potential loss of imatinib response in CML. We determined whether the BCR-ABL1 doubling time could distinguish nonadherence from resistance as the cause of lost response. Distinct groups were examined: (1) acquired clinical resistance because of blast crisis and/or BCR-ABL1 mutations and (2) documented imatinib discontinuation/interruption. Short doubling times occurred with blast crisis (median, 9.0 days range, 6.1-17.6 days n = 12 patients), relapse after imatinib discontinuation in complete molecular response (median, 9.0 days range, 6.9-26.5 days n = 17), and imatinib interruption during an entire measurement interval (median, 9.4 days range, 4.2-17.6 days n = 12 P = .72). Whereas these doubling times were consistently short and indicated rapid leukemic expansion, fold rises were highly variable: 71-, 9.5-, and 10.5-fold, respectively. The fold rise depended on the measurement interval, whereas the doubling time was independent of the interval. Longer doubling times occurred for patients with mutations who maintained chronic phase (CP: median, 48 days range, 17.3-143 days n = 29 P .0001). Predicted short and long doubling times were validated on an independent cohort monitored elsewhere. The doubling time revealed major differences in kinetics according to clinical context. Long doubling times observed with mutations in CP allow time for intervention. A short doubling time for a patient in CP should raise the suspicion of nonadherence.
Dynamic assessment of RBC‐transfusion dependency improves the prognostic value of the revised‐IPSS in MDS patients
Publisher: Wiley
Date: 20-03-2017
DOI: 10.1002/AJH.24704
Abstract: RBC-transfusion dependency (RBC-TD) is an independent prognostic factor for poor overall survival (OS) in the WHO classification-based prognostic scoring system (WPSS) for MDS patients. However, WPSS did not include cytopenia, whereas revised International Prognostic Scoring System (IPSS-R) did not include RBC-TD. Thus, neither of these prognostic scoring systems incorporates both cytopenia and RBC-TD. We aimed to test whether RBC-TD adds prognostic value to the IPSS-R. We analyzed MDS patients not treated with disease-modifying therapy, and enrolled in SA-MDS Registry (derivation cohort n = 295) and Dusseldorf registry (Germany validation cohort n = 113) using time-dependent Cox proportional regression and serial landmark analyses. In the derivation cohort, RBC-TD patients had inferior OS compared to RBC transfusion-independent (RBC-TI) patients (P < 0.0001) at 6- (18 vs. 64 months), 12- (24 vs. 71 months), and 24-months (40 vs. 87 months). In a Cox proportional regression analysis, RBC-TD was an independent adverse prognostic marker in addition to age, sex, and IPSS-R variables (P < 0.0001). A prognostic index (PI) was derived using these Cox-proportional regression model variables. In the validation cohort, this PI classified patients into four prognostic groups with significantly different OS (P < 0.001) as in the derivation cohort. In conclusion, multivariate analysis by Cox proportional hazards regression and serial landmark analyses clearly demonstrates that development of RBC-TD at any time during the course of MDS is associated with poor OS, independent of IPSS-R. This study demonstrates that dynamic assessment of RBC-TD provides additional prognostic value to IPSS-R and should be included in treatment decision algorithms for MDS patients.
Supplementary Movie from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Iron chelation for myelofibrosis‐related anaemia during treatment with a Janus kinase inhibitor
Publisher: Wiley
Date: 11-02-2022
DOI: 10.1111/BJH.18071
Delayed diagnosis leading to accelerated-phase chronic eosinophilic leukemia due to a cytogenetically cryptic, imatinib-responsive TNIP1-PDFGRB fusion gene.
Publisher: Springer Science and Business Media LLC
Date: 27-10-2015
DOI: 10.1038/LEU.2015.301
Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study
Publisher: American Society of Hematology
Date: 25-07-2013
DOI: 10.1182/BLOOD-2013-02-483750
Abstract: Approximately 40% of patients with undetectable minimal residual disease on imatinib can stop treatment without loss of molecular response. Patients in treatment-free remission still have detectable BCR-ABL DNA several years after stopping imatinib.
Treatment of chronic myeloid leukemia: assessing risk, monitoring response, and optimizing outcome.
Publisher: Informa UK Limited
Date: 09-05-2017
DOI: 10.1080/10428194.2017.1312377
Abstract: Over the past two decades, tyrosine kinase inhibitors have become the foundation of chronic myeloid leukemia (CML) treatment. The choice between imatinib and newer tyrosine kinase inhibitors (TKIs) needs to be balanced against the known toxicity and efficacy data for each drug, the therapeutic goal being to maximize molecular response assessed by BCR-ABL RQ-PCR assay. There is accumulating evidence that the early achievement of molecular targets is a strong predictor of superior long-term outcomes. Early response assessment provides the opportunity to intervene early with the aim of ensuring an optimal response. Failure to achieve milestones or loss of response can have erse causes. We describe how clinical and laboratory monitoring can be used to ensure that each patient is achieving an optimal response and, in patients who do not reach optimal response milestones, how the monitoring results can be used to detect resistance and understand its origins.
Clinical utility of genomic DNA Q-PCR for the monitoring of a patient with atypical e19a2 BCR-ABL1 transcripts in chronic myeloid leukemia
Publisher: Informa UK Limited
Date: 06-06-2020
Treatment-free remission after stopping second-line dasatinib
Publisher: Elsevier BV
Date: 12-2015
Busulfan is effective second-line therapy for older patients with Philadelphia-negative myeloproliferative neoplasms intolerant of or unresponsive to hydroxyurea
Publisher: Informa UK Limited
Date: 25-07-2016
DOI: 10.1080/10428194.2016.1187269
Abstract: Hydroxyurea (Hu) is widely used as first-line cytoreductive therapy for patients with high-risk Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPN), but a small proportion of patients have refractory disease or experience adverse effects. Studies have demonstrated busulfan (Bu) to be an active first-line agent, but data on its role as second-line or later therapy are minimal. To evaluate its efficacy and safety in this context, we undertook a multicenter audit of Ph-neg MPN patients who had received Bu as therapy for Hu intolerance or failure. Of 51 patients identified, 38 (75%) achieved either complete or partial hematological response following at least one Bu cycle. Bu was generally well tolerated, with only 21/135 (15%) cycles complicated by adverse effects, predominantly cytopenia only 6% of cycles were ceased due to treatment complications. Bu is an effective and well-tolerated agent in patients with Ph-neg MPN in the setting of Hu intolerance or unresponsiveness.
