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Mantle cell lymphoma (MCL) is a clinically heterogeneous B-cell neoplasm with unique clinicopathological features, accounting for 5% of all non-Hodgkin lymphoma. Although for many chemoimmunotherapy can lead to durable remissions, those with poor baseline prognostic factors, namely blastoid morphology, TP53 aberrancy and Ki67 >30%, will have less durable responses to conventional therapies. With this in mind, clinical trials have focused on novel targeted therapies to improve outcomes. This review details the recent advances in the understanding of MCL biology and outlines the recommended diagnostic strategies and evidence-based approaches to treatment., (© 2024 Royal Australasian College of Physicians.)

Background: Glofitamab monotherapy induces durable remission in patients with relapsed or refractory diffuse large B-cell lymphoma after two or more previous therapies, but has not previously been assessed as a second-line therapy. We investigated the efficacy and safety of glofitamab plus gemcitabine-oxaliplatin (Glofit-GemOx) versus rituximab (R)-GemOx in patients with relapsed or refractory diffuse large B-cell lymphoma., Methods: The phase 3, randomised, open-label STARGLO trial was done at 62 centres in 13 countries in Asia and Australia, Europe, and North America. We recruited transplant-ineligible patients (aged ≥18 years) with histologically confirmed relapsed or refractory diffuse large B-cell lymphoma after one or more previous therapies. Patients were randomly assigned in permuted blocks (block size of six) via an interactive voice or web response system (2:1; stratified by 1 vs ≥2 previous lines of therapy and relapsed vs refractory status) to Glofit-GemOx (intravenous gemcitabine 1000 mg/m 2 and oxaliplatin 100 mg/m 2 plus glofitamab step-up dosing to 30 mg; for a total of eight cycles, plus four additional cycles of glofitamab monotherapy) or R-GemOx (intravenous gemcitabine 1000 mg/m 2 and oxaliplatin 100 mg/m 2 plus rituximab 375 mg/m 2 ; for a total of eight cycles). The trial independent review committee, which evaluated all response-based endpoints, was masked to treatment assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat in all randomly assigned patients. We present results from both the primary analysis (cutoff: March 29, 2023) and updated analysis after all patients had completed study therapy (cutoff: Feb 16, 2024). Safety analyses included all patients who received any study treatment. This study is registered with ClinicalTrials.gov, NCT04408638, and is ongoing (closed to recruitment)., Findings: From Feb 23, 2021, to March 14, 2023, 274 patients were enrolled and randomly assigned to receive Glofit-GemOx (n=183) or R-GemOx (n=91). 158 (58%) patients were male and 116 (42%) were female; median age was 68 years (IQR 58-74). At the primary analysis after a median follow-up of 11·3 months (95% CI 9·6-12·7), overall survival was significantly improved with Glofit-GemOx versus R-GemOx (median not estimable [NE; 95% CI 13·8 months-NE] vs 9·0 months [7·3-14·4]; hazard ratio [HR] 0·59 [95% CI 0·40-0·89]; p=0·011). At the updated analysis after a median follow-up of 20·7 months (19·9-23·3), a consistent improvement in overall survival was observed with Glofit-GemOx versus R-GemOx (median 25·5 months [18·3-NE] vs 12·9 months [7·9-18·5]; HR 0·62 [0·43-0·88]). In the safety sets, 180 (100%) patients in the Glofit-GemOx group and 84 (96%) of 88 patients in the R-GemOx group had at least one adverse event during the study period. Cytokine release syndrome occurred in 76 (44%) of 172 glofitamab-exposed patients and was predominantly low grade. Deaths related to glofitamab or rituximab occurred in five (3%) patients in the Glofit-GemOx group and in one (1%) patient in the R-GemOx group., Interpretation: Glofit-GemOx had a significant overall survival benefit compared with R-GemOx, supporting its use in transplant-ineligible patients with relapsed or refractory diffuse large B-cell lymphoma after one or more previous lines of therapy., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests JSA has received grants or contracts from BMS, Cellectis, Merck, Mustang Bio, Regeneron, and Seagen; consulting fees from AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, BMS, Celgene, Cellectar, Caribou Biosciences, Century Therapeutics, Celgene, Epizyme, Foresight Diagnostics, Genentech, Gilead, Interius, Lilly, F Hoffmann-La Roche, Seagen, and Takeda; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BMS, Incyte, Janssen, MorphoSys, Novartis, and Regeneron. MKu has received grants or contracts and consulting fees from and participated on a data safety monitoring board or advisory board for F Hoffmann-La Roche; a grant from BeiGene; and consulting fees from AbbVie. MH has received grants from Janssen and F Hoffmann-La Roche; consulting fees from Takeda, F Hoffmann-La Roche, Otsuka, AbbVie, and Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, F Hoffmann-La Roche, Otsuka, AbbVie, Gilead, and Pfizer; and participated on a data safety monitoring board or advisory board for Takeda, F Hoffmann-La Roche, Otsuka, AbbVie, and Gilead. CPF has received grants or contracts from BeiGene, F Hoffmann-La Roche, Genmab, and AbbVie; consulting fees from AbbVie, AstraZeneca, Atarabio, BMS, Genmab, Gilead, Kite, Incyte, Janssen, Lilly, Morphosys, Ono, F Hoffmann-La Roche, SERB, and SOBI; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, Atarabio, BMS, GenMab, Gilead, Kite, Incyte, Janssen, Lilly, Morphosys, Ono, F Hoffmann-La Roche, SERB, SOBI, and Takeda; and participated on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, Atarabio, BMS, GenMab, Gilead, Kite, Incyte, Janssen, Lilly, Morphosys, Ono, F Hoffmann-La Roche, SERB, and SOBI. DHY has