Publications by authors named "John F Seymour"

324 Publications

Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial.

J Clin Oncol 2021 Jul 26:JCO2101210. Epub 2021 Jul 26.

Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland.

Purpose: Among Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL).

Methods: Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed noninferiority of progression-free survival (PFS).

Results: Overall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% 16.0%; = .02); among other selected secondary end points, grade 3 or higher infections (30.8% 30.0%) and Richter transformations (3.8% 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients.

Conclusion: In this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.
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http://dx.doi.org/10.1200/JCO.21.01210DOI Listing
July 2021

T-cell replete allogeneic stem cell transplant for mantle cell lymphoma achieves durable disease control, including against TP53-mutated disease.

Bone Marrow Transplant 2021 Jul 20. Epub 2021 Jul 20.

Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1038/s41409-021-01418-3DOI Listing
July 2021

Efficacy of venetoclax plus rituximab for relapsed CLL: Five-year follow-up of continuous or limited-duration therapy.

Blood 2021 Jun 3. Epub 2021 Jun 3.

Department of Hematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital; University of Melbourne, Australia.

We report long-term follow-up of the phase 1b study of venetoclax and rituximab (VenR) in patients with relapsed chronic lymphocytic leukemia (CLL), including outcomes with continuous or limited-duration therapy. Patients received venetoclax daily (200-600 mg) and rituximab over 6 months, then venetoclax monotherapy. Patients achieving complete response (CR), CR with incomplete marrow recovery (CRi), or undetectable minimal residual disease (uMRD) assessed by flow cytometry (<10-4 cutoff) were allowed, but not required, to discontinue therapy, while remaining on study and could be re-treated with VenR upon progression. Median follow-up for all patients (N=49) was 5.3 years. Five-year rates for overall survival, progression-free survival, and duration of response were 86% (95% CI, 72-94), 56% (40-70), and 58% (40-73), respectively. Of the 33 deep responders (CR/CRi or uMRD), 14 remained on venetoclax monotherapy (continuous therapy), and 19 stopped venetoclax therapy (limited-duration therapy) after a median of 1.4 years. Five-year estimates of ongoing response were similar between continuous (71% [95% CI, 39-88]) or limited-duration therapy (79% [49-93]). Six of 19 patients in the latter group had subsequent disease progression, all >2 years off venetoclax (range, 2.1-6.4). Four patients were re-treated with VenR, with partial responses observed in the 3 evaluable to date. VenR induced deep responses that were highly durable with either continuous or limited-duration therapy. Retreatment with VenR induced responses in patients with CLL progression after discontinuing therapy. Continuous exposure to venetoclax in deep responders does not appear to provide incremental benefit. ClinicalTrials.gov ID: NCT01682616.
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http://dx.doi.org/10.1182/blood.2020009578DOI Listing
June 2021

Should Undetectable Minimal Residual Disease Be the Goal of Chronic Lymphocytic Leukemia Therapy?

Hematol Oncol Clin North Am 2021 Aug 15;35(4):775-791. Epub 2021 May 15.

Department of Internal Medicine, Center of Integrated Oncology Cologne Bonn, University Hospital, German CLL Study Group, Gleueler Strasse 176, 50935 Cologne, Germany.

With the advent of highly effective novel therapies for chronic lymphocytic leukemia, conventional response assessment is not able to sensitively capture depth of response. To achieve a more precise assessment of response, minimal residual disease has been introduced to more accurately classify and quantify treatment outcomes. It is now considered a strong predictor of outcome in chronic lymphocytic leukemia, although its interpretation depends on the therapeutic context. This review discusses available methods of minimal residual disease measurement. It summarizes minimal residual disease data from pivotal clinical trials and discusses potential implications for future studies and minimal residual disease-based clinical strategies.
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http://dx.doi.org/10.1016/j.hoc.2021.03.007DOI Listing
August 2021

Prospective Phase II trial of radiation therapy in localised non-gastric marginal zone lymphoma with prospective evaluation of autoimmunity and Helicobacter pylori status: TROG 05.02/ALLG NHL15.

Eur J Cancer 2021 Jul 5;152:129-138. Epub 2021 Jun 5.

Peter MacCallum Cancer Centre, Melbourne, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; Department of Haematology, Royal Melbourne Hospital, Melbourne, Australia.

