ORCID Profile
0000-0002-1492-5966
Current Organisations
Royal Melbourne Hospital
,
Peter MacCallum Cancer Centre
,
Cabrini Hospital
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Publisher: American Society of Hematology
Date: 08-12-2011
DOI: 10.1182/BLOOD-2011-03-339879
Abstract: We report results from a study exploring the combination of romidepsin, bortezomib, and dexamethasone for the treatment of patients with multiple myeloma (MM) previously treated with 1 prior therapy. The primary objective was to determine the maximum tolerated dose (MTD) of the combination using a novel accelerated dose-escalation schedule in patients with relapsed or refractory MM. The secondary objective was to determine overall response (OR), time to progression (TTP), and overall survival (OS). The MTD identified was bortezomib 1.3 mg/m2 (days 1, 4, 8, and 11), dexamethasone 20 mg (days 1, 2, 4, 5, 8, 9, 11, and 12), and romidepsin 10 mg/m2 (days 1, 8, and 15) every 28 days. Thrombocytopenia (64%) was the most common ≥ grade 3 hematologic toxicity. Peripheral neuropathy occurred in 76% of patients (n = 19) (≥ grade 3, 8% 95% confidence interval [CI] 1%-26%). Maintenance romidepsin 10 mg/m2 (on days 1 and 8 of a 28-day cycle) proved feasible, with 12 patients receiving a median of 7.5 cycles (range: 1-29). An OR (M-protein) of minor response (MR) was seen in 18 of 25 patients (72%) 2 (8%) had complete remissions (CRs) and 13 (52%) had partial responses (PRs), including 7 (28%) with very good PRs (VGPRs). The median TTP was 7.2 (95% CI: 5.5-19.6) months, and the median OS was 36 months. This regimen shows activity with manageable toxicity and warrants further evaluation. This trial was registered at www.clinicaltrials.gov as NCT00431990.
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2023
DOI: 10.1158/2159-8290.23807943
Abstract: Supplementary Table S1. Bridging chemotherapies by ATC class and preferred term (safety set) Supplementary Table S2. Lymphodepleting chemotherapies (safety set) Supplementary Table S3. Cytokine release syndrome following YTB323 infusion Supplementary Table S4. Neurological adverse reactions following YTB323 infusion Supplementary Table S5. Summary of cellular kinetic parameters in peripheral blood by flow cytometry for YTB323 at DL1 and DL2 Supplementary Table S6. Summary of cellular kinetic parameters in peripheral blood by flow cytometry and qPCR for YTB323 at DL1 and DL2.
Publisher: Wiley
Date: 24-06-2019
DOI: 10.1111/BJH.16064
Abstract: De novo diffuse large B-cell lymphoma (DLBCL) presenting with synchronous central nervous system (CNS) and systemic disease (synDLBCL) is not well described and is excluded from clinical trials. We performed a retrospective analysis of 80 synDLBCL patients treated across 10 Australian and UK centres. Of these patients, 96% had extranodal systemic disease. CNS-directed treatment with combination intravenous cytarabine and high-dose methotrexate ("CNS-intensive") (n = 38) was associated with favourable survival outcomes compared with "CNS-conservative" strategies such as intravenous high-dose methotrexate monotherapy, intrathecal therapy and/or radiotherapy (2-year progression-free survival [PFS] 50% vs. 31%, P = 0·006 2-year overall survival [OS] 54% vs. 44%, P = 0·037). Outcomes were primarily dictated by the ability to control the CNS disease, with 2-year cumulative CNS relapse incidence of 42% and non-CNS relapse 21%. Two-year OS for CNS-relapse patients was 13% vs. 36% for non-CNS relapses (P = 0·02). Autologous stem cell transplantation as consolidation (n = 14) was not observed to improve survival in those patients who received CNS-intensive induction when matched for induction outcomes (2-year PFS 69% vs. 56%, P = 0·99 2-year OS 66% vs. 56%, P = 0·98). Hyperfractionated or infusional systemic treatment did not improve survival compared to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) (2-year OS 49% for both groups). Our study suggests that adequate control of the CNS disease is paramount and is best achieved by intensive CNS-directed induction.
Publisher: American Association for Cancer Research (AACR)
Date: 06-09-2023
Publisher: Elsevier BV
Date: 10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2023
DOI: 10.1158/1078-0432.C.6516061.V2
Abstract: AbstractPurpose: Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. Patients and Methods: Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC 2–3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). Results: Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months median follow-up: 24.3 months HR, 0.276 descriptive i P /i 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52% OR, 8.81 descriptive i P /i 0.0001 complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive i P /i 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and years. Conclusions: Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6516061.V1
Abstract: AbstractPurpose: Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. Patients and Methods: Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC 2–3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). Results: Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months median follow-up: 24.3 months HR, 0.276 descriptive i P /i 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52% OR, 8.81 descriptive i P /i 0.0001 complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive i P /i 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and years. Conclusions: Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2023
DOI: 10.1158/2159-8290.23807946
Abstract: Supplementary Fig. S1. Preclinical evaluation and characterization of YTB323 and CTL*019 for Donor 2 and 3 Supplementary Fig. S2. Differential gene expression of CTL*019 cells versus YTB323 cells (preclinical) Supplementary Fig. S3. Preclinical validation of YTB323 Supplementary Fig. S4. Dose-dependent expansion (Cmax and AUC0-21d) of YTB323 and CTL*019 in NSG mice with NALM6 Supplementary Fig. S5. CD4:CD8 ratio comparison of leukapheresis and cell products of YTB323 and tisagenlecleucel Supplementary Fig. S6. Stemness and memory differentiation gene signatures are retained or enriched for in YTB323 final product Supplementary Fig. S7. Differential gene expression of tisagenlecleucel versus YTB323 final product Supplementary Fig. S8. Naive/TSCM cells and a naive stem-like gene signature correlate with higher expansion and a better response Supplementary Fig. S9. T-cell subset and checkpoint inhibitor analysis by flow cytometry on PBMCs collected post-YTB323 infusion Supplementary Fig. S10. Pre-clinical T-cell gating strategies.
Publisher: Informa UK Limited
Date: 15-07-2021
DOI: 10.1080/10428194.2021.1953016
Abstract: Bispecific T-cell recruiting antibodies are emerging as a potent immunotherapeutic class in the treatment of B-cell malignancies and act by simultaneously targeting antigens on T-cells and malignant cells to effect tumor cell death. Glofitamab is a novel full-length IgG-like CD20-CD3 bispecific with a unique 2:1 configuration that provides an extended half-life and superior CD20 binding. Phase 1 monotherapy and combination data demonstrate clear activity in heavily treated aggressive and indolent B-cell lymphoma, including >50% complete responses at the recommended phase 2 dose. In this review, we provide an overview of the structure, mechanism of action and pharmacokinetics of glofitamab. Available efficacy and safety data from ongoing clinical trials are also presented. Glofitamab appears to be a welcome addition to the treatment possibilities for patients with B-cell lymphomas who otherwise have limited therapeutic options. The current data are sufficient to evaluate its role in combination and in earlier lines of therapy.
Publisher: Wiley
Date: 10-2019
DOI: 10.1111/IMJ.14453
Publisher: MDPI AG
Date: 17-08-2010
DOI: 10.3390/PH3082674
Publisher: Future Medicine Ltd
Date: 12-2013
DOI: 10.2217/FON.13.220
Abstract: Cutaneous T-cell lymphomas are relatively rare lymphomas and the most common form is mycosis fungoides. Its rare leukemic variant is Sezary syndrome. Advanced-stage disease is typically treated with bexarotene (a retinoid), IFN-α or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors that modify the epigenome are an attractive addition to the armamentarium. Based on two large Phase II studies, the US FDA approved intravenous romidepsin for patients with relapsed/refractory cutaneous T-cell lymphomas. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side-effect profile.
Publisher: Elsevier BV
Date: 05-2022
Publisher: Wiley
Date: 14-09-2009
DOI: 10.1111/J.1365-2141.2009.07837.X
Abstract: There are few treatment options for patients with Hodgkin Lymphoma (HL) who relapse after conventional therapies. Panobinostat is an orally available pan deacetylase inhibitor with evidence of activity in myeloid malignancies and cutaneous T cell lymphoma. Thirteen HL patients were treated with escalating doses of this novel agent in a phase IA/II multicentre study. A computed tomography partial response was achieved in 5/13(38%), and a metabolic response by (18)F-fluoro-2-deoxy-D-glucose positron emission tomography scanning in 7/12 (58%) evaluable patients. This report describes the preliminary evidence of anti-tumour activity seen in the early phase of this study, which recently closed to accrual.
Publisher: Wiley
Date: 23-08-2021
DOI: 10.1111/BJH.17789
Abstract: Richter syndrome (RS), an aggressive lymphoma occurring in the context of chronic lymphocytic leukaemia/small lymphocytic lymphoma, is associated with poor prognosis when treated with conventional immunochemotherapy, therefore, improved treatments are required. Immune checkpoint blockade has shown efficacy in some B-cell malignancies and modest responses in early clinical trials for RS. We investigated the immune checkpoint profile of RS as a basis to inform rational therapeutic investigations in RS. Formalin-fixed, paraffin-embedded biopsies of RS (n = 19), de novo diffuse large B-cell lymphoma (DLBCL n = 58), transformed indolent lymphomas (follicular [tFL], n = 16 marginal zone [tMZL], n = 24) and non-transformed small lymphocytic lymphoma (SLL n = 15) underwent gene expression profiling using the NanoString Human Immunology panel. Copy number assessment was performed using next-generation sequencing. Immunohistochemistry (IHC) for LAG3 and PD-1 was performed. LAG3 gene expression was higher in RS compared to DLBCL (P = 0·0002, log2FC 1·96), tFL (P < 0·0001, log2FC 2·61), tMZL (P = 0·0004, log2FC 1·79) and SLL (P = 0·0057, log2FC 1·45). LAG3 gene expression correlated with the gene expression of human leukocyte antigen Class I and II, and related immune genes and immune checkpoints. IHC revealed LAG3 protein expression on both malignant RS cells and tumour-infiltrating lymphocytes. Our findings support the investigation of LAG3 inhibition to enhance anti-tumour responses in RS.
