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Richter's transformation (RT) is a life-threatening evolution of chronic lymphocytic leukemia (CLL) into a more aggressive lymphoma, typically diffuse large B-cell lymphoma (DLBCL), marking a challenging juncture in CLL management due to the associated poor prognosis and limited treatment options. This review delves into the current therapeutic landscape for RT. Despite the modest efficacy of traditional chemoimmunotherapy (CIT) regimens such as R-CHOP and its variations, this regimen remains the most commonly recommended standard of care. Multiple therapeutic strategies are under investigation, including targeted kinase inhibitors, checkpoint inhibitors, bispecific antibodies, and CAR T therapy. Given the complex nature of RT and the evolving therapeutic paradigms, ongoing research is imperative to refine treatment strategies and integrate novel therapeutic agents to enhance survival and quality of life for people with RT. Given the lack of a clear standard of approach in the management of RT, patients with RT should be prioritized to enroll on clinical trials where feasible., Competing Interests: Disclosure Outside of this work, Jensen has received research funding (paid to institution) and consulting fees from AbbVie. Stephens has received research funding (paid to institution) from Novartis, Genentech, AbbVie, and AstraZeneca. She has received consulting fees from Abbvie, AstraZeneca, Beigene, BMS, Eli Lilly, Genentech, Janssen, and Pharmacyclics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established., Methods: We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated from the date of CAR-T infusion., Results: Sixty-nine patients were identified. The median age at CAR-T infusion was 64 years (range, 27-80). Patients had a median of four (range, 1-15) previous lines of therapy for CLL and/or RT, including previous Bruton tyrosine kinase inhibitor and/or BCL2 inhibitor therapy in 58 (84%) patients. The CAR-T product administered was axicabtagene ciloleucel in 44 patients (64%), tisagenlecleucel in 17 patients (25%), lisocabtagene maraleucel in seven patients (10%), and brexucabtagene autoleucel in one patient (1%). Eleven patients (16%) and 25 patients (37%) experienced grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, respectively. The overall response rate was 63%, with 46% attaining a complete response (CR). After a median follow-up of 24 months, the median PFS was 4.7 months (95% CI, 2.0 to 6.9); the 2-year PFS was 29% (95% CI, 18 to 41). The median OS was 8.5 months (95% CI, 5.1 to 25.4); the 2-year OS was 38% (95% CI, 26 to 50). The median duration of response was 27.6 months (95% CI, 14.5 to not reached) for patients achieving CR., Conclusion: CAR-T demonstrates clinical efficacy for patients with RT.

Abstract: Chimeric antigen receptor (CAR) T-cell (CAR-T) immunotherapy is an effective therapy for relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). However, data are limited on the impact of the convergence of race and social determinants of health on outcomes for patients treated with CAR-T therapy. We examined the impact of interactions between race and insurance type on health care use and outcomes in patients treated with CAR-T therapy for aggressive B-NHL. Adult patients with r/r B-NHL treated with CD19 CAR-Ts were identified between 2015 and 2021 across 13 US academic centers. Insurance type, demographic, and clinical data were collected and analyzed. In total, 466 adult patients were included in our analysis. Median follow-up after CAR-T therapy was 12.7 months. Median progression-free survival (mPFS) was longer for Caucasians (11.5 months) than for African Americans (3.5 months; hazard ratio [HR], 1.56 [1.03-2.4]; P = .04) or Asians (2.7 months; HR, 1.7 [1.02-2.67]; P = .04). Differences in median overall survival (mOS) were not significant. For Medicare (n = 206) vs Medicaid (n = 33) vs private insurance (n = 219) vs self-pay (n = 7): mPFS was 15.9 vs 4.2 vs 6.0 vs 0.9 months (P < .001), respectively; and mOS was 31.2 vs 12.8 vs 21.5 vs 3.2 months (P < .001), respectively. Our multicenter retrospective analysis showed that race and insurance status can affect outcomes for patients treated with CAR-T therapy., (© 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.)

Abstract: A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.

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.