Background: This Phase 2 multicentre trial in localised non-gastric marginal zone lymphoma (MZL) evaluated the effectiveness and safety of radiotherapy and documented markers of autoimmunity and Helicobacter pylori infection.

Patients And Methods: Eligible patients had Stages I and II or paired-organ, non-gastric MZL. Bone marrow evaluation, autoantibody panel, and H. pylori evaluation were mandatory. Involved-field or involved-site radiotherapy was delivered to 24-30.6 Gy. Detected H. pylori infections underwent eradication.

Results: Between 2006 and 2014, six centres enrolled 70 patients, and 68 commenced treatment. The median age was 59 (range: 23-84) years, and 31 (46%) were male. Overall, 55 patients had Stage I disease, nine patients had Stage II disease, and four patients had paired organ-confined disease. Involved extranodal sites with three or more cases were orbital (n = 18), conjunctiva (n = 13), lacrimal (n = 8), skin (n = 8), salivary (n = 7), and muscle (n = 4). Eight patients had primary nodal MZL. At the median follow-up of 5 years (range 0.7-9.4), progression-free survival and overall survival were 79% and 95%, respectively. One lymphoma-related death and two in-field failures (after 25 and 30 Gy, respectively) occurred. Distant relapse sites were skin (n = 2), lymph nodes (n = 2), duodenum, stomach, muscle, and conjunctiva (1 each). No paired-organ MZL relapsed. Apart from cataracts (n = 18), only three treatment-related late grade ≥3 adverse events occurred. Autoantibodies or autoimmune events were detected in 26 of 68 patients (38%). H. pylori infection was detected in 15 of 63 patients (24%) tested. Neither autoimmunity nor H. pylori was detected in 27 of 68 patients (40%).

Conclusions: Radiotherapy was a potentially curative treatment with low toxicity in localised non-gastric MZL. Autoimmunity, H. pylori infection or both were detected in 60% of patients.
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http://dx.doi.org/10.1016/j.ejca.2021.05.004DOI Listing
July 2021

Long-term Follow-up of Patients with Relapsed or Refractory Non-Hodgkin Lymphoma Treated with Venetoclax in a Phase I, First-in-Human Study.

Clin Cancer Res 2021 Jun 3. Epub 2021 Jun 3.

Department of Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.

Purpose: We previously reported a 44% overall response rate (ORR) with the oral BCL-2 inhibitor venetoclax in a phase I study of relapsed/refractory non-Hodgkin lymphoma (NHL). Complete response (CR) was observed in patients with mantle cell lymphoma [(MCL), 21%, = 6/28] and follicular lymphoma [(FL), 17%, = 5/29], and partial response (PR) noted in several patients with Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL). Here, we report the long-term outcomes of these four cohorts.

Patients And Methods: All patients ( = 106) received venetoclax monotherapy in dose cohorts of 200 to 1,200 mg daily until disease progression or unacceptable toxicity. ORR, progression-free survival (PFS), duration of response (DoR), and adverse events (AEs) were evaluated.

Results: At a median follow-up of 38.5 months (range, 30.0-46.5), the median PFS for all 106 patients was 5.4 [95% confidence interval (CI), 3.5-8.4] months (FL, 10.8; MCL, 11.3; MZL, 21.2; and WM, 30.4). The median DoR was 14.9 (95% CI, 9.7-27.6) months (FL, 26.6; MCL, 15.7; MZL, 20.1; and WM, 25.3). Achievement of CR versus PR predicted longer DoR in both MCL (31.5 vs. 10.1 months) and FL (37.6 vs. 9.7 months). All grade hematologic AEs were infrequent: neutropenia (19%), anemia (19%), and thrombocytopenia (17%), with no new cytopenias after 2 years on therapy. Nonhematologic AEs included nausea (49%), diarrhea (46%), fatigue (44%), with decreased incidence after 1 year.

Conclusions: Venetoclax monotherapy has a manageable safety profile and achieves durable responses in a subset of patients with FL, MCL, WM, and MZL, particularly in those who achieve CR. Further research is warranted on combination strategies to enhance the durability of response to venetoclax.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4842DOI Listing
June 2021

Hairy cell leukemia and COVID-19 adaptation of treatment guidelines.

Leukemia 2021 07 4;35(7):1864-1872. Epub 2021 May 4.

Haematology Department, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia.