received grants or contracts from AbbVie, BeiGene, Boryung, Celltrion, Kyowa Kirin, Janssen, Samyang, and Sanofi; consulting fees from Abclon, BeiGene, BMS, GI Cell, GC Cell, Verismo, Janssen, Novartis, F Hoffmann-La Roche, and Pharos Bio; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, Antengene, BMS, Boryung, GSK, Kyowa Kirin, Novartis, F Hoffmann-La Roche, Takeda, and Janssen; and participated on a data safety monitoring board or advisory board for Abclon, BeiGene, BMS, GI Cell, GC Cell, Verismo, Janssen, Novartis, F Hoffmann-La Roche, and Pharos Bio. HA has received grants or contracts from Morphosys, Genentech, Novartis, BMS, Epizyme, and Pfizer; consulting fees from Amgen, Genentech, Morphosys, Novartis, BMS, AstraZeneca, Acrotech, ADC Therapeutics, and AbbVie; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Genentech; and participated on a data safety monitoring board or advisory board for Amgen, Genentech, Morphosys, Novartis, BMS, AstraZeneca, Acrotech, ADC Therapeutics, and AbbVie. WT has received grants or contracts and support for attending meetings or travel from F Hoffmann-La Roche; consulting fees from and participated on a data safety monitoring board or advisory board for F Hoffmann-La Roche, Takeda, AbbVie, Sobi, and Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from F Hoffmann-La Roche, Takeda, Gilead, and AbbVie; and is grateful for and acknowledges funding and support from the University College London Hospitals NHS Foundation Trust Biomedical Research Centre. CH has received grants or contracts from Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from F Hoffmann-La Roche, Janssen-Cilag, AbbVie, and Gilead; and support for attending meetings or travel from Janssen-Cilag, AbbVie, and F Hoffmann-La Roche. JMZ has received consulting fees from and participated on a data safety monitoring board or advisory board for Pierre Fabre, Takeda, BMS, Gilead, Novartis, Pfizer, Amgen, F Hoffmann-La Roche, AstraZeneca, and AbbVie; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, F Hoffmann-La Roche, and AbbVie; and support for attending meetings or travel from F Hoffmann-La Roche and AbbVie. CYC has received grants or contracts from BMS, F Hoffmann-La Roche, AbbVie, MSD, and Lilly; consulting fees from F Hoffmann-La Roche, Janssen, Gilead, AstraZeneca, Lilly, BeiGene, Menarini, Dizal, AbbVie, Genmab, and BMS; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from F Hoffmann-La Roche, Janssen, Gilead, AstraZeneca, Lilly, BeiGene, Menarini, Dizal, AbbVie, Genmab, and BMS; and participated on a data safety monitoring board or advisory board for F Hoffmann-La Roche, Janssen, Gilead, AstraZeneca, Lilly, BeiGene, Menarini, Dizal, AbbVie, Genmab, and BMS. HG has received consulting fees from F Hoffmann-La Roche, BMS, and Takeda; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead, F Hoffmann-La Roche, BMS, AbbVie, and Takeda. SS is an employee of and has received grants or contracts from Genentech; and has stock or stock options with F Hoffmann-La Roche. VO-N is an employee of Genentech and has provided all support for the present manuscript for Genentech and F Hoffmann-La Roche. RT is an employee of Genentech and has provided all support for the present manuscript for, has received support for attending meetings or travel from, and has stock or stock options with Genentech and F Hoffmann-La Roche. JR is an employee of and has received grants or contracts from F Hoffmann-La Roche, and has stock or stock options with F Hoffmann-La Roche. MD is an employee of, has provided all support for the present manuscript for, and has stock or stock options with F Hoffmann-La Roche. MKa is an employee of F Hoffmann-La Roche, and has received grants or contracts from Roche Diagnostics International and F Hoffmann-La Roche. EM is an employee of, has received grants or contracts from, has received support for attending meetings or travel from, and has stock or stock options with F Hoffmann-La Roche. HH is an employee of F Hoffmann-La Roche. LL is an employee of, has received grants or contracts from, has received royalties or licences from, has patents planned, issued or pending with, and has stock or stock options with F Hoffmann-La Roche. GPG has received grants or contracts from BeiGene and Merck; consulting fees from Merck, Gilead, Novartis, BMS, Clinigen, F Hoffmann-La Roche, and Prelude Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead and F Hoffmann-La Roche; and participated on a data safety monitoring board or advisory board for Merck, Gilead, Novartis, BMS, Clinigen, F Hoffmann-La Roche and Prelude Therapeutics. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. 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Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin lymphoma which is often characterised by a pattern of continued relapse after frontline chemoimmunotherapy. Although patients are usually able to regain durable disease control with covalent Bruton's tyrosine kinase inhibitors (cBTKi) at first relapse, it is now appreciated that such responses are often not sustained and the management of such patients represents a significant area of unmet need. There is an imperative to better understand resistance mechanisms and identify high-risk subsets of patients for whom cBTKi responses may be particularly short. Allogeneic stem cell transplant has an established role in appropriate candidates, however contemporary consensus is to preferentially offer chimeric antigen receptor (CAR) T-cell therapy. In this Review, we consider the available data on both existing and emerging treatment options, including non-covalent BTK inhibitors, bispecific antibodies, antibody-drug conjugates and Bcl-2 inhibitors and propose a treatment strategy prioritising clinical trials where available.