Publisher: MDPI AG
Date: 26-10-2020
Abstract: Peripheral T-cell lymphomas (PTCLs) are distinct pathological entities with clinical advancements lagging behind their B-cell lymphoma counterpart. Frequently aggressive in their clinical behaviour, clinicians are constantly challenged with low complete remission rates, early relapses and failure to achieve long-term responses despite aggressive first-line chemotherapy, resulting in poor overall survival in the majority of patients. There is currently no consensus regarding the optimal therapy for PTCL and treatment approaches are mainly derived from prospective phase II studies, registry data and retrospective studies. Despite its biological heterogeneity, a less than satisfactory “one-size-fits-all” approach has been adopted to date. Although its role remains controversial, for many years, haematopoietic stem cell transplantation has been adopted by clinicians with the aim of overcoming poor outcomes by consolidating responses. In this review, we aim to define the role of both autologous and allogeneic stem cell transplantation in PTCL in both frontline and salvage settings, especially in the context of recent advancements in this field.
Publisher: Wiley
Date: 15-05-2020
DOI: 10.1111/IMJ.14859
Publisher: Springer Science and Business Media LLC
Date: 09-03-2018
DOI: 10.1038/S41409-018-0152-2
Abstract: Bortezomib-based induction is often used in transplant-eligible patients with myeloma. The optimal peripheral blood stem cell (PBSC) mobilisation strategy in this context is unclear. We reviewed the efficacy of G-CSF alone (G-alone) vs. G-CSF and cyclophosphamide (G-cyclo: standard dose: 1.5-2 g/m
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2023
DOI: 10.1158/2159-8290.C.6767337.V1
Abstract: Abstract CAR T-cell product quality and stemness (T sub stem /sub ) are major determinants of i in vivo /i expansion, efficacy, and clinical response. Prolonged i ex vivo /i culturing is known to deplete T sub stem /sub , affecting clinical outcome. YTB323, a novel autologous CD19-directed CAR T-cell therapy expressing the same validated CAR as tisagenlecleucel, is manufactured using a next-generation platform in days. Here, we report the preclinical development and preliminary clinical data of YTB323 in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL NCT03960840). In preclinical mouse models, YTB323 exhibited enhanced i in vivo /i expansion and antitumor activity at lower doses than traditionally manufactured CAR T cells. Clinically, at doses 25-fold lower than tisagenlecleucel, YTB323 showed (i) promising overall safety [cytokine release syndrome (any grade, 35% grade ≥3, 6%), neurotoxicity (any grade, 25% grade ≥3, 6%)] (ii) overall response rates of 75% and 80% for DL1 and DL2, respectively (iii) comparable CAR T-cell expansion and (iv) preservation of T-cell phenotype. Current data support the continued development of YTB323 for r/r DLBCL. Significance: Traditional CAR T-cell manufacturing requires extended i ex vivo /i cell culture, reducing naive and stem cell memory T-cell populations and diminishing antitumor activity. YTB323, which expresses the same validated CAR as tisagenlecleucel, can be manufactured in days while retaining T-cell stemness and enhancing clinical activity at a 25-fold lower dose. /
Publisher: Informa UK Limited
Date: 03-07-2022
Publisher: Wiley
Date: 21-07-2022
DOI: 10.1111/IMJ.15533
Abstract: Diffuse large B‐cell lymphoma (DLBCL) is the most common lymphoma subtype, accounting for 30–40% of lymphoma diagnoses. Although aggressive, cure is achievable in approximately 60% of cases with primary chemoimmunotherapy, and in a further substantial minority by salvage therapy and autologous stem cell transplantation. Despite promising activity in early phase clinical trials, no intensified or novel treatment regimen has improved outcomes over R‐CHOP21 in randomised studies. However, there remain several areas of controversy including the most appropriate prognostic markers, central nervous system prophylaxis and the optimal treatment for patients with high‐risk disease. This position statement presents an evidence‐based synthesis of the literature for application in Australasian practice.
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.BBMT.2011.10.002
Abstract: The role of the peripheral blood (PB) CD34(+) cell count in predicting the CD34(+) cell yield in hematopoietic progenitor cell apheresis collections is well established. However, sometimes unexpectedly poor CD34(+) cell yields are obtained. To determine the effect, if any, of a range of factors on the ability of the PB CD34(+) count to predict collection CD34(+) cell count, we performed a retrospective analysis on consecutive hematopoietic progenitor cell apheresis collections between 2004 and 2008. Factors investigated included mobilization regimen, PB white blood cell count, body weight, and disease. After exclusion of collections involving apheresis complications, a total of 1,225 PB CD34(+) cell results with corresponding collection CD34(+) cell results from 458 patients were analyzed. Although differences in the median PB CD34(+) cell counts and collection CD34(+) cell counts were seen between mobilized collections with chemotherapy plus granulocyte colony-stimulating factor and those with granulocyte colony-stimulating factor alone, the predictive capability of the PB CD34(+) cell count for the collection CD34(+) cell yield remained similar. Although poorer collection efficiencies were observed in the myelodysplastic syndrome/myeloproliferative disorder diagnostic subgroup, our findings confirm that PB CD34(+) cell analysis remains a powerful and irreplaceable tool for predicting hematopoietic progenitor cell apheresis CD34(+) cell yield.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-06-2021
DOI: 10.1200/JCO.20.03175
Abstract: Glofitamab is a T-cell–engaging bispecific antibody possessing a novel 2:1 structure with bivalency for CD20 on B cells and monovalency for CD3 on T cells. This phase I study evaluated glofitamab in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). Data for single-agent glofitamab, with obinutuzumab pretreatment ( Gpt) to reduce toxicity, are presented. Seven days before the first dose of glofitamab (0.005-30 mg), all patients received 1,000 mg Gpt. Dose-escalation steps were determined using a Bayesian continuous reassessment method with overdose control. Primary end points were safety, pharmacokinetics, and the maximum tolerated dose of glofitamab. Following initial single-patient cohorts, 171 patients were treated within conventional multipatient cohorts and received at least one dose of glofitamab. This trial included heavily pretreated patients with R/R B-NHL most were refractory to prior therapy (155 90.6%) and had received a median of three prior therapies. One hundred and twenty-seven patients (74.3%) had diffuse large B-cell lymphoma, transformed follicular lymphoma, or other aggressive histology, and the remainder had indolent lymphoma subtypes. Five (2.9%) patients withdrew from treatment because of adverse events. Cytokine release syndrome occurred in 86 of 171 (50.3%) patients (grade 3 or 4: 3.5%) two (1.2%) patients experienced grade 3, transient immune effector cell–associated neurotoxicity syndrome-like symptoms. The overall response rate was 53.8% (complete response [CR], 36.8%) among all doses and 65.7% (CR, 57.1%) in those dosed at the recommended phase II dose. Of 63 patients with CR, 53 (84.1%) have ongoing CR with a maximum of 27.4 months observation. In patients with predominantly refractory, aggressive B-NHL, glofitamab showed favorable activity with frequent and durable CRs and a predictable and manageable safety profile.
Publisher: Massachusetts Medical Society
Date: 03-01-2019
Publisher: Informa UK Limited
Date: 07-02-2017
Publisher: Informa UK Limited
Date: 18-12-2018
DOI: 10.1080/17474086.2019.1558399
Abstract: Brentuximab vedotin is an antibody-drug conjugate, which combines a CD30 monoclonal antibody with the microtubule-disrupting agent monomethylauristatin E. The utility of brentuximab vedotin has been explored in a number of diseases, with a recent focus on T-cell lymphoma, particularly systemic anaplastic large-cell lymphoma (sALCL) and cutaneous T-cell lymphoma (CTCL), as well as other peripheral T-cell lymphoma (PTCL) histologies. Areas covered: This review surveys current data on the efficacy of brentuximab vedotin in T-cell lymphoma, as well as embedding it in a therapeutic context by reviewing potential competitor agents in the clinic. Data are drawn from published literature, with a focus on clinical trial data rather than preclinical studies or case reports. Expert opinion: Brentuximab vedotin has a clear clinical benefit in CTCL and sALCL, and can achieve durable responses in a number of patients. Toxicities, particularly peripheral neuropathy, may limit treatment in some patients however, the agent is generally well tolerated. In this context, brentuximab vedotin has been globally approved for use in sALCL and certain CTCL subtypes, however, further information is required to enhance our understanding of when and in whom to best employ this agent, as well as exploring rational combinations to augment responses.
Publisher: American Society of Hematology
Date: 25-06-2020
Abstract: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon histologic variant, and the optimal treatment of stage I-II NLPHL is undefined. We conducted a multicenter retrospective study including patients ≥16 years of age with stage I-II NLPHL diagnosed from 1995 through 2018 who underwent all forms of management, including radiotherapy (RT), combined modality therapy (CMT RT+chemotherapy [CT]), CT, observation after excision, rituximab and RT, and single-agent rituximab. End points were progression-free survival (PFS), freedom from transformation, and overall survival (OS) without statistical comparison between management groups. We identified 559 patients with median age of 39 years: 72.3% were men, and 54.9% had stage I disease. Median follow-up was 5.5 years (interquartile range, 3.1-10.1). Five-year PFS and OS in the entire cohort were 87.1% and 98.3%, respectively. Primary management was RT alone (n = 257 46.0%), CMT (n = 184 32.9%), CT alone (n = 47 8.4%), observation (n = 37 6.6%), rituximab and RT (n = 19 3.4%), and rituximab alone (n = 15 2.7%). The 5-year PFS rates were 91.1% after RT, 90.5% after CMT, 77.8% after CT, 73.5% after observation, 80.8% after rituximab and RT, and 38.5% after rituximab alone. In the RT cohort, but not the CMT cohort, variant immunoarchitectural pattern and number of sites & were associated with worse PFS (P & .05). Overall, 21 patients (3.8%) developed large-cell transformation, with a significantly higher transformation rate in those with variant immunoarchitectural pattern (P = .049) and number of involved sites & (P = .0006). OS for patients with stage I-II NLPHL was excellent after all treatments.
