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Background: Mosunetuzumab is a CD20xCD3 T-cell engaging bispecific antibody approved in Europe and the United States for relapsed/refractory (R/R) follicular lymphoma (FL) after ≥ 2 prior therapies., Materials and Methods: We present interim safety data from the mosunetuzumab GO29781 (NCT02500407) phase I/II dose-escalation study in R/R non-Hodgkin lymphoma (NHL), focusing on FL., Results: Overall, 218 patients with R/R NHL, including 90 with R/R FL, received a median of eight 21-day cycles of intravenous mosunetuzumab with step-up dosing in Cycle (C) 1 (C1 Day [D] 1, 1 mg; C1D8, 2 mg; C1D15/C2D1, 60 mg; C3D1 and onwards, 30 mg). Cytokine release syndrome (CRS) was the most common adverse event (AE), occurring in 39.4% (NHL) and 44.4% (FL) of patients. Events occurred predominantly during C1 at the first loading dose; the majority were grade 1/2. CRS events were managed at the investigator's discretion with supportive care, steroids, and tocilizumab, based on protocol management guidelines. Immune effector cell-associated neurotoxicity syndrome was uncommon, reported in 0.9% (NHL) and 1.1% (FL) of patients. Neutropenia occurred in 27.5% (NHL) and 28.9% (FL) of patients (mostly grade 3/4) and could be effectively managed using granulocyte colony-stimulating factor. Tumor lysis syndrome occurred in 0.9% (NHL) and 1.1% (FL) of patients (all grade 3/4 with CRS; all resolved)., Conclusion: Mosunetuzumab monotherapy as treatment for R/R B-cell NHL, including FL, was associated with low rates of severe AEs (including CRS) and is suitable for outpatient administration in the community setting. Adapted protocol guidance for the management of select AEs during mosunetuzumab treatment is included., Competing Interests: Disclosure MM: employment (Rutgers Cancer Institute of New Jersey and RWJBarnabas Health), consultancy (ADC Therapeutics, AstraZeneca, Bayer, Daiichi Sankyo, Epizyme, F. Hoffmann-La Roche Ltd, Genentech, Inc., IMV Therapeutics, Juno Therapeutics, Karyopharm, Merck, MEI Pharma, Rocket Medical, Seattle Genetics, TG Therapeutics, Teva, Bayer), stockholder (Merck), research funding (AstraZeneca, Bayer, Genentech, Inc., IGM Biosciences, Janssen, Pharmacyclics, F. Hoffmann-La Roche Ltd, Seattle Genetics), honoraria (ADC Therapeutics, Bayer, Daiichi Sankyo, Epizyme, IMV Therapeutics, Janssen, MEI Pharma, Pharmacyclics, Genentech, Inc., F. Hoffmann-La Roche Ltd, Seattle Genetics). NLB: employment (Washington University School of Medicine), research funding (ADC Therapeutics, Autolus, Bristol Myers Squibb, Celgene, Forty Seven, Janssen, Kite Pharma, Merck, Millennium, Pharmacyclics, F. Hoffmann-La Roche Ltd/Genentech, Inc., Seattle Genetics), membership on an entity's Board of Directors or advisory committees (ADC Therapeutics, F. Hoffmann-La Roche Ltd/Genentech, Inc., Seattle Genetics). MS: consulting, advisory boards, steering committees, or data safety monitoring committees (AbbVie, Genentech, Inc., AstraZeneca, Sound Biologics, Pharmacyclics, BeiGene, Bristol Myers Squibb, MorphoSys/Incyte, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio, Regeneron, Merck, Fate Therapeutics, MEI Pharma, Atara Biotherapeutic), research funding (Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Inc., AbbVie, TG Therapeutics, BeiGene, AstraZeneca, Sunesis, Atara Biotherapeutics, Genmab, MorphoSys/Incyte, Vincrex). LEB: consultancy payments paid to City of Hope National Medical Center (Genentech, Inc., AstraZeneca, Kite Pharma, ADC Therapeutics), research grants given to City of Hope National Medical Center (Merck, Amgen, Mustang Bio, AstraZeneca). IF: consultancy payments paid to Sarah Cannon Research Institute (AbbVie, AstraZeneca, BeiGene, Century Therapeutics, Genentech, Genmab, Hutchison MediPharma, Iksuda Therapeutics, InnoCare Pharma, Janssen, Kite Pharma, MorphoSys, Myeloid Therapeutics, Novartis, Nurix Therapeutics, Pharmacyclics, F. Hoffmann-La Roche Ltd, Secura Bio, Servier Pharmaceuticals, Takeda, TG Therapeutics, Verastem, Vincerx Pharma, Xencor), research grants given to Sarah Cannon Research Institute (AbbVie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Biopath, Bristol