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We analyzed access barriers to anti-CD19+ chimeric antigen receptor T-cells (CART) for non-Hodgkin lymphoma (NHL) within a community-based transplant and cell therapy network registry. 357 intended recipients of FDA-approved anti-CD19+ CART were identified in the study period (2018 to 2022). Results showed that the median age at referral was 61 years, referral year was 2018 (4%), 2019 (14%), 2020 (18%), 2021 (26%), and 2022 (38%). Diagnoses were diffuse large B-cell (69%), follicular (13%), follicular/large (7%), mantle cell (4%), or other (7%). CART products infused were Axi-cel (62%), Tisa-cel (16%), Brexu-cel (13%) and Liso-cel (9%). 182 patients were infused with CART. The median durations between referral to consultation, consultation to apheresis, and collection to infusion were 11, 107, and 32 days, respectively. The median duration from consultation to CART infusion declined steadily from 207 days in 2019 to 108 days in 2022. [P <0.0001] 124 patients (41%) did not receive CART mostly for disease progression (34%) or poor health (15%). Multivariable logistic regression showed no significant differences in demographic, financial, or social determinants compared to those receiving CART. Notably, the proportion of ineligible patients declined from 53% in 2018-2020 to 34% by 2021-2022 [P=0.001]. In conclusion, 41% of community patients were unable to access timely CART therapy for NHL, mostly related to attrition from disease-related causes while overall time to infusion exceeded four months. Time to infusion as well as the proportion receiving CART improved over time. Reducing time to apheresis, early referral, and careful attention to salvage/bridging strategies are necessary., (Copyright © 2024 American Society of Hematology.)

Clinical bleeding events are reported here from 773 patients with B-cell malignancies receiving pirtobrutinib monotherapy from the phase 1/2 BRUIN study (ClinicalTrials.gov identifier: NCT03740529), either in the presence or absence of antithrombotic therapy (antithrombotic exposed [AT-E], n  = 216; antithrombotic nonexposed [AT-NE], n  = 557). Among the AT-E cohort, 51.9% received platelet aggregation inhibitors, 36.6% received direct factor Xa inhibitors, 18.5% received heparins, 5.6% received salicylic acid for indications other than platelet aggregation inhibition, and 2.3% received thrombolytics. Warfarin was not permitted. Any-grade bleeding/bruising events occurred in 97 patients (44.9%; 95% confidence interval [CI], 38.3-51.5) in the AT-E cohort and 181 patients (32.5%; 95% CI, 28.6-36.4) in the AT-NE cohort. Most bleeding/bruising events in both cohorts began within the first 6 months of treatment (AT-E: 65.4%; AT-NE: 72.5%). Contusion was the most common bleeding/bruising event in both cohorts (AT-E: 22.7%; AT-NE: 18.1%). Grade ≥3 bleeding/bruising events were reported in six patients (2.8%) in the AT-E cohort and 11 patients (2.0%) in the AT-NE cohort. Bleeding/bruising events requiring or prolonging hospitalization were reported in 2.3% and 1.6% of patients in the AT-E and AT-NE cohorts, respectively. No bleeding/bruising events led to pirtobrutinib dose reduction or permanent discontinuation in the AT-E cohort, and one patient (0.2%) in the AT-NE cohort experienced an event requiring dose reduction. These data support the safety of pirtobrutinib in patients requiring antithrombotic therapies., Competing Interests: NL reports research funding from Genentech, TG Therapeutics, BeiGene, AstraZeneca, AbbVie, MingSight, Eli Lilly and Company/Loxo@Lilly, Oncternal Therapeutics, and Octapharma, and consulting fees/honoraria from Genentech, Pharmacyclics, BeiGene, AstraZeneca, AbbVie, Adaptive Biotechnologies, Eli Lilly and Company/Loxo@Lilly, and Janssen. CST reports honoraria from Loxo@Lilly. JAW reports grants from the National Cancer Institute, Leukemia and Lymphoma Society, and CLL Global Society; consulting fees from AbbVie, AstraZeneca, BeiGene, Genentech, Janssen, Loxo@Lilly, Merck, Newave, and Pharmacyclics; and is on the advisory board of Gilead. AJA reports honoraria from Dr. Reddy's; is on advisory boards for Genentech, Eli Lilly and Company, Amgen, TG Therapeutics, Incyte, BeiGene, Janssen, Epizyme, and SeaGen; and reports research funding from Eli Lilly and Company, Incyte, and BeiGene. MLP reports participation on a data safety monitoring board or advisory board at Bristol‐Myers Squibb, Cellectar Biosciences, MustangBio, and Synthekine. PLZ reports membership on an entity's board of directors or advisory committee at AstraZeneca, Sandoz, Celltrion Healthcare, MSD, Secura Bio, Gilead, Janssen‐Cilag, Bristol‐Myers Squibb, Takeda, Roche, Servier Pharma, Kyowa Kirin, EUSA Pharma, Novartis, ADC Therapeutics, Incyte, and BeiGene; is on the speakers bureau of AstraZeneca, Celltrion Healthcare, MSD, Gilead, Janssen‐Cilag, Bristol‐Myers Squibb, Takeda, Roche, Servier Pharma, Kyowa Kirin, EUSA Pharma, Novartis, Incyte, and BeiGene; and has consultancy roles at MSD, EUSA Pharma, and Novartis. IWF reports consultancy roles at Genmab, BeiGene, Genentech, Secura Bio, Hutchison MediPharma, Kite Pharma, InnoCare Pharma, AbbVie, Novartis, Myeloid Therapeutics, Servier Pharma, Century Therapeutics, TG Therapeutics, and Vincerx Pharma. BF reports consultancy roles and membership on an entity's board of directors or advisory committee at BeiGene, AstraZeneca, ADC Therapeutics, AbbVie, Bristol‐Myers Squibb/Juno, Genentech, Genmab/AbbVie, Loxo@Lilly, and Pharmacyclics; and research funding from Genentech, Genmab/AbbVie, Loxo@Lilly, and Pharmacyclics. JBC reports research funding from Bristol‐Myers Squibb/Celgene, Novartis, Genentech, BioInvent, LAM Therapeutics, Takeda, ADC Therapeutics, AbbVie, and Loxo/Lilly; and consultancy roles at AstraZeneca, Janssen, BeiGene, and Loxo/Lilly. WJ reports research funding from Eli Lilly and Company; grants from AstraZeneca and BeiGene; and is on the advisory board for Eli Lilly and Company, AstraZeneca, and BeiGene. AK, HK, AC, and DET report full‐time employment with Loxo Oncology during the conduct of the study. ASR, RS, and LC report full‐time employment with Eli Lilly and Company during the conduct of the study., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) ineligible for available salvage therapies have limited options for long-term disease control, necessitating novel treatments. Previously, magrolimab (anti-cluster-of-differentiation-47 antibody) plus rituximab (M+R) demonstrated ability to induce complete responses (CR) in R/R DLBCL. Here we report 3-year follow-up data from this phase 1b/2 study (NCT02953509) assessing long-term safety and efficacy of M+R, and initial safety and efficacy of M+R plus gemcitabine-oxaliplatin (M+R-GemOx), in R/R DLBCL. After magrolimab priming, 4 M+R patient groups received 10-45 mg/kg magrolimab with 375 mg/m2 rituximab; M+R-GemOx patients received 30 or 45 mg/kg magrolimab with 375 mg/m2 rituximab, 1000 mg/m2 gemcitabine, and 100 mg/m2 oxaliplatin. Primary endpoints were treatment-emergent adverse events (TEAEs) and objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Of 132 patients treated, 99 received M+R and 33 received M+R-GemOx. Most common any-grade TEAEs were fatigue (M+R, 40%; M+R-GemOx, 70%), infusion-related reactions (M+R, 39%), or anemia (M+R-GemOx, 70%). Treatment-related TEAEs led to magrolimab discontinuation in 7% (M+R) and 6% (M+R-GemOx). One death was considered treatment related (M+R-GemOx, colitis). M+R ORR was 24% (CR, 12%), and median DOR was 9.3 months. Median PFS and OS were 1.8 and 9.2 months, respectively. M+R-GemOx ORR was 52% (CR, 39%); 12-month DOR rate was 66.6% (95% CI, 33.1-86.1%). Median PFS and OS were 3.9 months and not reached, respectively. These results demonstrate that M+R with/without GemOx is well tolerated, and M+R-GemOx has clinical activity in patients with R/R DLBCL., (Copyright © 2024 American Society of Hematology.)

Relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) is generally considered incurable with current treatment options. Previous phase 1b/2 results showed combining the anti-cluster-of-differentiation (CD) 47 activity of magrolimab with the anti-CD20 activity of rituximab (M+R) has antitumor activity against R/R iNHL. Here, we report 3-year follow-up data from this phase 1b/2 study (NCT02953509) assessing long-term safety and efficacy of M+R in R/R iNHL. After magrolimab priming, 4 groups of phase 1b M+R patients received 10-45 mg/kg magrolimab maintenance doses with 375 mg/m2 rituximab. Phase 2 explored 30 and 45 mg/kg magrolimab. Primary endpoints were treatment-emergent adverse events (TEAEs) and objective response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory analysis included assessment of circulating tumor DNA, biomarkers of magrolimab tumor penetration, and drug target expression. Of 46 patients treated in phase 1b/2, 42 had follicular lymphoma and 4 had marginal zone lymphoma. All patients experienced ≥1 any-grade TEAE, and 44 reported ≥1 treatment-related TEAE. No additional toxicities were reported during long-term follow-up, and there were no treatment-related deaths. Median follow-up was 36.7 (range, 1.2-62.3) months. The ORR was 52.2%, with 30.4% achieving a complete response. The median DOR was 15.9 (95% CI, 5.6-not estimable) months. The median time-to-response was 1.8 (range, 1.6-5.5) months; median PFS and OS were 7.4 (95% CI, 4.8-13.0) months and not reached, respectively. These results demonstrate the long-term safety and efficacy of M+R in patients with iNHL and support further exploration of CD47-based treatment combinations., (Copyright © 2024 American Society of Hematology.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Mosunetuzumab is a CD20xCD3 T-cell-engaging bispecific antibody administered as an off-the-shelf, fixed-duration treatment in an outpatient setting. We report an updated analysis of the durability of response, by investigator assessment, after an overall median follow-up of 3.5 years in patients with relapsed/refractory indolent or aggressive B-cell non-Hodgkin lymphoma (iNHL/aNHL) from the dose-escalation stage of a phase I/II study of mosunetuzumab (ClinicalTrials.gov identifier: NCT02500407). Across dose levels, 65.7% of patients with iNHL and 36.4% with aNHL achieved a complete or partial response to mosunetuzumab. Median duration of response (DoR) in patients with iNHL for all responders was 23.2 months (95% CI, 13.8 to not estimable [NE]), but was not reached in complete responders (95% CI, 21.0 to NE). After a median time on study of 38.9 months, no relapses were observed beyond 26 months in complete responders. In patients with aNHL, median DoR for all responders was 7.8 months (95% CI, 4.6 to 22.8). Among 12 complete responders who progressed postmosunetuzumab treatment and were retreated with mosunetuzumab, 83.3% had an objective response and 58.3% achieved a second complete response. Our study reports the longest follow-up using bispecific antibodies in patients with B-cell non-Hodgkin lymphoma and demonstrates that mosunetuzumab can mediate durable remissions with time-limited treatment.

The antibody-coupled T cell receptor (ACTR) platform is an autologous engineered T cell therapy combining the cell-killing ability of T cells and the tumor-targeting ability of coadministered antibodies. Activation of the T cell product ACTR707 is dependent on the engagement of antibody bound to target cells via the CD16 domain of the chimeric receptor (CD16V-CD28-CD3ζ). ACTR707 in combination with the anti-CD20 monoclonal antibody rituximab was evaluated in the ATTCK-20-03 study, a multisite, single-arm, open-label phase I trial in B cell non-Hodgkin lymphoma (NHL). The primary objectives of this study were to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Secondary objectives included evaluation of antitumor activity and ACTR T cell persistence. The study design included an ACTR707 cell dose escalation phase and an expansion phase at the RP2D. Escalating dose levels of ACTR707 in combination with rituximab were explored in 5 dose cohorts, with 25 subjects receiving study treatment. Subjects received lymphodepleting chemotherapy (cyclophosphamide 400 mg/m 2 /day and fludarabine 30 mg/m 2 /day) for 3 days, followed by rituximab 375 mg/m 2 and, 24 to 48 hours later, a single dose of ACTR707. Additional doses of rituximab were administered every 3 weeks until disease progression, unacceptable toxicity, or investigator decision. Blood samples were collected at various time points to assess levels of rituximab, cytokines, inflammatory markers, and ACTR707 T cells. The overall response rate of ACTR707 plus rituximab was 56% (14 of 25) across all dose levels. Ten subjects (40.0%) achieved a complete response, with the longest duration of 586 days (range, 85 to 586 days), and 4 subjects (16.0%) experienced a partial response, with the longest duration of 130 days (range, 44 to 130 days). Only 1 case of cytokine release syndrome (grade 2) and no events of neurotoxicity were reported. There were no dose-limiting toxicities or events leading to death. ACTR707 plus rituximab resulted in only 1 adverse event (neutropenia), leading to study discontinuation of rituximab. The ATTCK-20-03 trial serves as proof of principle regarding the ACTR approach that potentially could be used with other antibodies targeting other markers in other malignancies. Although the ACTR707 program has been discontinued, these results may support other programs in the use of similar novel approaches of antibody-coupled T cell activation., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by 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: We investigated the prognostic value of baseline positron emission tomography (PET) parameters for patients with treatment-naïve follicular lymphoma (FL) in the phase III RELEVANCE trial, comparing the immunomodulatory combination of lenalidomide and rituximab (R 2 ) versus R-chemotherapy (R-chemo), with both regimens followed by R maintenance therapy., Patients and Methods: Baseline characteristics of the entire PET-evaluable population (n = 406/1032) were well balanced between treatment arms. The maximal standard uptake value (SUV max ) and the standardized maximal distance between tow lesions (SD max ) were extracted, the standardized distance between two lesions the furthest apart, were extracted. The total metabolic tumor volume (TMTV) was computed using the 41% SUV max method., Results: With a median follow-up of 6.5 years, the 6-year progression-free survival (PFS) was 57.8%, the median TMTV was 284 cm 3 , SUV max was 11.3 and SD max was 0.32 m -1 , with no significant difference between arms. High TMTV (>510 cm 3 ) and FLIPI were associated with an inferior PFS (P = 0.013 and P = 0.006, respectively), whereas SUV max and SD max were not (P = 0.08 and P = 0.12, respectively). In multivariable analysis, follicular lymphoma international prognostic index (FLIPI) and TMTV remained significantly associated with PFS (P = 0.0119 and P = 0.0379, respectively). These two adverse factors combined stratified the overall population into three risk groups: patients with no risk factors (40%), with one factor (44%), or with both (16%), with a 6-year PFS of 67.7%, 54.5%, and 41.0%, respectively. No significant interaction between treatment arms and TMTV or FLIPI (P = 0.31 or P = 0.59, respectively) was observed. The high-risk group (high TMTV and FLIPI 3-5) had a similar PFS in both arms (P = 0.45) with a median PFS of 68.4% in the R-chemo arm versus 71.4% in the R 2 arm., Conclusions: Baseline TMTV is predictive of PFS, independently of FLIPI, in patients with advanced FL even in the context of antibody maintenance., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

CAR T-cell product quality and stemness (Tstem) are major determinants of in vivo expansion, efficacy, and clinical response. Prolonged ex vivo culturing is known to deplete Tstem, affecting clinical outcome. YTB323, a novel autologous CD19-directed CAR T-cell therapy expressing the same validated CAR as tisagenlecleucel, is manufactured using a next-generation platform in <2 days. Here, we report the preclinical development and preliminary clinical data of YTB323 in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL; NCT03960840). In preclinical mouse models, YTB323 exhibited enhanced in vivo expansion and antitumor activity at lower doses than traditionally manufactured CAR T cells. Clinically, at doses 25-fold lower than tisagenlecleucel, YTB323 showed (i) promising overall safety [cytokine release syndrome (any grade, 35%; grade ≥3, 6%), neurotoxicity (any grade, 25%; grade ≥3, 6%)]; (ii) overall response rates of 75% and 80% for DL1 and DL2, respectively; (iii) comparable CAR T-cell expansion; and (iv) preservation of T-cell phenotype. Current data support the continued development of YTB323 for r/r DLBCL., Significance: Traditional CAR T-cell manufacturing requires extended ex vivo cell culture, reducing naive and stem cell memory T-cell populations and diminishing antitumor activity. YTB323, which expresses the same validated CAR as tisagenlecleucel, can be manufactured in <2 days while retaining T-cell stemness and enhancing clinical activity at a 25-fold lower dose. See related commentary by Wang, p. 1961. This article is featured in Selected Articles from This Issue, p. 1949., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition., Methods: We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety., Results: A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event., Conclusions: In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.)., (Copyright © 2023 Massachusetts Medical Society.)

Purpose: Magrolimab is a monoclonal antibody that blocks cluster of differentiation 47, a don't-eat-me signal overexpressed on cancer cells. Cluster of differentiation 47 blockade by magrolimab promotes macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine, which increases expression of eat-me signals. We report final phase Ib data in patients with untreated higher-risk myelodysplastic syndromes (MDS) treated with magrolimab and azacitidine (ClinicalTrials.gov identifier: NCT03248479)., Patients and Methods: Patients with previously untreated Revised International Prognostic Scoring System intermediate-/high-/very high-risk MDS received magrolimab intravenously as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg once-weekly or once-every-2-week maintenance dose. Azacitidine 75 mg/m 2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and complete remission (CR) rate., Results: Ninety-five patients were treated. Revised International Prognostic Scoring System risk was intermediate/high/very high in 27%, 52%, and 21%, respectively. Fifty-nine (62%) had poor-risk cytogenetics and 25 (26%) had TP53 mutation. The most common treatment-emergent adverse effects included constipation (68%), thrombocytopenia (55%), and anemia (52%). Median hemoglobin change from baseline to first postdose assessment was -0.7 g/dL (range, -3.1 to +2.4). CR rate and overall response rate were 33% and 75%, respectively. Median time to response, duration of CR, duration of overall response, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. Median overall survival (OS) was not reached with 17.1-month follow-up. In TP53 -mutant patients, 40% achieved CR with median OS of 16.3 months. Thirty-four patients (36%) had allogeneic stem-cell transplant with 77% 2-year OS., Conclusion: Magrolimab + azacitidine was well tolerated with promising efficacy in patients with untreated higher-risk MDS, including those with TP53 mutations. A phase III trial of magrolimab/placebo + azacitidine is ongoing (ClinicalTrials.gov identifier: NCT04313881 [ENHANCE]).