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2023
DOI: 10.1158/1078-0432.22820218.V1
Abstract: Sensitivity analysis of interim overall survival in patients ≥65 years
Publisher: Springer Science and Business Media LLC
Date: 05-03-2014
DOI: 10.1007/S00277-014-2040-1
Abstract: The optimum follow-up of patients with transformed indolent lymphoma (TrIL) is not well defined. We sought to determine the utility of surveillance positron emission tomography-computed tomography (PET-CT) in patients with TrIL achieving complete metabolic remission (CMR) after primary therapy. We performed a retrospective analysis of patients with TrIL treated at Peter MacCallum Cancer Centre between 2002 and 2012 who achieved CMR after primary therapy who had ≥1 subsequent surveillance PET-CT. Of 55 patients with TrIL, 37 (67 %) received autologous stem cell transplantation as consolidation following chemoimmunotherapy. After a median follow-up of 34 (range 3-101) months, the actuarial 3-year progression-free (PFS) and overall survival (OS) were 77 % (95 %CI 62-86 %) and 88 % (75-94 %), respectively. Of 180 surveillance PET-CT scans, there were 153 true negatives, 4 false positives, 1 false negative, 7 indeterminate and 15 true positives. Considering indeterminate scans as false positives, the specificity of PET-CT for detecting relapse was 94 %, sensitivity was 83 %, positive predictive value was 63 % and negative predictive value was 98 %. All seven subclinical (PET detected) relapses were of low-grade histology in contrast, all nine relapses with diffuse large B cell lymphoma (DLBCL) were symptomatic. In our cohort of patients with TrIL achieving CMR, PET-CT detected subclinical low-grade relapses but all DLBCL relapses were accompanied by clinical symptoms. Thus, surveillance imaging of patients with TrIL achieving CMR is of limited clinical benefit. PET-CT should be reserved for evaluation of clinically suspected relapse.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.CCR-22-3136
Abstract: Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC 2–3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months median follow-up: 24.3 months HR, 0.276 descriptive P & 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52% OR, 8.81 descriptive P & 0.0001 complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P & 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and & years. Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2012
DOI: 10.1007/S11912-012-0258-4
Abstract: The transformation of follicular lymphoma to an aggressive lymphoma is a well-recognised complication that occurs at a rate of approximately 3 % a year for the first 10 years of observation. Transformation is accompanied by increased risk of refractoriness and a poor expectation of survival. Genetic and epigenetic triggers for transformation have been described. Prior to routine use of rituximab, transformed lymphoma was managed in a fashion similar to that for de novo diffuse large B-cell lymphoma, with generally poor results. Rituximab appears to have improved outcomes. Some centres, including our own, use high-dose chemotherapy with stem cell transplantation as consolidation for those with responsive disease. Here, we focus on transformed follicular lymphoma, and provide an overview of the current literature and our approach to management.
Publisher: Wiley
Date: 11-08-2009
Publisher: Informa UK Limited
Date: 14-08-2021
Publisher: American Society of Clinical Oncology (ASCO)
Date: 09-2013
Publisher: Informa UK Limited
Date: 08-2013
DOI: 10.1586/17474086.2013.814833
Abstract: Peripheral T-cell lymphoma (PTCL) is comprised of a rare heterogeneous group of diseases with erse clinical presentations however outcomes associated with conventional chemotherapy are generally poor in the majority of patients. Newer approaches, which include dose-intensification and agents with novel mechanisms of action, are needed to improve outcomes in this group of patients. In this review we examine the results of two recent large Phase II trials with romidepsin, a histone deacetylase inhibitor which shows considerable activity and good tolerability in patients with T-cell lymphoma. These initial results observed with single-agent romidepsin provide a foundation for exploring combination strategies and demonstrates proof-of-principle that other such drugs with similar mechanisms of action may be effective in T-cell lymphoma.
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1016/J.CLML.2021.01.012
Abstract: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphomas that are frequently associated with a poor prognosis. For many decades, the standard-of-care has been CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-based therapy, but it is well-recognized that survival outcomes are unsatisfactory, especially when compared with B-cell lymphomas. Major recent advances in cancer diagnosis and management have the potential to significantly improve PTCL outcomes. These include: (1) improved diagnostic techniques that incorporate molecular genetic data to further refine diagnosis and subtyping (2) the development of novel agents and (3) improved monitoring modalities, such as
Publisher: American Society of Hematology
Date: 26-10-2023
Publisher: BMJ
Date: 14-05-2018
DOI: 10.1136/JCLINPATH-2018-205195
Abstract: Multiple myeloma is a genomically complex haematological malignancy with many genomic alterations recognised as important in diagnosis, prognosis and therapeutic decision making. Here, we provide a summary of genomic findings identified through routine diagnostic next-generation sequencing at our centre. A cohort of 86 patients with multiple myeloma underwent diagnostic sequencing using a custom hybridisation-based panel targeting 104 genes. Sequence variants, genome-wide copy number changes and structural rearrangements were detected using an inhouse-developed bioinformatics pipeline. At least one mutation was found in 69 (80%) patients. Frequently mutated genes included TP53 (36%), KRAS (22.1%), NRAS (15.1%), FAM46C/DIS3 (8.1%) and TET2/FGFR3 (5.8%), including multiple mutations not previously described in myeloma. Importantly we observed TP53 mutations in the absence of a 17 p deletion in 8% of the cohort, highlighting the need for sequencing-based assessment in addition to cytogenetics to identify these high-risk patients. Multiple novel copy number changes and immunoglobulin heavy chain translocations are also discussed. Our results demonstrate that many clinically relevant genomic findings remain in multiple myeloma which have not yet been identified through large-scale sequencing efforts, and provide important mechanistic insights into plasma cell pathobiology.
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2023
DOI: 10.1158/1078-0432.22820209.V1
Abstract: Tabulated data supporting ZUMA-7 elderly analysisSupplementary Table S1. Patient-reported outcomes instrumentsSupplementary Table S2. Axi-cel delivery and administration timeSupplementary Table S3. Summary of efficacy and safety outcomes in patients ≥65 years versus all patients in ZUMA-7Supplementary Table S4. Serious adverse events in at least 3 patients in patients ≥65 yearsSupplementary Table S5. Summary of cytopenias present on or after 90 days from initiation of definitive therapy on protocol in patients ≥65 yearsSupplementary Table S6. Deaths in axi-cel and SOC arms for patients ≥65 years (safety analysis set)Supplementary Table S7. Summary of serum analytes in patients years versus ≥65 years in the axi-cel arm (N = 170)Supplementary Table S8. Most common adverse events, cytokine release syndrome, and neurologic events in patients ≥70 yearsSupplementary Table S9. Deaths in axi-cel and SOC arms for patients ≥70 years Supplementary Table S10. Baseline characteristics for quality-of-life analysis in patients ≥65 yearsSupplementary Table S11. Mixed model with repeated measures estimated difference in change from baseline forprespecified patient-reported outcomes measures (quality-of-life analysis set) in patients ≥65 years
Publisher: Informa UK Limited
Date: 07-11-2013
Publisher: American Society of Hematology
Date: 22-11-2021
DOI: 10.1182/BLOODADVANCES.2021004619
Abstract: Bromodomain and extraterminal (BET) proteins are transcriptional activators for multiple oncogenic processes in diffuse large B-cell lymphoma (DLBCL), including MYC, BCL2, E2F, and toll-like receptor signaling. We report results of a phase 1b dose-escalation study of the novel, subcutaneous BET inhibitor RO6870810 (RO) combined with the BCL-2 inhibitor venetoclax, and rituximab, in recurrent/refractory DLBCL. RO was delivered for 14 days of a 21-day cycle, whereas venetoclax was delivered continuously. A 3 + 3 escalation design was used to determine the safety of the RO+venetoclax doublet rituximab was added in later cohorts. Thirty-nine patients were treated with a median of 2.8 cycles (range, 1-11). Dose-limiting toxicities included grade 3 febrile neutropenia, grade 4 diarrhea, and hypomagnesemia for the doublet and grade 3 hyperbilirubinemia and grade 4 diarrhea when rituximab was added. The doublet maximum tolerated dose (MTD) was determined to be 0.65 mg/kg RO+600 mg venetoclax for RO+venetoclax+rituximab, the MTDs were 0.45 mg/kg, 600 mg, and 375 mg/m2, respectively. The most frequent grade 3 and 4 adverse events were neutropenia (28%) and anemia and thrombocytopenia (23% each). Responses were seen in all cohorts and molecular subtypes. Sustained decreases in CD11b on monocytes indicated pharmacodynamic activity of RO. Overall response rate according to modified Lugano criteria was 38.5% 48% of responses lasted for ≥180 days. Complete response was observed in 8 patients (20.5%). Optimization of the treatment schedule and a better understanding of predictors of response would be needed to support broader clinical use. This trial is registered on www.clinicaltrials.gov as NCT03255096.
Publisher: Informa Healthcare
Date: 16-09-2015
Publisher: American Association for Cancer Research (AACR)
Date: 30-05-2023
DOI: 10.1158/2159-8290.CD-22-1276
Abstract: Traditional CAR T-cell manufacturing requires extended ex vivo cell culture, reducing naive and stem cell memory T-cell populations and diminishing antitumor activity. YTB323, which expresses the same validated CAR as tisagenlecleucel, can be manufactured in & days while retaining T-cell stemness and enhancing clinical activity at a 25-fold lower dose.
Publisher: Wiley
Date: 29-10-2018
Publisher: Wiley
Date: 28-12-2022
DOI: 10.1111/EJH.13915
Abstract: Comprehensive clinical characteristics of Australian patients with classical Hodgkin Lymphoma (cHL) have not previously been systematically collected and described. We report real‐world data of 498 eligible patients from the first 5 years of the Lymphoma and Related Diseases Registry (LaRDR), including baseline characteristics, histologic subtype, and treatment patterns in first‐line therapy. Patient demographics and distribution of histopathological subtypes of cHL are similar to reported international cohorts. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was the most common therapy for both early and advanced‐stage disease, and 48% of patients with the early‐stage disease received radiotherapy. Treatment patterns are consistent with international guidelines. In comorbid patients ≥60 years of age with advanced‐stage disease, there is greater variation in treatment. In patients with a recorded response, the objective response rate (ORR) was 96% in early‐stage disease, and 88% in advanced‐stage disease. Early progression‐free survival data suggest Australian patients with cHL have good outcomes, similar to other international studies.
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2023
DOI: 10.1158/1078-0432.22820215.V1
Abstract: Mixed model with repeated measures for change from baseline for prespecified patient-reported outcomes endpoints in patients ≥65 years
Publisher: Wiley
Date: 02-2016
DOI: 10.1111/IMJ.12977
Publisher: Humana Press
Date: 23-09-2013
Publisher: Informa UK Limited
Date: 14-05-2022
DOI: 10.1080/10428194.2022.2074990
Abstract: Chimeric antigen receptor T-cell (CAR-T) therapy is a promising immunotherapy approved for hematological malignancies. Despite its effectiveness, clinically significant rates of toxicity, including immune effector cell associated neurotoxicity syndrome (ICANS), limit its widespread use. In certain contexts, ICANS may occur in up to one-third of patients using commercially available CAR-T therapies. The syndrome presents with a range of neurological signs and symptoms, as well as a variety of neuroimaging manifestations reported in the literature. A systematic review of the literature was performed. The systematic search strategy identified 24 studies discussing the neuroimaging appearances associated with ICANS. Imaging findings are more common in patients with higher grade neurotoxicity. The neuroimaging findings are heterogeneous, but can be grouped either anatomically (white matter, gray matter, brainstem, or leptomeninges) or pathologically (ischemic changes, hemorrhages, or cerebral edema). An understanding of the imaging manifestations of ICANS has the potential to impact the management of patients.