Myers Squibb, CALIBR, CALGB, Celgene, City of Hope National Medical Center, Constellation Pharmaceuticals, Curis, CTI Biopharma, Epizyme, Fate Therapeutics, Forma Therapeutics, Forty Seven, Genentech, Inc., Gilead Sciences, InnoCare Pharma, IGM Biosciences, Incyte, Infinity Pharmaceuticals, Janssen, Kite Pharma, Loxo, Merck, Millennium Pharmaceuticals, MorphoSys, Myeloid Therapeutics, Novartis, Nurix, Pfizer, Pharmacyclics, Portola Pharmaceuticals, Rhizen Pharmaceuticals, F. Hoffmann-La Roche Ltd, Seattle Genetics, Tessa Therapeutics, TCR2 Therapeutics, TG Therapeutics, Trillium Therapeutics, Triphase Research & Development Corp., Unum Therapeutics, Verastem). GPG: consulting and/or advisory role and honoraria (F. Hoffmann-La Roche Ltd, Janssen, MSD, Gilead, Novartis, AstraZeneca, LINK Clinigen), research funding (MSD, BeiGene, Janssen, AbbVie). WSK: research funding (Sanofi, BeiGene, Boryung, F. Hoffmann-La Roche Ltd, Kyowa Kirin, Dong-A). GH: consultancy (AbbVie, ADC Therapeutics, AstraZeneca, Bristol Myers Squibb, Genmab, Gilead/Kite, Incyte, Janssen, Lilly, Miltenyi, Novartis, F. Hoffmann-La Roche Ltd), honoraria (AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Genmab, Gilead, Incyte, Janssen, Lilly, F. Hoffmann-La Roche Ltd), research funding (AbbVie, Gilead/Kite, Incyte, Janssen, MorphoSys, Pfizer, F. Hoffmann-La Roche Ltd), travel grants (Gilead/Kite, Janssen), advisory board/data safety monitoring board (Miltenyi). DE-S: honoraria (AbbVie, AstraZeneca, BeiGene, Gilead, Janssen, Lily, F. Hoffmann-La Roche Ltd, Takeda), conference/travel support (AbbVie, Novartis, F. Hoffmann-La Roche Ltd), advisory boards (AbbVie, ASTEX, AstraZeneca, BeiGene, Janssen, Kyowa Kirin). CSD: consultancy, research funding (Bristol Myers Squibb, Genentech, Inc./F. Hoffmann-La Roche Ltd, Merck, MorphoSys), consultancy (Celgene, Genmab, IMAB, Kite), research funding (FATE Therapeutics, Incyte), equity (Gilead, MEI Pharma, Seattle Genetics). HH: employment (Hoffmann-La Roche Ltd). IT: employment and equity (Genentech, Inc.). JP: employment, stockholder, stock options, honoraria (F. Hoffmann-La Roche Ltd). MW: employment, stockholder (Genentech, Inc.). AK: employment, stockholder (F. Hoffmann-La Roche Ltd/Genentech, Inc.). SA: consultancy, honoraria (Genentech, Inc./F. Hoffmann-La Roche Ltd, AstraZeneca, Novartis, Bristol Myers Squibb, Gilead, Amgen, BeiGene, AbbVie, Paladin), research funding (Novartis)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Mantle cell lymphoma (MCL) is a moderately aggressive lymphoma subtype, generally viewed as incurable. For younger, fit patients, the standard of care remains various high-dose cytarabine-based induction regimens followed by autologous hematopoietic cell transplant and 3 years of rituximab maintenance. Despite reasonably good outcomes, with median progression-free survival in the range of 7 to 9 years, most patients eventually relapse, indicating a need to improve the safety and tolerability of remission induction strategies., Methods: Given the impressive activity of bendamustine/rituximab (BR) in older patients with MCL, we developed an induction regimen modeled after the Nordic Regimen but substituted BR in place of R-CHOP. In a second pilot study, we incorporated the second-generation Bruton tyrosine kinase inhibitor (BTKi), acalabrutinib, into the regimen. The primary endpoint of both studies was stem cell mobilization success rate., Results: All patients successfully underwent stem cell harvest in both studies., Conclusion: The experience from our single institution pilot study suggested that sequential rather than alternating BR and cytarabine/rituximab (CR) was easier to administer from the standpoint of toxicities and subsequent dose modifications. Safety and efficacy data from the 2 pilot studies, FitMCL 1.0 and 2.0, were similar. The pilot studies provided preliminary safety data supporting the development of the NCTN trial EA4181, assessing three different induction regimens with or without acalabrutinib., Competing Interests: Disclosure The authors do not have any disclosures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.)

