Publications by authors named "Bruce D Cheson"

325 Publications

Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1ε inhibitor, in relapsed/refractory lymphoid malignancies.

Blood Adv 2021 Sep 21. Epub 2021 Sep 21.

TG Therapeutics, Inc., New York, New York, United States.

Phosphoinositide 3-kinase-delta (PI3Kδ) inhibitors are active in lymphoid malignancies, though associated toxicities can limit their use. Umbralisib is a dual inhibitor of PI3Kδ and casein kinase-1ε (CK1ε). This study analyzed integrated comprehensive toxicity data from 4 open-label, phase 1 and 2 studies that included 371 adult patients (median age, 67 years) with relapsed/refractory non-Hodgkin lymphoma (follicular lymphoma [n = 147]; marginal zone lymphoma [n = 82]; diffuse large B-cell lymphoma/mantle cell lymphoma [n = 74]; chronic lymphocytic leukemia [n = 43]; and other [n = 25]) who were treated with recommended phase 2 dose of umbralisib 800 mg or higher once daily. At data cutoff, median duration of umbralisib treatment was 5.9 months (range, 0.1-75.1), and 107 patients (28.8%) received umbralisib for ≥12 months. Any-grade treatment-emergent adverse events (TEAEs) occurred in 366/371 patients (98.7%), with the most frequent being diarrhea (52.3%), nausea (41.5%), and fatigue (31.8%). Grade ≥3 TEAEs occurred in 189/371 of patients (50.9%), including neutropenia (11.3%), diarrhea (7.3%), and increased aminotransferases (5.7%). Treatment-emergent serious AEs occurred in 95/371 patients (25.6%). AEs of special interest were limited and included pneumonia (29/371 [7.8%]), noninfectious colitis (9/371 [2.4%]), and pneumonitis (4/371 [1.1%]). AEs led to discontinuation of umbralisib in 51 patients (13.7%). Four patients (1.1%) died due to AEs, none of which were deemed related to umbralisib. No cumulative toxicities were reported. The favorable long-term tolerability profile and low rates of immune-mediated toxicities support the potential use of umbralisib for the benefit of a broad population of patients with lymphoid malignancies.
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http://dx.doi.org/10.1182/bloodadvances.2021005132DOI Listing
September 2021

The evolving use of minimal residual disease (MRD) assessment in chronic lymphocytic leukemia: Q&A.

Clin Adv Hematol Oncol 2020 Jun;18 Suppl 10(6):15-17

CLL Program, Memorial Sloan Kettering Cancer Center, New York, New York.

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June 2020

A clinical perspective on minimal residual disease (MRD) assessment in chronic lymphocytic leukemia.

Authors:
Bruce D Cheson

Clin Adv Hematol Oncol 2020 Jun;18 Suppl 10(6):3-7

Lymphoma Research Foundation, New York, New York.

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June 2020

The evolving use of minimal residual disease (MRD) assessment in chronic lymphocytic leukemia.

Clin Adv Hematol Oncol 2020 Jun;18 Suppl 10(6):1-20

CLL Program, Memorial Sloan Kettering Cancer Center, New York, New York.

The treatment of chronic lymphocytic leukemia (CLL) has changed remarkably throughout the past decade, with patients achieving deeper and more durable responses. Importantly, this clinical activity has been found to translate to prolonged survival. With some treatments, these responses are now allowing patients to stop therapy after 1 or 2 years, a concept referred to as "fixed duration." However, not all patients experience these outcomes. How to determine which patients can safely stop treatment remains unclear. Minimal residual disease (MRD) is emerging as a prognostic biomarker. In CLL, undetectable MRD has been shown to correlate with prolonged progression-free survival and, in some cases, overall survival. The incorporation of MRD status into clinical decision-making is not yet widely done, primarily based on the lack of prospective clinical trial data. As the endpoint of MRD status becomes more common in clinical trials of CLL, the role in the clinical setting will become more clear. Furthermore, prognostic models will help to determine the utility of MRD as a surrogate endpoint in clinical studies. This monograph examines clinical trial data regarding the role of MRD in CLL, and provides recommendations on how to incorporate MRD assessment into clinical management.
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June 2020

Diffuse large B-cell lymphoma: new targets and novel therapies.

Blood Cancer J 2021 04 5;11(4):68. Epub 2021 Apr 5.

Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Newer, more effective and non-cytotoxic therapies are an unmet need for patients with diffuse large B-cell lymphoma (DLBCL) and other B-cell malignancies. Recently approved agents include polatuzumab with bendamustine and rituximab, selinexor, and tafasitamab plus lenalidomide. Three CAR-T cell products are currently approved by the FDA, with others in clinical trials. Additional agents in development include bispecific antibodies and antibody drug conjugates. Combinations of targeted therapies should lead to further improvement in the outcome of patients with B-cell malignancies.
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http://dx.doi.org/10.1038/s41408-021-00456-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021545PMC
April 2021

Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia.

Haematologica 2021 Sep 1;106(9):2364-2373. Epub 2021 Sep 1.

UC San Diego Moores Cancer Center, San Diego, CA.

B-cell receptor signalling inhibition by targeting Bruton tyrosine kinase (BTK) is effective in treating chronic lymphocytic leukemia (CLL). The BTK inhibitor ibrutinib may be intolerable for some patients. Acalabrutinib is a more selective BTK inhibitor that may be better tolerated by patients who are intolerant to ibrutinib. A phase 2 study of acalabrutinib was conducted in patients with relapsed/refractory CLL who were ibrutinib-intolerant and had continued disease activity. Intolerance was defined as having discontinued ibrutinib due to persistent grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs despite dose modification/interruption. Patients received oral acalabrutinib 100 mg twice daily until disease progression or intolerance. Sixty patients were treated. Overall response rate to acalabrutinib was 73% and three patients (5%) achieved complete remission. At median follow-up of 35 months, the median progressionfree and overall survival were not reached; 24-month estimates were 72% and 81%, respectively. The most frequent AEs with acalabrutinib were diarrhea (53%), headache (42%), contusion (40%), dizziness (33%), upper respiratory tract infection (33%), and cough (30%). Most common reasons for acalabrutinib discontinuation were progressive disease (23%) and AEs (17%). Most patients with baseline samples (49/52; 94%) and all with on-treatment samples (3/3; 100%) had no detectable BTK and/or PLCG2 mutations. Acalabrutinib is effective and tolerable in most patients with relapsed/refractory CLL who are intolerant of ibrutinib. Acalabrutinib may be useful for patients who may benefit from BTK inhibitor therapy but are ibrutinib intolerant.
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http://dx.doi.org/10.3324/haematol.2020.272500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409022PMC
September 2021

Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma.

J Clin Oncol 2021 05 8;39(15):1609-1618. Epub 2021 Mar 8.

IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia "Seràgnoli," Bologna, Italy.

Purpose: Phosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors. This phase IIb trial was designed to evaluate the efficacy and safety of umbralisib in patients with R/R iNHL.

Patients And Methods: In this multicohort, open-label, phase IIb study, 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, or SLL) unresponsive to prior treatments (≥ 1 MZL; ≥ 2 FL/SLL), including ≥ 1 anti-CD20-based therapy, were administered umbralisib 800 mg orally once daily until disease progression, unacceptable toxicity, or study withdrawal. Primary end point is overall response rate; secondary end points include time to response, duration of response, progression-free survival, and safety.

Results: The median follow-up is 27.7 months (efficacy) and 21.4 months (safety). The overall response rate was 47.1%, and tumor reduction occurred in 86.4% of patients. The median time to response was 2.7-4.6 months. The median duration of response was not reached for MZL, 11.1 months for FL, and 18.3 months for SLL. Median progression-free survival was not reached for MZL, 10.6 months for FL, and 20.9 months for SLL. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). A total of 31 patients (14.9%) discontinued because of a treatment-related adverse event. Grade ≥ 3 TEAEs reported in ≥ 10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥ 3) occurred in 6.7%/7.2% of patients.

Conclusion: Umbralisib achieved meaningful clinical activity in heavily pretreated patients with iNHL. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event-related discontinuations.
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http://dx.doi.org/10.1200/JCO.20.03433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148421PMC
May 2021

Copanlisib in the Treatment of Relapsed Follicular Lymphoma: Utility and Experience from the Clinic.

Cancer Manag Res 2021 25;13:677-692. Epub 2021 Jan 25.

Scientific Advisory Board, Lymphoma Research Foundation, Washington, DC, USA.