Publisher: American Society of Hematology
Date: 19-01-2022
DOI: 10.1182/BLOODADVANCES.2021004970
Abstract: KEYNOTE-204 (NCT02684292) demonstrated a progression-free survival advantage for pembrolizumab over brentuximab vedotin (BV) in patients who had relapsed or refractory classical Hodgkin lymphoma (R/R cHL) following, or who were ineligible for, autologous stem cell transplantation (ASCT). Health-related quality of life (HRQoL), measured by patient-reported outcomes (PROs) from KEYNOTE-204, are reported from patients who received ≥1 dose of study treatment and completed ≥1 PRO assessment. The EORTC QoL Questionnaire Core 30 (QLQ-C30) and EuroQoL EQ-5D were administered at baseline, every 6 weeks until week 24, and every 12 weeks thereafter. Prespecified end points included least squares mean (LSM) changes from baseline to week 24 and time to true deterioration (TTD ≥10-point decline from baseline). Comparisons were evaluated using 2-sided P values uncontrolled for multiplicity. High compliance at baseline (& %) and through week 24 (& %) was demonstrated across treatment groups (PRO analysis set: pembrolizumab, n = 146 BV, n = 150). The EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) score improved from baseline to week 24 on pembrolizumab and worsened on BV and demonstrated significant LSM differences at 24 weeks (GHS/QoL: 8.60 [95% confidence interval, 3.89-13.31] P = .0004). Significant improvements were observed in each QLQ-C30 domain except emotional and cognitive functioning. Compared with BV, pembrolizumab prolonged TTD for GHS/QoL (hazard ratio, 0.40 [95% CI, 0.22-0.74] P = .003) and each QLQ-C30 domain except cognitive functioning. In conclusion, pembrolizumab demonstrated overall improvements in PROs of HRQoL measures over BV in the KEYNOTE-204 study. These data and previously reported efficacy results support pembrolizumab as the preferred treatment option for patients with R/R cHL who are ineligible for or experience relapse after ASCT.
Publisher: Informa UK Limited
Date: 16-06-2015
DOI: 10.3109/10428194.2014.910656
Abstract: There are limited data regarding the role of (18)F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET-CT) scanning in primary mediastinal B-cell lymphoma (PMBL). We analyzed 28 patients with PMBL treated with chemotherapy, of whom 25 (89%) also received rituximab and 17 (61%) radiotherapy. PET-CT scans were interpreted using visual analysis and a 5-point scale. After a median follow-up of 2.6 years, four patients relapsed and two died. The 2-year progression-free survival and overall survival were 86% and 94%. PET-CT has excellent negative predictive value (interim, 86-87% end of treatment, 95%) but limited positive predictive value due to the high frequency of positive scans. Several patients with persistent metabolically active masses underwent biopsies, which showed necrosis but no lymphoma. Thus a negative PET-CT is an excellent predictor of subsequent outcome. However, residual metabolically active masses after treatment should be biopsied to confirm viable lymphoma prior to salvage therapy.
Publisher: Massachusetts Medical Society
Date: 17-02-2022
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22437829.V1
Abstract: Event-free survival per central review and objective response rate in patients ≥70 years
Publisher: Elsevier BV
Date: 04-2021
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2023
DOI: 10.1158/1078-0432.22820212.V1
Abstract: CAR T-cell levels in patients ≥65 years
Publisher: American Association for Cancer Research (AACR)
Date: 06-09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22437829
Abstract: Event-free survival per central review and objective response rate in patients ≥70 years
Publisher: MDPI AG
Date: 13-06-2018
DOI: 10.3390/IJMS19061758
Publisher: Informa UK Limited
Date: 25-08-2016
Publisher: Informa UK Limited
Date: 2006
DOI: 10.1080/10428190500305596
Abstract: Patients with localized follicular lymphoma are potentially curable however, the failure rate for local treatment suggests that a proportion of apparently localized disease is being under-staged. We report a case of incidentally diagnosed follicular lymphoma found in association with a stage II malignant melanoma, with immunohistochemical evidence of disseminated lymphoma in radiologically and clinically benign regional lymph nodes. This case provides some evidence to the cause of treatment failure in patients with clinically localized follicular lymphoma, and is a histologically proven ex le of the association between melanoma and lymphoma.
Publisher: Wiley
Date: 05-2023
DOI: 10.1111/IMJ.16091
Abstract: Since the recognition of BRAF V600E mutations in the majority of cases of hairy cell leukaemia, Erdheim–Chester disease and Langerhans cell histiocytosis, the targeted oral kinase inhibitors dabrafenib and vemurafenib have been adapted for their treatment. Like other targeted agents, these drugs produce high response rates and predictable but unique side effects. Physician familiarity is essential for the effective use of these agents. We review the Australian experience of BRAF/MEK inhibitor therapy in these rare haematological cancers.
Publisher: MDPI AG
Date: 03-2022
Abstract: Targeted therapies continue to change the landscape of lymphoma treatment, resulting in improved therapy options and patient outcomes. Numerous agents are now approved for use in the indolent lymphomas and many others under development demonstrate significant promise. In this article, we review the landscape of targeted agents that apply to the indolent lymphomas, predominantly follicular lymphoma, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinaemia and marginal zone lymphoma. The review covers small molecule inhibitors, immunomodulators and targeted immunotherapies, as well as presenting emerging and promising combination therapies.
Publisher: Wiley
Date: 16-12-2021
DOI: 10.1111/ORS.12584
Abstract: Primary lymphoma of the trigeminal nerve is very rare, with only 10 cases reported in the literature. It may present as unexplained paraesthesia of the trigeminal nerve, usually affecting all three isions of the nerve. To date, a collation of the known cases of primary trigeminal nerve lymphoma is lacking. This study presents a literature review on trigeminal nerve lymphoma, and presents a case to illustrate diagnosis and management. The case report of primary trigeminal lymphoma is presented, with long‐term follow‐up. A review of the known cases of primary trigeminal lymphoma is conducted, demonstrating the current understanding on diagnosis and management of these rare lesions. A 67‐year‐old man presented with a 4‐month history of infra‐orbital paraesthesia. Imaging showed an expanded infra‐orbital canal, with changes extending to the vidian canal. The lesion was biopsied via an endoscopic trans‐antral approach, and a diffuse large B‐cell lymphoma was confirmed. He was managed with multi‐agent chemotherapy with a good clinical response. Although rare, primary trigeminal lymphoma is an important additional differential diagnosis to consider when assessing a new finding of unexplained trigeminal nerve paraesthesia. Central nervous system imaging should be included in the work up of unexplained trigeminal paraesthesia.
Publisher: AMPCo
Date: 24-05-2020
DOI: 10.5694/MJA2.50612
Publisher: American Association for Cancer Research (AACR)
Date: 06-09-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2019
Publisher: Wiley
Date: 08-2022
DOI: 10.1111/IMJ.15868
Publisher: Cold Spring Harbor Laboratory
Date: 03-09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 06-09-2023
DOI: 10.1158/2159-8290.C.6767337
Abstract: Abstract CAR T-cell product quality and stemness (T sub stem /sub ) are major determinants of i in vivo /i expansion, efficacy, and clinical response. Prolonged i ex vivo /i culturing is known to deplete T sub stem /sub , affecting clinical outcome. YTB323, a novel autologous CD19-directed CAR T-cell therapy expressing the same validated CAR as tisagenlecleucel, is manufactured using a next-generation platform in days. Here, we report the preclinical development and preliminary clinical data of YTB323 in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL NCT03960840). In preclinical mouse models, YTB323 exhibited enhanced i in vivo /i expansion and antitumor activity at lower doses than traditionally manufactured CAR T cells. Clinically, at doses 25-fold lower than tisagenlecleucel, YTB323 showed (i) promising overall safety [cytokine release syndrome (any grade, 35% grade ≥3, 6%), neurotoxicity (any grade, 25% grade ≥3, 6%)] (ii) overall response rates of 75% and 80% for DL1 and DL2, respectively (iii) comparable CAR T-cell expansion and (iv) preservation of T-cell phenotype. Current data support the continued development of YTB323 for r/r DLBCL. Significance: Traditional CAR T-cell manufacturing requires extended i ex vivo /i cell culture, reducing naive and stem cell memory T-cell populations and diminishing antitumor activity. YTB323, which expresses the same validated CAR as tisagenlecleucel, can be manufactured in days while retaining T-cell stemness and enhancing clinical activity at a 25-fold lower dose. /
Publisher: Wiley
Date: 22-11-2021
DOI: 10.1111/IMJ.15503
Abstract: The management of Hodgkin lymphoma (HL) has undergone significant changes in recent years. Due to the predilection of HL to affect younger patients, balancing cure and treatment‐related morbidity is a constant source of concern for physicians and patients alike. Positron emission tomography adapted therapy has been developed for both early and advanced stage HL to try and improve the outcome of treatment, while minimising toxicities. The aim of this review is to digest the plethora of studies recently conducted and provide some clear, evidence‐based practice statements to simplify the management of HL.
Publisher: Wiley
Date: 05-2019
DOI: 10.1111/AJCO.13153
Abstract: Recently, obinutuzumab was included in the Australian Pharmaceutical Benefits Scheme for use in first line, advanced or bulky stage 2, follicular lymphoma, providing more immunochemotherapy treatment options available than ever before. Rituximab with chemotherapy has been the standard of care since reimbursement in the late 1990s however, obinutuzumab-based regimens have shown superior progression-free survival in comparison to rituximab-based options, albeit at an increased risk of grade ≥3 adverse events. As median overall survival approaches 20 years or more, the long-term effects and sequencing of any strategy should be considered. Here we discuss the considerations for selection of front-line therapy, based on evidence and local Australian clinician experience, in the management of first line follicular lymphoma.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22437817
Abstract: CAR T-cell levels in patients ≥65 years
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.BBMT.2014.07.015
Abstract: The role of allogeneic (allo-) and autologous stem cell transplantation (auto-SCT) in the management of patients with transformed indolent nonfollicular non-Hodgkin lymphoma is unknown. This is a multicenter, retrospective cohort study of patients with biopsy-proven indolent B cell nonfollicular non-Hodgkin lymphoma and simultaneous or subsequent biopsy-proven aggressive histology transformation who were treated with allo-SCT or auto-SCT between 1996 and 2013. All patients received myeloablative conditioning regimens. Outcomes were compared with a cohort of 246 patients with transformed follicular lymphoma who also underwent allo-SCT (n = 47) or auto-SCT (n = 199) across the same institutions and time frame. Thirty-four patients were identified with the following underlying indolent histologies: 15 (44%) marginal zone lymphoma, 11 (32%) chronic lymphocytic leukemia, 6 (18%) small lymphocytic lymphoma, and 2 (6%) lymphoplasmacytic lymphoma. Patients received various anthracycline or platinum-containing chemotherapy regimens for transformation, incorporating rituximab in 25 (74%). Twelve (35%) subsequently underwent allo-SCT, whereas 33 (65%) underwent auto-SCT. The 3-year overall survival rate after transplantation was 67% (allo-SCT 54%, auto-SCT 74%), and 3-year progression-free survival rate was 49% (allo-SCT 40%, auto-SCT 54%). The 3-year nonrelapse mortality rate was 14% (allo-SCT 15%, auto-SCT 7%). Transplant-related mortality at 100 days was 17% for allo-SCT and 0% for auto-SCT. Adjusted for type of stem cell transplantation, 3-year overall survival, progression-free survival, and nonrelapse mortality rates were similar to those of patients with transformed follicular lymphoma receiving allo-SCT and auto-SCT (P = .38, P = .69, and P = .54, respectively). Allo-SCT and auto-SCT may be reasonable treatments for selected patients with transformed nonfollicular indolent lymphoma, although medium-term outcomes and toxicity appear to be more favorable with auto-SCT.