Background: Extranodal natural killer/T-cell lymphoma (ENKTL) is rare and clinical data from non-Asian countries are lacking. It is unclear whether outcomes and disease natural history is similar to reported Asian series. We assessed characteristics and outcomes of patients with ENKTL from major North American centers., Patients and Methods: We retrospectively identified patients with newly-diagnosed CD56 + ENKTL and studied disease characteristics and clinical outcomes., Results: One hundred and twenty-one patients with ENKTL diagnosed between June 1990 and November 2012 were identified. Eighty-three patients (69%) had stage I/II disease and were treated with combined modality therapy (CMT) (n = 53), chemotherapy alone (CT) (n = 14) or radiotherapy alone (RT) (n = 16).  Thirty-eight patients (31%) had stage III/IV disease and were treated with CMT (n = 12), CT (n = 23), or RT (n = 3).  The median follow-up for the entire cohort was 51 months. Patients with stage I/II disease, compared to those with stage III/IV disease, had superior 2-year progression free survival (PFS) 43% vs 19% (P = .03) and overall survival (OS) 59% vs. 29% (P= .004). Outcomes were similar for stage I/II patients who received CMT vs. RT alone with 2-year PFS (53% vs. 47%; P= .91) and OS (67% vs. 67%; P= .58). No significant differences in outcomes were noted based on race/ethnicity., Conclusions: This series represents a large experience of ENKTL treated at several major North American academic centers.  Our data are consistent with Asian studies: (1) majority of patients present with early-stage disease; (2) overall poor outcome regardless of race/ethnicity; (3) CMT likely yields favorable outcomes for suitable candidates with early-stage disease., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Extranodal natural killer/T-cell lymphoma (ENKTL) is rare and clinicaldata from non-Asian countries are lacking. It is unclear whether outcomes and diseasenatural history is similar to reported Asian series. We assessed characteristics and outcomes of patients with ENKTL from major North American centers., Patients and Methods: We retrospectively identified patients with newly-diagnosedCD56 + ENKTL and studied disease characteristics and clinical outcomes., Results: 121 patients with ENKTL diagnosed between June 1990 and November 2012 were identified. Eighty-three patients (69%) had stage I/II disease and were treatedwith combined modality therapy (CMT) (n=53), chemotherapy alone (CT) (n=14) orradiotherapy alone (RT) (n=16). Thirty-eight patients (31%) had stage III/IV diseaseand were treated with CMT (n=12), CT (n=23), or RT (n=3). The median follow-up forthe entire cohort was 51 months. Patients with stage I/II disease, compared to thosewith stage III/IV disease, had superior 2-year progression free survival (PFS) 43% vs19% (p=0.03) and overall survival (OS) 59% vs 29% (p=0.004). Outcomes were similarfor stage I/II patients who received CMT vs RT alone with 2-year PFS (53% vs 47%;p=0.91) and OS (67% vs 67%; p=0.58). No significant differences in outcomes werenoted based on race/ethnicity., Conclusions: This series represents a large experience of ENKTL treated at several major North American academic centers., Our Data Are Consistent With Asian Studies: 1) majority of patients present with early-stage disease; 2) overall poor outcome regardless of race/ethnicity; 3) CMT likely yields favorable outcomes for suitable candidates with early-stage disease., Competing Interests: Disclosure The authors declare that they have no competing financial interests in relation to the work described., (Copyright © 2021. Published by Elsevier Inc.)