The phosphatidylinositol-3-kinase (PI3K) pathway is ubiquitous to multiple cellular processes and is intricately implicated in lymphomagenesis. The development of PI3K inhibitors has broadened treatment options for relapsed and/or refractory follicular lymphoma (FL) and currently three PI3K inhibitors have been approved in the third-line setting for FL, including idelalisib (oral), duvelisib (oral), and copanlisib (intravenous), with other agents under investigation. In this review, we discuss the clinical advance of copanlisib through preclinical to Phase III trials, its unique cellular targets and side effect profile that have poised it as a safer and equally efficacious option when compared to the older-generation oral PI3Kis, and its utility to the clinician as part of the therapeutic armamentarium for relapsed and/or refractory FL.
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http://dx.doi.org/10.2147/CMAR.S201024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846853PMC
January 2021

Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy.

Blood 2021 May;137(20):2817-2826

Duke University Medical Center, Durham, NC.

Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase δ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression-free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48-96), with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1-not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki-intolerant CLL population can result in durable well-tolerated responses.
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http://dx.doi.org/10.1182/blood.2020007376DOI Listing
May 2021

Biomarkers for Risk Stratification in Patients With Previously Untreated Follicular Lymphoma Receiving Anti-CD20-based Biological Therapy.

Am J Surg Pathol 2021 03;45(3):384-393

Cleveland Clinic, Cleveland, OH.

Follicular lymphoma (FL) is an indolent B-cell neoplasm of germinal center origin. Standard treatment regimens consist of anti-CD20 therapy with or without chemotherapy. While high response rates to initial therapy are common, patients ultimately relapse or have progressive disease. Clinical risk factors such as the Follicular Lymphoma International Prognostic Index (FLIPI) have been identified, but there is a need for prognostic and predictive biomarkers. We studied markers of lymphoma cells and tumor microenvironment by immunohistochemistry in tissue samples from patients enrolled in 1 of 4 phase 2 trials of anti-CD20-based biological therapy for previously untreated grades 1 to 2 or 3A FL. Results were correlated with progression-free survival (PFS) and PFS status at 24 months. The 4 trials included 238 patients (51.1% male, median age: 55 y) with stage III, IV, or bulky stage II disease. By FLIPI, 24.6% had low-risk, 56.8% had intermediate-risk, and 18.6% had high-risk disease. The outcome differed significantly for patients treated with lenalidomide and rituximab (CALGB 50803) compared with the other 3 trials (median: PFS not reached vs. 3.0 y, hazard ratio=3.47, 95% confidence interval: 2.11-5.72); therefore, data were stratified by clinical trial (CALGB 50803 vs. all others) and adjusted for FLIPI risk group. Among 154 patients with available tissue, interfollicular BCL6 positivity, interfollicular CD10 positivity, and elevated Ki67 proliferation index ≥30% within neoplastic follicles were each associated with inferior PFS and a high risk of the early event by PFS status at 24 months. We identify promising biomarkers for FL risk stratification that warrant further validation in phase 3 trials.
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http://dx.doi.org/10.1097/PAS.0000000000001609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878306PMC
March 2021

Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trial.

Lancet Haematol 2020 Nov 1;7(11):e808-e815. Epub 2020 Oct 1.

Division of Medical Oncology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN, USA.

Background: Hodgkin lymphoma is potentially curable. However, 15-35% of older patients (ie, >60 years) have a lower response rate, worse survival outcomes, and greater toxicity than younger patients. Brentuximab vedotin and nivolumab exhibit activity in patients with relapsed or refractory Hodgkin lymphoma. We therefore aimed to evaluate the safety and efficacy of brentuximab vedotin and nivolumab in untreated older patients with Hodgkin lymphoma or in younger patients considered unsuitable for standard ABVD (ie, doxorubicin, bleomycin, vinblastine, and dacarbazine) therapy.

Methods: We did a multicentre, single-arm, phase 2 trial at eight cancer centres in the USA. Previously untreated patients with classic Hodgkin lymphoma were eligible for study enrolment if they were 60 years or older, or younger than 60 years but considered unsuitable for standard chemotherapy because of a cardiac ejection fraction of less than 50%, pulmonary diffusion capacity of less than 80%, or a creatinine clearance of 30 mL/min or more but less than 60 mL/min, or those who refused chemotherapy. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients received brentuximab vedotin at 1·8 mg/kg (dose cap at 180 mg) and nivolumab at 3 mg/kg both intravenously every 21 days for 8 cycles. The primary endpoint was the overall response, defined as a partial metabolic response or complete metabolic response at the end of 8 cycles of treatment. A per protocol analysis was done including all patients who received treatment in the activity and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02758717.