Supplementary Methods from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Limited clinical value of regular bone marrow cytogenetic analysis in imatinib-treated chronic phase CML patients monitored by RQ-PCR for BCR-ABL.
Publisher: Springer Science and Business Media LLC
Date: 16-02-2006
Abstract: Real-time quantitative polymerase chain reaction (PCR) for BCR-ABL mRNA in the peripheral blood (RQ-PCR) provides an accurate and reliable measure of response to therapy in chronic myeloid leukaemia (CML). We wanted to determine in what circumstances additional clinically relevant information was provided by simultaneous cytogenetic analysis in RQ-PCR monitored patients receiving imatinib treatment. We analysed 828 simultaneous RQ-PCR and bone marrow cytogenetic analyses from 183 patients with chronic phase CML with a median follow-up of 20 months. Cytogenetic progression was defined as Philadelphia (Ph)-positive clonal evolution, loss of complete cytogenetic response or an increase of > or = 20% Ph-positive cells. Cytogenetic progression occurred in 24/183 (13%) patients. At the time of cytogenetic progression, none of the 24 patients had a major molecular response (MMR > or = 3-log reduction in BCR-ABL from standardised baseline). There were 320 RQ-PCR results from 95 patients indicating MMR. No abnormality was detected in any of the corresponding cytogenetic analyses. A policy of regular RQ-PCR monitoring with cytogenetic analysis targetted only to patients who have not achieved, or have lost MMR would represent a rational approach to monitoring and spare most patients the discomfort of multiple marrow aspirates. This approach depends upon availability of an accurate, reproducible RQ-PCR assay with ongoing quality assurance.
Treatment-free remission in patients with chronic myeloid leukaemia
Publisher: Springer Science and Business Media LLC
Date: 06-05-2020
Changing incidence of myeloproliferative neoplasms in Australia, 2003‐2014
Publisher: Wiley
Date: 12-02-2019
DOI: 10.1002/AJH.25407
Changing of the guard: Leukemia Research 2021.
Publisher: Elsevier BV
Date: 2021
Giant parallel tubular arrays in T lymphocytes
Publisher: American Society of Hematology
Date: 17-01-2013
Counterpoint: There is a best duration of deep molecular response for treatment‐free remission, but it is patient‐specific, and that is the challenge
Publisher: Wiley
Date: 10-11-2020
DOI: 10.1111/BJH.17111
A novel, somatic, transforming mutation in the extracellular domain of epidermal growth factor receptor identified in myeloproliferative neoplasm
Publisher: Springer Science and Business Media LLC
Date: 26-05-2017
DOI: 10.1038/S41598-017-02655-7
Abstract: We describe a novel ERBB1/EGFR somatic mutation (p. C329R c.985 T C) identified in a patient with JAK2 V617F Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFR C329R receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses EPO-induced differentiation. Clonal analysis shows that the dominant JAK2 V617F -positive clone in this PV patient harbors EGFR C329R , thus this mutation may contribute to clonal expansion. Somatic mutations affecting other ERBB and related receptor tyrosine kinases are observed in myeloproliferative neoplasms (MPN), and we show elevated EGFR levels in MPN s les, consistent with previous reports. Thus activation of this group of receptors, via multiple mechanisms, may contribute to clonal growth and survival of the JAK2 V617F disease clone in MPN.
Controlled three-dimensional manipulation of vanadium oxide nanotubes with optical tweezers
Publisher: AIP Publishing
Date: 15-12-2008
DOI: 10.1063/1.3039407
Abstract: We present a direct nanotube-microsphere tagging technique for the controlled three-dimensional (3D) manipulation and transportation of vanadium oxide nanotubes (VOx-NTs) with optical tweezers. The high scattering and absorptive nature of the VOx-NTs preclude the 3D optical trapping of such nanostructures. VOx-NTs are adhered to 3-aminopropyl-triethoxysilane functionalized silica microspheres, which act as handles for indirectly manipulating and transporting the nanotubes in three dimensions with optical tweezers. The optical tweezers can also operate as optical scissors that can remove the dielectric handles and trim these nanotubes. This technique may be extended to the optical manipulation of nanotubes of any material.
Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib
Publisher: American Society of Hematology
Date: 05-06-2014
DOI: 10.1182/BLOOD-2014-02-555607
Abstract: Imatinib achieves deep and durable remissions in patients with myeloid neoplasms bearing PDGFRB. Allogeneic stem cell transplantation is no longer indicated for patients with chronic myeloproliferative neoplasm bearing PDGFRB who respond to imatinib.