In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we assessed outcomes in ZUMA-1 after 5 years of follow-up. Eligible adults received lymphodepleting chemotherapy followed by axi-cel (2 × 106 cells per kg). Investigator-assessed response, survival, safety, and pharmacokinetics were assessed in patients who had received treatment. The objective response rate in these 101 patients was 83% (58% complete response rate); with a median follow-up of 63.1 months, responses were ongoing in 31% of patients at data cutoff. Median overall survival (OS) was 25.8 months, and the estimated 5-year OS rate was 42.6%. Disease-specific survival (excluding deaths unrelated to disease progression) estimated at 5 years was 51.0%. No new serious adverse events or deaths related to axi-cel were observed after additional follow-up. Peripheral blood B cells were detectable in all evaluable patients at 3 years with polyclonal B-cell recovery in 91% of patients. Ongoing responses at 60 months were associated with early CAR T-cell expansion. In conclusion, this 5-year follow-up analysis of ZUMA-1 demonstrates sustained overall and disease-specific survival, with no new safety signals in patients with refractory LBCL. Protracted B-cell aplasia was not required for durable responses. These findings support the curative potential of axi-cel in a subset of patients with aggressive B-cell lymphomas. This trial was registered at ClinicalTrials.gov, as #NCT02348216., (© 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.)

Purpose: Brexucabtagene autoleucel (KTE-X19) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL). Outcomes after a 3-year follow-up in the pivotal ZUMA-2 study of KTE-X19 in relapsed/refractory MCL are reported, including for subgroups by prior therapy (bendamustine and type of Bruton tyrosine kinase inhibitor [BTKi]) or high-risk characteristics., Methods: Patients with relapsed/refractory MCL (one to five prior therapies, including prior BTKi exposure) received a single infusion of KTE-X19 (2 × 10 6 CAR T cells/kg)., Results: After a median follow-up of 35.6 months, the objective response rate among all 68 treated patients was 91% (95% CI, 81.8 to 96.7) with 68% complete responses (95% CI, 55.2 to 78.5); medians for duration of response, progression-free survival, and overall survival were 28.2 months (95% CI, 13.5 to 47.1), 25.8 months (95% CI, 9.6 to 47.6), and 46.6 months (95% CI, 24.9 to not estimable), respectively. Post hoc analyses showed that objective response rates and ongoing response rates were consistent among prespecified subgroups by prior BTKi exposure or high-risk characteristics. In an exploratory analysis, patients with prior bendamustine benefited from KTE-X19, but showed a trend toward attenuated T-cell functionality, with more impact of bendamustine given within 6 versus 12 months of leukapheresis. Late-onset toxicities were infrequent; only 3% of treatment-emergent adverse events of interest in ZUMA-2 occurred during this longer follow-up period. Translational assessments revealed associations with long-term benefits of KTE-X19 including high-peak CAR T-cell expansion in responders and the predictive value of minimal residual disease for relapse., Conclusion: These data, representing the longest follow-up of CAR T-cell therapy in patients with MCL to date, suggest that KTE-X19 induced durable long-term responses with manageable safety in patients with relapsed/refractory MCL and may also benefit those with high-risk characteristics.

Background: We hypothesised that zanubrutinib, a highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor, would be a safe and active treatment for patients intolerant of ibrutinib, acalabrutinib, or both. We aimed to assess whether zanubrutinib would prolong treatment duration by minimising treatment-related toxicities and discontinuations in patients with previously treated B-cell malignancies., Methods: This ongoing, phase 2, multicentre, open-label, single-arm study was done in 20 centres in the USA. Patients aged 18 or older with previously treated B-cell malignancies (chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinaemia, or marginal zone lymphoma) who became intolerant of ibrutinib, acalabrutinib, or both, were orally administered zanubrutinib 160 mg twice daily or 320 mg once daily per investigator. The primary endpoint was recurrence and change in severity of ibrutinib or acalabrutinib intolerance events based on investigator-assessed adverse events. Secondary endpoints were investigator-assessed overall response rate; duration of response; disease control rate; and progression-free survival. Analyses included all patients who received any dose of the study drug. This study is registered with ClinicalTrials.gov, NCT04116437., Findings: Between Oct 14, 2019, and Sept 8, 2021, 67 patients (36 [54%] men and 31 [46%] women) who were intolerant of ibrutinib (n=57; cohort 1) or of acalabrutinib or acalabrutinib and ibrutinib (n=10; cohort 2) were enrolled. 63 (94%) patients were White, one (2%) had multiple ethnicities, and three (5%) had unreported or unknown ethnicity. Most intolerance events (81 [70%] of 115 for ibrutinib; 15 [83%] of 18 for acalabrutinib) did not recur with zanubrutinib. Of the recurring events, seven (21%) of 34 ibrutinib intolerance events and two (67%) of three acalabrutinib intolerance events recurred at the same severity with zanubrutinib; 27 (79%) ibrutinib intolerance events and one (33%) acalabrutinib intolerance event recurred at a lower severity with zanubrutinib. No events recurred at higher severity. No grade 4 intolerance events recurred. 64 (96%) of 67 patients had one or more adverse events with zanubrutinib; the most common adverse events were contusion (in 15 [22%] of 67 patients), fatigue (14 [21%]), myalgia (ten [15%]), arthralgia (nine [13%]), and diarrhoea (nine [13%]). Atrial fibrillation occurred in three (4%) patients (all grade 2). Eight (12%) of 67 patients had serious adverse events (anaemia, atrial fibrillation, bronchitis, COVID-19, COVID-19 pneumonia, febrile neutropenia, salmonella gastroenteritis, transfusion reaction, trigeminal nerve disorder, and urinary tract infection). No treatment-related deaths occurred. The median follow-up time was 12·0 months (IQR 8·2-15·6). Among the 64 efficacy-evaluable patients, disease control rate was 93·8% (60; 95% CI 84·8-98·3) and overall response rate was 64·1% (41; 95% CI 51·1-75·7). The median duration of response was not reached; the 12-month event-free duration of response rate was 95·0% (95% CI 69·5-99·3). Similarly, median progression-free survival was not reached; 18-month progression-free survival was 83·8% (95% CI 62·6-93·6)., Interpretation: Patients intolerant of previous BTK inhibitors have limited treatment options. These results suggest that zanubrutinib, a safe and viable treatment for patients with B-cell malignancies, might fill that unmet need for those who exhibit intolerance to ibrutinib or acalabrutinib., Funding: BeiGene., Competing Interests: Declaration of interests MS served as a consultant, and sat on advisory boards, steering committees or data safety monitoring committees for AbbVie, Genentech, 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, and Atara Biotherapeutics; and received research funding from Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, AbbVie, TG Therapeutics, BeiGene, AstraZeneca, Sunesis, Atara Biotherapeutics, Genmab, and MorphoSys/Incyte. IWF served as a consultant for AbbVie, AstraZeneca, BeiGene, Century Therapeutics, Genentech, Genmab, Gilead Sciences, Great Point Partners, Hutchison MediPharma, Iksuda Therapeutics, InnoCare Pharma, Janssen, Juno Therapeutics, Kite Pharma, MorphoSys, Novartis, Nurix Therapeutics, Pharmacyclics, Roche, Seattle Genetics, Servier Pharmaceuticals, Takeda, TG Therapeutics, Unum Therapeutics, Verastem, Vincerx Pharma, and Yingli Pharmaceuticals; and received funding support from 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, Fate Therapeutics, Forma Therapeutics, Forty Seven, Genentech, 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, Roche, Seattle Genetics, Tessa Therapeutics, TCR2 Therapeutics, TG Therapeutics, Trillium Therapeutics, Triphase Research & Development, Unum Therapeutics and Verastem. MYL served as a consultant for AbbVie, Amgen, Bristol Myers Squibb, Janssen Pharmaceuticals, Karyopharm, MorphoSys, Seattle Genetics, Takeda, AstraZeneca, BeiGene, Gilead Sciences, Jazz Pharmaceuticals, TG Therapeutics, Epizyme, GSK, Novartis, and Dova; and received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Janssen Pharmaceuticals, Karyopharm, Morphosys, Seattle Genetics, Takeda, AstraZeneca, BeiGene, Gilead Sciences, Jazz Pharmaceuticals, TG Therapeutics, Epizyme, GSK, Novartis, and Dova. JMB served as a consultant for BeiGene, Kymera, Bristol Myers Squibb, X4 Pharma, Seagen, TG Therapeutics, Lilly, Verastem, MorphoSys, Adaptive Biotechnologies, AstraZeneca, Roche/Genentech, Epizyme, Kura, and AbbVie; and received honoraria from BeiGene and Seagen. SFZ has received honoraria from Merck. HAY has served on speakers' bureaus for AstraZeneca, Janssen, BeiGene, GSK, Sanofi, Karyopharm, Amgen, and Pharmacyclics; and received stock from Karyopharm. MDG has received honoraria from GSK, TG Therapeutics, and Karyopharm. D-YC was employed with BeiGene at the time of the study, holds stock with BeiGene, and has received travel expenses from BeiGene. KB, YL and XZ are employed by BeiGene. RC is employed by BeiGene and holds stock with BeiGene, Pfizer, and GSK. LX, AI, and ACo are employed by BeiGene and hold stock with BeiGene. JH was employed at BeiGene at the time of the study; has a patent planned, issued, or pending with BeiGene; has a leadership position at BeiGene and Protara; holds stock with BeiGene and Roche; and has received research funding and royalties from BeiGene. JPS is employed by US Oncology Network, serves as a consultant at TG Therapeutics, Genentech, AbbVie, Acerta Pharma/AstraZeneca, BeiGene, Bristol Myers Squibb and Merck; and has received research funding from Pharmcyclics, Genentech, Celgene, Acerta Pharma, Gilead Sciences, Seattle Genetics, TG Therapeutics, Merck, and Takeda. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The RELEVANCE trial (ClinicalTrials.gov identifier: NCT01650701) showed that lenalidomide plus rituximab (R 2 ) provided similar efficacy to rituximab plus chemotherapy (R-chemo) in patients with advanced-stage, previously untreated follicular lymphoma (FL). We report the second interim analysis of the RELEVANCE trial after 6 years of follow-up. Patients with previously untreated grade 1-3a FL were assigned 1:1 to R 2 or R-chemo, followed by rituximab maintenance. Coprimary end points were complete response (confirmed/unconfirmed) at week 120 and progression-free survival (PFS). At median follow-up of 72 months, 6-year PFS was 60% and 59% for R 2 and R-chemo, respectively (hazard ratio = 1.03 [95% CI, 0.84 to 1.27]). Six-year overall survival was estimated to be 89% in both groups. Median PFS and overall survival were not reached in either group. Overall response after progression was 61% and 59%, and 5-year estimated survival rate after progression was 69% and 74% in the R 2 and R-chemo groups, respectively. The transformation rate per year in the R 2 and R-chemo groups was 0.68% and 0.45%, and secondary primary malignancies occurred in 11% and 13% ( P = .34), respectively. No new safety signals were observed. R 2 continues to demonstrate comparable, durable efficacy and safety versus R-chemo in previously untreated patients with FL and provides an acceptable chemo-free alternative.

