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Chaitra Ujjani, 1 Anthony Mato, 2 Brian T Hill, 3 John N Allan, 4 Erick Lansigan, 5 Ryan Jacobs, 6 Hande Tuncer, 7 John Pagel, 8 Danielle Brander, 9 Bruce Cheson, 10 Paul Barr, 11 Lindsey E Roeker, 2 Jeffrey Pu, 12 Nirav N Shah, 13 Andre Goy, 14 Stephen J Schuster, 15 Nicole Lamanna, 16 Alison Sehgal, 17 Constantine S Tam, 18 Mazyar Shadman 1 1Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 2Division of Hematological Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA; 4Division of Hematology and Medical Oncology, New York Presbyterian & Weill Cornell, New York, NY, USA; 5Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA; 6Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Charlotte, NC, USA; 7Lowell General Hospital, Tufts Medical Center, Boston, MA, USA; 8Center for Blood Disorders and Stem Cell Transplantation, Swedish Cancer Institute, Seattle, WA, USA; 9Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC, USA; 10Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, USA; 11Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; 12Division of Hematology/Oncology, SUNY Upstate Medical University, Syracuse, NY, USA; 13Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 14John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA; 15Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 16Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA; 17University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 18Peter McCallum Cancer Centre, University of Melbourne, East Melbourne, VI, AustraliaCorrespondence: Chaitra UjjaniSeattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, 825 Eastlake Ave E, Mail Stop CE3-300, Seattle, WA, USATel +1 206-606-1955Fax +1 206-606-1130Email ujjani@uw.eduIntroduction: Recent randomized trials have demonstrated the efficacy of ibrutinib-based therapy in the treatment of patients with CLL. In Alliance A041202, a higher than expected number of unexplained deaths were reported with front-line ibrutinib in a patient population aged at least 65 years compared to ECOG 1912, which included patients up to 70 years of age.Methods: Therefore, we conducted a retrospective analysis to investigate whether ibrutinib was associated with a greater mortality in older patients outside of a clinical trial setting. This multicenter analysis was performed by investigators at 20 academic and community practices.Results: Amongst the 391 patients included, there was no correlation between age and response rate, PFS, or OS. However, there was a trend to higher rate of deaths in patients > 65-years-old (8.7% vs 3.8%, p=0.097), with an increased number of early deaths (13 vs 4, p=0.3).Conclusion: These data suggest greater intolerance, and possibly mortality, with ibrutinib in an older population. Patients should be educated regarding the potential complications related to ibrutinib and symptoms of concern to report.Keywords: CLL, ibrutinib, elderly

Catherine Lai,1 Adrese Michael Kandahari,1 Chaitra Ujjani2 1Lombardi Comprehensive Cancer Center, Medstar Georgetown University Hospital, Washington, DC, USA; 2Seattle Cancer Care Alliance, Fred Hutchinson CRC, University of Washington, Seattle, WA, USACorrespondence: Catherine LaiLombardi Comprehensive Cancer Center, Medstar Georgetown University Hospital, Washington, DC, USATel +1-202-444-3735Fax +1-202-444-0939Email Catherine.lai@gunet.georgetown.eduAbstract: The arrival of the CD30 directed antibody-drug conjugate, brentuximab vedotin (BV), has altered the approach to patients with classical Hodgkin lymphoma. Since initial approval in 2011, BV has been extensively studied in previously untreated and relapsed/refractory patients. Treatment indications for the antibody-drug conjugate have been expanded from the previously treated population to include maintenance therapy after autologous stem cell transplantation and recently, combination with chemotherapy in newly diagnosed advanced stage patients. This article will review the evolution of BV in classical Hodgkin lymphoma, detailing the studies that led to the approved indications and discussion of recent trials in combination with chemotherapy and immunotherapy.Keywords: antibody-drug conjugate, brentuximab vedotin, CD30, immunotherapy, classical Hodgkin lymphoma, novel therapies