Success is built on failures: tackling the challenge of ponatinib failure
Publisher: Informa UK Limited
Date: 31-01-2018
Cardiac and hepatic siderosis in myelodysplastic syndrome, thalassemia and diverse causes of transfusion-dependent anemia: the TIMES study
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-05-2019
Supplementary Figure S1 from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Minimal residual disease: the advantages of digital over analog polymerase chain reaction
Publisher: Informa UK Limited
Date: 25-05-2011
Management of Pregnancy in Women With Chronic Myeloid Leukemia
Publisher: American Society of Clinical Oncology (ASCO)
Date: 09-2018
Red cell alloimmunization is associated with development of autoantibodies and increased red cell transfusion requirements in myelodysplastic syndrome
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 05-10-2017
A Method for Next-Generation Sequencing of Paired Diagnostic and Remission Samples to Detect Mitochondrial DNA Mutations Associated with Leukemia
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.JMOLDX.2017.05.009
Abstract: Somatic mitochondrial DNA (mtDNA) mutations have been identified in many human cancers, including leukemia. To identify somatic mutations, it is necessary to have a control tissue from the same in idual for comparison. When patients with leukemia achieve remission, the remission peripheral blood may be a suitable and easily accessible control tissue, but this approach has not previously been applied to the study of mtDNA mutations. We have developed and validated a next-generation sequencing approach for the identification of leukemia-associated mtDNA mutations in 26 chronic myeloid leukemia patients at diagnosis using either nonhematopoietic or remission blood s les as the control. The entire mt genome was lified by long-range PCR and sequenced using Illumina technology. Variant caller software was used to detect mtDNA somatic mutations, and an empirically determined threshold of 2% was applied to minimize false-positive results because of sequencing errors. Mutations were called against both nonhematopoietic and remission controls: the overall concordance between the two approaches was 81% (73/90 mutations). Some discordant results were because of the presence of somatic mutations in remission s les, because of either minimal residual disease or nonleukemic hematopoietic clones. This method could be applied to study somatic mtDNA mutations in leukemia patients who achieve minimal residual disease, and in patients with nonhematopoietic cancers who have a matched uninvolved tissue available.
Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-11-2018
Abstract: Pathological drug withdrawal syndrome is linked to accumulation of JAK2 phosphorylation in V617F myelofibrosis.
Need to Minimize Bias When Surveying Patient Attitudes to Stopping cml Treatment
Publisher: MDPI AG
Date: 12-2014
DOI: 10.3747/CO.21.2177
Abstract: Sanford et al. reported results from an interviewassisted survey of chronic myeloid leukemia (CML) patients, which indicated that neither treatment compliance nor the occurrence of side effects significantly affected patient willingness to stop tyrosine kinase inhibitor treatment1.[...]
Supplementary File 2 from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Supplementary Movie from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792303.V1
Abstract: JAK2-PK
Current and emerging tests for the laboratory monitoring of chronic myeloid leukaemia and related disorders.
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1080/00313020801916172
Abstract: Chronic myeloid leukaemia (CML) is a molecularly defined disease. The BCR-ABL fusion occurs in all cases of classical CML and leukaemic cells express a constitutively activated BCR-ABL tyrosine kinase. Other fusion oncogenes involving tyrosine kinases, including ABL and PDGFRA/B, have been identified, and are associated with leukaemic syndromes that may resemble CML. The discovery and treatment of these related disorders has been facilitated by our detailed understanding of CML. Imatinib mesylate has significantly improved the outcome of patients with CML, but there remains a significant minority of chronic phase CML patients for whom the response to treatment with standard dose imatinib is suboptimal. Cytogenetic and molecular monitoring of the response to treatment provides important prognostic information. Achievement of a major molecular response (MMR) in chronic phase patients treated de novo with imatinib confers near 100% freedom from progression to advanced phase, and MMR is now an important goal of therapy. Standardisation of BCR-ABL molecular monitoring is under way and should enable the accurate and reproducible identification of MMR in laboratories around the world. Point mutations in the kinase domain of BCR-ABL are the most common cause of acquired resistance to imatinib treatment. The susceptibility of a mutation to imatinib, nilotinib, or dasatinib may help to guide changes in therapy in a patient with resistance. In addition to these established methods of monitoring, there are new tests in development that may assist in determining prognosis and optimising therapy. Among patients receiving the same dose of imatinib, the plasma level of imatinib shows considerable inter-patient variation, and there is emerging evidence that higher levels may be associated with improved response to treatment. The intracellular concentration of imatinib also shows considerable variation, most likely related to differences in influx and efflux transport mechanisms. We discuss how these established and emerging assays might be used to optimise the treatment of CML patients.
Reverse transcription with random pentadecamer primers improves the detection limit of a quantitative PCR assay for BCR-ABL transcripts in chronic myeloid leukemia: implications for defining sensitivity in minimal residual disease.
Publisher: Oxford University Press (OUP)
Date: 09-2008
DOI: 10.1373/CLINCHEM.2008.105916
Abstract: Background: Real-time quantitative reverse transcription PCR (RQ-PCR) assay for BCR-ABL is used to monitor treatment response in chronic myeloid leukemia (CML). BCR-ABL transcript levels decline over several years of imatinib treatment, and increasing numbers of patients have BCR-ABL transcripts at or below the limit of detection. More sensitive PCR methods are required to assess whether these patients have a long-term continuing decline in residual disease. Methods: We used random pentadecamer (R15) primers for reverse transcription in RQ-PCR and compared the results with our established method that uses random hexamers. An increase in assay sensitivity would be detected as an increase in the number of BCR-ABL transcripts. Results: BCR-ABL transcripts increased by 86% with R15 primers. We used R15 primers to retest 19 s les from selected CML patients who had no BCR-ABL transcripts recently detectable with hexamer primers and detected BCR-ABL transcripts in 68% of the s les. Use of R15 primers showed variable increases in the transcripts for control genes BCR (breakpoint cluster region), ABL1 (c-abl oncogene 1, receptor tyrosine kinase), and GUSB (glucuronidase, beta), depending on the gene examined. The reported BCR-ABL/control gene ratio was affected, and the estimated detection limit of the assay, which was based on increased control gene copy number, was different for each control gene. Conclusions: This simple modification to the reverse transcription methodology improved the detection limit of the RQ-PCR assay for BCR-ABL transcripts. In the field of CML, these results have important implications for defining the detection limit of an assay when the BCR-ABL transcript is undetectable. Random pentadecamer primers may also be useful in other reverse transcription PCR assays for which the abundance of the target RNA is low.