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2023
DOI: 10.1158/1078-0432.C.6516061
Abstract: AbstractPurpose: Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. Patients and Methods: Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC 2–3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). Results: Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months median follow-up: 24.3 months HR, 0.276 descriptive i P /i 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52% OR, 8.81 descriptive i P /i 0.0001 complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive i P /i 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and years. Conclusions: Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL. /
Publisher: Wiley
Date: 07-09-2017
DOI: 10.1111/BJH.14919
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22437826.V1
Abstract: Overall survival (interim) and progression-free survival in patients ≥70 years
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.JBIOMECH.2013.05.011
Abstract: The objective of this study was to examine mechanisms underpinning the reduction in knee adduction moment (KAM) and changes in frontal plane knee-ground reaction force (GRF) lever arm with a modified shoe that incorporates both a variable-stiffness sole and lateral wedging. Thirty in iduals with symptomatic knee osteoarthritis (OA) and 30 overweight asymptomatic in iduals underwent gait analyses wearing modified and standard shoes. In both groups, there was a decrease in the lever arm (p<0.001), and a lateral shift in the center of pressure (COP) offset (p ≤ 0.001). There was no change in frontal plane or medial-lateral GRF magnitudes, lateral trunk lean or stance duration in either group. There was no significant change in the frontal plane hip-knee-ankle angle in the OA group but a significant decrease in the overweight group (p=0.003). In both groups, changes in lever arm and frontal plane GRF magnitude predicted change in peak KAM (p<0.01), but only change in lever arm predicted change in KAM impulse (p<0.001). In the OA group, changes in COP offset and medial-lateral GRF magnitude predicted change in lever arm (p<0.05), whereas changes in trunk lean and hip-knee-ankle angle predicted change in lever arm in the overweight group (p=0.01). In conclusion, the change in lever arm contributed the most to explaining change in KAM parameters with modified shoes. The change in the lever arm was driven by changes evident at the foot in the OA participants (COP and medial-lateral GRF), and by more proximal changes (hip-knee-ankle angle and trunk lean) in the overweight group.
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2023
DOI: 10.1158/1078-0432.22820209
Abstract: Tabulated data supporting ZUMA-7 elderly analysisSupplementary Table S1. Patient-reported outcomes instrumentsSupplementary Table S2. Axi-cel delivery and administration timeSupplementary Table S3. Summary of efficacy and safety outcomes in patients ≥65 years versus all patients in ZUMA-7Supplementary Table S4. Serious adverse events in at least 3 patients in patients ≥65 yearsSupplementary Table S5. Summary of cytopenias present on or after 90 days from initiation of definitive therapy on protocol in patients ≥65 yearsSupplementary Table S6. Deaths in axi-cel and SOC arms for patients ≥65 years (safety analysis set)Supplementary Table S7. Summary of serum analytes in patients years versus ≥65 years in the axi-cel arm (N = 170)Supplementary Table S8. Most common adverse events, cytokine release syndrome, and neurologic events in patients ≥70 yearsSupplementary Table S9. Deaths in axi-cel and SOC arms for patients ≥70 years Supplementary Table S10. Baseline characteristics for quality-of-life analysis in patients ≥65 yearsSupplementary Table S11. Mixed model with repeated measures estimated difference in change from baseline forprespecified patient-reported outcomes measures (quality-of-life analysis set) in patients ≥65 years
Publisher: Wiley
Date: 16-10-2020
DOI: 10.1111/BJH.17072
Abstract: High‐dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) are used as consolidation in first remission (CR1) in some centres for untreated, transformed indolent B‐cell lymphoma (Tr‐iNHL) but the evidence base is weak. A total of 319 patients with untreated Tr‐iNHL meeting prespecified transplant eligibility criteria [age , LVEF ≥45%, no severe lung disease, CR by positron emission tomography or computed tomography ≥3 months after at least standard cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R‐CHOP) intensity front‐line chemotherapy] were retrospectively identified. Non‐diffuse large B‐cell lymphoma transformations were excluded. About 283 (89%) patients had follicular lymphoma, 30 (9%) marginal‐zone lymphoma and six (2%) other subtypes. Forty‐nine patients underwent HDC/ASCT in CR1, and a 1:2 propensity‐score‐matched cohort of 98 patients based on age, stage and high‐grade B‐cell lymphoma with MYC, BCL2 and/or BCL6 rearrangements (HGBL‐DH) was generated. After a median follow‐up of 3·7 (range 0·1–18·3) years, ASCT was associated with significantly superior progression‐free survival [hazard ratio (HR) 0·51, 0·27–0·98 P = 0·043] with a trend towards inferior overall survival (OS HR 2·36 ·87–6·42 P = 0·1) due to more deaths from progressive disease (8% vs. 4%). Forty (41%) patients experienced relapse in the non‐ASCT cohort — 15 underwent HDC/ASCT with seven (47%) ongoing complete remission (CR) 10 chimeric antigen receptor‐modified T‐cell (CAR‐T) therapy with 6 (60%) ongoing CR 3 allogeneic SCT with 2 (67%) ongoing CR. Although ASCT in CR1 improves initial duration of disease control in untreated Tr‐iNHL, the impact on OS is less clear with effective salvage therapies in this era of CAR‐T.
Publisher: Elsevier BV
Date: 04-2021
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2023
DOI: 10.1158/1078-0432.22820215
Abstract: Mixed model with repeated measures for change from baseline for prespecified patient-reported outcomes endpoints in patients ≥65 years
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22437820
Abstract: Mixed model with repeated measures for change from baseline for prespecified patient-reported outcomes endpoints in patients ≥65 years
Publisher: Informa UK Limited
Date: 07-12-2018
Publisher: Informa UK Limited
Date: 09-05-2014
DOI: 10.3109/10428194.2013.792112
Abstract: Next-generation sequencing techniques are powerful high-throughput methods that have enabled the comprehensive documentation of genetic lesions in numerous hematological malignancies. In recent times, the genomes of multiple different B-cell lymphoproliferative disorders including chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma, splenic marginal zone lymphoma, mantle cell lymphoma, hairy cell leukemia and Waldenström macroglobulinemia have been documented. Between them, these studies have reinforced and provided insight into the mechanisms for the dysregulation of known pathways (e.g. nuclear factor-κB [NF-κB]), uncovered the importance of new pathways for oncogenesis (e.g. mRNA processing), identified disease-defining mutations and provided meaningful new targets which are already being translated into therapeutic interventions. This review summarizes the molecular lesions that have been discovered in B-cell lymphoproliferative disorders thus far by studies utilizing high-throughput sequencing techniques and the aberrations in the numerous intracellular pathways that have been shown to be involved.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22437823.V1
Abstract: Sensitivity analysis of interim overall survival in patients ≥65 years
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2023
DOI: 10.1158/1078-0432.22820212
Abstract: CAR T-cell levels in patients ≥65 years
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2023
DOI: 10.1158/1078-0432.22820218
Abstract: Sensitivity analysis of interim overall survival in patients ≥65 years
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22437823
Abstract: Sensitivity analysis of interim overall survival in patients ≥65 years
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22437826
Abstract: Overall survival (interim) and progression-free survival in patients ≥70 years
Publisher: Informa UK Limited
Date: 07-07-2015
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22437817.V1
Abstract: CAR T-cell levels in patients ≥65 years
Publisher: Springer Science and Business Media LLC
Date: 21-03-2022
DOI: 10.1038/S41591-022-01731-4
Abstract: High-risk large B-cell lymphoma (LBCL) has poor outcomes with standard first-line chemoimmunotherapy. In the phase 2, multicenter, single-arm ZUMA-12 study (ClinicalTrials.gov NCT03761056) we evaluated axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, as part of first-line treatment in 40 patients with high-risk LBCL. This trial has completed accrual. The primary outcome was complete response rate (CRR). Secondary outcomes were objective response rate (ORR), duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), assessment of safety, central nervous system (CNS) relapse and blood levels of CAR T cells and cytokines. The primary endpoint in efficacy-evaluable patients ( n = 37) was met, with 78% CRR (95% confidence interval (CI), 62–90) and 89% ORR (95% CI, 75–97). As of 17 May 2021 (median follow-up, 15.9 months), 73% of patients remained in objective response median DOR, EFS and PFS were not reached. Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in three patients (8%) and nine patients (23%), respectively. There were no treatment-related grade 5 events. Robust CAR T-cell expansion occurred in all patients with a median time to peak of 8 days. We conclude that axi-cel is highly effective as part of first-line therapy for high-risk LBCL, with a manageable safety profile.
Publisher: Springer Science and Business Media LLC
Date: 15-10-2010
Publisher: Elsevier BV
Date: 06-2015
Publisher: American Association for Cancer Research (AACR)
Date: 09-11-2022
DOI: 10.1158/1078-0432.CCR-22-1284
Abstract: Molibresib is a selective, small molecule inhibitor of the bromodomain and extra-terminal (BET) protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851). Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), Non–Hodgkin lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS as well as AML evolved from antecedent MDS) or cutaneous T-cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR). There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg daily (for MDS) and 60 mg daily (for CTCL) were selected. Most common Grade 3+ adverse events included thrombocytopenia (37%), anemia (15%), and febrile neutropenia (15%). Six patients achieved complete responses [3 in Part 1 (2 AML, 1 NHL), 3 in Part 2 (MDS)], and 7 patients achieved partial responses [6 in Part 1 (4 AML, 2 NHL), 1 in Part 2 (MDS)]. The ORRs for Part 1, Part 2, and the total study population were 10% [95% confidence interval (CI), 4.8–18.7], 25% (95% CI, 7.3–52.4), and 13% (95% CI, 6.9–20.6), respectively. While antitumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted.