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.
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http://dx.doi.org/10.1038/s41375-021-01257-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093591PMC
July 2021

How I treat chronic lymphocytic leukemia after venetoclax.

Blood 2021 Apr 19. Epub 2021 Apr 19.

Department of Hematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.

Venetoclax-based regimens have expanded the therapeutic options for patients with chronic lymphocytic leukemia (CLL), frequently achieving remissions with undetectable measurable residual disease (uMRD) and facilitating time-limited treatment without utilizing chemotherapy. Although response rates are high and durable disease control is common, longer-term follow-up of patients with relapsed and refractory (RR) disease, especially in the presence of TP53 aberrations, demonstrates frequent disease resistance and progression. Although the understanding of venetoclax resistance remains incomplete, progressive disease (PD) is typified by oligoclonal leukemic populations with distinct resistance mechanisms, including BCL2 mutations, upregulation of alternative BCL2 family proteins and genomic instability. Although most commonly observed in heavily pre-treated patients with disease refractory to fludarabine and harboring complex karyotype (CK), Richter transformation (RT) presents a distinct and challenging manifestation of venetoclax resistance. For patients with progressive CLL after venetoclax, treatment options include B-cell receptor pathway inhibitors (BCRis), allogeneic stem cell transplantation (SCT), chimeric antigen receptor (CAR) T-cells, and venetoclax re-treatment for those with disease relapsing after time-limited therapy. However, data to inform clinical decisions for these patients are limited. We review the biology of venetoclax resistance and outline an approach to the common clinical scenarios encountered after venetoclax-based therapy that will increasingly confront practising clinicians.
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http://dx.doi.org/10.1182/blood.2020008502DOI Listing
April 2021

Relapsed/Refractory International Prognostic Index (R/R-IPI): An international prognostic calculator for relapsed/refractory diffuse large B-cell lymphoma.

Am J Hematol 2021 05 18;96(5):599-605. Epub 2021 Mar 18.

Division of Hematology, Mayo Clinic, Rochester, Minnosata.

Disease progression after frontline therapy for Diffuse large B-cell lymphoma (DLBCL) is a clinically significant event. Patients who experience early progression or have refractory disease have especially poor outcomes. Simple, clinically applicable prognostic tools are needed for selecting patients for consideration for novel therapies and prognostication in the relapsed/refractory (R/R) setting. Model building was performed in patients from the Surrogate endpoints in aggressive lymphoma (SEAL) consortium with disease progression after frontline immunochemotherapy. The primary endpoint was overall survival (OS) measured from date of progression. Validation was performed in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and Danish National Lymphoma Register (LYFO) cohorts. Model performance was assessed using time-dependent concordance indices (c-statistic) and calibration with metrics evaluated at 2 years from progression. Note, 1234 of 5112 patients treated with frontline immunochemotherapy in the SEAL consortium developed progressive disease. Time to progression on immunochemotherapy and age at progression were strongly associated with post-progression OS (both p < 0.001). A prognostic model was developed incorporating spline fit for both variables. The model had good concordance in the discovery (0.67) and validation sets (LYFO c = 0.64, MER c = 0.68) with generally good calibration. Time to progression on frontline therapy is strongly associated with post-progression OS in DLBCL. We developed and validated a simple to apply clinical prognostic tool in the R/R setting. The useful prediction of expected outcomes in R/R DLBCL and can inform treatment decisions such as considerations for CAR-T therapy as well as trial designs. The model is available in smartphone-based point of care applications.
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http://dx.doi.org/10.1002/ajh.26149DOI Listing
May 2021

The impact of early discontinuation/dose modification of venetoclax on outcomes in patients with relapsed/refractory chronic lymphocytic leukemia: post-hoc analyses from the phase III MURANO study.

Haematologica 2020 12 17;Online ahead of print. Epub 2020 Dec 17.

Peter MacCallum Cancer Centre, Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC.