Findings: Between May 13, 2016, and Jan 30, 2019, the study accrued 46 patients. The median age was 71·5 years (IQR 64-77), with two (4%) of 46 patients younger than 60 years. Median follow-up was 21·2 months (IQR 15·6-29·9), and 35 (76%) of 46 patients completed all 8 cycles of therapy. At the interim analysis on Oct 11, 2019, the first 25 evaluable patients had an overall response rate of 64% ([95% CI 43-82] 16 of 25 patients; 13 [52%] had a complete metabolic response and three [12%] had a partial metabolic response). The trial was closed to accrual on Oct 14, 2019, after the interim analysis failed to meet the predefined criteria. In all 46 evaluable patients, 22 (48%) patients achieved a complete metabolic response and six (13%) achieved a partial metabolic response (overall response rate 61% [95% CI 45-75]). 14 (30%) of 46 patients had 16 dose adjustments, primarily due to neurotoxicity. 22 (48%) of 46 patients had peripheral neuropathy (five [11%] patients had grade 3 peripheral neuropathy). Grade 4 adverse events included increased aminotranferases (one [2%] of 46), increased lipase or amylase (two [4%]), and pancreatitis (one [2%]). One (2%) patient died from cardiac arrest, possibly treatment related.

Interpretation: Although the trial did not meet the prespecified activity criteria, brentuximab vedotin plus nivolumab is active in older patients with previously untreated Hodgkin lymphoma with comorbidities. The regimen was also well tolerated in the majority of patients in this older population. Future trials should be based on optimising the dose and schedule, perhaps combined with other targeted agents that might permit chemotherapy-free strategies in older patients with Hodgkin lymphoma.

Funding: Seattle Genetics and Bristol Myers Squibb.
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http://dx.doi.org/10.1016/S2352-3026(20)30275-1DOI Listing
November 2020

Copanlisib in the treatment of non-Hodgkin lymphoma.

Future Oncol 2020 Sep 13;16(26):1947-1955. Epub 2020 Jul 13.

Lymphoma Research Foundation, NY 10005, USA.

B-cell receptor signaling is important in the pathogenesis of non-Hodgkin lymphoma. The PI3K pathway is activated by B-cell receptor signaling. Recently, several PI3K inhibitors have been in development for the treatment of indolent non-Hodgkin lymphomas. Copanlisib is a PI3Kα and PI3Kδ inhibitor that has been approved for its use as third-line therapy in the treatment of relapsed or refractory follicular lymphoma. The two other PI3k inhibitors approved by the US FDA in this setting are idelalisib and duvelisib. In this review, we compare the efficacy and adverse event profile of these different PI3K inhibitors and discuss the advantages and challenges of using copanlisib along with a guide on managing routinely encountered adverse events in the clinics.
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http://dx.doi.org/10.2217/fon-2020-0195DOI Listing
September 2020

Successful Treatment of Ocular Chronic Lymphocytic Leukemia with Ibrutinib: Case Report and Review of the Literature.

Leuk Res Rep 2020 20;14:100200. Epub 2020 Apr 20.

Department of Hematology and Oncology, MedStar Georgetown University Hospital, Washington, DC.

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http://dx.doi.org/10.1016/j.lrr.2020.100200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265052PMC
April 2020

Long-Term Follow-up of CALGB (Alliance) 100001: Autologous Followed by Nonmyeloablative Allogeneic Transplant for Multiple Myeloma.

Biol Blood Marrow Transplant 2020 08 20;26(8):1414-1424. Epub 2020 Apr 20.

Roswell Park Comprehensive Cancer Center, Buffalo, New York.