Barbara Ma,1 Chaitra Ujjani2 1Department of Medicine, 2Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC, USA Abstract: Impressive progress has been made in recent decades for advanced-stage follicular lymphoma with the availability of anti-CD20 monoclonal antibodies, initially rituximab and more recently obinutuzumab. Obinutuzumab is a unique, third-generation, fully humanized glycoengineered IgG1 type II anti-CD20 monoclonal antibody. It has been shown to have increased antitumor activity compared to rituximab in preclinical studies, including whole-blood B-cell depletion assays, xenograft models, and primate models. This has spurred on the development of obinutuzumab through Phase I/II trials as monotherapy and in combination with chemotherapeutic agents and other targeted therapies. Its efficacy compared to rituximab and in rituximab-refractory disease has led to its continued development and eventual approval for the treatment of follicular lymphoma. Here in this review, we highlight the design and development of obinutuzumab in the treatment of advanced stage grade 1–3A follicular lymphoma and its future directions. Keywords: follicular lymphoma, obinutuzumab, anti-CD20 monoclonal antibody

Kruti Sheth Nair, Chaitra Ujjani Lombardi Comprehensive Cancer Center, Medstar Georgetown University Hospital, Washington, DC, USA Abstract: As the most prevalent form of adult leukemia, chronic lymphocytic leukemia (CLL) affects thousands of patients each year. Given the indolent nature of the disease, symptomatic patients frequently experience multiple relapses throughout their clinical course. Better therapeutic options are needed, particularly for the elderly population that characterizes the majority of affected patients. Bendamustine, a hybrid alkylating agent, has demonstrated remarkable activity in CLL in conjunction with a tolerable safety profile. Although historically used in relapsed and refractory disease, it has recently gained a role in the front-line setting, including younger, physically fit patients. Current investigatory efforts are focused on exploring the combination of bendamustine with novel therapies in CLL. Keywords: chronic lymphocytic leukemia, overall survival, aspartate aminotransferase, chlorambucil, bendamustine

PIRTOBRUTINIB IN COVALENT BTK-INHIBITOR PRE-TREATED MANTLE CELL LYMPHOMA: UPDATED RESULTS, SUBGROUP ANALYSIS FROM BRUIN WITH >3 YEARS FOLLOW-UP FROM START OF ENROLLMENT B Introduction: b Pirtobrutinib is a highly selective, non-covalent (reversible) BTK-inhibitor (BTKi). [Extracted from the article]

A PET/CT was performed after 8 cycles, and pts in CR were observed without further treatment. B Introduction: b Mosunetuzumab (mosun) is a CD3:CD20 bispecific antibody that has been FDA-approved for relapsed/refractory follicular lymphoma after two prior lines of therapy. Response-adapted mosunetuzumab for untreated follicular and marginal zone lymphomas: significant monotherapy activity seen in results of an interim efficacy analysis. [Extracted from the article]

Pts received a median of 1 prior therapy (range 1-8). B Background: b Ibrutinib (I) and venetoclax (V) have modest single-agent activity in relapsed/refractory follicular lymphoma (FL) (Gopal A, JCO 2018; Davids M, JCO 2017). Grade 3/4 adverse events (AE) included neutropenia (NTP) (21%), febrile NTP (14%), diarrhea (21%), nausea (14%), hypertension (14%), thrombocytopenia (7%), atrial fibrillation (7%), vomiting (7%), ALT/AST elevation (7%), COVID pneumonia (7%). [Extracted from the article]

The treatment of B-cell malignancies has been revolutionized by the availability of safe and effective monoclonal antibodies. The addition of rituximab to standard chemotherapy regimens prolongs the survival of patients with diffuse large B-cell lymphoma (DLBCL) and follicular non-Hodgkin lymphoma. Nevertheless, indolent and mantle cell lymphomas remain incurable, and 30% to 40% of patients with DLBCL still die from their disease. Much ongoing research has focused on optimizing monoclonal antibody use, integrating them into multiagent regimens, and developing newer antibodies. Attempts to improve on the efficacy of monoclonal antibody-based therapy have included altering the dosing schedule, optimizing patient selection, maintenance therapy, improving upon the rituximab molecule, radioimmunotherapy, as well as combinations with cytotoxic molecules and other novel agents. Preliminary data with a number of treatment regimens are promising in indolent and aggressive lymphomas. The eventual goal of targeted therapies is to individualize treatment to increase response and survival, while reducing treatment-related toxicity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. METHODS: We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. RESULTS: A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. CONCLUSIONS In this trial, pirtobrutinib showed efficacy in patients with heavily pr'etreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529). [ABSTRACT FROM AUTHOR]

Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms. [ABSTRACT FROM AUTHOR]

Abstract: Although Bruton tyrosine kinase inhibitors (BTKis) are generally well tolerated and less toxic than chemotherapy alternatives used to treat lymphoid malignancies, BTKis like ibrutinib have the potential to cause new or worsening hypertension (HTN). Little is known about the optimal treatment of BTKi-associated HTN. Randomly selected patients with lymphoid malignancies on a BTKi and antihypertensive drug(s) and with at least 3 months of follow-up data were sorted into 2 groups: those diagnosed with HTN before BTKi initiation (prior-HTN), and those diagnosed with HTN after BTKi initiation (de novo HTN). Generalized estimating equations assessed associations between time varying mean arterial pressures (MAPs) and individual anti-HTN drug categories. Of 196 patients included in the study, 118 had prior-HTN, and 78 developed de novo HTN. Statistically significant mean MAP reductions were observed in patients with prior-HTN who took β blockers (BBs) with hydrochlorothiazide (HCTZ), (-5.05 mmHg; 95% confidence interval [CI], 10.0 to -0.0596; P = .047), and patients diagnosed with de novo HTN who took either an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) with HCTZ (-5.47 mmHg; 95% CI, 10.9 to -0.001; P = .05). These regimens also correlated with the greatest percentages of normotensive MAPs. Treatment of HTN in patients taking a BTKi is challenging and may require multiple antihypertensives. Patients with prior-HTN appear to benefit from combination regimens with BBs and HCTZ, whereas patients with de novo HTN appear to benefit from ACEi/ARBs with HCTZ. These results should be confirmed in prospective studies., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent's toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

BTK inhibitors, Bcl-2 inhibitors, and other targeted therapies have significantly improved the outcomes of patients with chronic lymphocytic leukemia (CLL). With increased survivorship, monitoring disease and deciphering potential mechanisms of resistance to these agents are critical for devising effective treatment strategies. We used duplex sequencing, a technology that enables detection of mutations at ultra-low allelic frequencies, to identify mutations in five genes associated with drug resistance in CLL and followed their evolution in two patients who received multiple targeted therapies and ultimately developed disease progression on pirtobrutinib. In both patients we detected variants that expanded and reached significant cancer cell fractions (CCF). In patient R001, multiple known resistance mutations in both BTK and PLCG2 appeared following progression on zanubrutinib (BTK p.L528W, p.C481S; PLCG2 S707F, L845F, R665W, and D993H). In contrast, patient R002 developed multiple BTK mutations following acalabrutinib treatment, including known resistance mutations p.C481R, p.T474I and p.C481S. We found that pirtobrutinib was able to suppress, but not completely eradicate, BTK p.C481S mutations in both patients, but other resistance mutations such as mutations in PLCG2 and new BTK mutations increased while the patients were receiving pirtobrutinib. For example, BTK p.L528W in patient R001 increased in frequency more than 1,000-fold (from a CCF of 0.02% to 35%), and the CCF in p.T474I in patient R002 increased from 0.03% to 4.2% (more than 100-fold). Our data illuminate the evolutionary dynamics of resistant clones over the patients' disease course and under selective pressure from different targeted treatments.

The treatment landscape of chronic lymphocytic leukemia (CLL) has evolved considerably over the past decade due to the development of effective novel agents with varying mechanisms of action, including Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) inhibitors. Extrapolating upon the success of anti-CD20-directed chemoimmunotherapy, a dual-targeted approach has been explored in treatment-naive patients with CLL. Anti-CD20 monoclonal antibody combinations with BTK inhibitors as well as BCL2 inhibitors have demonstrated superiority over traditional cytotoxic chemoimmunotherapy regimens such as fludarabine, cyclophosphamide, and rituximab; bendamustine-rituximab; and obinutuzumab-chlorambucil. Impressive clinical benefit is seen in both younger and older patients, those with comorbidities, and, most importantly, those with poor prognostic features. Given this success, combinations of BTK inhibitors and venetoclax have been explored in clinical trials. These dual-targeted regimens provide remarkable efficacy while allowing for an all-oral approach and fixed duration of treatment. Current investigations under way are evaluating the utility of a triplet approach with the addition of obinutuzumab in comparison to a doublet approach., (Copyright © 2023 by The American Society of Hematology.)