Background: The addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy for diffuse large B-cell lymphoma (DLBCL) has led to improvements in progression-free survival and overall survival, although the exact mechanism of rituximab is not known. Rituximab administration often results in transient, non-life-threatening infusion reactions (IRs). We report a retrospective cohort of patients with DLBCL who received rituximab to determine the significance of IRs on clinical outcomes., Patients and Methods: We identified and analyzed a retrospective cohort of 229 patients with DLBCL. They were stratified into 2 cohorts; those who did and did not have an IR. Univariate and multivariate analyses were performed to evaluate the prognostic significance of rituximab-related IRs relative to DLBCL subtype, International Prognostic Index score, c-Myc translocations or amplifications, chemotherapy regimen, and Ki-67 proliferative index., Results: Baseline characteristics did not differ significantly between the 2 groups. Rituximab was included as initial treatment in all patients. Patients with an IR had a significantly higher overall survival (hazard ratio, 0.26; 95% confidence interval, 0.07-0.95) at 5 years. In addition, subgroup analysis showed a significantly higher progression-free survival in patients with the germinal center subtype of disease and c-Myc alterations who had a rituximab-related IR (log-rank P < .0001)., Conclusions: The presence of a rituximab-related IR is associated with a better overall survival in patients with DLBCL. Although limited by the small sample size and retrospective nature, these results provide rationale for further investigation into the mechanism of action of rituximab in order to optimize the efficacy of CD20 monoclonal antibodies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Until recently, advances in classic Hodgkin lymphoma (HL) treatment primarily consisted of minor modifications of highly effective decades-old chemotherapy and radiation approaches. In early-stage disease, excellent outcomes have been reported with fewer cycles of chemotherapy, lower doses, smaller radiation fields and in some circumstances, radiation elimination. In advanced-stage disease, maintaining the dose intensity of standard chemotherapy regimens has resulted in modest improvements in outcomes. During the past decade, the use of early interim positron emission tomography (PET) scans to escalate or de-escalate treatment has been the subject of intense investigation with the goal of maximizing efficacy and minimizing toxicity. Important updates from recent PET-directed trials include; elimination of bleomycin in patients with advanced-stage HL and negative interim PET findings, the benefit of therapy escalation in patients with unfavorable early-stage HL and positive interim PET findings, and the minimal benefit of consolidative radiotherapy in patients with unfavorable early-stage HL and negative interim PET findings. A more nuanced approach to consolidative radiotherapy is required for patients with favorable early-stage disease based on age, disease sites, secondary cancer risk, and cardiovascular disease. Brentuximab vedotin and nivolumab/pembrolizumab have provided promising new options with surprisingly high response rates and modest toxicity for patients with relapsed HL whose disease does not respond to standard treatments. Incorporating these agents into earlier therapy is an area of active investigation for all stages of HL. Although the overall prognosis for HL patients has seen incremental improvement, efforts to optimize treatment with more effective and less toxic approaches continue., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Lenalidomide and panobinostat have shown single-agent efficacy of 14% to 50% and 27% to 58%, respectively, in Hodgkin lymphoma (HL). This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide combined with panobinostat in relapsed/refractory HL., Patients and Methods: In the phase I trial, previously treated patients with classical or lymphocyte-predominant HL received escalating doses of lenalidomide on days 1 to 21 and panobinostat 3 times a week (TIW) every 28 days. Dose-limiting toxicity (DLT) was defined during cycle 1. When the MTD was determined, a phase II study was conducted to determine overall response (OR)., Results: Twenty-four patients enrolled; 11 in the phase I and 13 in phase II portions. No DLTs were observed but 2 patients who received 25 mg lenalidomide and 20 mg panobinostat experienced neutropenia and thrombocytopenia > 14 days in cycle 2, leading to selection of 25 mg lenalidomide on days 1 to 21 and 15 mg panobinostat TIW for the phase II dose. In all 24 patients, Grade 3 to 4 toxicities consisted of neutropenia (58%), thrombocytopenia (42%), lymphopenia (25%), and febrile neutropenia (25%). OR was 16.7% (2 complete response [CR] and 2 partial response). One patient with CR had lymphocyte-predominant HL and received 22 cycles. Median progression-free survival and overall survival were 3.8 and 16.4 months, respectively., Conclusion: Although the combination of panobinostat and lenalidomide appears safe in patients with relapsed/refractory HL, the limited efficacy and significant rates of neutropenia and febrile neutropenia observed do not support further evaluation of this combination in HL., (Copyright © 2017 Elsevier Inc. All rights reserved.)