Purpose: Ibrutinib is a Bruton's tyrosine kinase inhibitor used to treat multiple hematologic malignancies and graft-versus-host disease. Though less myelosuppressive than cytotoxic chemotherapy, increased infections, including invasive fungal infections (IFIs), have been reported with ibrutinib use. This study aimed to determine the characteristics and risk factors for infection associated with ibrutinib at our institution., Methods: Patients who received ibrutinib between June 2014 and August 2019 were included. Primary endpoints were the incidence of any infection and the incidence of serious infection (defined as hospitalization, parenteral antimicrobial therapy, or pneumonia regardless of hospitalization). Infection risk factors were assessed using logistic regression., Results: One hundred thirty-two patients were identified (78% male; median age, 71 years). The most common indications for ibrutinib were chronic lymphocytic leukemia (67%) and mantle cell lymphoma (12%). Infection and serious infection occurred in 94 (71%) and 47 (36%) patients, respectively; when pneumonia was excluded as a criterion for serious infection, the serious infection rate was 27%. The median time from ibrutinib initiation to first infection was 125 days. Prior allogeneic hematopoietic stem cell transplantation (allo-HSCT) (odds ratio [OR], 4.60; 95% CI, 1.22-17.4) and corticosteroid use (OR, 5.55; 95% CI, 1.52-20.3) were significant risk factors for serious infection. IFIs were diagnosed in 7 patients (5%): 5 had Pneumocystis jirovecii pneumonia and 2 were infected with invasive molds., Conclusion: Serious infection and IFI rates are high but similar to those previously described. Risk factors for serious infection included allo-HSCT and corticosteroid use. Targeted antimicrobial prophylaxis should be evaluated in prospective studies in patients on ibrutinib to reduce serious infections and IFI., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Genetic and gene expression heterogeneity is an essential hallmark of many tumors, allowing the cancer to evolve and to develop resistance to treatment. Currently, the most commonly used data types for studying such heterogeneity are bulk tumor/normal whole-genome or whole-exome sequencing (WGS, WES); and single-cell RNA sequencing (scRNA-seq), respectively. However, tools are currently lacking to link genomic tumor subclonality with transcriptomic heterogeneity by integrating genomic and single-cell transcriptomic data collected from the same tumor. To address this gap, we developed scBayes, a Bayesian probabilistic framework that uses tumor subclonal structure inferred from bulk DNA sequencing data to determine the subclonal identity of cells from single-cell gene expression (scRNA-seq) measurements. Grouping together cells representing the same genetically defined tumor subclones allows comparison of gene expression across different subclones, or investigation of gene expression changes within the same subclone across time (i.e., progression, treatment response, or relapse) or space (i.e., at multiple metastatic sites and organs). We used simulated data sets, in silico synthetic data sets, as well as biological data sets generated from cancer samples to extensively characterize and validate the performance of our method, as well as to show improvements over existing methods. We show the validity and utility of our approach by applying it to published data sets and recapitulating the findings, as well as arriving at novel insights into cancer subclonal expression behavior in our own data sets. We further show that our method is applicable to a wide range of single-cell sequencing technologies including single-cell DNA sequencing as well as Smart-seq and 10x Genomics scRNA-seq protocols., (© 2024 Qiao et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Patients with favorable risk limited-stage (LS) diffuse large b-cell lymphoma (DLBCL) have shown excellent outcomes without radiotherapy (RT). However, the role of RT for the remainder of LS-DLBCL patients is less well defined. We aimed to investigate whether the addition of RT provided an overall survival (OS) benefit in a real-world cohort of LS-DLBCL patients based on primary site at presentation., Materials and Methods: Retrospective data from 39,745 patients with stage I and II DLBCL treated with front-line combination chemotherapy alone or followed by RT were identified using the National Cancer Database from 2004 to 2015., Results: The addition of RT was associated with improved 5-year OS for all LS patients as compared to those treated with chemotherapy alone (85% vs. 80%, P < .001). RT was associated with improved 5-year OS in both the nodal and extranodal disease patients (nodal: 85% vs. 80%, P < .001; extranodal: 83% vs. 79%; P < .001). Extranodal sites with prolonged OS from the addition of RT include skin and soft tissue, head and neck, testicular, and thyroid sites (all P < .02). Breast, bone, lung and gastrointestinal extranodal primary sites had no OS benefit from the inclusion of RT. In multivariate analysis, the addition of RT was an independent factor for improved survival for all LS patients ([HR] 0.84, 95% [CI] 0.81-0.88; P < .001)., Conclusion: Though there is no consensus on optimal treatment indications for RT in LS-DLBCL, these data suggest certain subgroups may have benefit when RT is added to front-line chemotherapy., Competing Interests: Disclosure H.S.: Research funding: Seattle Genetics, AstraZeneca, Epizyme; D.S: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; JUNO: Research funding; Mingsight: Research funding; AstraZeneca: Consultancy; CSL Behring: Consultancy; Abbvie: Consultancy; Arqule: Research funding; Epizyme: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees. B.H: Celgene: Research Funding; Genentech: Research Funding; CRISPR Therapeutics: Research funding; TG Therapeutics: Consultancy; OncLive: Consultancy. D.E., V.V., L.F., R.T., D.G., have no conflicts of interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Nemtabrutinib is an orally bioavailable, reversible inhibitor of Bruton tyrosine kinase (BTK) and C481S mutant BTK. We evaluated the safety, pharmacology, and antitumor activity of nemtabrutinib in relapsed/refractory hematologic malignancies. Forty-eight patients with chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (NHL), or Waldenström macroglobulinemia (WM), relapsed/refractory after ≥2 prior therapies were enrolled in the open-label, single-arm, phase I MK-1026-001 study (NCT03162536) to receive nemtabrutinib 5 to 75 mg once daily in 28-day cycles. Dose finding progressed using a 3 + 3 dose escalation design. Primary endpoints were safety and the recommended phase II dose (RP2D). Among 47 treated patients, 29 had CLL, 17 had NHL, and 1 had WM. Grade ≥3 treatment-emergent adverse events occurred in 37 (89%), most commonly neutropenia (11; 23.4%), febrile neutropenia (7; 14.9%), and pneumonia (7; 14.9%). The RP2D was 65 mg daily. An overall response rate of 75% was observed in patients with CLL at 65 mg daily., Significance: This first-in-human phase I study demonstrates the safety and preliminary efficacy of nemtabrutinib in patients with relapsed/refractory B-cell malignancies. These data support further exploration of nemtabrutinib in larger clinical studies. This article is featured in Selected Articles from This Issue, p. 5., (©2023 American Association for Cancer Research.)

Background: Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes., Methods: The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases., Results: In front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p < 0.0001) and progression-free survival (PFS, p < 0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes (p < 0.0001 for OS and p = 0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort., Conclusions: The outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL., (© 2023. The Author(s).)

Maintenance rituximab in mantle cell lymphoma (MCL) has improved survival and supports exploration of maintenance with novel agents. We evaluated the safety and efficacy of ibrutinib maintenance (I-M) after induction in patients with treatment-naive MCL. Patients with MCL with complete response (CR) or partial response to frontline chemoimmunotherapy ± autologous stem cell transplantation (auto-SCT) received I-M 560 mg daily for up to 4 years. Primary objective was 3-year progression-free survival (PFS) rate from initiation of I-M. Minimal residual disease (MRD) assessments by next-generation sequencing (NGS) on peripheral blood were measured before I-M initiation and at 1, 6, and 18 to 24 months after initiation. Among 36 patients, the median age was 60 years (range, 46-90). For frontline treatment, 18 patients (50%) had consolidation with auto-SCT in CR1 before I-M. At median follow-up of 55.7 months, 17 patients (47%) completed full course I-M (median, 37.5 cycles; range, 2-52). The 3-year PFS and overall survival (OS) rates were 94% and 97%, respectively. With prior auto-SCT, 3-year PFS and OS rates were both 100%. The most common treatment-related adverse event with I-M was infection (n = 31; 86%), typically low grade; the most common grade 3/4 toxicities were hematologic. In 22 patients with MRD assessments, all were MRD negative after induction. Six became MRD positive on I-M, with 2 reverting to MRD-negative status with continued I-M, and all maintain radiographic CR with the exception of 1 with disease progression. I-M is feasible in MCL after frontline chemoimmunotherapy with manageable toxicities although significant. Changes in NGS-MRD were noted in limited patients during maintenance with few progression and survival events. This trial was registered at www.clinicaltrials.gov as #NCT02242097., (© 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.)

Sixteen cycles of Brentuximab vedotin (BV) after autologous stem cell transplant (ASCT) in high-risk relapsed/refractory classical Hodgkin lymphoma demonstrated an improved 2-year progression-free survival (PFS) over placebo. However, most patients are unable to complete all 16 cycles at full dose due to toxicity. This retrospective, multicenter study investigated the effect of cumulative maintenance BV dose on 2-year PFS. Data were collected from patients who received at least one cycle of BV maintenance after ASCT with one of the following high-risk features: primary refractory disease (PRD), extra-nodal disease (END), or relapse <12 months (RL<12) from the end of frontline therapy. Cohort 1 had patients with >75% of the planned total cumulative dose, cohort 2 with 51-75% of dose, and cohort 3 with ≤50% of dose. The primary outcome was 2-year PFS. A total of 118 patients were included. Fifty percent had PRD, 29% had RL<12, and 39% had END. Forty-four percent of patients had prior exposure to BV and 65% were in complete remission before ASCT. Only 14% of patients received the full planned BV dose. Sixty-one percent of patients discontinued maintenance early and majority of those (72%) were due to toxicity. The 2-year PFS for the entire population was 80.7%. The 2-year PFS was 89.2% for cohort 1 (n=39), 86.2% for cohort 2 (n=33), and 77.9% for cohort 3 (n=46) (P=0.70). These data are reassuring for patients who require dose reductions or discontinuation to manage toxicity.