Publisher: Oxford University Press (OUP)
Date: 13-10-2020
DOI: 10.1111/BJD.18522
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3705300
Publisher: Massachusetts Medical Society
Date: 17-02-2022
Publisher: Springer Science and Business Media LLC
Date: 20-07-2021
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.BBMT.2019.07.036
Abstract: Herpes zoster (HZ) can have a substantial impact on quality of life (QoL). The vaccine efficacy (VE) of a recombinant zoster vaccine (RZV) was 68.2% (95% confidence interval [CI], 55.6% to 77.5%) in a phase 3 study in adult autologous hematopoietic stem cell transplant (HSCT) recipients (NCT01610414). Herein, we report the impact of RZV on patients' QoL. Autologous HSCT recipients were randomized 1:1 to receive 2 doses of RZV or placebo, given 1 to 2 months apart. QoL was measured by the Short Form Survey-36 and Euro-QoL-5 Dimension at baseline, 1 month, and 1 year postdose 2 and during suspected HZ episodes with the Zoster Brief Pain Inventory (ZBPI). The RZV impact on ZBPI burden of illness and burden of interference scores was estimated. The 2 scores were calculated from the area under the curve (days 0 to 182) of the ZBPI worst pain and ZBPI activities of daily living scores, respectively, assuming a score of 0 for patients not having a confirmed HZ episode. The ZBPI maximum worst pain score was significantly lower in the RZV than placebo group (mean: 5.8 versus 7.1, P = .011). Consequently, the VE estimates for HZ burden of illness (82.5% 95% CI, 73.6 to 91.4) and burden of interference (82.8% 95% CI, 73.3 to 92.3) were higher than the HZ VE estimate (ie, 68.2%). RZV showed significantly better QoL scores than placebo 1 week following rash onset among patients with confirmed HZ. In addition to reducing the risk of HZ and its complications, RZV significantly reduced the impact of HZ on patients' QoL in those who developed breakthrough disease.
Publisher: American Society of Hematology
Date: 04-02-2022
DOI: 10.1182/BLOODADVANCES.2021005954
Abstract: Glofitamab, a novel CD20xCD3, T-cell–engaging bispecific antibody, exhibited single-agent activity in Study NP30179, a first-in-human, phase 1 trial in relapsed/refractory B-cell non-Hodgkin lymphoma. Preclinical studies showed that glofitamab leads to T-cell activation, proliferation, and tumor cell killing upon binding to CD20 on malignant cells. Here, we provide evidence of glofitamab’s clinical activity, including pharmacodynamic profile, mode of action, and factors associated with clinical response, by evaluating biomarkers in patient s les from the dose-escalation part of this trial. Patients enrolled in Study NP30179 received single-dose obinutuzumab pretreatment (1000 mg) 7 days before IV glofitamab (5 µg-25 mg). Glofitamab treatment lasted ≤12 cycles once every 2 or 3 weeks. Blood s les were collected at predefined time points per the clinical protocol T-cell populations were evaluated centrally by flow cytometry, and cytokine profiles were analyzed. Immunohistochemical and genomic biomarker analyses were performed on tumor biopsy s les. Pharmacodynamic modulation was observed with glofitamab treatment, including dose-dependent induction of cytokines, and T-cell margination, proliferation, and activation in peripheral blood. Gene expression analysis of pretreatment tumor biopsy s les indicated that tumor cell intrinsic factors such as TP53 signaling are associated with resistance to glofitamab, but they may also be interlinked with a diminished effector T-cell profile in resistant tumors and thus represent a poor prognostic factor per se. This integrative biomarker data analysis provides clinical evidence regarding glofitamab’s mode of action, supports optimal biological dose selection, and will further guide clinical development. This trial was registered at www.clinicaltrials.gov as #NCT03075696.
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2023
DOI: 10.1158/1078-0432.22820221.V1
Abstract: Overall survival (interim) and progression-free survival in patients ≥70 years
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22437814
Abstract: Tabulated data supporting ZUMA-7 elderly analysis Supplementary Table S1. Patient-reported outcomes instruments Supplementary Table S2. Axi-cel delivery and administration time Supplementary Table S3. Summary of efficacy and safety outcomes in patients ≥65 years versus all patients in ZUMA-7 Supplementary Table S4. Serious adverse events in at least 3 patients in patients ≥65 years Supplementary Table S5. Summary of cytopenias present on or after 90 days from initiation of definitive therapy on protocol in patients ≥65 years Supplementary Table S6. Deaths in axi-cel and SOC arms for patients ≥65 years (safety analysis set) Supplementary Table S7. Summary of serum analytes in patients years versus ≥65 years in the axi-cel arm (N = 170) Supplementary Table S8. Most common adverse events, cytokine release syndrome, and neurologic events in patients ≥70 years Supplementary Table S9. Deaths in axi-cel and SOC arms for patients ≥70 years Supplementary Table S10. Baseline characteristics for quality-of-life analysis in patients ≥65 years Supplementary Table S11. Mixed model with repeated measures estimated difference in change from baseline for prespecified patient-reported outcomes measures (quality-of-life analysis set) in patients ≥65 years
Publisher: Informa UK Limited
Date: 17-12-2021
DOI: 10.1080/10428194.2021.2015345
Abstract: Salvage chemotherapy and autologous stem cell transplant remain a standard of care in the management of diffuse large B cell lymphoma (DLBCL) at first relapse. However, this paradigm is increasingly being challenged by novel immunotherapies, such as chimeric antigen receptor T-cells (CART-cells). Traditional positron emission tomography-based (PET) prognostication takes place after salvage and before autologous stem cell transplant (ASCT), and while useful, for many patients this information comes too late and at the expense of unnecessary toxicity. In this edition of Leukemia & Lymphoma, two groups present their findings on the use of early quantitative PET markers and the correlation with outcomes in patients embarking on second line salvage chemotherapy. These approaches have the potential to better identify patients who are destined for treatment failure and help guide appropriate sequencing of alternative therapies or the development of PET-adapted clinical trials.
Publisher: Elsevier BV
Date: 2021
Publisher: Massachusetts Medical Society
Date: 13-07-2023
Publisher: American Association for Cancer Research (AACR)
Date: 13-06-2017
DOI: 10.1158/1078-0432.CCR-17-0466
Abstract: Histone deacetylase inhibitors (HDACi) are epigenome-targeting small molecules approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma. They have also demonstrated clinical activity in acute myelogenous leukemia, non–small cell lung cancer, and estrogen receptor–positive breast cancer, and trials are underway assessing their activity in combination regimens including immunotherapy. However, there is currently no clear strategy to reliably predict HDACi sensitivity. In colon cancer cells, apoptotic sensitivity to HDACi is associated with transcriptional induction of multiple immediate-early (IE) genes. Here, we examined whether this transcriptional response predicts HDACi sensitivity across tumor type and investigated the mechanism by which it triggers apoptosis. Fifty cancer cell lines from erse tumor types were screened to establish the correlation between apoptotic sensitivity, induction of IE genes, and components of the intrinsic apoptotic pathway. We show that sensitivity to HDACi across tumor types is predicted by induction of the IE genes FOS, JUN, and ATF3, but that only ATF3 is required for HDACi-induced apoptosis. We further demonstrate that the proapoptotic function of ATF3 is mediated through direct transcriptional repression of the prosurvival factor BCL-XL (BCL2L1). These findings provided the rationale for dual inhibition of HDAC and BCL-XL, which we show strongly cooperate to overcome inherent resistance to HDACi across erse tumor cell types. These findings explain the heterogeneous responses of tumor cells to HDACi-induced apoptosis and suggest a framework for predicting response and expanding their therapeutic use in multiple cancer types.
Publisher: Springer Science and Business Media LLC
Date: 12-2010
Publisher: Springer Science and Business Media LLC
Date: 23-04-2019
DOI: 10.1038/S41598-019-42858-8
Abstract: Next Generation Sequencing is now routinely used in the practice of diagnostic pathology to detect clinically relevant somatic and germline sequence variations in patient s les. However, clinical assessment of copy number variations (CNVs) and large-scale structural variations (SVs) is still challenging. While tools exist to estimate both, their results are typically presented separately in tables or static plots which can be difficult to read and are unable to show the context needed for clinical interpretation and reporting. We have addressed this problem with CNspector, a multi-scale interactive browser that shows CNVs in the context of other relevant genomic features to enable fast and effective clinical reporting. We illustrate the utility of CNspector at different genomic scales across a variety of s le types in a range of case studies. We show how CNspector can be used for diagnosis and reporting of exon-level deletions, focal gene-level lifications, chromosome and chromosome arm level lifications/deletions and in complex genomic rearrangements. CNspector is a web-based clinical variant browser tailored to the clinical application of next generation sequencing for CNV assessment. We have demonstrated the utility of this interactive software in typical applications across a range of tissue types and disease contexts encountered in the context of diagnostic pathology. CNspector is written in R and the source code is available for download under the GPL3 Licence from github.com/PapenfussLab/CNspector .
Publisher: Wiley
Date: 09-06-2010
DOI: 10.1111/J.1365-2141.2010.08162.X
Abstract: The utility of ([18F])fluoro-2-deoxy- d-glucose positron-emission tomography (FDG-PET) for predicting outcome after autologous stem cell transplantation (ASCT) for diffuse large B cell lymphoma (DLBCL) is uncertain - existing studies include a range of histological subtypes or have a limited duration of follow-up. Thirty-nine patients with primary-refractory or relapsed DLBCL with pre-ASCT PET scans were analysed. The median follow-up was 3 years. The 3-year progression-free survival (PFS) for patients with positive PET scans pre-ASCT was 35% vs. 81% for those who had negative PET scans (P = 0.003). The overall survival (OS) in these groups was 39% and 81% (P = 0.01), respectively. In a multivariate analysis, PET result, number of salvage cycles and the presence of relapsed or refractory disease were shown to predict a longer PFS PET negativity (P = 0.04) was predictive of a longer OS. PET is useful for defining those with an excellent prognosis post-ASCT. Although those with positive scans can still be salvaged with current treatments, PET may useful for selecting patients eligible for novel consolidation strategies after salvage therapies.