iLLUMINATE is a randomized, open-label phase III study of ibrutinib plus obinutuzumab (n=113) versus chlorambucil plus obinutuzumab (n=116) as first-line therapy for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. Eligible patients were aged ≥65 years, or <65 years with coexisting conditions. Patients received oral ibrutinib 420 mg once daily until disease progression or unacceptable toxicity or six cycles of oral chlorambucil, each in combination with six cycles of intravenous obinutuzumab. After a median follow-up of 45 months (range, 0.2-52), median progression-free survival continued to be significantly longer in the ibrutinib plus obinutuzumab arm than in the chlorambucil plus obinutuzumab arm (median not reached versus 22 months; hazard ratio=0.25; 95% confidence interval: 0.16-0.39; P<0.0001). The best overall rate of undetectable minimal residual disease (<0.01% by flow cytometry) remained higher with ibrutinib plus obinutuzumab (38%) than with chlorambucil plus obinutuzumab (25%). With a median treatment duration of 42 months, 13 months longer than the primary analysis, no new safety signals were identified for ibrutinib. As is typical for ibrutinib-based regimens, common grade ≥3 adverse events were most prevalent in the first 6 months of ibrutinib plus obinutuzumab treatment and generally decreased over time, except for hypertension. In this final analysis with up to 52 months of follow-up (median 45 months), ibrutinib plus obinutuzumab showed sustained clinical benefit, in terms of progression- free survival, in first-line treatment of chronic lymphocytic leukemia, including in patients with high-risk features. ClinicalTrials.gov identifier: NCT02264574.