Abstract: The multicenter, prospective phase 2 Australasian Leukaemia & Lymphoma Group NHL29 trial was conducted to assess the addition of ibrutinib to R-mini-CHOP (dose attenuated R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients aged ≥75 years with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Treatment consisted of six 21-day cycles of ibrutinib-R-mini-CHOP followed by two 21-day cycles of R-ibrutinib. Coprimary end points were deliverability and 2-year overall survival (OS). The median average relative total dose and average relative dose intensity for the entire regimen were both 97% (interquartile range, 82-100 and 88-100, respectively). With a median follow-up of 35.5 months, the 2-year OS was 68% (95% confidence interval [CI], 55.6-77.4) with a 2-year progression-free survival (PFS) of 60.0% (95% CI, 47.7-70.3). Median OS and PFS were 72 months (95% CI, 35 to not reached) and 40 months (95% CI, 20.4 to not reached), respectively. The overall response rate was 76% (61/79) of patients, with a complete response rate of 71% (56/79). Deaths occurred in 34 of 79 patients (43%), including 17 from progressive disease and 5 treatment related. Overall, 67% patients experienced at least 1 serious adverse event. Most common adverse events were infections and diarrhea (the majority grade 1-2). In both health-related quality of life measures, there was an improvement in functional and symptom scales, median health state classification score, and median visual analogue scale in responders over time. In conclusion, this study showed that the addition of ibrutinib to R-mini-CHOP was both deliverable and efficacious in elderly DLBCL patients., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Mosunetuzumab, a CD20xCD3 T-cell engaging bispecific antibody, redirects T cells to eliminate malignant B cells. We present updated efficacy and safety data of a pivotal phase 1/2 study after a median follow-up of 37.4 months in 90 patients with relapsed/refractory (R/R) follicular lymphoma (FL) and ≥2 prior lines of therapy treated with fixed-duration mosunetuzumab. Investigator-assessed complete response (CR) rate and objective response rate (ORR) were 60.0% (95% confidence interval [CI], 49.1-70.2) and 77.8% (95% CI, 67.8-85.9), respectively. Among 70 responders, median duration of response was 35.9 months (95% CI, 20.7-not estimable [NE]). Among 54 patients who achieved CR, 49 remained in CR at the end of treatment; median duration of complete response was not reached (NR) (95% CI, 33.0-NE); Kaplan-Meier-estimated 30-month remission rate was 72.4% (95% CI, 59.2-85.6). Estimated 36-month overall survival (OS) rate was 82.4% (95% CI, 73.8-91.0); median OS was NR (95% CI, NE-NE). Median progression-free survival was 24.0 months (95% CI, 12.0-NE). Median time to CD19+ B-cell recovery was 18.4 months (95% CI, 12.8-25.0) following 8 cycles of mosunetuzumab treatment. No new cytokine release syndrome events or fatal, serious, or Grade ≥3 adverse events were reported. With extended follow-up, mosunetuzumab demonstrated high response rates, durable remissions and manageable safety with no long-term concerns. This supports outpatient mosunetuzumab administration as an off-the-shelf, fixed-duration, safe and effective treatment for patients with R/R FL, including those with high-risk disease. Trial registration: www.clinicaltrials.gov (NCT02500407)., (Copyright © 2024 American Society of Hematology.)

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

Follicular lymphoma (FL) treatment initiation is largely determined by tumor burden and symptoms. In the pre-rituximab era, the Group d'Etude des Lymphomes Folliculaires (GELF) developed widely adopted criteria to identify high tumor burden FL patients to harmonize clinical trial populations. The utilization of GELF criteria (GELFc) in routine therapeutic decision- making is poorly described. This multicenter retrospective study evaluated patterns of GELFc at presentation and GELFc utilization in therapeutic decision-making in newly diagnosed, advanced-stage rituximab-era FL. Associations between GELFc, treatment given, and patient survival were analyzed in 300 eligible cases identified between 2002-2019. One hundred and sixty-three (54%) had ≥1 GELFc at diagnosis. The presence or cumulative number of GELFc did not predict progression-free survival in patients undergoing watch-and-wait (W&W) or those receiving systemic treatment. Of interest, in patients with ≥1 GELFc, 16 of 163 (10%) underwent initial W&W (comprising 22% of the W&W cohort). In those receiving systemic therapy +/- radiotherapy, 74 of 215 (34%) met no GELFc. Our data suggest clinicians are using adjunctive measures to make decisions regarding treatment initiation in a significant proportion of patients. By restricting FL clinical trial eligibility only to those meeting GELFc, reported outcomes may not be applicable to a significant proportion of patients treated in routine care settings.