Lineage of measurable residual disease in patients with chronic myeloid leukemia in treatment-free remission
Publisher: Springer Science and Business Media LLC
Date: 25-11-2019
DOI: 10.1038/S41375-019-0647-X
Abstract: Approximately half of patients with chronic myeloid leukemia (CML) in sustained deep molecular response who discontinue tyrosine kinase inhibitors (TKIs) remain in treatment-free remission (TFR). Some of these patients have measurable residual disease (MRD) by BCR-ABL1 mRNA testing, and most have detectable BCR-ABL1 DNA by highly sensitive methods. We used fluorescence-activated cell sorting and BCR-ABL1 DNA PCR to investigate the lineage of residual CML cells in TFR. Twenty patients in TFR for >1 year provided blood for sorting into granulocytes, monocytes, B cells, T cells, and NK cells. MRD was identified predominantly in the lymphoid compartment and never in granulocytes. B cells were more often BCR-ABL1 positive than T cells (18 vs 11/20 patients) and at higher levels (median 10
TP53 mutation in therapy-related myeloid neoplasm defines a distinct molecular subtype.
Publisher: American Society of Hematology
Date: 02-03-2022
Assessment of early paraprotein response to vincristine-doxorubicin-dexamethasone chemotherapy may help guide therapy in multiple myeloma.
Publisher: Wiley
Date: 09-2004
DOI: 10.1111/J.1445-5994.2004.00689.X
Abstract: Vincristine, doxorubicin and dexamethasone (VAD) are commonly used as the initial chemotherapy in myeloma patients prior to high‐dose therapy and autologous stem cell transplantation. We reviewed monoclonal protein responses and survival of 62 patients treated in this way. Among patients with IgG paraprotein, achievement of at least 50% reduction in paraprotein after the first cycle of VAD correlated with significantly better event‐free survival at 3 years, compared with those having less than 50% response. We postulate that early paraprotein response may be used to identify high risk patients. (Intern Med J 2004 34: 576−578)
Acute myeloid leukaemia presenting as galactorrhoea.
Publisher: Wiley
Date: 15-12-2007
DOI: 10.1111/J.1365-2257.2006.00845.X
Abstract: The clinical presentation of acute myeloid leukaemia is variable. We report a 40-year-old woman who presented with a 1-month history of galactorrhoea with an elevated prolactin level. The blood counts were normal, but she was found to have acute myeloid leukaemia with monocytic differentiation. The serum prolactin level normalized after chemotherapy. In the absence of evidence of CNS involvement, the hyperprolactinaemia is presumed to be a paraneoplastic phenomenon. We discuss the potential mechanism of prolactin production in this case.
Patient perceptions of treatment-free remission in chronic myeloid leukemia
Publisher: Informa UK Limited
Date: 15-06-2017
DOI: 10.1080/10428194.2017.1337114
Abstract: Around half of patients with chronic myeloid leukemia (CML) who achieve a stable deep molecular response would remain in treatment-free remission (TFR) if their tyrosine kinase inhibitors (TKIs) were stopped. TFR is increasingly becoming a goal of treatment. Eighty-seven patients answered a survey exploring patient perceptions of TFR, incorporating CML-specific factors (disease history, treatment toxicity, and adherence) and questions concerning health beliefs. 81% of participants (95% CI: 72%-89%) indicated that they would be willing to attempt TFR. No demographic or CML-related variable in the survey was significantly associated with willingness. In qualitative analysis, the commonest motivations for TFR included TKI toxicity (n = 26) and convenience (n = 18). The leading reason for reluctance was fear of consequences of stopping TKI (n = 16). Reluctance was often associated with needs for additional information or incomplete understanding of the current data. Understanding patient motivations and concerns is important if TFR is to become a part of CML management.
Early BCR-ABL1 kinetics are predictive of subsequent achievement of treatment-free remission in chronic myeloid leukemia
Publisher: American Society of Hematology
Date: 04-03-2021
Abstract: With treatment-free remission (TFR) rapidly becoming the ultimate goal of therapy in chronic myeloid leukemia (CML), there is a need to develop strategies to maximize sustained TFR by improving our understanding of its key determinants. Chronic-phase CML patients attempting TFR were evaluated to identify the impact of multiple variables on the probability of sustained TFR. Early molecular response dynamics were included as a predictive variable, assessed by calculating the patient-specific halving time of BCR-ABL1 after commencing tyrosine kinase inhibitor (TKI) therapy. Overall, 115 patients attempted TFR and had ≥12 months of follow-up. The probability of sustained TFR, defined as remaining in major molecular response off TKI therapy for 12 months, was 55%. The time taken for the BCR-ABL1 value to halve was the strongest independent predictor of sustained TFR: 80% in patients with a halving time of & .35 days (first quartile) compared with only 4% if the halving time was & .85 days (last quartile) (P & .001). The e14a2 BCR-ABL1 transcript type and duration of TKI exposure before attempting TFR were also independent predictors of sustained TFR. However, the BCR-ABL1 value measured at 3 months of TKI was not an independent predictor of sustained TFR. A more rapid initial BCR-ABL1 decline after commencing TKI also correlated with an increased likelihood of achieving TFR eligibility. The association between sustained TFR and the time taken for BCR-ABL1 to halve after commencing TKI was validated using an independent dataset. These data support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.