Purpose: NF-κB, a transcription factor essential for inflammatory responses, is constitutively activated in many lymphomas. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor activity in vitro . Here we report the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity from the first-in-human phase I study of pelabresib in patients with relapsed/refractory lymphomas (NCT01949883)., Experimental Design: Sixty-four patients with relapsed/refractory lymphoma (median of 4 prior lines of therapy) were treated with either capsule (6, 12, 24, 48, 80, 120, 170, 230, 300 mg) or tablet (125, 225 mg) doses of pelabresib orally once daily on a 14 days on, 7 days off schedule., Results: The MTD was determined as the 225 mg tablet daily. The most frequent adverse events were fatigue, nausea, and decreased appetite. Thrombocytopenia, a class effect for all BET inhibitors, was dose-dependent, reversible, and noncumulative. Pelabresib exhibited dose-proportional increases in systemic exposure, rapid absorption, and a half-life of approximately 15 hours (supporting once daily dosing). The bioavailability of the tablet formulation was 60% greater than the capsules. Pelabresib suppressed IL8 and CCR1 mRNA at doses above 120 and 170 mg, respectively. Four patients (6.2%) had an objective response (2 complete response and 2 partial response) and 5 patients had prolonged stable disease., Conclusions/discussion: Pelabresib is capable of BET target gene suppression in an exposure-dependent manner with an acceptable safety profile leading to the recommended phase II dose of the 125 mg tablet once daily., Significance: BET proteins inhibition can potentially modify the pathogenic pathways which contribute to many diseases including malignancies. Pelabresib (CPI-0610), a potent and selective small molecule BET proteins inhibitor, has a MTD of 225 mg once daily for 14 days with a 7-day break, clear pharmacokinetic/pharmacodynamic relationship, and manageable clinical safety profile. These findings are part of the foundation for the ongoing pivotal study of pelabresib in patients with myelofibrosis., Competing Interests: K.A. Blum reports grants from Constellation Pharmaceuticals during the conduct of the study. J.G. Supko reports other from Constellation Pharmaceuticals during the conduct of the study. M.B. Maris reports other from Constellation Pharmaceuticals during the conduct of the study. I.W. Flinn reports grants from Constellation Pharmaceuticals during the conduct of the study; other from Abbvie, other from Astrazeneca, other from Beigene, other from Century Therapeutics, other from Genentech, other from Gilead Sciences, other from Great Point Partners, other from Hutchison Medipharma, other from Iksuda Therapeutics, other from Innocare Pharma, other from Janssen, other from Juno Therapeutics, other from Kite Pharma, other from Morphosys, other from Nurix Therapeutics, other from Pharmacyclics, other from Roche, other from Seattle Genetics, other from Servier Pharmaceuticals, other from Takeda, other from TG Therapeutics, other from Unum Therapeutics, other from Verastem, other from Vincerx Pharma, other from Yingli Pharmaceuticals, grants from Abbvie, grants from Acerta Pharma, grants from Agios, grants from Arqule, grants from Astrazeneca, grants from Beigene, grants from Biopath, grants from Bristol Myers Squibb, grants from Calibr, grants from Calgb, grants from Celgene, grants from City of Hope National Medical Center, grants from Constellation Pharmaceuticals, grants from Curis, grants from CTI Biopharma, grants from Fate Therapeutics, grants from Forma Therapeutics, grants from Forty Seven, grants from Genentech, grants from Gilead Sciences, grants from Innocare Pharma, grants from IGM Biosciences, grants from Incyte, grants from Infinity Pharmaceuticals, grants from Janssen, grants from Kite Pharma, grants from Loxo, grants from Merck, grants from Millennium Pharmaceuticals, grants from Morphosys, grants from Myeloid Therapeutics, grants from Novartis, grants from Nurix, grants from Pfizer, grants from Pharmacyclics, grants from Portola Pharmaceuticals, grants from Rhizen Pharmaceuticals, grants from Roche, grants from Seattle Genetics, grants from Tessa Therapeutics, grants from TCR2, grants from TG Therapeutics, grants from Trillium Therapeutics, grants from Triphase Research & Development Corp, grants from Unum Therapeutics, and grants from Verastem outside the submitted work. A. Goy reports other from Acerta, personal fees and other from AstraZeneca, personal fees and other from Bristol Myers, personal fees and other from Celgene, other from Genentech, personal fees and other from Hoffman La Roche, other from Infinity, personal fees and other from Janssen, other from Karyopharm, personal fees and other from Kite Pharma, personal fees and other from MorphoSys, other from Pharmacyclics, other from Seattle Genetics, other from Verastem, personal fees and other from Alloplex, personal fees and other from Clinical Advances in Hematology & Oncology, personal fees and other from COTA, personal fees and other from Elsevier's PracticeUpdate Oncology, personal fees and other from GENOMIC TESTING COOPERATIVE, LCA, personal fees and other from Gilead, personal fees and other from Medscape, personal fees and other from Michael J Hennessey Associates, INC, personal fees and other from Novartis, personal fees and other from Onclive Peer Exchange, personal fees and other from Physcians Education Resource, LLC, personal fees and other from Rosewell Park, personal fees and other from Resilience, personal fees and other from Vincerx, and personal fees and other from Xcenda-Amerisource outside the submitted work. A. Younes reports other from AstraZeneca during the conduct of the study; other from AstraZeneca outside the submitted work. A.M. Senderowicz reports a patent to USE PELABRESIB IN MYELOFIBROSIS pending. G. Colak reports being an employee of Constellation Pharmaceuticals. J.S. Abramson reports grants from Constellation during the conduct of the study. No other disclosures were reported., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Background: Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL., Methods: We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13·1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13·1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m 2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m 2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m 2 of body surface area on day 1 of cycles 2-6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided α of 0·05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment., Findings: Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13·1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26·2 months (IQR 23·7-29·6), median progression-free survival per independent review committee was not reached in either group (group A 95% CI not estimable [NE] to NE; group B 28·1 months to NE). Progression-free survival was significantly improved in group A versus group B (HR 0·42 [95% CI 0·28 to 0·63]; two-sided p<0·0001). The most common grade 3 or worse adverse event was neutropenia (27 [11%] of 240 patients in group A, 116 [51%] of 227 in group B, and 17 [15%] of 111 patients in group C). Serious adverse events occurred in 88 (37%) of 240 patients in group A, 113 (50%) of 227 patients in group B, and 45 (41%) of 111 patients in group C. Adverse events leading to death occurred in 11 (5%) of 240 patients in group A, 12 (5%) of 227 patients in group B, and three (3%) of 111 patients in group C, most commonly due to COVID-19 (four [2%] of 240 patients in group A), diarrhoea, and aspiration pneumonia (two each [1%] of 227 patients in group B)., Interpretation: Zanubrutinib significantly improved progression-free survival versus bendamustine-rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL., Funding: BeiGene., Competing Interests: Declaration of interests CST reports receiving funding from AbbVie and Janssen; and honoraria from AbbVie, BeiGene, Janssen, Novartis, and Roche, outside the submitted work. JRB reports receiving funding from Gilead, Lilly–LOXO, TG Therapeutics, Verastem–SecuraBio, and Sun; consulting fees from AbbVie, Acerta–AstraZeneca, BeiGene, Bristol Myers Squibb–Juno–Celgene, Catapult Therapeutics, Dynamo Therapeutics, Eli Lilly, Genentech/Roche, Gilead, Janssen, Kite, LOXO, MEI Pharma, MorphoSys, Nextcea, Novartis, Octapharma, Pfizer, Pharmacyclics, Rigel, Sunesis, TG Therapeutics, and Verastem; honoraria from Janssen; and participation on an advisory board for Invectys and MorphoSys, outside of the submitted work. BSK reports receiving funding from BeiGene paid to Washington University School of Medicine (St Louis, MO, USA), and receiving consulting fees from AbbVie, AstraZeneca, BeiGene, Janssen, and Pharmacyclics, outside the submitted work. PG reports receiving funding from BeiGene with regards to the submitted work; funding from AbbVie, AstraZeneca, Janssen, Gilead, Novartis, and Sunesis; consulting fees from and participating on an advisory board for AbbVie, AstraZeneca, ArQule–MSD, Celgene–Juno–Bristol Myers Squibb, Janssen, Lilly–LOXO, and Roche; and receiving honoraria from AbbVie, AstraZeneca, Janssen, and MSD, outside the submitted work. KG reports receiving consulting fees and honoraria from BeiGene, with regards to the submitted work; funding from AbbVie, Amgen, AstraZeneca, Janssen, Novartis, Roche, Sanofi-Genzyme, and Takeda and paid to the Next Generation Hematology Association; receiving consulting fees from GSK and Sandoz; receiving honoraria from AbbVie, Amgen, AstraZeneca, BeiGene, Gilead, GSK, Janssen, Karyopharm, Novartis, Pfizer, Roche, Sandoz, Takeda, and Teva; receiving financial support for attending meetings or travel, or both, from Janssen, Roche, and Sanofi-Genzyme; participating on an advisory board for AbbVie, Amgen, AstraZeneca, Gilead, GSK, Janssen, Novartis, Roche, Sandoz, and Takeda; and a leadership role at the Next Generation Hematology Association, outside the submitted work. WJ reports receiving funding from BeiGene and Janssen, with regards to the submitted work, and funding from AstraZeneca and TG Therapeutics, outside the submitted work. MŠ reports receiving consulting fees from AbbVie and AstraZeneca; receiving honoraria from AbbVie and Janssen-Cilag; participating on an advisory board for AbbVie, AstraZeneca, and Janssen-Cilag; and stock or stock options, or both, from AbbVie, AstraZeneca, Eli Lilly, Johnson & Johnson, and Merck, outside the submitted work. MS reports receiving funding from BeiGene paid to Fred Hutchinson Cancer Research Center and the University of Washington (Seattle, WA, USA), with regards to the submitted work; funding from AbbVie, AstraZeneca, Atara Biotherapeutics, BeiGene, GenMab, Genentech, Gilead, Mustang Bio, Bristol Myers Squibb, Celgene, Pharmacyclics, Sunesis, and TG Therapeutics; and receiving consulting fees from AbbVie, Adaptimmune, Adaptive Biotechnologies, AstraZeneca, Atara Biotherapeutics, BeiGene, Bristol Myers Squibb, Eli Lilly, Epizyme, Genentech, InnatePharma, Kite Pharma, MorphoSys, Mustang Bio, Pharmacyclics, Sound Biologics, and TG Therapeutics, outside the submitted work. PW reports receiving consulting fees from Acerta and BeiGene, outside the submitted work. SO reports receiving funding from BeiGene paid to Monash University (Clayton, VIC, Australia), with regards to the submitted work; and honoraria and participating on an advisory board for BeiGene, outside the submitted work. HCh reports receiving financial support for attending meetings or travel, or both, from Celgene and Janssen, and participating on an advisory board for AbbVie, Eusa, and Janssen, outside the submitted work. RG reports receiving consulting fees from AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Janssen, Merck, MSD, Novartis, Roche, and Takeda; honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Merck, MSD, Novartis, Roche, Takeda, and Sandoz; financial support for attending meetings or travel, or both, from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Janssen, MSD, Novartis, and Roche; and participating on an advisory board for AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Janssen, Merck, MSD, Novartis, Roche, and Takeda, outside the submitted work. MTr reports receiving consulting fees from AbbVie, Amgen, Janssen, Bristol Myers Squibb, Gilead Sciences, Incyte, MorphoSys, Novartis, Roche, Takeda; receiving honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Gilead Sciences, Incyte, Janssen, Roche, MorphoSys, Novartis, Portolla, and Takeda; receiving financial support for attending meetings or travel, or both, from AbbVie, Bristol Myers Squibb, Gilead, Janssen, Roche, and Takeda; participating on an advisory board for AbbVie, Bristol Myers Squibb, Incyte, Janssen, MorphoSys, Novartis, Portolla, Roche, and Takeda; and employment at Charles University General Hospital in Prague, outside the submitted work. DMB reports receiving funding from AbbVie, ArQule, Ascentage, AstraZeneca, BeiGene, DTRM, Genetech, Juno–Celgene–Bristol Myers Squibb, LOXO, MEI Pharma, Novaris, Pharmacyclics, and TG Therapeutics; receiving consulting fees from AbbVie, Genentech, Pharmacyclics, Pfizer, TG Therapeutics, and Verastem; participating on an advisory board for AbbVie, Genentech, Novartis, Pharmacyclics, Pfizer, TG Therapeutics, and Verastem; and a leadership role with NCCN (panel member), informCLL registry (steering committee; AbbVie), and Biosimilars outcomes research panel (Pfizer), outside the submitted work. IWF reports receiving funding from AbbVie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Curis, Forma Therapeutics, Forty Seven, Genentech, Gilead Sciences, IGM Biosciences, Incyte, Infinity Pharmaceuticals, Janssen, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma, LOXO, Merck, MorphoSys, Novartis, Pfizer, Pharmacyclics, Portola Pharmaceuticals, Rhizen Pharmaceuticals, Roche, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium Therapeutics, Triphase Research & Development, Unum Therapeutics, and Verastem, paid to the Sarah Cannon Research Institute; and consulting fees from AbbVie, AstraZeneca, BeiGene, Century Therapeutics, Genentech, Gilead Sciences, Great Point Partners, Hutchison MediPharma, Iksuda Therapeutics, Janssen, Juno Therapeutics, Kite Pharma, MorphoSys, Novartis, Nurix Therapeutics, Pharmacyclics, Roche, Seattle Genetics, Servier Pharmaceuticals, Takeda, TG Therapeutics, Unum Therapeutics, Verastem, Vincerx Pharma, and Yingli Pharmaceuticals, paid to the Sarah Cannon Research Institute, outside the submitted work. AT reports receiving consulting fees from AbbVie, AstraZeneca, BeiGene, and Janssen; and honoraria from AbbVie, AstraZeneca, BeiGene, and Janssen, outside the submitted work. TT, LZ, CM, JCP, and AC are employees of BeiGene, with regards to the submitted work, and report stocks or stock options, or both, from BeiGene, outside the submitted work. JH is an employee of BeiGene, with regards to the submitted work; reports receiving royalties from BeiGene; receiving financial support for attending meetings or travel, or both, from BeiGene and Protara; patents with BeiGene; a leadership role with BeiGene and Protara; and stock or stock options, or both, from BeiGene and Protara, outside the submitted work. TR reports receiving funding from BeiGene, with regards to the submitted work; receiving funding from AbbVie, AstraZeneca, Janssen, and Roche; and participating on an advisory board for AbbVie, AstraZeneca, BeiGene, Janssen, and Roche. PH reports receiving funding from AbbVie, Gilead, Janssen, Pharmacyclics, and Roche; honoraria from AbbVie, AstraZeneca, BeiGene, Janssen, Pharmacyclics, and SOBI; and financial support for attending meetings or travel, or both, from AbbVie and Janssen, outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma., Methods: We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed., Results: Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group., Conclusions: Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: The prognosis of patients with early relapsed or refractory large B-cell lymphoma after the receipt of first-line chemoimmunotherapy is poor., Methods: In this international, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival according to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed., Results: A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; P<0.001). A response occurred in 83% of the patients in the axi-cel group and in 50% of those in the standard-care group (with a complete response in 65% and 32%, respectively). In an interim analysis, the estimated overall survival at 2 years was 61% in the axi-cel group and 52% in the standard-care group. Adverse events of grade 3 or higher occurred in 91% of the patients who received axi-cel and in 83% of those who received standard care. Among patients who received axi-cel, grade 3 or higher cytokine release syndrome occurred in 6% and grade 3 or higher neurologic events in 21%. No deaths related to cytokine release syndrome or neurologic events occurred., Conclusions: Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.)., (Copyright © 2021 Massachusetts Medical Society.)