Abstract: Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR) in this phase 1b trial. Prior covalent BTKi therapy was allowed, but not prior treatment with venetoclax. Patients were assigned to receive PV (n = 15) or PVR (n = 10) for 25 cycles. Most patients (68%) had received prior covalent BTKi therapy. At the data cutoff date, the median time on study was 27.0 months for PV and 23.3 months for PVR. Overall response rates were 93.3% (95% confidence interval [CI], 68.1-99.8) for PV and 100% (95% CI, 69.2-100.0) for PVR, with 10 complete responses (PV: 7; PVR: 3). After 12 cycles of treatment, 85.7% (95% CI, 57.2-98.2) of PV and 90.0% (95% CI, 55.5-99.7) of PVR patients achieved undetectable minimal residual disease (<10-4) in peripheral blood. Progression-free survival at 18 months was 92.9% (95% CI, 59.1-99.0) for PV patients and 80.0% (95% CI, 40.9-94.6) for PVR patients. No dose-limiting toxicities were observed during the 5-week assessment period. The most common grade ≥3 adverse events (AEs) for all patients included neutropenia (52%) and anemia (16%). AEs led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi. This trial was registered at www.clinicaltrials.gov as #NCT03740529., (© 2024 American Society of Hematology. Published by Elsevier Inc. 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.)

Primary results (median follow-up, 10.7 months) from the pivotal EPCORE ® NHL-1 study in relapsed or refractory (R/R) large B-cell lymphoma (LBCL) demonstrated deep, durable responses with epcoritamab, a CD3xCD20 bispecific antibody, when used as monotherapy. We report long-term efficacy and safety results in patients with LBCL (N = 157; 25.1-month median follow-up). As of April 21, 2023, overall response rate was 63.1% and complete response (CR) rate was 40.1%. Estimated 24-month progression-free survival (PFS) and overall survival (OS) rates were 27.8% and 44.6%, respectively. An estimated 64.2% of complete responders remained in CR at 24 months. Estimated 24-month PFS and OS rates among complete responders were 65.1% and 78.2%, respectively. Of 119 minimal residual disease (MRD)-evaluable patients, 45.4% had MRD negativity, which correlated with longer PFS and OS. CR rates were generally consistent across predefined subgroups: 36% prior chimeric antigen receptor (CAR) T-cell therapy, 32% primary refractory disease, and 37% International Prognostic Index ≥3. The most common treatment-emergent adverse events were cytokine release syndrome (51.0%), pyrexia (24.8%), fatigue (24.2%), and neutropenia (23.6%). These results underscore the long-term benefit of epcoritamab for treating R/R LBCL with deep responses across subgroups, including patients with hard-to-treat disease and expected poor prognosis (ClinicalTrials.gov Registration: NCT03625037)., (© 2024. The Author(s).)

Background: Richter transformation usually presents as an aggressive diffuse large B-cell lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukaemia, has no approved therapies, and is associated with a poor prognosis. Pirtobrutinib has shown promising efficacy and tolerability in patients with relapsed or refractory B-cell malignancies, including those who progress on covalent Bruton tyrosine kinase (BTK) inhibitors. This study aims to report the safety and activity of pirtobrutinib monotherapy in a subgroup of patients with Richter transformation from the multicentre, open-label, phase 1/2 BRUIN study., Methods: This analysis included adult patients (aged ≥18 years) with histologically confirmed Richter transformation, an Eastern Cooperative Oncology Group performance status score of 0-2, and no limit of previous therapies, with patients receiving first-line treatment added in a protocol amendment (version 9.0, Dec 15, 2021). Pirtobrutinib 200 mg was administered orally once a day in 28-day cycles. The primary endpoint of phase 1 of the BRUIN trial as a whole, which has been previously reported, was to establish the recommended phase 2 dose for pirtobrutinib monotherapy and the phase 2 primary endpoint was overall response rate. Safety and activity were measured in all patients who received at least one dose of pirtobrutinib monotherapy. This BRUIN phase 1/2 trial was registered with ClinicalTrials.gov and is closed to enrolment (NCT03740529)., Findings: Between Dec 26, 2019, and July 22, 2022, 82 patients were enrolled, of whom five were enrolled during phase 1 and 77 during phase 2. All but one patient received a starting dose of 200 mg pirtobrutinib once a day as the recommended phase 2 dose. The remaining patient received 150 mg pirtobrutinib once a day, which was not escalated to 200 mg. The median age of patients was 67 years (IQR 59-72). 55 (67%) of 82 patients were male and 27 (33%) were female. Most patients were White (65 [79%] of 82). 