Previous studies have demonstrated low rates of seroconversion to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines in patients with chronic lymphocytic leukemia (CLL). In this national collaboration of 11 cancer centers in the United States, we aimed to further characterize and understand vaccine-induced immune responses, including T-cell responses, and the impact of CLL therapeutics (#NCT04852822). Eligible patients were enrolled in 2 cohorts (1) at the time of initial vaccination and (2) at the time of booster vaccination. The serologic response rates (anti-S) from 210 patients in the initial vaccination cohort and 117 in the booster vaccination cohort were 56% (95% confidence interval [CI], 50-63) and 68% (95% CI, 60-77), respectively. Compared with patients not on therapy, those receiving B-cell-directed therapy were less likely to seroconvert (odds ratio [OR], 0.27; 95% CI, 0.15-0.49). Persistence of response was observed at 6 months; anti-S titers increased with the administration of booster vaccinations. In the initial vaccination cohort, positive correlations were observed between the quantitative serologic response and CD4 T-cell response for the Wuhan variant and, to a lesser degree, for the Omicron variant (Spearman P = 0.45 Wuhan; P = 0.25 Omicron). In the booster vaccination cohort, positive correlations were observed between serologic responses and CD4 T-cell responses for both variants (P = 0.58 Wuhan; P = 0.57 Omicron) and to a lesser degree for CD8 T-cell responses (P = 0.33 Wuhan; P = 0.22 Omicron). Although no deaths from coronavirus disease 2019 (COVID-19) have been reported after booster vaccinations, patients should use caution as newer variants emerge and escape vaccine-induced immunity. This trial was registered at www.clinicaltrials.gov as #NCT04852822., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: This study assessed treatment discontinuation patterns and reasons among chronic lymphocytic leukemia (CLL) patients initiating first-line (1L) and second-line (2L) treatments in real-world settings., Materials and Methods: Using deidentified electronic medical records from the CLL Collaborative Study of Real-World Evidence, premature treatment discontinuation was assessed among FCR, BR, BTKi-based, and BCL-2-based regimen cohorts., Results: Of 1364 1L patients (initiated in 1997-2021), 190/13.9% received FCR (23.7% discontinued prematurely); 255/18.7% received BR (34.5% discontinued prematurely); 473/34.7% received BTKi-based regimens, of whom 28.1% discontinued prematurely; and 43/3.2% received venetoclax-based regimens, of whom 16.3% discontinued prematurely (venetoclax monotherapy: 7/0.5%, of whom 42.9% discontinued; VG/VR: 36/2.6%, of whom 11.1% discontinued). The most common reasons for treatment discontinuation were adverse events (FCR: 25/13.2%; BR: 36/14.1%; BTKi-based regimens: 75/15.9%) and disease progression (venetoclax-based: 3/7.0%). Of 626 2L patients, 20/3.2% received FCR (50.0% discontinued); 62/9.9% received BR (35.5% discontinued); 303/48.4% received BTKi-based regimens, of whom 38.0% discontinued; and 73/11.7% received venetoclax-based regimens, of whom 30.1% discontinued (venetoclax monotherapy: 27/4.3%, of whom 29.6% discontinued; VG/VR: 43/6.9%, of whom 27.9% discontinued). The most common reasons for treatment discontinuation were adverse events (FCR: 6/30.0%; BR: 11/17.7%; BTKi-based regimens: 60/19.8%; venetoclax-based: 6/8.2%)., Conclusion: The findings of this study highlight the continued need for tolerable therapies in CLL, with finite therapy offering a better tolerated option for patients who are newly diagnosed or relapsed/refractory to prior treatments., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Bone marrow biopsies (BMB) are performed before/after therapy to confirm complete response (CR) in patients with lymphoma on clinical trials. We sought to establish whether BMB add value in assessing response or predict progression-free survival (PFS) or overall survival (OS) outcomes in follicular lymphoma (FL) subjects in a large, multicenter, multitrial cohort., Methods: Data were pooled from seven trials of 580 subjects with previously untreated FL through Alliance for Clinical Trials in Oncology (Alliance) and SWOG Cancer Research Network (SWOG) completing enrollment from 2008 to 2016., Results: Only 5/580 (0.9%) had positive baseline BMB, CR on imaging, and subsequent positive BMB ( P < .0001). Therefore, BMB were irrelevant to response in 99% of subjects. A sensitivity analysis of 385 FL subjects treated on an Eastern Cooperative Oncology Group study was included. In the Eastern Cooperative Oncology Group cohort, 5/385 (1.3%) had BMB that affected response assessment. Since some subjects do not undergo confirmatory BMB, we performed a landmark survival analysis from first radiologic CR with data from 580 subjects from Alliance and SWOG. Of subjects with CR on imaging (n = 187), PFS and OS were not significantly different among those with negative BMB to confirm CR (n = 47) versus those without repeat BMB (n = 140; PFS: adjusted hazard ratio, 1.10, 95% CI, 0.62 to 1.94, log-rank P = .686; OS: hazard ratio, 0.59, 95% CI, 0.23 to 1.53, log-rank P = .276)., Conclusion: We conclude that BMB add little value to response assessment in subjects with FL treated on clinical trials and we recommend eliminating BMB from clinical trial requirements. BMB should also be removed from diagnostic guidelines for FL except in scenarios in which it may change management including confirmation of limited stage and assessment of cytopenias. This would reduce cost, patient discomfort, resource utilization, and potentially remove a barrier to trial enrollment.