Supplementary File 1 from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Persistence of myelofibrosis treated with ruxolitinib: biology and clinical implications.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 21-01-2021
DOI: 10.3324/HAEMATOL.2020.262691
Abstract: Activation of JAK-STAT signaling is one of the hallmarks of myelofibrosis, a myeloproliferative neoplasm that leads to inflammation, progressive bone marrow failure, and a risk of leukemic transformation. Around 90% of patients with myelofibrosis have a mutation in JAK2, MPL, or CALR: so-called ‘driver’ mutations that lead to activation of JAK2. Ruxolitinib, and other JAK2 inhibitors in clinical use, provide clinical benefit but do not have a major impact on the abnormal hematopoietic clone. This phenomenon is termed ‘persistence’, in contrast to usual patterns of resistance. Multiple groups have shown that type 1 inhibitors of JAK2, which bind the active conformation of the enzyme, lead to JAK2 becoming resistant to degradation with consequent accumulation of phospho-JAK2. In turn, this can lead to exacerbation of inflammatory manifestations when the JAK inhibitor is discontinued, and it may also contribute to disease persistence. The ways in which JAK2 V617F and CALR mutations lead to activation of JAK-STAT signaling are incompletely understood. We summarize what is known about pathological JAK-STAT activation in myelofibrosis and how this might lead to future novel therapies for myelofibrosis with greater disease-modifying potential.
Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study
Publisher: Springer Science and Business Media LLC
Date: 20-02-2017
DOI: 10.1038/LEU.2017.63
Chronic myeloid leukaemia and tyrosine kinase inhibitor therapy: assessment and management of cardiovascular risk factors
Publisher: Wiley
Date: 31-01-2018
DOI: 10.1111/IMJ.13716
Abstract: Several BCR-ABL1 tyrosine kinase inhibitors (TKIs) are approved for the first-line treatment of chronic phase chronic myeloid leukaemia (CML). Disease control is achieved in the vast majority of patients and disease-specific survival is excellent. Consequently, there is now emphasis on managing comorbidities and minimising treatment-related toxicity. Second-generation TKIs have cardiovascular risks that are greater than with imatinib treatment, but these risks must be balanced against the superior CML responses encountered with more potent TKIs. Cardiovascular risk should be assessed at baseline using a locally validated model based on the Framingham risk equation. Clinicians involved in the care of CML patients should be aware of the vascular complications of TKIs and manage cardiovascular risk factors early to mitigate treatment-related risks. Reversible risk factors, such as dyslipidaemia, smoking, diabetes and hypertension, should be addressed. We summarise the available data on cardiovascular complications in CML patients treated with TKIs. Using the latest evidence and collective expert opinion, we provide practical advice for clinicians to assess, stratify and manage cardiovascular risk in people with CML receiving TKI therapy.
Childhood acute myeloid leukemia shows a high level of germline predisposition.
Publisher: American Society of Hematology
Date: 02-12-2021
Philadelphia-negative secondary acute myeloid leukaemia during imatinib treatment for chronic phase chronic myeloid leukaemia.
Publisher: Informa UK Limited
Date: 2007
Apparent 'JAK2-negative' polycythaemia vera due to compound mutations in exon 14
Publisher: Wiley
Date: 02-05-2017
DOI: 10.1111/BJH.14126
Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR
Publisher: Springer Science and Business Media LLC
Date: 02-09-2010
DOI: 10.1038/LEU.2010.185
Abstract: Around 40-50% of patients with chronic myeloid leukemia (CML) who achieve a stable complete molecular response (CMR undetectable breakpoint cluster region-Abelson leukemia gene human homolog 1 (BCR-ABL1) mRNA) on imatinib can stop therapy and remain in CMR, at least for several years. This raises the possibility that imatinib therapy may not need to be continued indefinitely in some CML patients. Two possible explanations for this observation are (1) CML has been eradicated or (2) residual leukemic cells fail to proliferate despite the absence of ongoing kinase inhibition. We used a highly sensitive patient-specific nested quantitative PCR to look for evidence of genomic BCR-ABL1 DNA in patients who sustained CMR after stopping imatinib therapy. Seven of eight patients who sustained CMR off therapy had BCR-ABL1 DNA detected at least once after stopping imatinib, but none has relapsed (follow-up 12-41 months). BCR-ABL1 DNA levels increased in all of the 10 patients who lost CMR soon after imatinib cessation, whereas serial testing of patients in sustained CMR showed a stable level of BCR-ABL1 DNA. This more sensitive assay for BCR-ABL1 provides evidence that even patients who maintain a CMR after stopping imatinib may harbor residual leukemia. A search for intrinsic or extrinsic (for ex le, immunological) causes for this drug-free leukemic suppression is now indicated.
Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline
Publisher: American Society of Hematology
Date: 24-07-2014
DOI: 10.1182/BLOOD-2014-03-566323
Abstract: Among patients with % BCR-ABL1, at 3 months, the poorest-risk group can be distinguished by the rate of BCR-ABL1 decline from baseline. Patients with BCR-ABL1 values on a constant downward trajectory may rapidly reach the level considered optimal with additional follow-up.