CALGB (Alliance) 100001 was a phase II study evaluating autologous stem cell transplant (ASCT) followed by nonmyeloablative allogeneic stem cell transplant (alloSCT) in patients with multiple myeloma who had received no more than 18 months of prior therapy and had experienced no more than 1 prior progression event. Conditioning for ASCT was with high-dose melphalan (200 mg/m). The alloSCT reduced-intensity conditioning (RIC) regimen consisted of fludarabine (30 mg/m/d i.v. on days -7 through -3) and cyclophosphamide (1 g/m/d i.v. on days -4 through -3). The primary objective was to determine the 6-month post-alloSCT treatment-related mortality (TRM) rate. Additional objectives included determining the proportion of patients who could complete this tandem ASCT-alloSCT approach in a cooperative group setting, overall response rates, rates of donor chimerism, rates of graft-versus-host disease (GVHD), disease-free survival, and overall survival (OS). Sixty patients were enrolled, of whom 57 (95%) completed ASCT and 49 (82%) completed tandem ASCT-alloSCT. The TRM rate was 2% (1/49; 90% confidence interval, 0.10% to 9.3%). Moderate to severe (grades 2 to 3) acute GVHD was observed in 13 of 49 alloSCT patients (27%). One patient died due to GVHD within 9 months of alloSCT. Twenty-seven of the 49 patients (55%) who underwent alloSCT reported chronic GVHD as either limited (15/49; 31%) or extensive (12/49; 24%) in the first year post-alloSCT and prior to the start of nonprotocol therapy for progressive disease. With a median follow-up for survival of 11 years, the median OS time is 6.6 years and the median time to disease progression is 3.6 years. Similar to other studies, this study confirmed that tandem ASCT/alloSCT is associated with durable disease control in a subset of patients. This study demonstrated the feasibility of performing tandem ASCT/alloSCT in a cooperative group setting and determined that a fludarabine/cyclophosphamide RIC regimen is associated with a very low TRM rate.
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http://dx.doi.org/10.1016/j.bbmt.2020.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371544PMC
August 2020

Management of Adverse Events From the Combination of Rituximab and Lenalidomide in the Treatment of Patients With Follicular and Low-Grade Non-Hodgkin Lymphoma.

Clin Lymphoma Myeloma Leuk 2020 09 20;20(9):563-571. Epub 2020 Mar 20.

Department of Medicine, Weill Medical College of Cornell University, New York, NY.

Frontline treatment for patients with indolent non-Hodgkin lymphoma often includes immunochemotherapy. Although the disease of most patients responds to initial treatment, relapse is common. Recent results from the phase 3 Augment trial showed that combining rituximab with the immunomodulatory drug lenalidomide (R) significantly improved efficacy over rituximab monotherapy in patients with recurrent non-Hodgkin lymphoma. As a result of these data, R was approved in the US (Food and Drug Administration) and Japan (Pharmaceuticals and Medical Devices Agency) for previously treated adult patients with follicular and marginal zone lymphoma; and by the European Medicine Agency and the Swiss Agency for Therapeutic Products (Swissmedic) for previously treated adult patients with follicular lymphoma. R has also been studied as initial treatment, where results have been comparable, but not superior, to chemoimmunotherapy. The resulting expanded use of R reinforces the need for a detailed review of its safety profile and management, as presented here. Tolerability of R has been consistent among trials, with most adverse events (AEs) being predictable and manageable. Hematologic AEs, particularly grade 3/4 neutropenia; low-grade cutaneous reactions, such as rash; and gastrointestinal AEs represent the most common AEs associated with R. The general R safety profile and optimal strategies for AE management are discussed.
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http://dx.doi.org/10.1016/j.clml.2020.03.009DOI Listing
September 2020

Predicting the future for DLBCL.

Authors:
Bruce D Cheson

Blood 2020 04;135(16):1308-1309

Lymphoma Research Foundation.

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http://dx.doi.org/10.1182/blood.2020005002DOI Listing
April 2020

Prognostic value of interim FDG-PET in diffuse large cell lymphoma: results from the CALGB 50303 Clinical Trial.

Blood 2020 06;135(25):2224-2234

Department Medicine, Washington University School of Medicine, St. Louis, MO.