Chimeric antigen receptor T-cell (CAR T) therapy has shown promising efficacy in relapsed and refractory diffuse large B cell lymphoma (DLBCL). While most patients undergo CAR T infusion with active disease, the impact of some clinical variables, such as responsiveness to the pre-CAR T chemotherapy on the response to CAR T, is unknown. In this single-institution study, we studied the impact of several pre-CAR T variables on the post-CAR outcomes. Sixty patients underwent apheresis for axicabtagene-ciloleucel (axi-cel) and 42 of them (70.0%) had primary refractory disease. Bridging therapy between apheresis and lymphodepletion was given in 34 patients (56.7%). After axi-cel, the overall response rate was 63.3%. Responsiveness to the immediate pre-CAR T therapy did not show a significant association with response to axi-cel, progression-free (PFS) or overall (OS) survival. Multivariable analysis determined that bulky disease before lymphodepletion was independently associated with inferior outcomes, and patients that presented with high-burden disease unresponsive to immediate pre-CAR T therapy had a dismal outcome. This data supports proceeding with treatment in CAR T candidates regardless of their response to immediate pre-CAR T therapy. Interim therapeutic interventions should be considered in patients who have known risk factors for poor outcomes (bulky disease, high LDH)., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Obinutuzumab (G) chemoimmunotherapy demonstrated improved progression-free survival (PFS) vs rituximab-based chemoimmunotherapy in patients with previously untreated follicular lymphoma (FL) in the GALLIUM trial. Atezolizumab (atezo) is a programmed death-ligand 1 inhibitor with a complementary mechanism of action to G by restoring cytotoxic T-cell function. We evaluated the safety and efficacy of atezo-G-bendamustine in patients with previously untreated FL in a phase Ib/II trial (#NCT02596971). A safety run-in phase was followed by an expansion phase with atezo-G-bendamustine induction and atezo-G maintenance for ≤24 months. Forty patients with previously untreated FL were enrolled and treated with atezo-G-bendamustine. The primary endpoint, complete response (CR) rate, assessed by an independent review committee (IRC; modified Lugano 2014 criteria) was 75.0% (95% confidence interval [CI], 61.3% to 85.8%). Three-year investigator-assessed PFS and overall survival rates were 80.9% (95% CI, 63.9% to 90.5%) and 89.3% (95% CI, 73.9% to 95.9%), respectively. At baseline, 21/40 patients had circulating lymphoma-specific clonotypes and underwent repeat testing at end of induction; all were minimal residual disease negative (10-5 sensitivity), with 16 (76.2%) CRs, 3 (14.3%) partial responses, and 2 (9.5%) with stable disease (IRC assessed). Grade 5 (fatal) adverse events (AEs) were reported in 5 patients. The efficacy of atezo-G-bendamustine in previously untreated FL did not appear superior to G-bendamustine efficacy as seen in the GALLIUM trial, and the addition of atezo to G-bendamustine was associated with an increased risk of AEs. Particularly due to the unfavorable safety profile, this regimen cannot be recommended in patients with previously untreated FL. This trial was registered at www.clinicaltrials.gov as #NCT02596971., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved in recent years. Targeted therapy with Bruton's tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors has emerged as an effective chemotherapy-free option for patients with previously untreated or relapsed/refractory CLL/SLL. Undetectable minimal residual disease after the end of treatment is emerging as an important predictor of progression-free and overall survival for patients treated with fixed-duration BCL-2 inhibitor-based treatment. These NCCN Guidelines Insights discuss the updates to the NCCN Guidelines for CLL/SLL specific to the use of chemotherapy-free treatment options for patients with treatment-naïve and relapsed/refractory disease.