Peripheral neuropathy on imatinib treatment for chronic myeloid leukaemia: suspected adverse drug interaction with amlodipine
Publisher: Wiley
Date: 10-2009
Extramedullary relapse of chronic myeloid leukemia in blast crisis: more questions than answers
Publisher: Informa UK Limited
Date: 2009
Data from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.C.6762722.V1
Abstract: Abstract Selective inhibitors of Janus kinase (JAK) 2 have been in demand since the discovery of the JAK2 V617F mutation present in patients with myeloproliferative neoplasms (MPN) however, the structural basis of V617F oncogenicity has only recently been elucidated. New structural studies reveal a role for other JAK2 domains, beyond the kinase domain, that contribute to pathogenic signaling. Here we evaluate the structure-based approaches that led to recently-approved type I JAK2 inhibitors (fedratinib and pacritinib), as well as type II (BBT594 and CHZ868) and pseudokinase inhibitors under development (JNJ7706621). With full-length JAK homodimeric structures now available, superior selective and mutation-specific JAK2 inhibitors are foreseeable. Significance: The JAK inhibitors currently used for the treatment of MPNs are effective for symptom management but not for disease eradication, primarily because they are not strongly selective for the mutant clone. The rise of computational and structure-based drug discovery approaches together with the knowledge of full-length JAK dimer complexes provides a unique opportunity to develop better targeted therapies for a range of conditions driven by pathologic JAK2 signaling. /
The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study
Publisher: American Society of Hematology
Date: 14-02-2022
DOI: 10.1182/BLOODADVANCES.2021006043
Abstract: Idasanutlin, an MDM2 antagonist, showed clinical activity and a rapid reduction in JAK2 V617F allele burden in patients with polycythemia vera (PV) in a phase 1 study. This open-label phase 2 study evaluated idasanutlin in patients with hydroxyurea (HU)-resistant/-intolerant PV, per the European LeukemiaNet criteria, and phlebotomy dependence prior ruxolitinib exposure was permitted. Idasanutlin was administered once daily on days 1 through 5 of each 28-day cycle. The primary end point was composite response (hematocrit control and spleen volume reduction & 35%) in patients with splenomegaly and hematocrit control in patients without splenomegaly at week 32. Key secondary end points included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n = 27) received idasanutlin 16 had response assessment (week 32). Among responders with baseline splenomegaly (n = 13), 9 (69%) attained any spleen volume reduction, and 1 achieved composite response. Nine patients (56%) achieved hematocrit control, and 8 patients (50%) achieved CHR. Overall, 43% of evaluable patients (6/14) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (week 32). Nausea (93%), diarrhea (78%), and vomiting (41%) were the most common adverse events, with grade ≥ 3 nausea or vomiting experienced by 3 patients (11%) and 1 patient (4%), respectively. Reduced JAK2 V617F allele burden occurred early (after 3 cycles), with a median reduction of 76%, and was associated with achieving CHR and hematocrit control. Overall, the idasanutlin dosing regimen showed clinical activity and rapidly reduced JAK2 allele burden in patients with HU-resistant/- intolerant PV but was associated with low-grade gastrointestinal toxicity, leading to poor long-term tolerability. This trial was registered at www.clinincaltrials.gov as #NCT03287245.
Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.BCD-22-0189
Abstract: The JAK inhibitors currently used for the treatment of MPNs are effective for symptom management but not for disease eradication, primarily because they are not strongly selective for the mutant clone. The rise of computational and structure-based drug discovery approaches together with the knowledge of full-length JAK dimer complexes provides a unique opportunity to develop better targeted therapies for a range of conditions driven by pathologic JAK2 signaling.
Supplementary File 2 from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792312
Abstract: JAK2-monomer-500ns.pdb. (Structure of human JAK2 monomer at 500 ns simulation).
Supplementary File 1 from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792315
Abstract: JAK2-monomer-0ns.pdb. (Model of human JAK2 monomer used for molecular dynamics simulation).
Recommendations for the use of pegylated interferon‐α in the treatment of classical myeloproliferative neoplasms
Publisher: Wiley
Date: 08-2019
DOI: 10.1111/IMJ.14154
Abstract: The classical myeloproliferative neoplasms (MPN) are uncommon clonal haemopoietic malignancies characterised by excessive production of mature blood cells. Clinically, they are associated with thrombosis, haemorrhage, varying degrees of constitutional disturbance and a risk of progression to myelofibrosis or acute myeloid leukaemia. Many of the disease manifestations may be ameliorated by treatment with interferon-α (IFN), but its use in Australian MPN patients has been limited due to the inconvenience of frequent injections and side-effects. The pegylated form of IFN is a long-acting preparation, which is better tolerated, and its Pharmaceutical Benefits Scheme listing is likely to lead to increased usage. We review the literature on risks and benefits of IFN treatment for MPN, suggest criteria for patient selection in each of these diseases and discuss strategies to manage the side-effects of pegylated IFN.
Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease
Publisher: American Society of Hematology
Date: 30-08-2018
DOI: 10.1182/BLOOD-2018-02-832253
Abstract: Next-generation sequencing revealed variants in cancer-associated genes at diagnosis of CML more frequently in patients with poor outcomes. All patients at BC had mutated cancer genes, including fusions, that predated BCR-ABL1 kinase domain mutations in a majority.
A case-based discussion of clinical problems in the management of patients treated with ruxolitinib for myelofibrosis.
Publisher: Wiley
Date: 03-2017
DOI: 10.1111/IMJ.13341
Abstract: Ruxolitinib is a dual janus kinase 1 (JAK1)/JAK2 inhibitor used to treat splenomegaly and symptoms associated with myelofibrosis (MF). Current therapeutic options for symptomatic MF include supportive care, myelosuppressive therapy (such as hydroxycarbamide) and janus kinase (JAK) inhibitors (in particular ruxolitinib). Allogeneic stem cell transplantation remains the only potentially curative treatment for MF, and younger transplant-eligible patients should still be considered for allogeneic stem cell transplantation however, this is applicable only to a small proportion of patients. There is now increasing and extensive experience of the efficacy and safety of ruxolitinib in MF, both in clinical trials and in 'real-world' practice. The drug has been shown to be of benefit in intermediate-1 risk patients with symptomatic splenomegaly or other MF-related symptoms, and higher risk disease. Optimal use of the drug is required to maximise clinical benefit, requiring an understanding of the balance between dose-dependent responses and dose-limiting toxicities. There is also increasing experience in the use of ruxolitinib in the pre-transplantation setting. This paper aims to utilise several 'real-life' cases to illustrate several strategies that may help to optimise clinical practice.
Supplementary File 1 from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792315.V1
Abstract: JAK2-monomer-0ns.pdb. (Model of human JAK2 monomer used for molecular dynamics simulation).