Fixed-duration venetoclax plus rituximab (VenR) has a manageable safety profile and improves survival in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). We present data from the phase III MURANO study on the impact of venetoclax modification or premature discontinuation on outcomes in patients with R/R CLL. Time-dependent Cox proportional hazards regression models, stratified by 17p deletion and risk status, evaluated the impact of venetoclax discontinuation/modification on investigator-assessed progression-free survival (PFS) and overall survival (OS). Analyses were performed retrospectively (without type-1 error control) in intention-to-treat patients from the VenR arm of MURANO. Overall, 140/194 (72%) patients in the VenR arm completed 2 years of therapy; 54/194 (28%) patients prematurely discontinued treatment. Inferior PFS was observed in patients prematurely discontinuing venetoclax for any reason (disease progression excluded; p.
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http://dx.doi.org/10.3324/haematol.2020.266486DOI Listing
December 2020

BCL2 Expression in First-Line Diffuse Large B-Cell Lymphoma Identifies a Patient Population With Poor Prognosis.

Clin Lymphoma Myeloma Leuk 2021 Apr 10;21(4):267-278.e10. Epub 2020 Nov 10.

Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.

Introduction: The prognostic value of B-cell lymphoma 2 (BCL2) expression in de novo diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy is of interest to define a target patient population for clinical development of BCL2 inhibitors. We aimed to develop a reproducible immunohistochemistry algorithm and assay to determine BCL2 protein expression and assess the prognostic value of BCL2 in newly diagnosed DLBCL cohorts.

Patients And Methods: The prospectively defined algorithm incorporated BCL2 staining intensity and percentage of BCL2-positive cells. Functionally relevant cutoffs were based on the sensitivity of lymphoma cell lines to venetoclax. This assay was highly reproducible across laboratories. The prognostic impact of BCL2 expression was assessed in DLBCL patients from the phase 3 MAIN (n = 230) and GOYA (n = 366) trials, and a population-based registry (n = 310).

Results: Approximately 50% of tumors were BCL2 positive, with a higher frequency in high International Prognostic Index (IPI) and activated B-cell-like DLBCL subgroups. BCL2 expression was associated with poorer progression-free survival in the MAIN study (hazard ratio [HR], 1.66; 95% confidence interval [CI], 0.81-3.40; multivariate Cox regression adjusted for IPI and cell of origin). This trend was confirmed in the GOYA and registry cohorts in adjusted multivariate analyses (GOYA: HR, 1.72; 95% CI, 1.05-2.82; registry: HR, 1.89; 95% CI, 1.29-2.78). Patients with BCL2 immunohistochemistry-positive and IPI-high disease had the poorest prognosis: 3-year progression-free survival rates were 51% (GOYA) and 37% (registry).

Conclusion: Findings support use of our BCL2 immunohistochemistry scoring system and assay to select patients with BCL2-positive tumors for future studies.
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http://dx.doi.org/10.1016/j.clml.2020.11.004DOI Listing
April 2021

Reply to Y. Myoken et al.

J Clin Oncol 2021 01 8;39(2):173-174. Epub 2020 Dec 8.

Ie-Wen Sim, MBBS(Hons), BMedSci, FRACP, Melbourne Medical School, University of Melbourne, Melbourne, Australia, Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Australia; Gelsomina L. Borromeo, BDSc, BSc, MScMed, PhD, FRACDS, Melbourne Dental School, University of Melbourne, Melbourne, Australia; John F. Seymour, MBBS, PhD, FRACP, Melbourne Medical School, University of Melbourne, Melbourne, Australia, Department of Haematology, Peter MacCallum Cancer Centre & Royal Melbourne Hospital, Melbourne, Australia; and Peter R. Ebeling, MBBS, MD, FRACP, Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Australia.

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http://dx.doi.org/10.1200/JCO.20.02906DOI Listing
January 2021

High-Risk Mantle Cell Lymphoma: Definition, Current Challenges, and Management.

J Clin Oncol 2020 12 19;38(36):4302-4316. Epub 2020 Oct 19.

Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX.

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http://dx.doi.org/10.1200/JCO.20.02287DOI Listing
December 2020

Immune recovery in patients with mantle cell lymphoma receiving long-term ibrutinib and venetoclax combination therapy.

Blood Adv 2020 10;4(19):4849-4859

ACRF Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, VIC, Australia.