Publisher: Wiley
Date: 05-2021
DOI: 10.1111/IMJ.15247
Abstract: Australia and New Zealand have achieved excellent community control of COVID‐19 infection. In light of the imminent COVID‐19 vaccination roll out in both countries, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID‐19 vaccination in patients with haematological disorders. It is our recommendation that patients with haematological malignancies, and some benign haematological disorders, should have expedited access to high‐efficacy COVID‐19 vaccines, given that these patients are at high risk of morbidity and mortality from COVID‐19 infection. Vaccination should not replace other public health measures in these patients, given that the effectiveness of COVID‐19 vaccination, specifically in patients with haematological malignancies, is not known. Given the limited available data, prospective collection of safety and efficacy data of COVID‐19 vaccination in this patient group is a priority.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.CLML.2012.09.017
Abstract: The routine use of recombinant human granulocyte-colony stimulating factor (rhG-CSF) after high-dose chemotherapy and autologous stem cell transplantation (auto-SCT) is associated with increased costs. We prospectively explored a strategy that used prophylactic delayed filgrastim only in patients with risk factors. This sequential cohort analysis compared the outcomes of consecutive patients, treated on the risk-adapted protocol (RAP) (risk factors: prior febrile neutropenia age >60 years and CD34+ cell infused dose of <2 × 10(6/)/kg), who received filgrastim from day +6 after auto-SCT with a historical cohort (historical day-1 cohort [HD1]), who received filgrastim from day +1. Eighty-two patients were treated in the RAP cohort and compared with 115 patients in the HD1 cohort. There were no differences in median age (55 years) or median CD34+ cell dose (5.21 × 10(6)/kg [range, 2-62.2 × 10(6)/kg] vs. 5.24 × 10(6)/kg [range, 2.4-29.8 × 10(6)/kg]). Filgrastim was used for 6 fewer days in the RAP cohort (median 5 days [range, 0-11 days] vs. 11 days [range, 9-47 days]). There was a small absolute but significant difference in median time to neutrophil recovery in the HD1 cohort for the whole group, 10 days (range, 8-46 days) vs. 11 days (range, 9-22 days) (P = .03) and in patients with myeloma 10 days (range, 9-14 days) vs. 11 days (range, 9-18 days) (P < .0001) as compared to the RAP cohort. There was no difference in median inpatient duration, 13 days (range, 10-26 days) vs. 12 days (range, 1-38 days) (P = .22) and 3-year survival (79% vs. 83% [P = .43]) between HD1 and RAP cohorts respectively. The use of a RAP to identify patients likely to benefit from prophylactic filgrastim is safe and results in cost savings. Patients with myeloma benefit from earlier introduction of filgrastim in terms of neutrophil recovery this disease-specific observation is an important consideration for future studies.
Publisher: American Association for Cancer Research (AACR)
Date: 06-09-2023
Publisher: Informa UK Limited
Date: 28-02-2017
DOI: 10.1080/10428194.2017.1295141
Abstract: We examine the infective complications occurring during azacitidine (AZA) therapy in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). A retrospective review of patients receiving ≥1 cycle of AZA for MDS or AML was performed. Patient demographics, infection prophylaxis/episodes and outcomes were evaluated. Sixty eight patients received 884 AZA cycles. Bacterial infections occurred in 25% of cycle-1 and 27% of cycle-2 AZA therapy. Febrile neutropenia complicated 5.3% of AZA cycles, bacteremia 2% and invasive Aspergillosis 0.3%. Using Poisson modeling, a very high IPSS-R (RR 10.26, 95% CI 1.20, 87.41, p= .033) was identified as an independent risk factor for infection. Infection-related attributable mortality was 23%. The burden of infection is high in AZA-treated patients, associated with high attributable mortality. Over 25% of AZA cycles 1 and 2 were complicated by infection, predominantly bacterial, rates dropping to <10% after cycle-5.
Publisher: Informa Healthcare
Date: 03-07-2013
DOI: 10.1517/13543784.2013.815165
Abstract: Histone deacetylase inhibitors (HDACIs) are a class of antineoplastic agent targeting the epigenome, specifically chromatin remodelling, resulting in modulation of genes responsible for apoptosis and cell cycle regulation, and also hyperacetylation of many non-histone proteins. Panobinostat is a potent pan-histone inhibitor of HDAC enzymes implicated in cancer development and progression. Activity has been demonstrated in hematological diseases, such as cutaneous T-cell lymphoma (CTCL), Hodgkin lymphoma (HL), myeloma and myeloid malignancies. We discuss basic pharmacology, followed by early phase trial results and analyse recent large Phase II trials in HL, CTCL, myeloid malignancies and Waldenstrom's macroglobulinemia (WM). Future directions for drug development including potential predictive biomarkers are considered. The results of Phase II trials prove that oral panobinostat is deliverable with dosing regimens of three times per week, either weekly or biweekly. The major hematologic side-effect of myelosuppression, in particular thrombocytopenia, is transient and manageable, as are the non-hematologic side-effects. Encouraging responses are observed in HL, CTCL, myelofibrosis and WM. The safety and efficacy results from studies of combination therapy with azacitidine in acute myeloid leukemia and myelodysplastic syndromes suggest that this agent may find a place in the management of a range of hematologic cancers.
Publisher: American Society of Hematology
Date: 2015
DOI: 10.1182/BLOOD-2014-07-588236
Abstract: Chemotherapy results in a short median time to next treatment in patients with mycosis fungoides/Sézary syndrome. α-interferon achieves a superior time to next treatment compared with chemotherapy, regardless of stage.
Publisher: Wiley
Date: 05-2009
DOI: 10.1111/J.1445-5994.2008.01824.X
Abstract: Osteonecrosis of the Jaw (ONJ) is a recently recognised and potentially highly morbid complication of bisphosphonate therapy in the setting of metastatic malignancy, including myeloma. Members of the Medical and Scientific Advisory Group of the Myeloma Foundation of Australia formulated guidelines for the management of bisphosphonates around the issue of ONJ, based on the best available evidence in June 2008. Prior to commencement of therapy, patients should have an oral health assessment and be educated about the risks of ONJ. Dental assessment should occur 6 monthly during therapy. If tooth extraction is required, sufficient time should be allowed for complete healing to occur prior to commencement of bisphosphonate. As the risk of ONJ increases with duration of bisphosphonate therapy, we recommend annual assessment of dose with modification to 3 monthly i.v. therapy or to oral therapy with clodronate for those with all but the highest risk of skeletal-related event. Established ONJ should be managed conservatively a bisphosphonate "drug holiday" is usually indicated and invasive surgery should generally be avoided. These recommendations will assist with clinical decision making for myeloma patients who are at risk of bisphosphonate-associated ONJ.
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1038/MT.2013.154
Publisher: Springer Science and Business Media LLC
Date: 23-06-2020
DOI: 10.1038/S41598-020-67205-0
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Informa UK Limited
Date: 05-10-2013
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2023
DOI: 10.1158/1078-0432.22820224.V1
Abstract: Event-free survival per central review and objective response rate in patients ≥70 years
Publisher: Springer Science and Business Media LLC
Date: 17-12-2021
DOI: 10.1038/S41591-021-01622-0
Abstract: Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor-T cell therapy with clinically meaningful outcomes demonstrated in patients with relapsed/refractory (r/r) B-cell lymphoma. In a previous pilot study of tisagenlecleucel in r/r follicular lymphoma (FL), 71% of patients achieved a complete response (CR). Here we report the primary, prespecified interim analysis of the ELARA phase 2 multinational trial of tisagenlecleucel in adults with r/r FL after two or more treatment lines or who relapsed after autologous stem cell transplant (no. NCT03568461). The primary endpoint was CR rate (CRR). Secondary endpoints included overall response rate (ORR), duration of response, progression-free survival, overall survival, pharmacokinetics and safety. As of 29 March 2021, 97/98 enrolled patients received tisagenlecleucel (median follow-up, 16.59 months interquartile range, 13.8-20.21). The primary endpoint was met. In the efficacy set (n = 94), CRR was 69.1% (95% confidence interval, 58.8-78.3) and ORR 86.2% (95% confidence interval, 77.5-92.4). Within 8 weeks of infusion, rates of cytokine release syndrome were 48.5% (grade ≥3, 0%), neurological events 37.1% (grade ≥3, 3%) and immune effector cell-associated neurotoxicity syndrome (ICANS) 4.1% (grade ≥3, 1%) in the safety set (n = 97), with no treatment-related deaths. Tisagenlecleucel is safe and effective in extensively pretreated r/r FL, including in high-risk patients.
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2023
DOI: 10.1158/2159-8290.23807946.V1
Abstract: Supplementary Fig. S1. Preclinical evaluation and characterization of YTB323 and CTL*019 for Donor 2 and 3 Supplementary Fig. S2. Differential gene expression of CTL*019 cells versus YTB323 cells (preclinical) Supplementary Fig. S3. Preclinical validation of YTB323 Supplementary Fig. S4. Dose-dependent expansion (Cmax and AUC0-21d) of YTB323 and CTL*019 in NSG mice with NALM6 Supplementary Fig. S5. CD4:CD8 ratio comparison of leukapheresis and cell products of YTB323 and tisagenlecleucel Supplementary Fig. S6. Stemness and memory differentiation gene signatures are retained or enriched for in YTB323 final product Supplementary Fig. S7. Differential gene expression of tisagenlecleucel versus YTB323 final product Supplementary Fig. S8. Naive/TSCM cells and a naive stem-like gene signature correlate with higher expansion and a better response Supplementary Fig. S9. T-cell subset and checkpoint inhibitor analysis by flow cytometry on PBMCs collected post-YTB323 infusion Supplementary Fig. S10. Pre-clinical T-cell gating strategies.
Publisher: Informa UK Limited
Date: 09-06-2021
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 11-02-2016
Publisher: American Association for Cancer Research (AACR)
Date: 07-2012
DOI: 10.1158/1078-0432.CCR-11-3144
Abstract: Cutaneous T-cell lymphomas (CTCL) are relatively rare lymphomas with an annual incidence of approximately 0.2 to 0.8/100,000 and comprise a variety of clinical entities mycosis fungoides or its leukemic variant Sezary syndrome account for the majority of cases. Advanced-stage disease is typically treated with bexarotene (a retinoid), interferon, or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors, which modify the epigenome, are an attractive addition to the armamentarium. On the basis of 2 large phase II studies, the U.S. Food and Drug Administration approved intravenous romidepsin for patients with relapsed and/or refractory CTCL. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side effect profile. Clin Cancer Res 18(13) 3509–15. ©2012 AACR.