Significant heterogeneity in management of calreticulin-mutated essential thrombocythemia and its progression to myelofibrosis: results of a national survey
Publisher: Informa UK Limited
Date: 13-08-2023
Supplementary Figure S1 from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792318
Abstract: Figure showing X-ray crystal structure of pseudokinase domain inhibitor
Supplementary Figure S1 from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Remembrance of things past — discontinuation of second-generation TKI therapy for CML
Publisher: Springer Science and Business Media LLC
Date: 07-02-2017
Rapid isolation of translocation breakpoints in chronic myeloid and acute promyelocytic leukaemia
Publisher: Wiley
Date: 22-03-2010
DOI: 10.1111/J.1365-2141.2009.08071.X
Abstract: Isolation and sequencing of the translocation breakpoint in chronic myeloid leukaemia-(CML) and acute promyelocytic leukaemia (APML) may help to elucidate the mechanism of translocation and provide a molecular marker for monitoring of minimal residual disease. Amplification across the translocation breakpoint was performed in s les from 91 patients with CML and 15 patients with APML using single-tube multiplex polymerase chain reaction (PCR) involving 308 primers for CML and 40 primers for APML. Nonspecific lification was removed by a modification of PCR, termed sequential hybrid primer PCR (SHP-PCR), which involved two sequential rounds of PCR, each of which used a low concentration of a specially designed hybrid primer. The resultant lified material was sequenced. The method as finally developed was simple quick and robust. The translocation breakpoint was successfully isolated and sequenced in all 106 s les. The strategy of highly multiplexed PCR followed by SHP-PCR is thus an effective method for isolating the translocation breakpoint in CML and APML. It may also be applicable to other haematological disorders characterised by translocation, deletion or inversion.
Prediction of thrombosis in post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a study on 1258 patients
Publisher: Springer Science and Business Media LLC
Date: 30-08-2022
DOI: 10.1038/S41375-022-01673-3
Abstract: Patients with Philadelphia-negative myeloproliferative neoplasms are at high risk of thrombotic events (TEs). Predisposing factors have been identified in essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (primary MF, PMF), while yet not recognized in post PV/ET-MF (known as secondary MF, SMF). Within the 1258 SMF of the MYSEC (MYelofibrosis SECondary to PV and ET) dataset, 135 (10.7%) developed a TE at a median follow-up of 3.5 years (range, 1-21.4), with an incidence of 2.3% patients per year. Venous events accounted for two-thirds of the total. Cox multivariable analysis, supported by Fine-Gray models with death as competitive risk, showed that being on cytoreductive therapy at time of SMF evolution is associated with an absolute risk reduction of thrombosis equal to 3.3% within 3 years. Considering in idually cytoreductive therapies, univariate regression model found that both conventional cytoreduction, mainly hydroxyurea, (HR 0.41, 95% CI: 0.26-0.65, p = 0.0001) and JAK inhibitors, mostly ruxolitinib, (HR 0.50, 95% CI: 0.24-1.02, p = 0.05) were associated with fewer thrombosis. Our study informs treating physicians of a non-low incidence of TEs in post PV/ET-MF and of the potential protective role of cytoreductive therapy in terms of thrombotic events.
Supplementary Methods from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792309.V1
Abstract: Supplementary Information: Figure S1 X-ray crystal structure of JNJ-77006621(ball and stick, C-atoms in green) bound to JAK2-PK domain (cartoon, yellow). Key residues are displayed in sticks [C-atoms in green near the optimisation domain (Peuleo et al. 2017, Liosi et al 2020) and C-atoms in yellow at the dimerization domain]. Supplementary Methods.
Lineage-specific detection of residual disease predicts relapse in chronic myeloid leukemia patients stopping therapy
Publisher: American Society of Hematology
Date: 24-08-2023
Abstract: Chronic myeloid leukemia (CML) patients who are eligible for treatment-free remission (TFR) may still relapse after tyrosine kinase inhibitor (TKI) cessation. There is a need for accurate predictors of outcome to enable patients with a favorable profile to proceed while avoiding futile attempts. Sensitive detection of residual disease in total leukocytes at treatment cessation is associated with relapse, but is not highly discriminatory, likely because it is a composite measure of residual leukemia derived from different cell lineages whereas only some lineages are relevant for relapse. We prospectively measured BCR::ABL1 DNA as a predictive yes/no binary test in five cellular fractions from 48 patients meeting conventional criteria for TKI discontinuation. The median BCR::ABL1 DNA level was higher in granulocytes and in T cells, but not in other lineages, in patients who relapsed. In the 40 patients undergoing a first TFR attempt we defined three groups with differing relapse risk: granulocytes-positive (100%), granulocytes-negative/T cells-positive (67%), and granulocytes-negative /T cells-negative (25%). These data show the critical importance of lineage-specific assessment of residual disease in the selection of patients who can attempt TFR with a high expectation of success, and concurrently defer patients who have a high probability of relapse.
Practical management of myelofibrosis with ruxolitinib
Publisher: Wiley
Date: 12-2015
DOI: 10.1111/IMJ.12921
Abstract: Treatment for the majority of patients with myelofibrosis is primarily based on symptom control as curative allogeneic stem cell transplantation is typically offered only to younger patients, especially those with poor prognosis disease. Around 50% of patients with myelofibrosis have the JAK2(V617F) mutation, but almost all patients have aberrant activation of the JAK-STAT signalling pathway. Recent efforts have focussed on the clinical use of JAK2 inhibitors to treat myelofibrosis. In this article, we present our recommendations for the practical management of myelofibrosis with ruxolitinib, a selective inhibitor of both JAK1 and JAK2. Ruxolitinib can significantly improve the quality of life of patients with myelofibrosis. There is also increasing evidence of a positive impact on survival. Consistent with the physiological role of JAK signalling the major toxicity of ruxolitinib is cytopenia. Managing cytopenia is key to maximising the therapeutic benefit of ruxolitinib. Further research into the safety of ruxolitinib in patients with thrombocytopenia is warranted, as is its role in special subgroups of patients, such as those undergoing stem cell transplantation and those experiencing thrombosis as a major manifestation of myelofibrosis.