The multicenter, phase Ib CC-122-DLBCL-001 dose-expansion study (NCT02031419) explored the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122) plus rituximab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients received avadomide 3 mg/day 5 days on/2 days off plus rituximab 375 mg/m 2 on day 8 of cycle 1, day 1 of cycles 2 through 6, and day 1 of every third subsequent cycle for 2 years. Primary endpoints were safety and tolerability; preliminary efficacy was a secondary endpoint. A total of 68 patients were enrolled (DLBCL [ n  = 27], FL [ n  = 41; 31 lenalidomide-naïve, 10 lenalidomide-treated]). Median age was 62 years (range, 33-84 years), and patients had received a median of 3 (range, 1-8) prior regimens. Among patients with DLBCL, 66.7% had primary refractory disease (partial response or less to initial therapy). Among patients with FL, 65.9% were rituximab-refractory at study entry and 10.0% were lenalidomide-refractory. The most common any-grade avadomide-related adverse events (AEs) were neutropenia (63.2%), infections/infestations (23.5%), fatigue (22.1%), and diarrhea (19.1%). The most common grade 3/4 avadomide-related AEs were neutropenia (55.9%) infections/infestations (8.8%), and febrile neutropenia (7.4%). In patients with DLBCL, overall response rate (ORR) was 40.7% and median duration of response (mDOR) was 8.0 months. In patients with FL, ORR was 80.5% and mDOR was 27.6 months; response rates were similar in lenalidomide-naïve and -treated patients. Avadomide plus rituximab was well tolerated, and preliminary antitumor activity was observed in patients with R/R DLBCL and FL, including subgroups with typically poor outcomes. These results support further investigation of novel CELMoD agents in combination with rituximab in R/R DLBCL and FL., Competing Interests: Loretta J. Nastoupil received honoraria from ADC Therapeutics, Bayer, Celgene, a Bristol Myers Squibb Company, Epizyme, Genentech, Gilead, Janssen, MorphoSys, Novartis, Pfizer, and TG Therapeutics; and received research funding from Bristol Myers Squibb/Celgene, Epizyme, Genentech, Janssen, Novartis, and TG Therapeutics. John Kuruvilla received honoraria from Amgen, Antengene, AstraZeneca, Celgene, a Bristol Myers Squibb company Gilead, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche, Seattle Genetics, and TG Therapeutics; served as a consultant or advisor for AbbVie, Bristol Myers Squibb, Gilead, Karyopharm, Merck, Roche, and Seattle Genetics; and received research funding from AstraZeneca, Janssen, Roche, and Merck. Julio C. Chavez served as a consultant or advisor for AstraZeneca, Bayer, Celgene, a Bristol Myers Squibb Company, Genentech, Karyopharm, Morphosys, Novartis, Verastem, and Pfizer; received research funding from Merck; and served on the speaker's bureau for Genentech and AstraZeneca. Fontanet Bijou served as consultant or advisor for Bristol Myers Squibb and AbbVie. Armando Santoro served as consultant or advisor for Arqule, Bayer, Bristol Myers Squibb, Eisai, Gilead, Merck Sharp & Dohme, Pfizer, Sanofi, and Servier, and served on speaker's bureau for AbbVie, Amgen, Arqule, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, a Bristol Myers Squibb Company, Eisai, Gilead, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sandoz, Servier, and Takeda. Ian W. Flinn served as consultant or advisor for AbbVie, AstraZeneca, BeiGene, Genentech, Gilead Sciences, Great Point Partners, Iksuda Therapeutics, Janssen, Juno Therapeutics, Kite Pharma, MorphoSys, Novartis, Nurix Therapeutics, Pharmacyclics, Roche, Seattle Genetics, Takeda, TG Therapeutics, Unum Therapeutics, Verastem, and Yingli Pharmaceuticals; and received research funding from AbbVie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Calithera Biosciences, Celgene, a Bristol Myers Squibb Company, Constellation Pharmaceuticals, Curis, Forma Therapeutics, Forty‐Seven, Genentech, Gilead Sciences, IGM Biosciences, Incyte, Infinity Pharmaceuticals, Janssen, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma, Loxo, Merck, MorphoSys, Novartis, Pfizer, Pharmacyclics, Portola Pharmaceuticals, Rhizen Pharmaceuticals, Roche, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium Therapeutics, Triphase Research & Development Corp., Unum Therapeutics, and Verastem. Vaishalee P. Kenkre received research funding from AbbVie, Celgene, a Bristol Myers Squibb Company, MEI Pharma, and Novartis. P. Corradini received honoraria from AbbVie, ADC Therapeutics, Amgen, Celgene, a Bristol Myers Squibb Company, Daiichi Sankyo, Gilead, Incyte, Janssen, Kite, KyowaKirin, Novartis, Roche, Sanofi, and Takeda; served as consultant or advisor for AbbVie, ADC Therapeutics, Amgen, Celgene, a Bristol Myers Squibb Company, Daiichi Sankyo, Gilead, Incyte, Janssen, Kite, KyowaKirin, Novartis, Roche, Sanofi, and Takeda; and received travel funding from Novartis, Janssen, Celgene, a Bristol Myers Squibb Company, Bristol Myers Squibb, Takeda, Gilead, Amgen, and AbbVie. Iris Isufi served as a consultant or advisor for AstraZeneca, Bayer, Celgene, a Bristol Myers Squibb Company, Epizyme, and Kite. David J. Andorsky served as consultant or advisor for AbbVie and Bristol Myers Squibb and received research funding from AstraZeneca, Celgene, a Bristol Myers Squibb company, and Epizyme. Daniel Greenwald served as consultant or advisor for AstraZeneca and served on the speaker's bureau for Genentech and Jazz. R. Sangha received honoraria from AbbVie, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli‐Lilly, Merck, Mylan, Pfizer, Roche/Genentech, Sanofi, Takeda, and Teva, and served as consultant or advisor for AbbVie, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli‐Lilly, Merck, Roche/Genentech, Sanofi, Takeda, and Teva. Patrick Hagner, Nian Gong, Shailaja Uttamsingh, and Michael Pourdehnad are employed by and have equity ownership with Bristol Myers Squibb. Frank Shen, Yan Li, and Juergen Dobmeyer are employed by Bristol Myers Squibb. Vincent Ribrag received honoraria from AstraZeneca, Bristol Myers Squibb, Incyte, Merck Sharp & Dohme, Novartis, and Roche; served as a consultant or advisor for AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche; received research funding from argenX, Astex, and GlaxoSmithKline; and received travel funding from AstraZeneca. No disclosures were reported by the other authors., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Mosunetuzumab is a bispecific antibody targeting CD20 and CD3 that redirects T cells to engage and eliminate malignant B cells and is being developed for relapsed or refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHLs)., Methods: This first-in-human trial (ClinicalTrials.gov identifier: NCT02500407) evaluated the safety and tolerability and efficacy of mosunetuzumab in patients with R/R B-NHL and established the recommended phase II dose. Data from dose escalation are presented. Single-agent mosunetuzumab was administered intravenously in 3-week cycles, at full dose in cycle 1 day 1 (group A) or with ascending (step-up) doses during cycle 1 on days 1, 8, and 15 (group B), for eight or 17 cycles on the basis of tumor response., Results: Two hundred thirty patients were enrolled. Doses up to 2.8 mg and 60 mg were assessed in groups A and B, respectively; maximum tolerated dose was not exceeded. In group B (n = 197), common adverse events (≥ 20% of patients) were neutropenia (28.4%), cytokine release syndrome (27.4%), hypophosphatemia (23.4%), fatigue (22.8%), and diarrhea (21.8%). Cytokine release syndrome was mostly low-grade (grade ≥ 3: 1.0%) and mainly confined to cycle 1. Across the doses investigated (group B), best overall response rates were 34.9% and 66.2% in patients with aggressive and indolent B-NHL, respectively, and complete response rates were 19.4% and 48.5%. Among patients with a complete response, the median duration of response was 22.8 months (95% CI, 7.6 to not estimable) and 20.4 (95% CI, 16 to not estimable) in patients with aggressive and indolent B-NHL, respectively., Conclusion: Mosunetuzumab, administered with step-up dosing, has a manageable safety profile and induces durable complete responses in R/R B-NHL. The expansion stage of the study is ongoing at the dose level of 1/2/60/60/30 mg selected for further study., Competing Interests: Lihua E. BuddeConsulting or Advisory Role: Roche/Genentech, Kite/Gilead, Novartis, BeiGeneResearch Funding: Merck, Amgen, MustangBio, AstraZenecaPatents, Royalties, Other Intellectual Property: CCR4 CAR T cells for treatment of patients with CCR4-positive cancer. CD33CAR for treatment of patients with CD33+ acute myeloid leukemiaTravel, Accommodations, Expenses: Roche/Genentech, Kite/Gilead, AstraZeneca Sarit AssoulineStock and Other Ownership Interests: Knight PharmaceuticalsHonoraria: Janssen Oncology, Pfizer, AbbVie, Novartis Canada Pharmaceuticals Inc, AstraZeneca, BMSConsulting or Advisory Role: Roche/Genentech, BeiGeneResearch Funding: Roche Canada (Inst), Takeda (Inst), Astex Pharmaceuticals (Inst), BeiGene (Inst), Novartis (Inst)Travel, Accommodations, Expenses: Roche Canada Laurie H. SehnHonoraria: Amgen, Apobiologix, AbbVie, Celgene, Gilead Sciences, Janssen-Ortho, Karyopharm Therapeutics, Kite, a Gilead company, Lundbeck, Merck, Roche/Genentech, Seattle Genetics, Takeda, Teva, TG Therapeutics, AstraZeneca, Acerta Pharma, morphosys, Incyte, Debiopharm Group, Sandoz-Novartis, Verastem, GenmabConsulting or Advisory Role: Celgene, AbbVie, Seattle Genetics, TG Therapeutics, Janssen, Amgen, Roche/Genentech, Gilead Sciences, Lundbeck, Amgen, apobiologix, Karyopharm Therapeutics, Kite, a Gilead company, Merck, Takeda, Teva, TG therapeutics, AstraZeneca, Acerta Pharma, MorphoSys, Incyte, Debiopharm Group, Sandoz-Novartis, Genmab, VerastemResearch Funding: Roche/Genentech (Inst), Teva (Inst) Stephen J. SchusterConsulting or Advisory Role: Celgene, Nordic Nanovector, Novartis, AbbVie, Acerta Pharma/AstraZeneca, Alimera Sciences, BeiGene, Juno Therapeutics, Loxo Oncology, Tessa Therapeutics, Genentech/RocheResearch Funding: Novartis (Inst), Pharmacyclics (Inst), Adaptive Biotechnologies (Inst), Merck (Inst), Genentech/Roche (Inst), Celgene (Inst), Juno Therapeutics (Inst), AbbVie (Inst), Incyte (Inst), TG Therapeutics (Inst), DTRM (Inst)Patents, Royalties, Other Intellectual Property: Patent Combination Therapies of CAR and PD-1 Inhibitors (via University of Pennsylvania with royalties to Novartis) Sung-Soo YoonHonoraria: NovartisConsulting or Advisory Role: Janssen, Takeda, Amgen, Celgene/JazzResearch Funding: Kyowa Kirin, Roche/Genentech, Yuhan Dok Hyun YoonHonoraria: Celltrion, Roche, Janssen, Amgen, Celgene, Samyang, Kirin Pharmaceuticals, TakedaConsulting or Advisory Role: Roche, Janssen, Amgen, Celgene, Green Cross, NovartisResearch Funding: Samyang, Abclone, Roche/Genentech, Janssen Oncology, Amgen, Genmab, Boryung, Eutilex Matthew J. MatasarStock and Other Ownership Interests: MerckHonoraria: Genentech, Roche, Bayer, Pharmacyclics, Seattle Genetics, Takeda, Immunovaccine, ADC Therapeutics, Karyopharm TherapeuticsConsulting or Advisory Role: Genentech, Bayer, Merck, Juno Therapeutics, Roche, Teva, Rocket Medical, Seattle Genetics, Daiichi Sankyo, TakedaResearch Funding: Genentech, Roche, GlaxoSmithKline, Bayer, Pharmacyclics, Janssen, Rocket Medical, Seattle Genetics, Immunovaccine, IGM Biosciences , IGM BiosciencesTravel, Accommodations, Expenses: Genentech, Roche, Seattle Genetics, Bayer Francesc BoschConsulting or Advisory Role: AstraZeneca, Roche/Genentech, Janssen-Cilag, Lilly, AbbVie, Kite, a Gilead company, BeiGene, NovartisSpeakers' Bureau: AbbVie, Janssen, Roche, AstraZenecaResearch Funding: Janssen, AstraZeneca Loretta J. NastoupilHonoraria: Celgene, Gilead Sciences, Novartis, Bayer, Janssen Oncology, Pfizer, Gamida Cell, TG Therapeutics, Bristol Myers Squibb, ADC Therapeutics, Morphosys, Epizyme, GenmabResearch Funding: TG Therapeutics, Janssen Biotech, Celgene, Genentech/Roche, LAM Therapeutics, Epizyme, Novartis, IgM Biosciences, Caribou Biosciences, Gilead Sciences, Allogene Therapeutics, Takeda Ian W. FlinnConsulting or Advisory Role: AbbVie (Inst), Seattle Genetics (Inst), TG Therapeutics (Inst), Verastem (Inst), Roche (Inst), Gilead Sciences (Inst), Kite, a Gilead company (Inst), Janssen (Inst), BeiGene (Inst), Takeda (Inst), AstraZeneca (Inst), Juno Therapeutics (Inst), Unum Therapeutics (Inst), MorphoSys (Inst), Nurix (Inst), Shanghai Yingli Pharmaceuticals (Inst), Genentech (Inst), Great Point Partners (Inst), Iksuda Therapeutics (Inst), Novartis (Inst), Pharmacyclics (Inst), Century Therapeutics (Inst), Hutchison MediPharma (Inst), SERVIER (Inst), Vincerx Pharma (Inst), Genmab (Inst), InnoCare Pharma (Inst)Research Funding: Acerta Pharma (Inst), Agios (Inst), Calithera Biosciences (Inst), Celgene (Inst), Constellation Pharmaceuticals (Inst), Genentech (Inst), Gilead Sciences (Inst), Incyte (Inst), Infinity Pharmaceuticals (Inst), Janssen (Inst), Karyopharm Therapeutics (Inst), Kite, a Gilead company (Inst), Novartis (Inst), Pharmacyclics (Inst), Portola Pharmaceuticals (Inst), Roche (Inst), TG Therapeutics (Inst), Trillium Therapeutics (Inst), AbbVie (Inst), ArQule (Inst), BeiGene (Inst), Curis (Inst), FORMA Therapeutics (Inst), Forty Seven (Inst), Merck (Inst), Pfizer (Inst), Takeda (Inst), Teva (Inst), Verastem (Inst), AstraZeneca (Inst), Juno Therapeutics (Inst), Unum Therapeutics (Inst), MorphoSys (Inst), Seattle Genetics (Inst), IGM Biosciences (Inst), Loxo (Inst), Rhizen Pharmaceuticals (Inst), Triact Therapeutics (Inst) Mazyar ShadmanConsulting or Advisory Role: AbbVie, Genentech, AstraZeneca, Sound Biologics, Cellectar, Pharmacyclics, BeiGene, Bristol Myers Squibb/Celgene, MorphoSys, Innate Pharma, Kite, a Gilead company, Adaptive Biotechnologies, EpizymeResearch Funding: Pharmacyclics (Inst), Acerta Pharma (Inst), Merck (Inst), TG Therapeutics (Inst), BeiGene (Inst), Celgene (Inst), Genentech (Inst), MustangBio (Inst), AbbVie (Inst), Sunesis Pharmaceuticals (Inst), Bristol Myers Squibb/Celgene Catherine DiefenbachStock and Other Ownership Interests: Gilead SciencesConsulting or Advisory Role: Seattle Genetics, Bayer, Bristol Myers Squibb, Genentech/Roche, Merck, Janssen, Celgene, MorphoSysResearch Funding: Seattle Genetics (Inst), Genentech (Inst), Incyte (Inst), LAM Therapeutics (Inst), Merck (Inst), Bristol Myers Squibb (Inst), Millennium (Inst), Roche/Genentech (Inst), Janssen (Inst), MEI Pharma (Inst), Trillium Therapeutics (Inst), Astex Pharmaceuticals (Inst)Expert Testimony: Jim Harmon Carol O'HearEmployment: Genentech/RocheStock and Other Ownership Interests: Genentech/RochePatents, Royalties, Other Intellectual Property: Antibody bufferingTravel, Accommodations, Expenses: Genentech/Roche Huang HuangEmployment: Roche Canada Antonia KwanEmployment: Genentech/RocheStock and Other Ownership Interests: Roche/Genentech Chi-Chung LiEmployment: Roche/GenentechStock and Other Ownership Interests: Roche/GenentechPatents, Royalties, Other Intellectual Property: Patent applications pertaining to the development and dosing of bispecific antibodies Emily C. PiccioneEmployment: GenentechStock and Other Ownership Interests: Roche/Genentech Michael C. WeiEmployment: Genentech/RocheStock and Other Ownership Interests: RocheTravel, Accommodations, Expenses: Genentech/Roche Shen YinEmployment: GenentechStock and Other Ownership Interests: GenentechTravel, Accommodations, Expenses: Genentech Nancy L. BartlettConsulting or Advisory Role: Seattle Genetics, Roche/Genentech, ADC Therapeutics, BTG, Acerta PharmaResearch Funding: Seattle Genetics (Inst), Kite, a Gilead company (Inst), Merck (Inst), Bristol Myers Squibb (Inst), Celgene (Inst), Immune Design (Inst), Forty Seven (Inst), Janssen (Inst), Pharmacyclics (Inst), Millennium (Inst), ADC Therapeutics (Inst), Autolus (Inst), Roche/Genentech (Inst), Pfizer (Inst), Affimed Therapeutics (Inst)No other potential conflicts of interest were reported.