Prior reports evaluating SARS-CoV-2 vaccine efficacy in chronic lymphocytic leukaemia (CLL) used semiquantitative measurements of anti-S to evaluate immunity; however, neutralization assays were used to assess functional immunity in the trials leading to vaccine approval. Here, we identified decreased rates of seroconversion in vaccinated CLL patients and lower anti-S levels compared to healthy controls. Notably, we demonstrated similar results with the Roche anti-S assay and neutralization activity. Durable responses were seen at six months; augmentation with boosters was possible in responding patients. Absence of normal B cells, frequently seen in patients receiving Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors, was a strong predictor of lack of seroconversion., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

The management of follicular lymphoma (FL) in the relapsed and refractory setting is challenging and an area of ongoing investigation. Epigenetic dysregulation has recently been shown to be a hallmark of FL. Mutations in histone-modifying genes are likely early, driver events in FL pathogenesis, and so are attractive targets to drug. Gain-of-function mutations in the histone methyltransferase EZH2 are common in FL and maintained through disease evolution. With mounting data supporting a critical role for EZH2 as an oncogenic driver for FL, the small molecule inhibitor, tazemetostat, was developed. Tazemetostat has shown promising activity in preclinical models and early phase trials. Importantly, responses were seen in patients with high-risk features. Based on these data, tazemetostat was approved in the US in 2020 for EZH2 mut patients with FL who had received at least two prior lines of systemic therapy, or for EZH2 wt patients without alternative treatment options. Here, we will review the biology of FL as it pertains to tazemetostat, the available clinical trial data, and future directions for this new therapy., Competing Interests: CU reports consulting for Epizyme, AbbVie, Atara, Pharmacyclics, Gilead, Janssen, Beigene, Lilly, and Incyte. The authors report no other conflicts of interest in this work., (© 2022 Raychaudhuri and Ujjani.)

The management of chronic lymphocytic leukemia (CLL) has undergone unprecedented changes over the last decade. Modern targeted therapies are incorporated into clinical practice. Unfortunately, patients have begun to develop resistance or intolerance to multiple classes. Symptomatic patients previously treated with a BTK inhibitor (BTKi) and venetoclax represent a new and rapidly growing unmet need in CLL. Here, we define unmet needs in a modern treatment context. We also critically review the literature for PI3K inhibitors and chemoimmunotherapy and lack of data to support their utility following BTKis and venetoclax. Finally, we suggest opportunities to ensure the continued innovation for patients with CLL., (©2021 American Association for Cancer Research.)