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.)

Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of patients with relapsed aggressive B-cell lymphomas after CAR-T failure. To define CPI therapy efficacy more definitively in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 US academic centers. Most patients (53%) had diffuse large B-cell lymphoma, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 vs 51 days) and OS (387 vs 131 days) were significantly longer in patients with late (>180 days) vs early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of patients treated with CPI. Most patients (83%) died, commonly because of progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of patients with aggressive B-cell lymphoma treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post-CAR-T outcomes., (© 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.)

Background: Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma., Methods: We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 10 6 (dose level 1) or 100 × 10 6 (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198., Findings: Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis)., Interpretation: A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable., Funding: Juno Therapeutics, a Bristol-Myers Squibb Company., Competing Interests: Declaration of interests TS discloses institutional support to conduct this study and manuscript writing support for this manuscript from Bristol Myers Squibb (BMS); fees for speakers’ bureaus from BMS, AstraZeneca, and BeiGene; participation on a data safety monitoring board for BeiGene; participation on an advisory board for AbbVie, BeiGene, BMS, Celgene, a BMS Company, AstraZeneca, and Gilead. DGM discloses institutional research funding from Kite, Juno Therapeutics, a BMS Company, Celgene, a BMS Company, Legend Biotech, and BMS; consulting fees from A2 Biotherapeutics, Navan Technologies, Chimeric Therapeutics, Genentech, BMS, ImmPACT Bio, Gilead Sciences, and Interius; rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics, a BMS Company; advisory boards for BMS, Caribou Biosciences, Celgene, a BMS Company, Genentech, Incyte, Janssen, Juno Therapeutics, a BMS Company, Mustang Bio, MorphoSys, Kite, Lilly, Novartis, and Umoja; and stock options from A2 Biotherapeutics and Navan Technologies. SSK discloses grants or contracts from Novartis, Kite/Gilead, Juno Therapeutics, a BMS Company, Lentigen, Humanigen, MorphoSys, Tolero Pharmaceuticals, Sunesis Pharmaceuticals/Viracta Therapeutics, and LEAH Labs; royalties or licences from Novartis, Humanigen, Mettaforge Therapeutics, Sendero, and Mustang Bio; participation on a scientific advisory board for Kite, Juno Therapeutics, a BMS Company, Novartis, Humanigen, Calibr, Torque, Capstan Therapeutics, Lentigen, LEAH Labs, and Luminary Therapeutics; participation on a data safety monitoring board for Humanigen; and research funding from Novartis, Kite/Gilead, Juno Therapeutics, a BMS Company, Lentigen, Humanigen, MorphoSys, Tolero Pharmaceuticals, Sunesis Pharmaceuticals/Viracta Therapeutics, and LEAH Labs. DMB discloses grants paid to their institution (Duke University) and the role of site principal investigator for clinical trials from AbbVie, ArQule/Merck, Ascentage, Acerta, BeiGene, Catapult, DTRM Biopharma, Genentech, Celgene, a BMS Company, Juno Therapeutics, a BMS Company, BMS, MEI Pharma, Newave, Novartis, and TG Therapeutics; consulting fees from Genentech, AbbVie, and Pharmacyclics; participation on a panel of the National Comprehensive Cancer Network for chronic lymphocytic leukaemia or small lymphocytic lymphoma and hairy cell leukaemia, a registry steering committee for informCLL (Pharmacyclics) and CORE (AbbVie), and an expert medical council for Chronic Lymphocytic Leukemia Society (unpaid), and being a leukaemia committee member and trial champion of S1925 for Alliance in Clinical Trials (unpaid); and writing support for abstracts or manuscripts from AbbVie, BeiGene, Pharmacyclics, and TG Therapeutics. KD discloses institutional research funding for this study from BMS; institutional grants or contracts from BMS, Kite/Gilead, and Genmab; consulting fees for participation on an advisory board for BMS; and honoraria for participation in American Society of Hematology Congress Connect. JS discloses consulting fees from AbbVie, AstraZeneca, BeiGene, BMS, Roche, Seattle Genetics, and TG Therapeutics; and research funding paid to their institution from Adaptive Biotechnologies, BeiGene, BostonGene, Genentech/Roche, GlaxoSmithKline, Moderna, Takeda, and TG Therapeutics. PAR discloses consulting fees from AbbVie, BMS, Janssen, Novartis, BeiGene, Kite/Gilead, Intellia Therapeutics, Sana Biotechnology, CVS Caremark, Genmab, Pharmacyclics, Takeda, Karyopharm Therapeutics, Nektar Therapeutics, Nurix Therapeutics, and ADC Therapeutics; honoraria from Kite/Gilead; and support for attending meetings or travel from Nektar Therapeutics. NNS discloses support for this manuscript from Juno Therapeutics, a BMS Company; research funding from Loxo@Lilly and Miltenyi Biotec; consulting fees from Loxo@Lilly and Miltenyi Biotec; participation on a data safety monitoring board for Incyte; participation on an advisory board for Epizyme, Janssen, Kite Pharma, Incyte, Seattle Genetics, Novartis, Juno Therapeutics, a BMS Company, TG Therapeutics, and Umoja Biopharma; travel support from Loxo@Lilly and Miltenyi Biotec; stock or stock options from Tundra Targeted Therapeutics; and is a scientific advisory board member and founder of Tundra Targeted Therapeutics. RN discloses consulting fees from Actinium Pharmaceuticals; consulting fees for participation on an advisory board for Incyte; and stock or stock options from Pfizer. BF discloses research funding from BMS; consulting fees from AbbVie, Adaptive Biotechnologies, AstraZeneca, BeiGene, BMS, Genentech, Genmab, Loxo@Lilly, Pharmacyclics, and TG Therapeutics; honoraria from Curio Science and Medscape; support for attending meetings or travel from AbbVie and Loxo@Lilly; and participation on a guideline panel for chronic lymphocytic leukaemia and hairy cell leukaemia for the National Comprehensive Cancer Network (unpaid). DMS discloses grants or contracts from Celgene, a BMS Company, Novartis, AstraZeneca, Merck, MingSight Pharmaceuticals, and Newave; consulting fees from Lilly, Genentech, Pharmacyclics/Janssen, Karyopharm Therapeutics, BeiGene, Innate Pharma, AstraZeneca, AbbVie, CSL Behring, Celgene, a BMS Company, TG Therapeutics, and Innate Pharma; and research funding from Acerta Pharma, Gilead Sciences, Karyopharm Therapeutics, MingSight Pharmaceuticals, ArQule, Novartis, Verastem Oncology, and Juno Therapeutics, a BMS Company. SM discloses institutional funding from Juno Therapeutics, a BMS Company, BeiGene, Loxo@Lilly, AstraZeneca, and AbbVie; consulting fees from TG Therapeutics; honoraria from AstraZeneca, BeiGene, Janssen, Lilly, and Pharmacyclics; and participation on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, BeiGene, BMS, Genentech, and Janssen. TF discloses consulting fees from Seattle Genetics, BMS, Genmab, ADC Therapeutics, and AstraZeneca; speakers’ bureau fees from Seattle Genetics and Kite; travel expenses from Seattle Genetics and Takeda; honoraria from Seattle Genetics, Pharmacyclics/Janssen, AbbVie, BMS, Kite, Bayer, and Takeda; and research funding from BMS, Seattle Genetics, Portola Pharmaceuticals, Eisai, Kyowa Kirin, Amgen, Viracta Therapeutics, Cell Medica, Roche, Trillium Therapeutics, and Pfizer. SJS discloses consulting fees from Caribou Biosciences, Genentech/Roche, Genmab, Kite Pharma, Incyte, Legend Biotech, MorphoSys, Mustang Bio, Nordic Nanovector, and Novartis; honoraria from Novartis and Takeda; a patent for combination therapies of chimeric antigen receptor and programmed cell death protein-1 inhibitors licensed to Novartis; research funding from Merck and Genentech/Roche; and travel accommodations from Genentech/Roche and Novartis. SKP is an employee of BMS and a shareholder of BMS and Autolus. SAT, S-SO, EP, LP, and YC are employees and shareholders of BMS. WGW discloses travel expenses