74 (90%) of 82 patients received at least one previous Richter transformation-directed therapy. Most patients (61 [74%] of 82) had received previous covalent BTK inhibitor therapy for chronic lymphocytic leukaemia or Richter transformation. The overall response rate was 50·0% (95% CI 38·7-61·3). 11 (13%) of 82 patients had a complete response and 30 (37%) of 82 patients had a partial response. Eight patients with ongoing response electively discontinued pirtobrutinib to undergo stem-cell transplantation. The most common grade 3 or worse adverse event was neutropenia (n=19). There were no treatment-related deaths., Interpretation: Pirtobrutinib shows promising safety and activity among patients with Richter transformation, most of whom received previous Richter transformation-directed therapy, including covalent BTK inhibitors. These data suggest that further investigation is warranted of pirtobrutinib as a treatment option for patients with relapsed or refractory Richter transformation after treatment with a covalent BTK inhibitor., Funding: Loxo Oncology., Competing Interests: Declaration of interests WGW reports research funding from Numab Therapeutics, Loxo Oncology–Lilly, Janssens Biotech, NIH P30 CA016672/MDACC Cancer Center Support Grant, GlaxoSmithKline, AbbVie, Cyclacel, Nurix Therapeutics, Juno Therapeutics, Bristol Myers Squibb (Juno & Celgene), AstraZeneca–Acerta Pharma Miragen, Oncternal Therapeutics, Janssens Biotech, Accutar Biotechnology, Sunesis, KITE Pharma, Gilead Sciences, Genentech, Pharmacyclics, GlaxoSmithKline–Novartis; consultancy fees from AbbVie, Cyclacel Nurix Therapeutics, Bristol Myers Squibb (Juno & Celgene), AstraZeneca–Acerta Pharma; a non-relevant financial relationship with the National Comprehensive Cancer Network; support from the National Institutes of Health and National Cancer Institute under award number P30 CA016672; and use of MDACC Cancer Center Support Grant shared resources. NNS reports consultancy fees from Umoja, Janssen, Bristol Myers Squibb–Juno, LOXO Oncology–Lilly, TG therapeutic, Novartis, Seattle Genetics, Gilead–Kite, Incyte, AbbVie, Lilly Oncology, and Miltenyi Biotec; research funding from Miltenyi Biotec and Lilly Oncology; having stock options in a privately-held company with Tundra Therapeutics; and travel support from Epizyme and Miltenyi Biotec. CYC reports consultancy fees, honoraria, and having an advisory role for Roche, Janssen, Gilead, AstraZenecca, Eli Lilly, BeiGene, AbbVie, Menarini, Daizai, and Genmab, and research funding from Roche, MSD, Eli Lilly, Bristol Myers Squibb, and AbbVie. DL reports consultancy fees from Kite, BeiGene, Roche, Eli Lilly, and Janssen and membership on an entity's board of directors or advisory committees with Kite, BeiGene, Roche, Eli Lilly, and Janssen. MSH reports consultancy fees and honoraria from Pharmacyclics. CCC reports consultancy fees from LOXO Oncology–Eli Lilly, BeiGene, AstraZeneca, Genentech, AbbVie, Octapharma, Allogene, Janssen, TG Therapeutics, MEI Pharma, and Mingsight; honoraria from LOXO Oncology–Eli Lilly, BeiGene, AstraZeneca, Genentech, AbbVie; research funding paid to an institution from LOXO Oncology–Eli Lilly, AbbVie, and CarnaBio; membership on an entity's board of directors or advisory committees with BeiGene, AstraZeneca, Genentech, and AbbVie; being an equity holder in a publicly-traded company with Bluebird Bio, Geron, and Pfizer; and receiving travel support from LOXO Oncology–Eli Lilly. NL reports consultancy fees from Genentech, Pharmacyclics, BeiGene, AstraZeneca, AbbVie, Adaptive Biotechnologies, Janssen, and research funding from Genentech, TG Therapeutics, BeiGene, AstraZeneca, AbbVie, MingSight, LOXO Oncology–Eli Lilly, Oncternal, and Octapharma. SM reports consultancy fees from AstraZeneca, Juno–Bristol Myers Squibb, AbbVie, Genentech, Janssen Pharmaceuticals, BeiGene; membership on a board of directors or advisory committee with AstraZeneca, Juno–Bristol Myers Squibb, Janssen Pharmaceuticals, Eli Lilly, Loxo Oncology, and BeiGene; research funding from AstraZeneca, Juno–Bristol Myers Squibb, AbbVie, Janssen Pharmaceuticals, Eli Lilly–Loxo Oncology, BeiGene; and speakers bureau with AstraZeneca, Eli Lilly–Loxo Oncology, and BeiGene. DJ reports research funding from Seagen, Trillium Pharmaceuticals, Regeneron Pharmaceuticals, MEI Pharma, Loxo Oncology, Debio Pharma, ATARA Biotherapeutics, AstraZeneca and membership on a board of directors or advisory committees with Affimed and Daiichi Sankyo. TM reports consultancy fees from BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie; honoraria from BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie; membership on a board of directors or advisory committees on BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, Abbvie; research