As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial fluorodeoxyglucose positron emission tomography (FDG-PET) at baseline, after 2 cycles of chemotherapy (interim PET [i-PET]), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by 2 imaging experts, using the visual Deauville 5-point scale (5-PS), and by calculating percent change in FDG uptake (change in standardized uptake value [ΔSUV]). Visual scores of 1 through 3 and ΔSUV ≥66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (hazard ratio [HR] = 0.99; 95% confidence interval [CI], 0.97-1.00; P = .02) and overall survival (OS) (HR, 0.98; 95% CI, 0.97-0.99; P = .03). ΔSUV ≥66% was predictive of OS (HR, 0.31; 95% CI, 0.11-0.85; P = .02) but not PFS (HR, 0.47; 95% CI, 0.19-1.13; P = .09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL, although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00118209.
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http://dx.doi.org/10.1182/blood.2019003277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316220PMC
June 2020

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy.

Clin Cancer Res 2020 07 20;26(14):3589-3596. Epub 2020 Mar 20.

Division of Malignant Hematology, Moffitt Cancer Center, Tampa, Florida.

Purpose: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.

Experimental Design: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].

Results: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve ( = 130), and 81% were idelalisib naïve ( = 263). ORR to BTKi was 84% ( = 44) in BTKi-naïve patients versus 54% ( = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.

Conclusions: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3815DOI Listing
July 2020

Bortezomib consolidation or maintenance following immunochemotherapy and autologous stem cell transplantation for mantle cell lymphoma: CALGB/Alliance 50403.

Am J Hematol 2020 06 6;95(6):583-593. Epub 2020 Apr 6.

Hematology-Oncology, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.

Immunochemotherapy followed by autologous transplant (ASCT) in CALGB/Alliance 59909 achieved a median progression-free survival (PFS) in mantle cell lymphoma (MCL) of 5 years, but late recurrences occurred. We evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM) to this regimen in CALGB/Alliance 50403, a randomized phase II trial. Following augmented-dose R-CHOP/ methotrexate, high-dose cytarabine-based stem cell mobilization, cyclophosphamide/carmustine/etoposide (CBV) autotransplant, and rituximab, patients were randomized to BC (1.3 mg/m IV days 1, 4, 8, 11 of a 3-week cycle for four cycles) or BM (1.6 mg/m IV once weekly × 4 every 8 weeks for 18 months) beginning day 90. The primary endpoint was PFS, measured from randomization for each arm. Proliferation signature, Ki67, and postinduction minimal residual disease (MRD) in bone marrow were assessed. Of 151 patients enrolled; 118 (80%) underwent ASCT, and 102 (68%) were randomized. Both arms met the primary endpoint, with median PFS significantly greater than 4 years (P < .001). The 8-year PFS estimates in the BC and BM arms were 54.1% (95% CI 40.9%-71.5%) and 64.4% (95% 51.8%-79.0%), respectively. Progression-free survival was significantly longer for transplanted patients on 50403 compared with those on 59909. Both the PFS and OS were significantly better for those who were MRD-negative post-induction. The high risk proliferation signature was associated with adverse outcome. Both BM and BC were efficacious and tolerable, although toxicity was significant. The comparison between studies 50403 and 59909 with long-term follow up suggests a PFS benefit from the addition of BC or BM post- transplant.
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http://dx.doi.org/10.1002/ajh.25783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486983PMC
June 2020

Acalabrutinib monotherapy in patients with Waldenström macroglobulinemia: a single-arm, multicentre, phase 2 study.

Lancet Haematol 2020 Feb 19;7(2):e112-e121. Epub 2019 Dec 19.

Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA.

Background: Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia.

Methods: This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling.

Findings: Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0-29·7), 13 (93% [95% CI 66-100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86-98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3-4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3-4 atrial fibrillation occurred in one (1%) patient and grade 3-4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma).

Interpretation: This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies.

Funding: Acerta Pharma.
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http://dx.doi.org/10.1016/S2352-3026(19)30210-8DOI Listing
February 2020

Targeted Therapies in Chronic Lymphocytic Leukemia: Is 2 (or 3) Better Than 1?

Cancer J 2019 Nov/Dec;25(6):449-454

Division of Hematology-Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC.