from AbbVie, Genentech, and Eli Lilly; and research funding from AbbVie, Acerta Pharma, BMS, Cyclacel Pharmaceuticals, Genentech, Gilead Sciences, GlaxoSmithKline, Loxo@Lilly, Novartis, and Oncternal Therapeutics. SRS declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Chimeric antigen receptor T-cell therapy (CART) has extended survival of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). However, limited durability of response and prevalent toxicities remain problematic. Identifying patients who are at high risk of disease progression, toxicity, and death would inform treatment decisions. Although the cumulative illness rating scale (CIRS) has been shown to correlate with survival in B-cell malignancies, no prognostic score has been independently validated in CART recipients. We retrospectively identified 577 patients with relapsed/refractory DLBCL indicated for CART at 9 academic centers to form a learning cohort (LC). Random survival forest modeling of overall survival (OS) and progression-free survival (PFS) was performed to determine the most influential CIRS organ systems and severity grades. The presence of a severe comorbidity (CIRS score ≥ 3) in the respiratory, upper gastrointestinal, hepatic, or renal system, herein termed "Severe4," had the greatest impact on post-CART survival. Controlling for other prognostic factors (number of prior therapies, Eastern Cooperative Oncology Group performance status, BCL6 translocation, and molecular subtype), Severe4 was strongly associated with shorter PFS and OS in the LC and in an independent single-center validation cohort (VC). Severe4 was also a significant predictor of grade ≥3 cytokine release syndrome in the LC, while maintaining this trend in the VC. Thus, our results indicate that adverse outcomes for patients with DLBCL meant to receive CART can be predicted using a simplified CIRS-derived comorbidity index., (© 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: Chronic lymphocytic leukemia (CLL) commonly affects older adults. However, few studies have examined the relationship between baseline geriatric domains and clinical outcomes in this population. Here, we aim to evaluate the use of a comprehensive geriatric assessment in older (>65 years) untreated patients with CLL to predict outcomes., Materials and Methods: We conducted a planned analysis of 369 patients with CLL age 65 or older treated in a phase 3 randomized trial of bendamustine plus rituximab versus ibrutinib plus rituximab versus ibrutinib alone (A041202). Patients underwent evaluations of geriatric domains including functional status, psychological status, social activity, cognition, social support, and nutritional status. We examined associations among baseline geriatric domains with grade 3+ adverse events using multivariable logistic regression and overall survival (OS) and progression-free survival (PFS) using multivariable Cox regression models., Results: In this study, the median age was 71 years (range: 65-87). In the combined multivariable model, the following geriatric domains were significantly associated with PFS: Medical Outcomes Study (MOS) - social activities survey score (hazard ratio [HR] [95% confidence interval (CI)] 0.974(0.961, 0.988), p = 0.0002) and nutritional status (≥5% weight loss in the preceding six months: (HR [95% CI] 2.717[1.696, 4.354], p < 0.001). MOS - social activities score [HR (95% CI) 0.978(0.958, 0.999), p = 0.038] was associated with OS. No geriatric domains were significantly associated with toxicity. There were no statistically significant interactions between geriatric domains and treatment., Discussion: Geriatric domains of social activity and nutritional status were associated with OS and/or PFS in older adults with CLL. These findings highlight the importance of assessing geriatric domains to identify high-risk patients with CLL who may benefit from additional support during treatment., Competing Interests: Declaration of Competing Interest PCJ has consulted for AstraZeneca, ADC Therapeutics, and Seagen. JAW has consulted for Abbvie, AstraZeneca, Beigene, Genentech, Janssen, Pharmacyclics, Loxo/Lilly, Merck, and Newave. RAN received equity stock payment from TimeDoc. CO has consulted for Janssen, Beigene, AbbVie, Astrazeneca, Merck and Roche. WD has consulted for Merck, BeiGene, MEI pharama, Alexion and Octapharma. DMS has consulted for Pharmacyclics/Janssen, Karyopharm Therapeutics, Beigene, Innate, AstraZeneca, Abbvie, CSL Behring, Celegene, TG Therapeutics, and Innate Pharma. ASR served on a DSMC for Telios and is an employee of Eli Lilly, although employment began after this work was completed. RS has consulted for GlaxoSmithKline, Hermavant, Takeda, Abbvie, Amgen, AvenCell, BerGenBio, Cellularity, CTI pharma, Jazz, Kura Onc, Rigel, Syros, Novartis, Actinium, Arog, BMS, Boston Pharmaceuticals, and Janssen., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Importance: The COVID-19 pandemic has led to a reduction in routine in-person medical care; however, it is unknown whether there have been any changes in visit rates among patients with hematologic neoplasms., Objective: To examine associations between the COVID-19 pandemic and in-person visits and telemedicine use among patients undergoing active treatment for hematologic neoplasms., Design, Setting, and Participants: Data for this retrospective observational cohort study were obtained from a nationwide electronic health record-derived, deidentified database. Data for patients with hematologic neoplasms who had received at least 1 systemic line of therapy between March 1, 2016, and February 28, 2021, were included. Treatments were categorized into 3 types: oral therapy, outpatient infusions, and inpatient infusions. The data cutoff date was April 30, 2021, when study analyses were conducted., Main Outcomes and Measures: Monthly visit rates were calculated as the number of documented visits (telemedicine or in-person) per active patient per 30-day period. We used time-series forecasting methods on prepandemic data (March 2016 to February 2020) to estimate expected rates between March 1, 2020, and February 28, 2021 (if the pandemic had not occurred)., Results: This study included data for 24 261 patients, with a median age of 68 years (IQR, 60-75 years). A total of 6737 patients received oral therapy, 15 314 received outpatient infusions, and 8316 received inpatient infusions. More than half of patients were men (14 370 [58%]) and non-Hispanic White (16 309 [66%]). Early pandemic months (March to May 2020) demonstrated a significant 21% reduction (95% prediction interval [PI], 12%-27%) in in-person visit rates averaged across oral therapy and outpatient infusions. Reductions in in-person visit rates were also significant for all treatment types for multiple myeloma (oral therapy: 29% reduction; 95% PI, 21%-36%; P = .001; outpatient infusions: 11% reduction; 95% PI, 4%-17%; P = .002; inpatient infusions: 55% reduction; 95% PI, 27%-67%; P = .005), for oral therapy for chronic lymphocytic leukemia (28% reduction; 95% PI, 12%-39%; P = .003), and for outpatient infusions for mantle cell lymphoma (38% reduction; 95% PI, 6%-54%; P = .003) and chronic lymphocytic leukemia (20% reduction; 95% PI, 6%-31%; P = .002). Telemedicine visit rates were highest for patients receiving oral therapy, with greater use in the early pandemic months and a subsequent decrease in later months., Conclusions and Relevance: In this cohort study of patients with hematologic neoplasms, documented in-person visit rates for those receiving oral therapy and outpatient infusions significantly decreased during the early pandemic months but returned to close to projected rates in the later half of 2020. There were no statistically significant reductions in the overall in-person visit rate for patients receiving inpatient infusions. There was higher telemedicine use in the early pandemic months, followed by a decline, but use was persistent in the later half of 2020. Further studies are needed to ascertain associations between the COVID-19 pandemic and subsequent cancer outcomes and the evolution of telemedicine use for care delivery.