Funding from Janssen, AbbVie; and speakers bureau for BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie. YW reports research funding from Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab, and AbbVie; membership on an advisory board with Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, AstraZeneca, and Genmab; consultancy fees from Innocare and AbbVie; and honoraria from Kite. TAE reports membership on an entity's Board of Directors or advisory committees from Loxo Oncology, Incyte, BeiGene, AstraZeneca, KITE, AbbVie, Roche, Gilead, Secura Bio; speakers bureau from Loxo Oncology, Eli Lilly, Incyte, BeiGene, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Medscape, Janssen, Gilead, PeerView; research funding from BeiGene and AstraZeneca; consultancy fees from Eli Lilly, Incyte, Beigene, Autolus, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Janssen, and Gilead; and honoraria from Eli Lilly, BeiGene, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Janssen, and Gilead. JMR reports consultancy fees from Pharmacyclics, Jannsen, Genentech, GenMab, AstraZeneca, Morphosys, ADC Therapeutics, Epizyme, BeiGene, and AbbVie; research funding from Pharmacyclics, Velosbio, Loxo Oncology, Acerta, Oncternal Pharmaceuticals, Epizyme, and AbbVie; and honoraria from SeaGen. MM reports consultancy from Bayer, ADC therapeutics, Epizyme, Genentech, F Hoffmann-La Roche, and Incyte; research funding from BeiGene, Janssen, F Hoffmann-La Roche– Genentech, Celgene–Bristol Myers Squibb, and Incyte; and speakers bureau with ADC therapeutics, BeiGene, and Kite–Gilead. CT reports honoraria from Loxo Oncolgy. WJ reports consultancy fees from AbbVie, AstraZeneca, BeiGene, Eli Lilly, Pfizer, Roche, SOBI, and Takeda and research funding from AbbVie, AstraZeneca, Bayer, BeiGene, Celgene, Janssen, Eli Lilly, Roche, SOBIm, and Takeda. KI reports honoraria from Eli Lilly, SymBio Pharmaceuticals, Meiji Seika, Nihon Kayaku, Takeda, AstraZeneca, Janssen, Genmab, MSD, Pfizer, AbbVie, Ono Pharmaceuticals, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Chugai Pharma, and Kyowa Kirin; consultancy fees from Takeda, AstraZeneca, Genmab, AbbVie, Otsuka, Eisai, Ono Pharmaceuticals, Nippon Shinyaku, Mitsubishi Tanabe Pharma, and Zenyaku Kogyo; and research funding from AstraZeneca, Genmab, MSD, Pfizer, AbbVie, Otsuka, Eisai, Regeneron, Loxo Oncology, BeiGene, Daiichi Sankyo, Yakult, Novartis, Bristol Myers Squibb, Incyte, Astellas Amgen, Chugai Pharma, Kyowa Kirin. AA reports membership on a board of directors or advisory committees with Genentech, Eli Lilly and Company, Amgen, TG Therapeutics, Incyte, BeiGene, Epizyme, Janssen, and SeaGen; research funding from Eli Lilly, Incyte, and BeiGene; and honoraria from Dr Reddy. MP reports consulting fees from Kura, Accutar, Mitsubishi; participating on a data safety monitoring board or advisory board with lema, Nurix, Daiichi, Kura, and Janssen; leadership with ION Pharma; honoraria from Janssen Oncology; and participating in a consulting or advisory role with Olema Pharmaceuticals, Daiichi Sankyo–UCB Japan, Kura Oncology, Accutar Biotech, and Kura. JFS reports honoraria from Hoffmann-La Roche, AbbVie, AstraZeneca, Janssen, Bristol Myers Squibb, Gilead, and BeiGene; consultancy fees from Hoffmann-La Roche, TG Therapeutics, Bristol Myers Squibb; participating on a data safety monitoring board or advisory board with Genor Bio, Hoffmann-La Roche, AbbVie, AstraZeneca, Janssen, Bristol Myers Squibb, Gilead, and BeiGene; speakers bureau with Hoffmann-La Roche, AbbVie, and BeiGene; and research funding from F Hoffmann-La Roche and AbbVie. JAW reports consultancy from Newave, Loxo Oncology, BeiGene, AstraZeneca, AbbVie, Janssen, and Pharmacyclics and research funding from Schrodinger, Morphosys, Karyopharm, Janssen, and Pharmacyclics. PAT reports consultancy and honoraria from AbbVie, Adaptive Biotechnologies, Ascentage AstraZeneca, BeiGene, Genentech, Genmab, Janssen, Lilly, Merck, Pharmacyclics; speakers bureau from AbbVie, Adaptive Biotechnologies, AstraZeneca, Janssen, and Merck; research funding from AbbVie, Pharmacyclics, Genentech, Lilly, and Adaptive Biotechnologies; and travel support from Merck. PA is a current employee of and equity holder in Eli Lilly. CH reports being an equity holder in Eli Lilly and Foundation Medicine and travel support from Eli Lilly. SCM reports current employment with, being an equity holder in, and travel support from Eli Lilly. NM reports being a current equity holder in Eli Lilly and current employment with Loxo Oncology. BN, CW, BCN, and DET reports current employment with and current equity holder in Eli Lilly. ASR reports current employment with and being equity holder in Eli Lilly and consultancy work with Telios Pharma. HL reports current employment