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2023
DOI: 10.1101/2023.06.03.23290918
Abstract: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a relatively common consequence of chimeric antigen receptor T-cell (CAR-T) therapy, with a wide range of possible cognitive presentations. The aim of this study was to characterise a real-word cognitive and psychological status of patients with advanced haematologic and solid organ malignancies planned for CAR-T. We also aimed to examine utility of two cognitive screening approaches. Patients underwent specialist cognitive assessment, including a self-report questionnaire of psychopathology and subjective cognitive function. A subset of in iduals also completed the Montreal Cognitive Assessment (MoCA). Of 60 patients included, 15-16 (25%-27%) presented with evidence of cognitive impairment, with six unique patterns of dysfunction. Impaired patients were more likely to have B-cell acute lymphoblastic leukaemia ( BF 10 =9.30), be younger ( BF 10 =7.76), have bone marrow involvement ( BF 10 =5.18), report history of anxiety ( BF 10 =4.85), or have evidence of psychopathology ( BF 10 =31.30). Analyses did not support the utility of cognitive screening. Of those patients who completed a self-report measure of psychopathology, nine (15.8%) were elevated on at least one symptom domain. The findings demonstrate a broad spectrum of dysfunction and psychopathology in this cohort, emphasising the importance of baseline evaluation for detecting cognitive neurotoxicity symptoms that might arise after CAR-T infusion.
Publisher: Informa UK Limited
Date: 13-02-2012
Publisher: Wiley
Date: 08-2014
DOI: 10.1111/IMJ.12486
Abstract: Optimal therapy for men relapsing after initial chemotherapy for germ cell tumours (GCT) is poorly defined. Both conventional dose salvage regimens and high-dose chemotherapy with autologous stem cell transplantation (HDCT-ASCT) have been utilised. To examine patients who received HDCT-ASCT for relapsed GCT within a single Australian centre. Records between 2000 and 2012 were analysed for baseline characteristics, treatment-related toxicity and survival. Prognosis at the time of HDCT-ASCT was classified according to the International Prognostic Factors Study Group (IPFSG). Seventeen patients received HDCT-ASCT, median age 34 (21-46), with 41% having primary refractory disease and 53% with high/very high risk disease by IPFSG. The most common regimen utilised was paclitaxel/ifosfamide followed by high-dose carboplatin/etoposide (TI-CE n = 12). The median duration of grade 4 (G4) neutropenia was 11 days (range 9-17) with febrile neutropenia in 90% resulting in four intensive care unit admissions (8%). Median duration of G4 thrombocytopenia was 10 days (range 8-19) requiring a median of two pooled platelets bags (range 0-33) per episode. Transplant-related mortality occurred in one patient (veno-occlusive disease). Twenty-seven per cent of HDCT-ASCT cycles were associated with grade 3 mucositis (median total parenteral nutrition days = 5 (0-23)). Two-year progression-free survival (PFS) and overall survival (OS) rates were 59% and 71%. Patients who received HDCT-ASCT as second or subsequent relapse fared worse than those treated with HDCT-ASCT at first relapse (hazard ratio 0.23 (95% confidence interval: 0.04, 1.37 P-value 0.09). Three-year OS for those who received TI-CE at first relapse was 90%. HDCT-ASCT for relapsed GCT is effective with acceptable toxicity. There was encouraging PFS/OS, particularly in a poor-prognosis cohort.
Publisher: Massachusetts Medical Society
Date: 15-12-2022
Publisher: Springer Science and Business Media LLC
Date: 27-06-2013
DOI: 10.1038/BJC.2013.338
Publisher: Elsevier BV
Date: 11-2020
Publisher: American Association for Cancer Research (AACR)
Date: 06-09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22437820.V1
Abstract: Mixed model with repeated measures for change from baseline for prespecified patient-reported outcomes endpoints in patients ≥65 years
Publisher: American Society of Hematology
Date: 20-12-2018
DOI: 10.1182/BLOOD-2018-06-855221
Abstract: Azacitidine treatment of myelodysplastic syndromes (MDSs) generally exacerbates thrombocytopenia during the first treatment cycles. A Study of Eltrombopag in Myelodysplastic Syndromes Receiving Azacitidine (SUPPORT), a phase 3, randomized, double-blind, placebo-controlled study, investigated the platelet supportive effects of eltrombopag given concomitantly with azacitidine. International Prognostic Scoring System intermediate-1, intermediate-2, or high-risk MDS patients with baseline platelets & × 109/L were randomized 1:1 to eltrombopag (start, 200 mg/d [East Asians, 100 mg/d], maximum, 300 mg/d [East Asians, 150 mg/d]) or placebo, plus azacitidine (75 mg/m2 subcutaneously once daily for 7 days every 28 days). The primary end point was the proportion of patients platelet transfusion-free during cycles 1 through 4 of azacitidine therapy. Based on planned interim analyses, an independent data monitoring committee recommended stopping the study prematurely because efficacy outcomes crossed the predefined futility threshold and for safety reasons. At termination, 28/179 (16%) eltrombopag and 55/177 (31%) placebo patients met the primary end point. Overall response (International Working Group criteria complete, marrow, or partial response) occurred in 20% and 35% of eltrombopag and placebo patients, respectively, by investigator assessment. There was no difference in hematologic improvement in any cell lineage between the 2 arms. There was no improvement in overall or progression-free survival. Adverse events with ≥10% occurrence in the eltrombopag vs placebo arm were febrile neutropenia and diarrhea. Compared with azacitidine alone, eltrombopag plus azacitidine worsened platelet recovery, with lower response rates and a trend toward increased progression to acute myeloid leukemia. This trial was registered at www.clinicaltrials.gov as #NCT02158936.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.CLML.2013.04.006
Abstract: The B-lymphocyte stimulator (BLYS) protein is known to regulate immunoglobulin in normal B cells, and be overexpressed in B-cell malignancies, including Waldenstrom macroglobulinemia (WM). This trial evaluated the safety and activity of belimumab, a monoclonal antibody targeting BLYS, in 12 patients with WM in a single-arm phase II study. Ten patients had stable disease with therapy, although no objective responses were seen. Correlative studies showed patients to have low or undetectable baseline serum levels of BLYS, with the administration of belimumab having no effect on B-cell numbers. Belimumab cannot be recommended as a single-agent therapy for the treatment of symptomatic WM, although further evaluation in combination with other agents would be justified.
Publisher: Springer Science and Business Media LLC
Date: 29-07-2014
DOI: 10.1038/BJC.2014.405
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2023
DOI: 10.1158/1078-0432.22820224
Abstract: Event-free survival per central review and objective response rate in patients ≥70 years
Publisher: Informa UK Limited
Date: 07-10-2020
Publisher: Informa UK Limited
Date: 02-08-2023
Publisher: American Society of Hematology
Date: 22-11-2022
DOI: 10.1182/BLOODADVANCES.2022008150
Abstract: The ELARA trial indicates tisagenlecleucel (tisa-cel) is an effective anti-CD19 chimeric antigen receptor T-cell therapy for relapsed or refractory follicular lymphoma (r/r FL). As ELARA is a single-arm trial, this study compares tisa-cel outcomes from the ELARA trial with usual care from a real-world cohort. ELARA enrolled 98 patients as of 29 March 2021 (median follow-up: 15 months from enrollment). Usual care data were obtained from ReCORD-FL, a global retrospective study of patients with r/r FL, who met similar eligibility criteria to ELARA. With a data cutoff date of 31 December 2020, 187 patients with ≥2 preceding treatment lines were included in the ReCORD-FL (median follow-up: 57 months from third-line) study. An indirect treatment comparison was performed for 97 patients from the ELARA trial and 143 patients from the ReCORD-FL study with no missing data on baseline factors. The line of therapy for which outcomes were assessed was selected or matched between cohorts using propensity score modeling. After baseline factor adjustment via weighting by odds, complete response rate (CRR 95% confidence interval) was 69.1% (59.8%-78.3%) for tisa-cel vs. 37.3% (26.4%-48.3%) for usual care overall response rate was 85.6% (78.7%-92.5%) vs. 63.6% (52.5%-74.7%). Kaplan-Meier probability of being progression/event-free at 12 months was 70.5% (61.4%-79.7%) for tisa-cel vs. 51.9% (40.6%-63.3%) for usual care, with hazard ratio (HR)=0.60 (0.34-0.86) 12-month overall survival was 96.6% (92.9%-100%) vs. 71.7% (61.2%-82.2%), with HR=0.2 (0.02-0.38). In conclusion, tisa-cel was associated with a 1.9-fold higher complete response rate and a 1.4-fold higher rate of being progression or event free at 12 months vs usual care, as well as a death risk reduction of 80%. The findings provide additional evidence on the benefit of tisa-cel in patients with r/r FL after ≥2 treatment lines. This trial was registered at www.clinicaltrials.gov as NCT03568461
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22437814.V1
Abstract: Tabulated data supporting ZUMA-7 elderly analysis Supplementary Table S1. Patient-reported outcomes instruments Supplementary Table S2. Axi-cel delivery and administration time Supplementary Table S3. Summary of efficacy and safety outcomes in patients ≥65 years versus all patients in ZUMA-7 Supplementary Table S4. Serious adverse events in at least 3 patients in patients ≥65 years Supplementary Table S5. Summary of cytopenias present on or after 90 days from initiation of definitive therapy on protocol in patients ≥65 years Supplementary Table S6. Deaths in axi-cel and SOC arms for patients ≥65 years (safety analysis set) Supplementary Table S7. Summary of serum analytes in patients years versus ≥65 years in the axi-cel arm (N = 170) Supplementary Table S8. Most common adverse events, cytokine release syndrome, and neurologic events in patients ≥70 years Supplementary Table S9. Deaths in axi-cel and SOC arms for patients ≥70 years Supplementary Table S10. Baseline characteristics for quality-of-life analysis in patients ≥65 years Supplementary Table S11. Mixed model with repeated measures estimated difference in change from baseline for prespecified patient-reported outcomes measures (quality-of-life analysis set) in patients ≥65 years
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2023
DOI: 10.1158/2159-8290.23807943.V1
Abstract: Supplementary Table S1. Bridging chemotherapies by ATC class and preferred term (safety set) Supplementary Table S2. Lymphodepleting chemotherapies (safety set) Supplementary Table S3. Cytokine release syndrome following YTB323 infusion Supplementary Table S4. Neurological adverse reactions following YTB323 infusion Supplementary Table S5. Summary of cellular kinetic parameters in peripheral blood by flow cytometry for YTB323 at DL1 and DL2 Supplementary Table S6. Summary of cellular kinetic parameters in peripheral blood by flow cytometry and qPCR for YTB323 at DL1 and DL2.
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2023
DOI: 10.1158/1078-0432.22820221
Abstract: Overall survival (interim) and progression-free survival in patients ≥70 years
Publisher: Medical Journals Sweden AB
Date: 2021
No related grants have been discovered for Michael Dickinson.