Combination venetoclax plus ibrutinib for the treatment of mantle cell lymphoma (MCL) has demonstrated efficacy in the relapsed or refractory setting; however, the long-term impact on patient immunology is unknown. In this study, changes in immune subsets of MCL patients treated with combination venetoclax and ibrutinib were assessed over a 4-year period. Multiparameter flow cytometry of peripheral blood mononuclear cells showed that ≥12 months of treatment resulted in alterations in the proportions of multiple immune subsets, most notably CD4+ and CD8+ effector and central memory T cells and natural killer cells, and normalization of T-cell cytokine production in response to T-cell receptor stimulation. Gene expression analysis identified upregulation of multiple myeloid genes (including S100 and cathepsin family members) and inflammatory pathways over 12 months. Four patients with deep responses stopped study drugs, resulting in restoration of normal immune subsets for all study parameters except myeloid gene/pathway expression, suggesting long-term combination venetoclax and ibrutinib irreversibly affects this population. Our findings demonstrate that long-term combination therapy is associated with immune recovery in MCL, which may allow responses to subsequent immunotherapies and suggests that this targeted therapy results in beneficial impacts on immunological recovery. This trial was registered at www.clinicaltrials.gov as #NCT02471391.
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http://dx.doi.org/10.1182/bloodadvances.2020002810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556128PMC
October 2020

Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study.

J Clin Oncol 2020 12 28;38(34):4042-4054. Epub 2020 Sep 28.

Royal Melbourne Hospital, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia.

Purpose: In previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics.

Patients And Methods: Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed.

Results: Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC ( = .042); higher GC was associated with shorter PFS. Higher MRD positivity rates were seen with and mutations at EOCT and with , , , and mutations at EOT.

Conclusion: Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS.
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http://dx.doi.org/10.1200/JCO.20.00948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768340PMC
December 2020

Venetoclax plus obinutuzumab therapy for front-line treatment of chronic lymphocytic leukaemia.

Authors:
John F Seymour

Lancet Oncol 2020 09;21(9):1128-1130

Department of Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC 3000, Australia. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(20)30484-8DOI Listing
September 2020

Follicular Lymphoma Evaluation Index (FLEX): A new clinical prognostic model that is superior to existing risk scores for predicting progression-free survival and early treatment failure after frontline immunochemotherapy.

Am J Hematol 2020 12 16;95(12):1503-1510. Epub 2020 Sep 16.

Wilmot Cancer Institute, University of Rochester, New York, New York, USA.

Patients with advanced-stage follicular lymphoma (FL) who progress early after receiving first-line therapy have poor overall survival (OS). Currently applied clinical prognostic models such as FL International Prognostic Index [FLIPI], FLIPI-2 and PRIMA-Prognostic Index [PRIMA-PI] have suboptimal sensitivity and specificity to predict this poor prognosis subgroup. The primary objective was to develop a novel prognostic model, the FL Evaluation Index (FLEX) score, to identify high-risk patients and compare its performance with FLIPI, FLIPI-2 and PRIMA-PI. Progression-free survival (PFS) after first-line immunochemotherapy was the key endpoint, while OS and progression of disease within 24 months (POD24) were also assessed. The model, which includes nine clinical variables, was developed using a cohort of patients with previously untreated advanced-stage FL from the phase 3 GALLIUM trial (NCT01332968). The performance of the model was validated using data from the SABRINA trial (NCT01200758). In GALLIUM (n = 1004; 127 with and 877 without POD24), FLEX increased the intergroup (low-risk/high-risk) difference in 2-year and 3-year PFS rates and demonstrated superior intergroup differences in 2-year and 3-year OS rates compared with FLIPI, FLIPI-2 and PRIMA-PI. Sensitivity for a high-risk score to predict POD24 was 60% using FLEX compared with 53% for FLIPI and FLIPI-2, and 69% for PRIMA-PI, while specificity was 68% for FLEX compared with 58% for FLIPI, 59% for FLIPI-2 and 48% for PRIMA-PI. The prognostic value of FLEX in SABRINA was similar to FLIPI. Therefore, FLEX appears to perform better than existing prognostic models in previously untreated FL, in particular for the newer treatment regimens.
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http://dx.doi.org/10.1002/ajh.25973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756469PMC
December 2020

Zanubrutinib for the treatment of patients with Waldenström macroglobulinemia: 3 years of follow-up.

Blood 2020 10;136(18):2027-2037

Haematology Department, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.

Inhibitors of Bruton's tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenström macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients with WM who were either treatment-naïve (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per International Workshop on Waldenström Macroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n = 50) or 320 mg once daily (n = 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0 months for patients with R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24 months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with single-agent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.
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http://dx.doi.org/10.1182/blood.2020006449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596846PMC
October 2020

The evolving definition of bulky disease for lymphoma.