There is a need for additional treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122), the selective, ATP-competitive mammalian target of rapamycin kinase inhibitor CC-223, and the potent, selective, covalent Bruton tyrosine kinase inhibitor CC-292 in patients with relapsed/refractory (R/R) DLBCL. In the multicenter, phase Ib CC-122-DLBCL-001 study (NCT02031419), the dose-escalation portion explored combinations of CC-122, CC-223, and CC-292 administered as doublets or triplets with rituximab in patients with chemorefractory DLBCL. Primary endpoints were safety, tolerability, and dose-limiting toxicities; additional endpoints included pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy. As of December 1, 2017, 106 patients were enrolled across four cohorts. The median age was 65 years (range 24-84 years), and patients had a median of 3 (range 1-10) prior to regimens. A total of 101 patients (95.3%) discontinued, most commonly due to disease progression (49.1%). The most common any-grade adverse events (AEs) across treatment arms were gastrointestinal and hematologic; the most common grade 3/4 AEs were hematologic. CC-122 was well tolerated, with no unexpected safety concerns. Preliminary efficacy was observed in three of four treatment arms. CC-122 plus rituximab was considered suitable for dose expansion, whereas CC-223 and CC-292 combinations were associated with enhanced toxicity and/or insufficient improvement in responses. CC-122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi-arm dose-finding design., Competing Interests: Vincent Ribrag received honoraria from Gilead, Infinity, ArgenX, Merck Sharp & Dohme, Bristol Myers Squibb, Epizyme, Nanostring, Incyte, Roche, and AstraZeneca; served as a consultant or advisor for Servier; and received research funding from ArgenX. Julio C. Chavez served as a consultant or advisor for Novartis, Celgene, a Bristol‐Myers Squibb Company, Bayer, Morphosys, Karyopharm, AstraZeneca, Verastem, Pfizer, and Genentech; received research funding from Merck; and served on the speaker's bureau for Genentech and AstraZeneca. Jason Kaplan served as a consultant or advisor for and received research funding from Seattle Genetics, and received travel funding from Curis. Jason C. Chandler served as a consultant or advisor for Janssen and Axess Oncology. Armando Santoro served as a consultant or advisor for ArQule, Sanofi, Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, and Merck Sharpe and Dohme; and served on the speaker's bureau for Takeda, Bristol Myers Squibb, Roche, AbbVie, Amgen, Celgene, a Bristol‐Myers Squibb company, Servier, Gilead, AstraZeneca, Pfizer, ArQule, Lilly, Sandoz, Eisai, Novartis, Bayer, and Merck Sharpe and Dohme. Paolo Corradini received honoraria from Janssen, Gilead, AbbVie, Takeda, Roche, Novartis, and Celgene, a Bristol‐Myers Squibb Company; served as a consultant or advisor for Novartis, Janssen, Celgene, a Bristol‐Myers Squibb company, and Gilead; received travel funding from Novartis, AbbVie, and Gilead; and served on the speaker's bureau for Novartis. Ian W. Flinn received research funding from AbbVie, Acerta, Agios, ArQule, BeiGene, Calithera, Celgene, a Bristol‐Myers Squibb Company, Constellation, Curis, Forma, Forty‐Seven Inc, Genentech, Gilead, Incyte, Infinity, Janssen, Karyopharm, Kite, Merck, Novartis, Pfizer, Portola, Roche, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium, and Verastem. Ranjana Advani served as a consultant or advisor for AstraZeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Genentech/Roche, Gilead Kite Pharma, Kyowa, Seattle Genetics, and Takeda; and received research funding from Agensys, Celgene, a Bristol‐Myers Squibb company, Forty‐Seven Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, and Seattle Genetics. Philippe A. Cassier received honoraria from Amgen, AstraZeneca, Blueprint Medicines, Novartis, and Roche/Genentech; received research funding from AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Celgene, a Bristol‐Myers Squibb Company, GlaxoSmithKline, Innate Pharma, Janssen, Lilly, Loxo, Merck Serono, Merck Sharp & Dohme, Novartis, Plexxikon, Roche/Genentech, Taiho Pharmaceutical, Toray Industries, and Transgene; and received travel funding from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Netris Pharma, Novartis, and Roche. Randeep Sangha received honoraria from Pfizer, Boehringer Ingelheim, AstraZeneca, Roche, Lundbeck, Bristol Myers Squibb, Merck, AbbVie, and Takeda; served as a consultant or advisor for Boehringer Ingelheim, Roche, Lundbeck, Bristol Myers Squibb, Merck, AbbVie, Takeda, and Teva; and received research funding from Bristol Myers Squibb, AbbVie, Takeda, Pharmacyclics, Morphosys, Roche, Merck, Celgene, a Bristol‐Myers Squibb company, and Novartis. Iris Isufi served as a consultant or advisor for AstraZeneca, Celgene, a Bristol‐Myers Squibb company/Jazz Pharmaceuticals, and Kite Pharma; and received travel funding from Celgene, a Bristol‐Myers Squibb company, and Kite Pharma. Shailaja Uttamsingh, Patrick R. Hagner, Anita K. Gandhi, and Michael Pourdehnad are employed by and have equity ownership with Bristol Myers Squibb. Harald Haeske has equity ownership with Pieris AG and served as a consultant or advisor for Celgene, a Bristol‐Myers Squibb company, and 4SC AG. Kristen Hege is employed by and holds patents with Bristol Myers Squibb; has equity ownership with Bristol Myers Squibb, Arcus Biosciences, and Mersana Therapeutics; and served on the Board of Directors for Arcus Biosciences, Mersana Therapeutics, and the Society for Immunotherapy of Cancer. John Kuruvilla received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, a Bristol‐Myers Squibb Company, Gilead, Janssen, Karyopharm Therapeutics, Merck, Novartis, Roche, and Seattle Genetics; and served as a consultant or advisor for AbbVie, Bristol Myers Squibb, Gilead Sciences, Karyopharm Therapeutics, Merck, Roche, and Seattle Genetics; and received research funding from Janssen and Roche. All other authors declare no conflict of interest., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