Supplementary File 1 from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Supplementary Movie from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792303
Abstract: JAK2-PK
BCR-ABL1 expression, RT-qPCR and treatment decisions in chronic myeloid leukaemia
Publisher: BMJ
Date: 02-02-2016
DOI: 10.1136/JCLINPATH-2015-203538
Abstract: RT-qPCR is used to quantify minimal residual disease (MRD) in chronic myeloid leukaemia (CML) in order to make decisions on treatment, but its results depend on the level of BCR-ABL1 expression as well as leukaemic cell number. The aims of the study were to quantify inter-in idual differences in expression level, to determine the relationship between expression level and response to treatment, and to investigate the effect of expression level on interpretation of the RT-qPCR result. BCR-ABL1 expression was studied in 248 s les from 65 patients with CML by determining the difference between MRD quantified by RT-qPCR and DNA-qPCR. The results were analysed statistically and by simple indicative modelling. Inter-in idual levels of expression approximated a normal distribution with an SD of 0.36 log. Expression at diagnosis correlated with expression during treatment. Response to treatment, as measured by the number of leukaemic cells after 3, 6 or 12 months of treatment, was not related to the level of expression. Indicative modelling suggested that interpretation of RT-qPCR results in relation to treatment guidelines could be affected by variation in expression when MRD was around 10% at 3 months and by both expression variation and Poisson variation when MRD was around or below the limit of detection of RT-qPCR. Variation between in iduals in expression of BCR-ABL1 can materially affect interpretation of the RT-qPCR when this test is used to make decisions on treatment.
Supplementary Movie from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Durable complete molecular remission of chronic myeloid leukemia following dasatinib cessation, despite adverse disease features
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 09-08-2011
Novel protein C gene mutation in a compound heterozygote resulting in catastrophic thrombosis in early adulthood: diagnosis and long‐term treatment with subcutaneous protein C concentrate
Publisher: Wiley
Date: 24-06-2015
DOI: 10.1111/BJH.13538
A tale of two siblings: two cases of AML arising from a single pre-leukemic DNMT3A mutant clone.
Publisher: Springer Science and Business Media LLC
Date: 09-03-2015
DOI: 10.1038/LEU.2015.67
Supplementary Methods from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792309
Abstract: Supplementary Information: Figure S1 X-ray crystal structure of JNJ-77006621(ball and stick, C-atoms in green) bound to JAK2-PK domain (cartoon, yellow). Key residues are displayed in sticks [C-atoms in green near the optimisation domain (Peuleo et al. 2017, Liosi et al 2020) and C-atoms in yellow at the dimerization domain]. Supplementary Methods.
Supplementary File 2 from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792312.V1
Abstract: JAK2-monomer-500ns.pdb. (Structure of human JAK2 monomer at 500 ns simulation).
Data from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
DOI: 10.1158/2643-3230.C.6762722
Abstract: Abstract Selective inhibitors of Janus kinase (JAK) 2 have been in demand since the discovery of the JAK2 V617F mutation present in patients with myeloproliferative neoplasms (MPN) however, the structural basis of V617F oncogenicity has only recently been elucidated. New structural studies reveal a role for other JAK2 domains, beyond the kinase domain, that contribute to pathogenic signaling. Here we evaluate the structure-based approaches that led to recently-approved type I JAK2 inhibitors (fedratinib and pacritinib), as well as type II (BBT594 and CHZ868) and pseudokinase inhibitors under development (JNJ7706621). With full-length JAK homodimeric structures now available, superior selective and mutation-specific JAK2 inhibitors are foreseeable. Significance: The JAK inhibitors currently used for the treatment of MPNs are effective for symptom management but not for disease eradication, primarily because they are not strongly selective for the mutant clone. The rise of computational and structure-based drug discovery approaches together with the knowledge of full-length JAK dimer complexes provides a unique opportunity to develop better targeted therapies for a range of conditions driven by pathologic JAK2 signaling. /
Supplementary Methods from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Supplementary File 2 from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Novel modes of MPL activation in triple-negative myeloproliferative neoplasms
Publisher: Elsevier BV
Date: 02-2023
DOI: 10.1016/J.PATHOL.2022.05.015
Abstract: The identification of a somatic mutation associated with myeloid malignancy is of diagnostic importance in myeloproliferative neoplasms (MPNs). In iduals with no mutation detected in common screening tests for variants in JAK2, CALR, and MPL are described as 'triple-negative' and pose a diagnostic challenge if there is no other evidence of a clonal disorder. To identify potential drivers that might explain the clinical phenotype, we used an extended sequencing panel to characterise a cohort of 44 previously diagnosed triple-negative MPN patients for canonical mutations in JAK2, MPL and CALR at low variant allele frequency (found in 4/44 patients), less common variants in the JAK-STAT signalling pathway (12 patients), or other variants in recurrently mutated genes from myeloid malignancies (18 patients), including hotspot variants of potential clinical relevance in eight patients. In one patient with thrombocytosis we identified biallelic germline MPL variants. Neither MPL variant was activating in cell proliferation assays, and one of the variants was not expressed on the cell surface, yet co-expression of both variants led to thrombopoietin hypersensitivity. Our results highlight the clinical value of extended sequencing including germline variant analysis and illustrate the need for detailed functional assays to determine whether rare variants in JAK2 or MPL are pathogenic.
Data from Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Cancer treatment with kinase inhibitors: what have we learnt from imatinib?
Publisher: Springer Science and Business Media LLC
Date: 2004
BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 05-07-2018
Sensitive monitoring of acute promyelocytic leukemia byPML-RARADNA Q-PCR
Publisher: Informa UK Limited
Date: 30-11-2016
Chronic myeloid leukaemia: going off piste
Publisher: Elsevier BV
Date: 06-2018
Related Organisations
Imperial College London
Location: United Kingdom of Great Britain and Northern Ireland
South Australian Health And Medical Research Institute
Location: Australia
Related Funding Activities
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE200100168
Start Date: 06-2020
End Date: 09-2023
Amount: $550,000.00
Funder: Australian Research Council
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