Consensus Panel 5 (CP5) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11; held in October 2022) was tasked with reviewing the current data on the coronavirus disease-2019 (COVID-19) prophylaxis and management in patients with Waldenstrom's Macroglobulinemia (WM). The key recommendations from IWWM-11 CP5 included the following: Booster vaccines for SARS-CoV-2 should be recommended to all patients with WM. Variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4.5 strain, are important as novel mutants emerge and become dominant in the community. A temporary interruption in Bruton's Tyrosine Kinase-inhibitor (BTKi) or chemoimmunotherapy before vaccination might be considered. Patients under treatment with rituximab or BTK-inhibitors have lower antibody responses against SARS-CoV-2; thus, they should continue to follow preventive measures, including mask wearing and avoiding crowded places. Patients with WM are candidates for preexposure prophylaxis, if available and relevant to the dominant SARS-CoV-2 strains in a specific area. Oral antivirals should be offered to all symptomatic WM patients with mild to moderate COVID-19 regardless of vaccination, disease status or treatment, as soon as possible after the positive test and within 5 days of COVID-19-related symptom onset. Coadministration of ibrutinib or venetoclax with ritonavir should be avoided. In these patients, remdesivir offers an effective alternative. Patients with asymptomatic or oligosymptomatic COVID-19 should not interrupt treatment with a BTK inhibitor. Infection prophylaxis is essential in patients with WM and include general preventive measures, prophylaxis with antivirals and vaccination against common pathogens including SARS-CoV-2, influenza, and S. pneumoniae., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Survivors of non-Hodgkin lymphoma (NHL) have increased secondary malignancy (SM) risk. We quantified this risk by patient and treatment factors., Methods: Standardized incidence ratios (SIR, observed-to-expected [O/E] ratio) were assessed in 142,637 NHL patients diagnosed from 1975 to 2016 in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Comparisons were made between subgroups in terms of their SIRs relative to respective endemic populations., Results: In total, 15,979 patients developed SM, more than the endemic rate (O/E 1.29; p < 0.05). Compared with white patients, relative to respective endemic populations, ethnic minorities had a higher risk of SM (white O/E 1.27, 95% CI 1.25-1.29; black O/E 1.40, 95% CI 1.31-1.48; other O/E 1.59, 95% CI 1.49-1.70). Relative to respective endemic populations, patients who received radiotherapy had similar SM rates to those who did not (O/E 1.29 each), but irradiated patients had increased breast cancer (p < 0.05). Patients who received chemotherapy had higher SM rates than those who did not (O/E 1.33 vs. 1.24, p < 0.05) including more leukemia, Kaposi sarcoma, kidney, pancreas, rectal, head and neck, and colon cancers (p < 0.05)., Conclusions: This is the largest study to examine SM risk in NHL patients with the longest follow-up. Treatment with radiotherapy did not increase overall SM risk, while chemotherapy was associated with a higher overall risk. However, certain subsites were associated with a higher risk of SM, and they varied by treatment, age group, race and time since treatment. These findings are helpful for informing screening and long-term follow-up in NHL survivors., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Radiotherapy (RT) utilization for early-stage, low-grade follicular lymphoma (FL) is low despite treatment guideline recommendations. We compare treatment trends for early-stage FL in the era of involved-site RT and rituximab. We identified 11,645 patients in the National Cancer Database (NCDB) with stage I-II, grade 1-2 nodal or extranodal FL diagnosed 2011-2017, with median follow-up of 44 months. From 2011 to 2017, RT utilization rates decreased from 33.4% to 22.4%, observation decreased from 65.3% to 49.7%, chemoimmunotherapy increased from 0.5% to 15.0%, immuno-monotherapy increased from 0.6% to 10.2%, and RT + systemic therapy increased from 0.6% to 2.5%. RT utilization remains low in the involved-site RT and rituximab era.