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

Anti-CD20 antibody treatments, such as obinutuzumab, have been associated with infusion-related reactions (IRRs). In the phase 3 iLLUMINATE study of ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab in first-line chronic lymphocytic leukemia/small lymphocytic lymphoma, IRRs were substantially reduced with ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab. We prospectively analyzed inflammatory cytokines to evaluate the impact of ibrutinib on circulating cytokine levels following obinutuzumab infusion. In iLLUMINATE, ibrutinib or chlorambucil was given approximately 30-120 min before the first obinutuzumab infusion. Cytokines evaluated were IFNγ, IL-6, IL-8, IL-10, IL-18, MCP-1, MIP-1α, MIP-1β, and TNFα. Changes in peak cytokine levels from baseline (immediately before obinutuzumab) to post-obinutuzumab infusion were compared between arms and between patients with versus without IRRs using Wilcoxon rank sum test. Of 228 treated patients, 95 on ibrutinib-obinutuzumab (15 with IRRs, 80 without) and 88 on chlorambucil-obinutuzumab (45 with IRRs, 43 without) with cytokine data were included. Irrespective of IRR occurrence, median increase in cytokines was lower with ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab for all cytokines (P < 0.01) except MIP-1β. Across treatment arms, post-obinutuzumab median increase in all cytokines except MIP-1β was greater in patients with versus without IRRs (P < 0.001). IL-6 and IL-8 elevations were associated with IRRs in both treatment arms. Among patients with IRRs, those receiving ibrutinib-obinutuzumab had lower post-obinutuzumab increases in IL-6, IL-8, IL-10, and MCP-1 (P < 0.04) than patients receiving chlorambucil-obinutuzumab. For patients in the ibrutinib-treatment arm, we observed a reduction in both the rate of clinically apparent IRRs and the levels of IRR-related cytokines and chemokines. This observation supports an immunomodulatory mechanism of action for ibrutinib. Clinical Trial Registration: NCT02264574.

Purpose: We prospectively evaluated the feasibility of SPECT-CT/planar organ dosimetry-based radiation dose escalation radioimmunotherapy in patients with recurrent non-Hodgkin's lymphoma using the theranostic pair of 111 In and 90 Y anti-CD20 ibritumomab tiuxetan (Zevalin ® ) at myeloablative radiation-absorbed doses with autologous stem cell support. We also assessed acute non-hematopoietic toxicity and early tumor response in this two-center outpatient study., Methods: 24 patients with CD20-positive relapsed or refractory rituximab-sensitive, low-grade, mantle cell, or diffuse large-cell NHL, with normal organ function, platelet counts > 75,000/mm 3 , and <35% tumor involvement in the marrow were treated with Rituximab (375 mg/m 2 ) weekly for 4 consecutive weeks, then one dose of cyclophosphamide 2.5 g/m 2 with filgrastim 10 mcg/kg/day until stem cell collection. Of these, 18 patients with successful stem cell collection (at least 2 × 10 6 CD34 cells/kg) proceeded to RIT. A dosimetric administration of 111 In ibritumomab tiuxetan (185 MBq) followed by five sequential quantitative planar and one SPECT/CT scan was used to determine predicted organ radiation-absorbed dose. Two weeks later, 90 Y ibritumomab tiuxetan was administered in an outpatient setting at a cohort- and patient-specific predicted organ radiation-absorbed dose guided by a Continuous Response Assessment (CRM) methodology with the following cohorts for dose escalation: 14.8 MBq/kg, and targeted 18, 24, 28, and 30.5 Gy to the liver. Autologous stem cell infusion occurred when the estimated marrow radiation-absorbed dose rate was predicted to be <1 cGy/h. Feasibility, short-term toxicities, and tumor response were assessed., Results: Patient-specific hybrid SPECT/CT + planar organ dosimetry was feasible in all 18 cases and used to determine the patient-specific therapeutic dose and guide dose escalation (26.8 ± 7.3 MBq/kg (mean), 26.3 MBq/kg (median) of 90 Y (range: 12.1-41.4 MBq/kg)) of ibritumomab tiuxetan that was required to deliver 10 Gy to the liver. Infused stem cells engrafted rapidly. The most common treatment-related toxicities were hematological and were reversible following stem cell infusion. No significant hepatotoxicity was seen. One patient died from probable treatment-related causes-pneumonia at day 27 post-transplant. One patient at dose level 18 Gy developed myelodysplastic syndrome (MDS), 4 patients required admission post- 90 Y RIT for febrile neutropenia, 16/18 patients receiving 90 Y ibritumomab tiuxetan (89%) responded to the therapy, with 13 CR (72%) and 3/18 PR (17%), at 60 days post-treatment. Two patients had progressive disease at sixty days. One patient was lost to follow-up. Median time to progression was estimated to be at least 13 months. MTD to the liver is greater than 28 Gy, but the MTD was not reached as the study was terminated due to unexpected discontinuation of availability of the therapeutic agent., Conclusions: Patient-specific outpatient 90 Y ibritumomab tiuxetan RIT with myeloablative doses of RIT up to a targeted 30.5 Gy to the liver is feasible, guided by prospective SPECT/CT + planar imaging with the theranostic pair of 111 In and 90 Y anti-CD20, with outpatient autologous stem cell transplant support. Administered activity over 5 times the standard FDA-approved activity was well-tolerated. The non-hematopoietic MTD in this study exceeds 28 Gy to the liver. Initial tumor responses were common at all dose levels. This study supports the feasibility of organ dosimetry-driven patient-specific dose escalation in the treatment of NHL with stem cell transplant and provides additional information on the radiation tolerance of the normal liver to radiopharmaceutical therapy.

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