Introduction: Polatuzumab vedotin is approved therapy in the United States for relapsed/refractory diffuse large B-cell lymphoma in combination with bendamustine and rituximab (Pola+BR). However, the safety and efficacy of Pola+BR outside of a clinical trial setting is unknown., Patients and Methods: We analyzed use of pola-based therapy at 5 centers in the United States, including dose, response rates, progression-free survival (PFS), survival, and toxicity., Results: Sixty-nine patients with aggressive B-cell lymphoma, including 66 with diffuse large B-cell lymphoma/high-grade B-cell lymphoma and 84% refractory to prior therapy, were treated. Responses occurred in of 50%, including 24% complete response. Median duration of response was 5.1 months, PFS was 2.0 months, and survival was 5.3 months, at 4 months median follow-up. Inferior PFS was associated with prior refractory disease (median, 57 days vs. not reached; P = .003) and lack of response to Pola+BR (PFS, 27 days vs. 152 days; P < .001). Discontinuation owing to planned cellular therapy was seen in 36% and owing to toxicity occurred in 12%; unplanned hospitalizations occurred in 36%., Conclusions: We conclude that commercial Pola is applied to highly refractory lymphomas at our centers, often with intent to bridge to subsequent therapy. Although some clinical benefit was observed, efficacy was inferior to clinical trial data, especially among those with refractory disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In January 2020, the first documented patient in the United States infected with severe acute respiratory syndrome coronavirus 2 was diagnosed in Washington State. Since that time, community spread of coronavirus disease 2019 (COVID-19) in the state has changed the practice of oncologic care at our comprehensive cancer center in Seattle. At the Seattle Cancer Care Alliance, the primary oncology clinic for the University of Washington/Fred Hutchinson Cancer Consortium, our specialists who manage adult patients with hematologic malignancies have rapidly adjusted clinical practices to mitigate the potential risks of COVID-19 to our patients. We suggest that our general management decisions and modifications in Seattle are broadly applicable to patients with hematologic malignancies. Despite a rapidly changing environment that necessitates opinion-based care, we provide recommendations that are based on best available data from clinical trials and collective knowledge of disease states.

Purpose: Double-hit lymphomas and triple-hit lymphomas (DHL/THL), also known as high-grade B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements, are associated with chemoresistance and inferior survival. However, whether radiation therapy (RT) efficacy is altered in DHL/THL is less well characterized. Among patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), we compared rates and durability of response between patients with and without DHL/THL., Methods and Materials: We retrospectively reviewed consecutive R/R LBCL patients who were irradiated at a single institution from January 2008 to June 2017. Patients in whom c-MYC rearranged status was known were evaluated for response to RT, in-field control, progression-free, and overall survival., Results: Among 245 irradiated patients with LBCL, 41 patients with confirmed c-MYC status were treated for R/R disease (14 DHL/THL, 27 non-DHL/THL) and formed our cohort. Compared with non-DHL/THL, more DHL/THL patients had progressive disease at RT (71% vs 48%), had larger gross tumor volumes (GTV; median 696 mL vs 117 mL), and were treated with palliative intent (71% vs 41%). Despite similar RT doses (median 35 Gy), radiographic complete response rate was lower among DHL/THL patients: 14.3% versus 64.7% (P = .01). With a median 2 years of follow-up, one in-field failure was observed in each group. DHL/THL patients had inferior progression-free survival (7% vs 46%; P = .02) and overall survival (14% vs 68%; P = .03) at 6 months., Conclusions: R/R LBCL is responsive to RT, although rates of response are lower among DHL/THL patients. Given poor survival after RT, in-field control was hard to evaluate in this cohort. Larger cohorts are required to better elucidate whether differences in response rates are driven by larger disease burden at RT versus tumor biology. These findings are of increasing pertinence in light of use of RT as bridging therapy to cellular immunotherapies., (Copyright © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

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.

Recent advances in diffuse large B-cell lymphomas have included both identification of high-risk subtypes characterized by multiply relapsed and/or refractory disease as well as novel treatment in the form of cellular therapy. Chimeric antigen receptor (CAR)-T cell therapy is a recently developed approach to address the poor outcomes in this patient population. The CAR-T cell construct has evolved although several iterations as it transitioned from the lab to the clinic. Three major studies have evaluated the efficacy of CD19-directed CAR-T cell therapy in aggressive B-cell non-Hodgkin lymphoma; each demonstrating durable complete remissions in heavily pretreated patients. The cost of this remarkable therapy, however, includes cytokine release syndrome and neurotoxicity shortly after administration as well as delayed infectious complications due to B-cell aplasia. Future investigations are focused on the optimizing both safety and efficacy of CAR-T cell therapy., (© 2018 John Wiley & Sons, Ltd.)