Purpose: Dual blockade of Bruton's tyrosine kinase with ibrutinib and selinexor has potential to deepen responses for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL)., Patients and Methods: In this phase I study (clinicaltrials.gov: NCT02303392), adult patients with CLL/NHL, relapsed/refractory to ≥1 prior therapy were enrolled. Patients received weekly oral selinexor and daily oral ibrutinib in 28-day cycles until progression or intolerance. Primary objective was to determine MTD., Results: Included patients had CLL (n = 16) or NHL (n = 18; 9 Richter transformation, 6 diffuse large B-cell lymphoma, and 3 mantle cell lymphoma). Median prior therapies were 4 (range = 1-14) and 59% previously received ibrutinib. The established MTD was 40 mg of selinexor (days 1, 8, 15) and 420 mg daily ibrutinib. Common nonhematologic adverse events were fatigue (56%), nausea (53%), anorexia (41%), and diarrhea (41%) and were mostly low grade. Overall response rate was 32%. An additional 47% achieved stable disease (SD), some prolonged (up to 36 months). Median progression-free survival for patients with CLL and NHL was 8.9 [95% confidence interval (CI), 3.9-16.1] and 2.7 (95% CI, 0.7-5.4) months, respectively. For patients with CLL who did not receive prior ibrutinib, only 20% (1/5) progressed. Estimated 2-year overall survival was 73.7% (95% CI, 44.1-89.2) and 27.8% (95% CI, 10.1-48.9) for patients with CLL and NHL, respectively., Conclusions: The selinexor and ibrutinib combination has demonstrated tolerability in patients with relapsed/refractory CLL/NHL. Responses were durable. Notable responses were seen in patients with CLL with minimal prior therapy. Future study of this combination will focus on efforts to deepen remissions in patients with CLL receiving ibrutinib therapy., (©2022 American Association for Cancer Research.)

Purpose: Previous studies have shown an increased risk of second primary malignancies (SPMs) in survivors of diffuse large B-cell lymphoma (DLBCL). Survivors live longer due to the intensification of and improvements in therapy; thus, we aimed to characterize SPM patterns in patients with DLBCL by treatment modality., Methods and Materials: Standardized incidence ratio and absolute excess risk of SPMs were assessed in patients with primary DLBCL from 1975 to 2016 in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. A subgroup analyses based on, sex, race, age at the time of diagnosis, latency, and treatment modality were performed. Propensity score-adjusted cumulative incidence curves were generated, stratified by treatment and accounting for death as a competing risk., Results: In total, 45,946 patients with DLBCL were identified with a mean follow up of 70 months. Overall, 9.2% of patients developed an SPM with a standardized incidence ratio of 1.23 (95% confidence interval, 1.20-1.27). There was no difference in SPM risk between men and women or Black and White patients. Patients age <25 years were particularly susceptible to the development of SPMs, with a risk 2.5 times greater than patients aged 50 to 74 years. Temporal patterns showed increasing risk of solid malignancies and decreasing risk of hematologic malignancies over time, with bladder cancer posing the greatest absolute excess risk of any cancer type after 15 years. Patients treated with radiation therapy (RT), chemotherapy (CT), and chemoradiation therapy (CRT) all had an increased risk of SPM development compared with the general population. The cumulative incidence of SPMs was the lowest in patients treated with RT and the highest when treated with CRT. In the modern treatment era, the cumulative incidence of SPM for patients treated with CT versus CRT was not significantly different., Conclusions: In this large population-based study, we demonstrate unique SPM risk patterns based on age, latency, and treatment modality that have important implications for the treatment and screening of patients diagnosed with DLBCL., (© 2022 The Author(s).)

Introduction: The utility of dose escalation after positive positron emission tomography following 2 cycles of ABVD (PET2) for Hodgkin Lymphoma (HL) remains controversial. We describe the United States real-world practice patterns for PET2 positive patients., Patients and Methods: Data was collected from 15 sites on PET2 positive HL patients after receiving frontline treatment between January, 2015 and June, 2019. Descriptive analyses between those with therapy change and those continuing initial therapy were assessed., Results: A total of 129 patients were identified; 111 (86%) were treated with ABVD therapy and 18 (14%) with an alternate regimen. At PET2 assessment, 74.4% (96/129) had Deauville score (DS) 4 and 25.6% (33/129) had DS 5. Of the 66 limited stage (LS) patients with PET2 DS score of 4/5, 77.3% (51/66) continued initial therapy and 22.7% (15/66) changed to escalated therapy. The 12-month progression-free survival (PFS) for DS 4/5 LS patients was 67.0% (95% CI; 54.9-81.7) for patients without escalation compared with 51.4% (95% CI; 30.8-85.8) for those who escalated. Of the 63 DS 4/5 patients with advanced stage (AS) disease, 76.2% (48/63) continued initial therapy and 23.8% (15/63) changed to escalated therapy. The 12-month PFS for DS 4/5 AS patients was 38.3% (95% CI: 26.3%-55.7%) for patients without escalation compared with 57.1% (95% CI: 36.3-89.9) for those with escalation., Conclusion: A minority of PET2 positive HL patients undergo therapy escalation and outcomes remain overall suboptimal. Improved prognostics markers and better therapeutics are required to improve outcomes for high-risk PET2 positive HL patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation BTK inhibitor with greater BTK selectivity. This analysis characterizes pooled CV adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: NCT02029443, NCT02475681, NCT02970318 and NCT02337829). Acalabrutinib was given orally at total daily doses of 100-400 mg, later switched to 100 mg twice daily, and continued until disease progression or toxicity. Data from 762 patients (median age: 67 years [range, 32-89]; median follow-up: 25.9 months [range, 0-58.5]) were analyzed. Cardiac AE of any grade were reported in 129 patients (17%; grade ≥3, n=37 [5%]) and led to treatment discontinuation in seven patients (1%). The most common any-grade cardiac AE were atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). Overall, 91% of patients with cardiac AE had CV risk factors before acalabrutinib treatment. Among 38 patients with atrial fibrillation/flutter events, seven (18%) had prior history of arrhythmia or atrial fibrillation/flutter. Hypertension AE were reported in 67 patients (9%), 43 (64%) of whom had a preexisting history of hypertension; no patients discontinued treatment due to hypertension. No sudden cardiac deaths were reported. Overall, these data demonstrate a low incidence of new-onset cardiac AE with acalabrutinib in patients with CLL. Findings from the head-to-head, randomized trial of ibrutinib and acalabrutinib in patients with highrisk CLL (clinicaltrials gov. Identifier: NCT02477696) prospectively assess differences in CV toxicity between the two agents.

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.