Leuk Lymphoma 2020 07 20;61(7):1525-1528. Epub 2020 Jul 20.

Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia.

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http://dx.doi.org/10.1080/10428194.2020.1797014DOI Listing
July 2020

Teriparatide Promotes Bone Healing in Medication-Related Osteonecrosis of the Jaw: A Placebo-Controlled, Randomized Trial.

J Clin Oncol 2020 09 2;38(26):2971-2980. Epub 2020 Jul 2.

Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.

Purpose: Medication-related osteonecrosis of the jaw (MRONJ) is an infrequent but morbid and potentially serious condition associated with antiresorptive and antiangiogenic therapies. Although MRONJ can be prevented by optimizing oral health, management of established cases is supportive and remains challenging. Teriparatide, an osteoanabolic agent that improves bone healing in preclinical studies and in chronic periodontitis, represents a potential treatment option.

Patients And Methods: In a double-blind, randomized, controlled trial, 34 participants with established MRONJ, with a total of 47 distinct MRONJ lesions, were allocated to either 8 weeks of subcutaneous teriparatide (20 µg/day) or placebo injections, in addition to calcium and vitamin D supplementation and standard clinical care. Participants were observed for 12 months, with primary outcomes that included the clinical and radiologic resolution of MRONJ lesions. Secondary outcomes included osteoblastic responses as measured biochemically and radiologically and changes in quality of life.

Results: Teriparatide was associated with a greater rate of resolution of MRONJ lesions (odds ratio [OR], 0.15 0.40; = .013), and 45.4% of lesions resolved by 52 weeks compared with 33.3% in the placebo group. Teriparatide was also associated with reduced bony defects at week 52 (OR, 8.1; = .017). The incidence of adverse events was balanced between groups, including nausea, anorexia, and musculoskeletal pain, most of mild severity.

Conclusion: Teriparatide improves the rate of resolution of MRONJ lesions and represents an efficacious and safe treatment for it.
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http://dx.doi.org/10.1200/JCO.19.02192DOI Listing
September 2020

Response in patients with -mutated relapsed/refractory chronic lymphocytic leukemia treated with fixed-duration venetoclax and rituximab.

Haematologica 2020 07;105(7):e382-e383

Royal Melbourne Hospital, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Australia.

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http://dx.doi.org/10.3324/haematol.2020.253849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327665PMC
July 2020

A predictive tool for early-stage CLL.

Blood 2020 05;135(21):1820-1821

Peter MacCallum Cancer Centre; University of Melbourne; The Royal Melbourne Hospital.

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http://dx.doi.org/10.1182/blood.2020005426DOI Listing
May 2020

The urgent need for integrated science to fight COVID-19 pandemic and beyond.

J Transl Med 2020 05 19;18(1):205. Epub 2020 May 19.

Universal Scientific Education and Research Network (USERN),.

The COVID-19 pandemic has become the leading societal concern. The pandemic has shown that the public health concern is not only a medical problem, but also affects society as a whole; so, it has also become the leading scientific concern. We discuss in this treatise the importance of bringing the world's scientists together to find effective solutions for controlling the pandemic. By applying novel research frameworks, interdisciplinary collaboration promises to manage the pandemic's consequences and prevent recurrences of similar pandemics.
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http://dx.doi.org/10.1186/s12967-020-02364-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236639PMC
May 2020

Durable Complete Remission and Long-Term Survival in FDG-PET Staged Patients with Stage III Follicular Lymphoma, Treated with Wide-Field Radiation Therapy.

Cancers (Basel) 2020 Apr 17;12(4). Epub 2020 Apr 17.

Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.

Advanced-stage follicular lymphoma (FL) is generally considered incurable with conventional systemic therapies, but historic series describe long-term disease-free survival in stage III disease treated with wide-field radiation therapy (WFRT), encompassing all known disease sites. We report outcomes for patients staged with F-fluorodeoxyglucose positron emission tomography (FDG-PET) and treated with CT-planned WFRT, given as either comprehensive lymphatic irradiation (CLI) or total nodal irradiation (TNI). This analysis of a prospective cohort includes PET-staged patients given curative-intent WFRT as a component of initial therapy, or as sole treatment for stage III FL. Thirty-three PET-staged patients with stage III FL received WFRT to 24-30Gy between 1999 and 2017. Fifteen patients also received planned systemic therapy (containing rituximab in 11 cases) as part of their primary treatment. At 10 years, overall survival and freedom from progression (FFP) were 100% and 75%, respectively. None of the 11 rituximab-treated patients have relapsed. Nine relapses occurred; seven patients required treatment, and all responded to salvage therapies. A single death occurred at 16 years. The principal acute toxicity was transient hematologic; one patient had residual grade two toxicity at one year. With FDG-PET staging, most patients with stage III FL experience prolonged FFP after WFRT, especially when combined with rituximab.
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http://dx.doi.org/10.3390/cancers12040991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226391PMC
April 2020