Small molecule inhibitors, including B-cell receptor antagonists and B-cell lymphoma - 2 inhibitors, have revolutionized the treatment of chronic lymphocytic leukemia (CLL). These agents have improved outcomes for patients of all prognostic backgrounds, thus securing their role in the frontline setting. Impressive activity has been demonstrated both with monotherapy and in combination with other targeted therapeutics. The most important remaining question is whether to administer small molecule inhibitors in a sequential fashion or in combination with each other and/or anti-CD20-directed therapy. Together, a number of retrospective and prospective clinical trials have provided insight into patient outcomes with different sequencing and combination strategies. While rituximab does not appear to provide significant additional benefit to ibrutinib, the incorporation of venetoclax appears to enable a deeper response and allow for a shorter duration of therapy. How durable of a response this produces and whether patients can be effectively retreated with venetoclax remain unclear. As various targeted therapy doublets and triplets are explored, it is important to investigate whether they produce significant long-term benefits over monotherapy and whether these approaches are appropriate for all patients.
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http://dx.doi.org/10.1097/PPO.0000000000000410DOI Listing
August 2020

Introduction by the Guest Editor: Staying Ahead of the Rapidly Evolving World of Chronic Lymphocytic Leukemia.

Authors:
Bruce D Cheson

Cancer J 2019 Nov/Dec;25(6):373

From the Georgetown University Hospital, Lombardi Comprehensive Cancer Center, 3800 Reservoir Rd, N.W. Washington, DC 20007.

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http://dx.doi.org/10.1097/PPO.0000000000000415DOI Listing
August 2020

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia.

Br J Haematol 2020 03 4;188(6):918-923. Epub 2019 Nov 4.

Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.
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http://dx.doi.org/10.1111/bjh.16271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528953PMC
March 2020

MRD response in relapsed/refractory FL after obinutuzumab plus bendamustine or bendamustine alone in the GADOLIN trial.

Leukemia 2020 02 28;34(2):522-532. Epub 2019 Aug 28.

Georgetown University Hospital, Washington, DC, USA.

We report assessment of minimal residual disease (MRD) status and its association with outcome in rituximab-refractory follicular lymphoma (FL) in the randomized GADOLIN trial (NCT01059630). Patients received obinutuzumab (G) plus bendamustine (Benda) induction followed by G maintenance, or Benda induction alone. Patients with a clonal marker (t[14;18] translocation and/or immunoglobulin heavy or light chain rearrangement) detected at study screening were assessed for MRD at mid-induction (MI), end of induction (EOI), and every 6-24 months post-EOI/discontinuation by real-time quantitative PCR. At MI, 41/52 (79%) patients receiving G-Benda were MRD-negative vs. 17/36 (47%) patients receiving Benda alone (p = 0.0029). At EOI, 54/63 (86%) patients receiving G-Benda were MRD-negative vs. 30/55 (55%) receiving Benda alone (p = 0.0002). MRD-negative patients at EOI had improved progression-free survival (HR, 0.33, 95% CI, 0.19-0.56, p < 0.0001) and overall survival (HR, 0.39, 95% CI, 0.19-0.78, p = 0.008) vs. MRD-positive patients, and maintained their MRD-negative status for longer if they received G maintenance than if they did not. These results suggest that the addition of G to Benda-based treatment during induction can significantly contribute to the speed and depth of response, and G maintenance in MRD-negative patients potentially delays lymphoma regrowth.
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http://dx.doi.org/10.1038/s41375-019-0559-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214251PMC
February 2020

Targeting Biology in Non-Hodgkin Lymphoma.

Hematol Oncol Clin North Am 2019 08 7;33(4):727-738. Epub 2019 May 7.

Lombardi Comprehensive Cancer Center, Medstar Georgetown University Hospital, Lombardi Comprehensive Cancer Center Podium A, 3800 Reservoir Road Northwest, Washington, DC 20007, USA. Electronic address:

Chemotherapy nonspecifically affects all cells undergoing DNA replication and has severe side effects. Understanding of the biology of non-Hodgkin lymphomas has led to development of drugs that target specific lymphoma cell functions and tumor microenvironment. Targeted agents used in combination with chemotherapy pave the way to a chemotherapy-free world. These drugs target multiple oncogenic pathways and modulate the immune system, with better outcomes. Such combinations should be administered only in clinical trials. Incorporating studies of the biology and genetics of these tumors into therapeutic studies may lead to a chemotherapy-free world with improved outcomes and reduced toxicities.
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http://dx.doi.org/10.1016/j.hoc.2019.03.006DOI Listing
August 2019

Randomized trial of ofatumumab and bendamustine versus ofatumumab, bendamustine, and bortezomib in previously untreated patients with high-risk follicular lymphoma: CALGB 50904 (Alliance).

Cancer 2019 10 7;125(19):3378-3389. Epub 2019 Jun 7.

Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.

Background: This multicenter, randomized phase 2 trial evaluated complete responses (CRs), efficacy, and safety with ofatumumab and bendamustine and with ofatumumab, bendamustine, and bortezomib in patients with untreated, high-risk follicular lymphoma (FL).

Methods: Patients with grade 1 to 3a FL and either a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 with 1 lymph node >6 cm or an FLIPI score of 3 to 5 were randomized to arm A (ofatumumab, bendamustine, and maintenance ofatumumab) or to arm B (ofatumumab, bendamustine, bortezomib, and maintenance ofatumumab and bortezomib).

Results: One hundred twenty-eight patients (66 in arm A and 62 in arm B) received treatment. The median age was 61 years, and 61% had disease >6 cm; 29% had an FLIPI score of 2, and 71% had an FLIPI score of 3 to 5. In arm A, 86% completed induction, and 64% completed maintenance. In arm B, 66% and 52% completed induction and maintenance, respectively. Dose modifications were required in 65% and 89% in arms A and B, respectively. Clinically significant grade 3 to 4 toxicities included neutropenia (A, 36%; B, 31%), nausea/vomiting (A, 0%; B, 8%), diarrhea (A, 5%; B, 11%), and sensory neuropathy (A, 0%; B, 5%). The estimated CR rates were 62% (95% confidence interval [CI], 50%-74%) and 60% (95% CI, 47%-72%) in arms A and B, respectively (P = .68). With a median follow-up of 3.3 years, the estimated 2-year progression-free survival (PFS) and overall survival (OS) rates were 80% and 97%, respectively, for arm A and 76% and 91%, respectively, for arm B.

Conclusions: The CR rates, PFS, and OS were not improved with the addition of bortezomib to ofatumumab and bendamustine in patients with high-risk FL. Although grade 3 to 4 toxicities were similar, more patients treated with bortezomib required dose modifications and early discontinuation.
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http://dx.doi.org/10.1002/cncr.32289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744328PMC
October 2019

A retrospective comparison of venetoclax alone or in combination with an anti-CD20 monoclonal antibody in R/R CLL.

Blood Adv 2019 05;3(10):1568-1573

Swedish Cancer Center, Seattle, WA.

Venetoclax (VEN) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (VENmono) or in combination with rituximab. Whether VEN plus anti-CD20 (VENcombo) is superior to VENmono is unknown. We conducted a multicenter, retrospective cohort analysis comparing 321 CLL patients treated with VENmono vs VENcombo across the United States and the United Kingdom. We examined demographics, baseline characteristics, dosing, adverse events, response rates, and outcomes. The primary endpoints were progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier method, in patients treated with VENmono vs VENcombo. Univariate and bivariate analyses were performed with COX regression. Three hundred twenty-one CLL patients were included (3 median prior treatments, 78% prior ibrutinib). The overall response rates (ORRs) were similar (VENmono, 81% ORR, 34% complete remission [CR] vs VENcombo, 84% ORR, 32% CR). With a median follow-up of 13.4 months, no differences in PFS and OS were observed between the groups. In unadjusted analyses, the hazard ratios (HRs) for PFS and OS for VENmono vs VENcombo were HR 1.0 (95% confidence interval [CI], 0.6-1.8; = .7) and HR 1.2 (95% CI, 0.6-2.3; = .5), respectively. When adjusting for differences between the cohorts, the addition of an anti-CD20 antibody in combination with VEN did not impact PFS (HR, 1.0; 95% CI, 0.5-2.0; = .9) or OS (HR, 1.1; 95% CI, 0.4-2.6; = .8). We demonstrate comparable efficacy between VENmono and VENcombo in a heavily pretreated, high-risk, retrospective cohort, in terms of both response data and survival outcomes. Prospective studies are needed to validate these findings.
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http://dx.doi.org/10.1182/bloodadvances.2019000180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538868PMC
May 2019

Tumor Lysis, Adverse Events, and Dose Adjustments in 297 Venetoclax-Treated CLL Patients in Routine Clinical Practice.

Clin Cancer Res 2019 07 19;25(14):4264-4270. Epub 2019 Apr 19.

Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.

Purpose: Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.

Experimental Design: This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.

Results: The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated , 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose.

Conclusions: These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020996PMC
July 2019
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