Introduction: Frontline treatment of hairy cell leukemia (HCL) with a single course of the purine nucleoside analog (PNA) produces a high rate of complete remission (CR) with prolonged durations. At the time of relapse, although treatment guidelines recommend re-treatment with a PNA alone or in combination with rituximab (R), practice patterns vary and data supporting each approach are limited., Methods: We conducted a multisite outcomes analysis of patients treated for HCL between 1995 and 2018 at six US medical centers. All patients were treated with frontline PNA and subsequently required treatment with a PNA alone (PNA) or with R (+R)., Results: Of the 88 patients analyzed, 56 (63.6%) received second-line PNA and 22 (36.4%) received a PNA + R. Baseline characteristics of both groups were similar. There was no difference in median PFS [67 months (95% CI 43.8 non-reached (NR)) vs. 65 months (95% CI 60-NR)] or 5-year OS [98% (95% CI 0.94-1) vs. 94% (95% CI 0.83-1), p = .104] in the PNA versus PNA + R cohorts, respectively., Conclusion: To our knowledge, this is the largest study evaluating the role of R in treatment of relapsed HCL and suggests that there is no advantage to the addition of R to PNA therapy at the time of first re-treatment., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 × 106 or 100 × 106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2-11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100 × 106 CAR+ T cells. This trial was registered at clinicaltrials.gov as NCT03331198., (© 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.)

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need., (© 2022 by The American Society of Hematology.)

Anti-CD20 monoclonal antibodies (mAbs) have revolutionized the treatment of chronic lymphocytic leukemia (CLL) by improving survival of patients with CLL in conjunction with chemotherapy. However, the novel targeted agents such as Bruton tyrosine kinase inhibitors (BTKis) and venetoclax have now mostly replaced chemotherapy in frontline treatment of CLL. Several clinical trials have been conducted to examine the role of anti-CD20 mAbs in combination with BTK inhibitors and venetoclax. Addition of rituximab to ibrutinib does not improve progression-free survival (PFS) of treatment-naive patients with CLL, possibly related to ibrutinib's antagonistic effect on anti-CD20 antibodies. Alternatively, addition of a glycoengineered anti-CD20 mAb obinutuzumab to a more selective BTKi acalabrutinib may improve PFS but does not improve overall survival of patients with CLL in the frontline setting, pending long-term follow-up. Thus, we suggest that the addition of an anti-CD20 mAb to a BTKi is of most benefit to patients with autoimmune cytopenia or rapidly progressive disease. In contrast to BTKis, combination of fixed-duration venetoclax and anti-CD20 mAb can induce deep remission with high rates of undetectable minimal residual disease, correlating with improved survival of patients with CLL in both frontline and relapsed/refractory settings. In this review, we discuss clinical trials of BTKis and venetoclax that have investigated the role of anti-CD20 mAbs in frontline and relapsed settings of CLL treatment. We also provide an algorithm suggesting how anti-CD20 mAbs may be incorporated in the treatment of patients with CLL, including specific scenarios., (Copyright © 2021 by The American Society of Hematology.)

Bruton tyrosine kinase (BTK) inhibition is an effective therapy for many B-cell malignancies. Acalabrutinib is a next-generation, potent, highly selective, covalent BTK inhibitor. To characterize acalabrutinib tolerability, we pooled safety data from 1040 patients with mature B-cell malignancies treated with acalabrutinib monotherapy in nine clinical studies (treatment-naïve: n = 366 [35%], relapsed/refractory: n = 674 [65%]; median [range] age: 67 [32-90] years; median [range] prior treatments: 1 [0-13]; median [range] duration of exposure: 24.6 [0.0-58.5] months). The most common adverse events (AEs) were headache (38%), diarrhea (37%), upper respiratory tract infection (22%), contusion (22%), nausea (22%), fatigue (21%), and cough (21%). Serious AEs (SAEs) occurred in 39% of patients; pneumonia (6%) was the only SAE that occurred in ≥2%. Deaths due to AEs occurred in 52 patients (5%); pneumonia (n = 8) was the only fatal AE to occur in ≥3 patients. AEs led to treatment discontinuation in 9%. Rates for the AEs of interest (all grades) included infections (67%), hemorrhages (46%), neutropenia (16%), anemia (14%), second primary malignancies (12%), thrombocytopenia (9%), hypertension (8%), and atrial fibrillation (4%). This pooled analysis confirmed acalabrutinib's tolerability and identified no newly emerging late toxicities, supporting acalabrutinib as a long-term treatment for patients with mature B-cell malignancies., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Chronic lymphocytic leukemia (CLL) patients who develop Hodgkin lymphoma (HL) have limited survival. No current therapeutic standard of care exists. We conducted a multi-center retrospective study of patients with Hodgkin Transformation (HT) of CLL. Clinicobiologic characteristics, treatment type, and survival outcomes were analyzed and compared with historic case series. Ninety-four patients were identified. Median age at HT was 67 years (range, 38-85). Median time from CLL diagnosis to HT was 5.5 years (range, 0-20.2). Prior to HT, patients received a median of 2 therapies for CLL (range, 0-12). As initial therapy for HT, 61% (n=62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine). Seven (7%) patients received hematopoietic cell transplantation (HCT) while in first complete remission (CR1). The median number of treatments for HT per patient was 1 (range, 0-5) with 59 (61%) patients only receiving one line of therapy. After HT, patients had a median follow-up of 1.6 years (range, 0-15.1). Two-year overall survival (OS) after HT diagnosis was 72% (95%CI 62-83%). The patients who received standard ABVD-based therapy had a median OS of 13.2 years. Although limited by small sample size, the patients who underwent HCT for HT in CR1 had a similar 2-year OS (n=7; 67%) compared to patients who did not undergo HCT for HT in CR1 (n=87; 72%; p=0.46). In this multi-center study, HT patients treated with ABVD-based regimens had prolonged survival supporting the use of these regimens as standard of care for these patients.

Bruton tyrosine kinase inhibitors (BTKi) have significantly changed the treatment landscape for patients with B-cell malignancies, including chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Unfortunately, patients with BTKi-resistant disease have shortened survival. Clinical and molecular risk factors, such as number of prior therapies and presence of TP53 mutations, can be used to predict patients at the highest risk of developing BTKi resistance. Many mechanisms of BTKi resistance have been reported with mutations in BTK and phospholipase C γ2 supported with the most data. The introduction of venetoclax has lengthened the survival of patients with BTKi-resistant disease. Ongoing clinical trials with promising treatment modalities, such as next-generation BTKi and chimeric antigen receptor T-cell therapy, have reported promising efficacy in patients with BTKi-resistant disease. Continued research focusing on resistance mechanisms and methods of how to circumvent resistance is needed to further prolong the survival of patients with BTKi-resistant B-cell malignancies., (© 2021 by The American Society of Hematology.)