Burden and clinical outcomes of hospital-coded infections in patients with cancer: an 11-year longitudinal cohort study at an Australian cancer centre.

Support Care Cancer 2020 Dec 15;28(12):6023-6034. Epub 2020 Apr 15.

National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Purpose: Patients with cancer are at increased risk for infection, but the relative morbidity and mortality of all infections is not well understood. The objectives of this study were to determine the prevalence, incidence, time-trends and risk of mortality of infections associated with hospital admissions in patients with haematological- and solid-tumour malignancies over 11 years.

Methods: A retrospective, longitudinal cohort study of inpatient admissions between 1 January 2007 and 31 December 2017 at the Peter MacCallum Cancer Centre was conducted using administratively coded and patient demographics data. Descriptive analyses, autoregressive integrated moving average, Kaplan-Meier and Cox regression modelling were applied.

Results: Of 45,116 inpatient hospitalisations consisting of 3033 haematological malignancy (HM), 18,372 solid tumour neoplasm (STN) patients and 953 autologous haematopoietic stem cell transplantation recipients, 67%, 29% and 88% were coded with ≥ 1 infection, respectively. Gastrointestinal tract and bloodstream infections were observed with the highest incidence, and bloodstream infection rates increased significantly over time in both HM- and STN-cohorts. Inpatient length of stay was significantly higher in exposed patients with coded infection compared to unexposed in HM- and STN-cohorts (22 versus 4 days [p < 0.001] and 15 versus 4 days [p < 0.001], respectively). Risk of in-hospital mortality was higher in exposed than unexposed patients in the STN-cohort (adjusted hazard ratio [aHR] 1.61 [95% CI 1.41-1.83]; p < 0.001)) and HM-cohort (aHR 1.30 [95% CI 0.90-1.90]; p = 0.166).

Conclusion: Infection burden among cancer patients is substantial and findings reflect the need for targeted surveillance in high-risk patient groups (e.g. haematological malignancy), in whom enhanced monitoring may be required to support infection prevention strategies.
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http://dx.doi.org/10.1007/s00520-020-05439-4DOI Listing
December 2020

BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax.

Blood 2020 06;135(25):2266-2270

Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Highly active BTK inhibitors (BTKis) and the BCL2 inhibitor venetoclax have transformed the therapeutic landscape for chronic lymphocytic leukemia (CLL). Results of prospective clinical trials demonstrate the efficacy of venetoclax to salvage patients with disease progression on BTKis, but data on BTKi therapy after disease progression on venetoclax are limited, especially regarding durability of benefit. We retrospectively evaluated the records of 23 consecutive patients with relapsed/refractory CLL who received a BTKi (ibrutinib, n = 21; zanubrutinib, n = 2) after stopping venetoclax because of progressive disease. Median progression-free survival (PFS) and median overall survival after BTKi initiation were 34 months (range, <1 to 49) and 42 months (range, 2-49), respectively. Prior remission duration ≥24 months and attainment of complete remission or undetectable measurable residual disease on venetoclax were associated with longer PFS after BTKi salvage (P = .044 and P = .029, respectively). BTKi therapy achieved durable benefit for patients with the BCL2 Gly101Val venetoclax resistance mutation (estimated 24-month PFS, 69%). At a median survivor follow-up of 33 months (range, 2-53), 11 patients remained on BTKi and 12 had stopped therapy because of disease progression (n = 8) or toxicity (n = 4). Our findings indicate that BTKi therapy can provide durable CLL control after disease progression on venetoclax.
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http://dx.doi.org/10.1182/blood.2020004782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316215PMC
June 2020

Abscopal Regressions of Lymphoma After Involved-Site Radiation Therapy Confirmed by Positron Emission Tomography.