Background: Prolonged periods of confined living on a cruise ship increase the risk for respiratory disease transmission. We describe the epidemiology and clinical characteristics of a SARS-CoV-2 outbreak in Australian passengers on the Diamond Princess cruise ship and provide recommendations to mitigate future cruise ship outbreaks., Methods: We conducted a retrospective cohort study of Australian passengers who travelled on the Diamond Princess from 20 January until 4 February 2020 and were either hospitalised, remained in Japan or repatriated. The main outcome measures included an epidemic curve, demographics, symptoms, clinical and radiological signs, risk factors and length of time to clear infection., Results: Among 223 Australian passengers, 56 were confirmed SARS-CoV-2 positive. Forty-nine cases had data available and of these over 70% had symptoms consistent with COVID-19. Of symptomatic cases, 17% showed signs and symptoms before the ship implemented quarantine and a further two-thirds had symptoms within one incubation period of quarantine commencing. Prior to ship-based quarantine, exposure to a close contact or cabin mate later confirmed SARS-CoV-2 positive was associated with a 3.78 fold (95% CI, 2.24-6.37) higher risk of COVID-19 acquisition compared to non-exposed passengers. Exposure to a positive cabin mate during the ship's quarantine carried a relative risk of 6.18 (95% CI, 1.96-19.46) of developing COVID-19. Persistently asymptomatic cases represented 29% of total cases. The median time to the first of two consecutive negative PCR-based SARS-CoV-2 assays was 13 days for asymptomatic cases and 19 days for symptomatic cases (p = 0.002)., Conclusion: Ship based quarantine was effective at reducing transmission of SARS-CoV-2 amongst Australian passengers, but the risk of infection was higher if an individual shared a cabin or was a close contact of a confirmed case. Managing COVID-19 in cruise ship passengers is challenging and requires enhanced health measures and access to onshore quarantine and isolation facilities., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Comorbid medical conditions define a subset of patients with chronic lymphocytic leukemia (CLL) with poor outcomes. However, which comorbidities are most predictive remains understudied., Experimental Design: We conducted a retrospective analysis from 10 academic centers to ascertain the relative importance of comorbidities assessed by the cumulative illness rating scale (CIRS). The influence of specific comorbidities on event-free survival (EFS) was assessed in this derivation dataset using random survival forests to construct a CLL-specific comorbidity index (CLL-CI). Cox models were then fit to this dataset and to a single-center, independent validation dataset., Results: The derivation and validation sets comprised 570 patients (59% receiving Bruton tyrosine kinase inhibitor, BTKi) and 167 patients (50% receiving BTKi), respectively. Of the 14 CIRS organ systems, three had a strong and stable influence on EFS: any vascular, moderate/severe endocrine, moderate/severe upper gastrointestinal comorbidity. These were combined to create the CLL-CI score, which was categorized into 3 risk groups. In the derivation dataset, the median EFS values were 58, 33, and 20 months in the low, intermediate, and high-risk groups, correspondingly. Two-year overall survival (OS) rates were 96%, 91%, and 82%. In the validation dataset, median EFS values were 81, 40, and 23 months (two-year OS rates 97%/92%/88%), correspondingly. Adjusting for prognostic factors, CLL-CI was significantly associated with EFS in patients treated with either chemo-immunotherapy or with BTKi in each of our 2 datasets., Conclusions: The CLL-CI is a simplified, CLL-specific comorbidity index that can be easily applied in clinical practice and correlates with survival in CLL., (©2021 American Association for Cancer Research.)

Acalabrutinib has demonstrated significant efficacy and safety in relapsed chronic lymphocytic leukemia (CLL). Efficacy and safety of acalabrutinib monotherapy were evaluated in a treatment-naive CLL cohort of a single-arm phase 1/2 trial (ACE-CL-001). Adults were eligible for enrollment if chemotherapy was declined or deemed inappropriate due to comorbidities (N = 99). Patients had a median age of 64 years and 47% had Rai stage III/IV disease. Acalabrutinib was administered orally 200 mg once daily, or 100 mg twice daily until progression or intolerance. A total of 99 patients were treated; 57 (62%) had unmutated immunoglobulin heavy-chain variable gene, and 12 (18%) had TP53 aberrations. After median follow-up of 53 months, 85 patients remain on treatment; 14 discontinued treatment, mostly because of adverse events (AEs) (n = 6) or disease progression (n = 3). Overall response rate was 97% (90% partial response; 7% complete response), with similar outcomes among all prognostic subgroups. Because of improved trough BTK occupancy with twice-daily dosing, all patients were transitioned to 100 mg twice daily. Median duration of response (DOR) was not reached; 48-month DOR rate was 97% (95% confidence interval, 90-99). Serious AEs were reported in 38 patients (38%). AEs required discontinuation in 6 patients (6%) because of second primary cancers (n = 4) and infection (n = 2). Grade ≥3 events of special interest included infection (15%), hypertension (11%), bleeding events (3%), and atrial fibrillation (2%). Durable efficacy and long-term safety of acalabrutinib in this trial support its use in clinical management of symptomatic, untreated patients with CLL., (© 2021 by The American Society of Hematology.)

Aim: Chronic lymphocytic leukemia (CLL) has been shown to cluster in families. First-degree relatives of individuals with CLL have an ~8 fold increased risk of developing the malignancy. Strong heritability suggests pedigree studies will have good power to localize pathogenic genes. However, CLL is relatively rare and heterogeneous, complicating ascertainment and analyses. Our goal was to identify CLL risk loci using unique resources available in Utah and methods to address intra-familial heterogeneity., Methods: We identified a six-generation high-risk CLL pedigree using the Utah Population Database. This pedigree contains 24 CLL cases connected by a common ancestor. We ascertained and genotyped eight CLL cases using a high-density SNP array, and then performed shared genomic segment (SGS) analysis - a method designed for extended high-risk pedigrees that accounts for heterogeneity., Results: We identified a genome-wide significant region ( P = 1.9 × 10 -7 , LOD-equivalent 5.6) at 2q22.1. The 0.9 Mb region was inherited through 26 meioses and shared by seven of the eight genotyped cases. It sits within a ~6.25 Mb locus identified in a previous linkage study of 206 small CLL families. Our narrow region intersects two genes, including CXCR4 which is highly expressed in CLL cells and implicated in maintenance and progression., Conclusion: SGS analysis of an extended high-risk CLL pedigree identified the most significant evidence to-date for a 0.9 Mb CLL disease locus at 2q22.1, harboring CXCR4. This discovery contributes to a growing literature implicating CXCR4 in inherited risk to CLL. Investigation of the segregating haplotype in the pedigree will be valuable for elucidating risk variant(s).