Int J Radiat Oncol Biol Phys 2020 09 7;108(1):204-211. Epub 2020 Mar 7.

The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; Department of Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.

Purpose: Patients with abscopal regressions of lymphoma after palliative involved-site radiation therapy (ISRT), detected on sequential F-fluorodeoxyglucose positron emission tomography (FDG-PET), were identified by audit. A retrospective analysis was subsequently conducted to estimate the frequency of abscopal regression in follicular lymphoma (FL).

Methods And Materials: Potential cases were identified at multidisciplinary lymphoma meetings and fulfilled these criteria: (1) palliative ISRT given for histologically confirmed lymphoma, (2) >2 lesions visualized on FDG-PET, (3) >1 unirradiated lesion(s) outside ISRT volume, (4) no systemic therapy delivered <2 months before radiation therapy or between radiation therapy and response assessment, (5) complete metabolic response (CMR) in ≥1 unirradiated lesions detected on serial FDG-PET/CT. All ISRT patients with FL treated in 2016 to 2018 were systematically reviewed.

Results: Seven cases of abscopal regression were identified, including 4 patients with FL. In all cases, a CMR was apparent both within the ISRT volume and in ≥1 unirradiated lesions. One patient each was identified with mantle cell lymphoma (4 Gy in 2 fractions), Hodgkin lymphoma (20 Gy in 3 fractions, then 30 Gy in 15 fractions to the same volume), and Richter transformation of chronic lymphatic leukemia (30 Gy in 10 fractions). The 4 patients with FL received either 4 Gy in 2 fractions (n = 3) or 4 Gy followed 8 months later by 30 Gy in 15 fractions (n = 1). From 2016 to 2018, 29 courses of ISRT were prescribed for multifocal FL, after which 4 of 29 (13.8%) abscopal responses were detected, including in 4 of 9 (44.4%) patients with serial PET scans. Two patients, with relapsed disease after initial abscopal responses, experienced durable CMRs with immunotherapies.

Conclusions: In 4 of 7 cases, PET-detected abscopal regression of lymphoma occurred after 4 Gy, in 2 of 7 cases after repeated ISRT to the same volume, and in 2 of 7 was associated with subsequent complete response to immunotherapy, consistent with an immune basis for the abscopal effect. Abscopal regressions in FL appear to be more common than previously suspected.
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http://dx.doi.org/10.1016/j.ijrobp.2020.02.636DOI Listing
September 2020

Undetectable peripheral blood MRD should be the goal of venetoclax in CLL, but attainment plateaus after 24 months.

Blood Adv 2020 01;4(1):165-173

Department of Clinical Haematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, Australia.

The highly selective BCL2 inhibitor venetoclax achieves deep responses in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), including undetectable minimal residual disease (uMRD). We retrospectively reviewed 62 patients with CLL treated with venetoclax to investigate the performance of peripheral blood (PB) compared with bone marrow (BM) assessment of MRD; the kinetics, clinicopathological associations, and longer-term outcomes of uMRD attainment and recrudescence; and the ability of venetoclax dose escalation to deepen responses. Among 16 patients who achieved PB uMRD and had contemporaneous BM assessments, 13 (81%) had confirmed BM uMRD, and patients with PB uMRD had outcomes at least as favorable as those with BM uMRD for time to progression, overall survival, and MRD recrudescence. Excluding 2 patients lacking earlier assessment, the median time to PB uMRD was 18 (range, 5-26) months, with 90% of instances achieved by 24 months. There was no new PB uMRD attainment after 24 months without treatment intensification. The dominant association with earlier attainment of uMRD was concurrent rituximab (P = .012). Complex karyotype was associated with inferior uMRD attainment after 12 months of therapy (P = .015), and patients attaining uMRD whose disease harbored TP53 abnormalities demonstrated a trend toward earlier recrudescence (P = .089). Of patients who received venetoclax dose escalations, 4 (27%) of 15 achieved improvements in response. For patients with R/R CLL receiving venetoclax, PB uMRD commonly correlates with BM uMRD and is associated with a comparable longer-term prognosis. Concurrent rituximab augments uMRD attainment, but dose escalation and further treatment beyond 24 months infrequently deepen responses.
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http://dx.doi.org/10.1182/bloodadvances.2019000864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960473PMC
January 2020
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