with Loxo Oncology. LER reports serving as a consultant for AbbVie, Ascentage, AstraZeneca, BeiGene, Janssen, Loxo Oncology, Pharmacyclics, Pfizer, and TG Therapeutics; membership of a data safety monitoring committee for Ascentage; serving as a CME speaker for DAVA, Curio, Medscape, and PeerView; holding minority ownership interest in Abbott Laboratories; having received travel support from LOXO Oncology; and having received research funding (paid to the institution) from Adaptive Biotechnologies, AstraZeneca, Genentech, AbbVie, Pfizer, Loxo Oncology, Aptose Biosciences, Dren Bio, and Qilu Puget Sound Biotherapeutics. PG reports consultancy, fees, honoraria, and research funding from Janssen, Eli Lilly–Loxo Oncology, MSD, Roche, AbbVie, BMS, BeiGene, and AstraZeneca., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The B cell receptor (BCR) signalling pathway has an integral role in the pathogenesis of many B cell malignancies, including chronic lymphocytic leukaemia, mantle cell lymphoma, diffuse large B cell lymphoma and Waldenström macroglobulinaemia. Bruton tyrosine kinase (BTK) is a key node mediating signal transduction downstream of the BCR. The advent of BTK inhibitors has revolutionized the treatment landscape of B cell malignancies, with these agents often replacing highly intensive and toxic chemoimmunotherapy regimens as the standard of care. In this Review, we discuss the pivotal trials that have led to the approval of various covalent BTK inhibitors, the current treatment indications for these agents and mechanisms of resistance. In addition, we discuss novel BTK-targeted therapies, including covalent, as well as non-covalent, BTK inhibitors, BTK degraders and combination doublet and triplet regimens, to provide insights on the best current treatment paradigms in the frontline setting and at disease relapse., Competing Interests: Competing interests A.V.D. has received research funding and consultancy fees from Abbvie, AstraZeneca, Beigene, Bristol Myers Squibb, GenMab, Lilly Oncology, MEI Pharma, Nurix Therapeutics and Presage; research funding from Bayer, Cyclacel and Incyte; and consultancy fees from Genentech, Janssen, Merck and Regeneron. J.J.C. reports consulting or advisory roles for AbbVie/Pharmacyclics, BeiGene, Cellectar, Janssen, Kite Pharma/Gilead, Loxo Oncology/Lilly, Mustang Bio and Roche/Genentech, and institutional research funding from AbbVie, AstraZeneca, BeiGene, Cellectar, Loxo/Lilly, Pharmacyclics and TG Therapeutics. A.J.A. has received consultancy fees from Amgen, BeiGene, Epizyme, Genentech, Incyte, Janssen, Kite, Lilly, Seagen, and TG Therapeutics and research funding from BeiGene, Incyte and Loxo Oncology. J.C.C. has received consultancy fees from AbbVie, ADC Therapeutics, Adicet, AstraZeneca, BeiGene, Bristol Myers Squibb, Cellectar, Genentech, Genmab, Janssen, Kite Pharma/Gilead and Novartis; honoraria from AstraZeneca, BeiGene and Lilly; research funding from AstraZeneca, Janssen and Merck; and has served as a Data and Safety Monitoring Board member for Atara and the National Cancer Institute. C.Y.C. has received consultancy fees or honoraria from AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Dizal, Genmab, Gilead, Janssen, Lilly, Menarini, Novartis, Roche, and TG Therapeutics and research funding from AbbVie, Bristol Myers Squibb, Lilly, MSD and Roche. Y.W. has received institutional research funding from Genentech, Genmab, Incyte, InnoCare, Lilly, Loxo Oncology, MorphoSys, and Novartis and institutional honoraria from Kite Pharma; has served on advisory boards (compensation to institution) for AstraZeneca, BeiGene, Incyte, InnoCare, Jansen, Kite Pharma/Gilead, Lilly, Loxo Oncology and TG Therapeutics; has consulted for (compensation to institution) AbbVie and Innocare; and has an immediate family member who is employed by and has stock ownership in Merck. M.T. has received consultancy fees from AstraZeneca, Loxo Oncology/Lilly and Pharmacyclics/Janssen; honoraria from the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy, Curio Science, Dava Oncology, Intellisphere, the Massachusetts Medical Society, MJH Life Sciences, and VJHemOnc and institutional research funding from Abbvie, AstraZeneca, Beigene, Genentech, Genmab and Nurix Therapeutics. P.G. has received honoraria from AbbVie, ArQule/MSD, AstraZeneca, BeiGene, Celgene/Juno/Bristol Myers Squibb, Janssen, Loxo Oncology/Lilly, MEI Pharma, Roche, and Sanofi and research funding from AbbVie, AstraZeneca, Bristol Myers Squibb, Janssen and Sunesis. J.P.A. has received consultancy fees from AbbVie, ADC Therapeutics, Genentech, and Regeneron and research funding from AbbVie, ADC Therapeutics, BeiGene and Genmab. M.D.S., S.M., C.C. and J.T. declare no competing interests., (© 2024. Springer Nature Limited.)

Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) accounts for the majority of extra-nodal DLBCL. Even so, literature is lacking on early, localised presentations. We studied a cohort of patients with stage I disease, diagnosed between 2006 and 2018, from six centres between Australia, Canada and Denmark. Our goal was to characterise outcomes, review treatment and investigate the role of interim positron emission tomography (iPET). Thirty-seven eligible patients were identified. The median duration of follow-up was 42.2 months. All received chemoimmunotherapy with 91.9% (n = 34) given rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). 35.1% (n = 13) underwent consolidative radiotherapy. Eighteen patients were H. pylori positive and 11 had the documentation of H. pylori eradication therapy. The 4-year progression-free survival and overall survival of R-CHOP was 88% (95% CI: 71-95) and 91% (95% CI: 75-97) respectively. All patients who achieved a partial metabolic response or complete metabolic response on iPET went on to achieve complete response at the end of treatment. R-CHOP-based therapy with iPET assessment appears to offer favourable outcomes, with radiotherapy and H. pylori eradication therapy implemented on a case-by-case basis., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma subtype, accounting for 15-20% of all lymphoma diagnoses. Although typically slow-growing and responsive to frontline therapies, advanced-stage FL remains incurable with current treatments and typically follows a chronic relapsing/remitting course with increasingly shorter responses to subsequent lines of therapy. Outcomes are highly variable; some patients experience prolonged first remissions that may approximate a 'functional cure'. By contrast, a significant minority of patients experience disease progression shortly after frontline treatment resulting in high rates of lymphoma-related mortality. Reflecting on the heterogeneous natural history of FL, clinical practice varies widely, particularly in controversial areas, including appropriate disease staging, selection of management strategies and duration of clinical follow-up. This position statement presents an evidence-based synthesis of the literature for application in Australasian practice., (© 2024 Royal Australasian College of Physicians.)

Purpose: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL., Methods: Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation., Results: We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41)., Conclusion: In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

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.

Background: Despite recent advances, optimal therapeutic approaches applicable to subpopulations with primary central nervous system (CNS) lymphoma outside of clinical trials remain to be determined., Methods: We performed a retrospective study of immunocompetent, adult patients with histologically confirmed diffuse large B-cell lymphoma of the CNS (PCNSL). 190/204 (93%) patients (median age: 65) received one of five high-dose methotrexate (HD-MTX) containing chemotherapy regimens: MPV/Ara-C (HD-MTX, procarbazine, and vincristine, followed by cytarabine [Ara-C]) ( n  = 94, 50%), MATRix (HD-MTX, Ara-C, thiotepa, and rituximab) ( n  = 19, 10%), HD-MTX/Ara-C ( n  = 31, 16%), HD-MTX monotherapy ( n  = 35, 18%) and MBVP (HD-MTX, carmustine, teniposide, prednisolone) ( n  = 11, 6%)., Results: Cumulative median HD-MTX and Ara-C doses were 17 g/m 2 (range: 1-64 g/m 2 ) and 12 g/m 2 (0-32 g/m 2 ) respectively. Using 14 g/m 2 as the reference dose, the median HD-MTX relative dose intensity (HD-MTX-RDI) was 1.25 (0.27-4.57) with 84% receiving > 0.75. The overall response rate (ORR) was 72% (complete response: 50%) after completing HD-MTX. At a median follow-up of 3.41 years (0.06-9.42), progression-free survival (PFS) and overall survival (OS) were different between chemotherapy cohorts, with the best outcomes achieved in the MPV/Ara-C cohort (2-year PFS 74%, 2-year OS 82%; p  = 0.0001 and p  = 0.0024 respectively). On multivariate analysis, MPV/Ara-C administration and HD-MTX-RDI > 0.75 were associated with longer PFS and OS., Conclusion: Sequential, response-adapted approaches can improve outcomes, even in older patients who are ineligible for a high-intensity concurrent chemotherapy approach and do not undergo traditional consolidative strategies., Competing Interests: Katharine Louise Lewis: Consultancy/Honoraria: Jansen Roche. Trial steering committee: Loxo/Lilly. Advisory: IQVIA and MSD; Pietro R. Di Ciaccio: Honoraria/travel funding: Janssen, Astra Zeneca, and Gilead/Kite; Chan Y. Cheah: Research funding: Beigene. Advisory: Janssen Cilag. Joel Wight: Honoraria: Janssen, MDI, Beigene, MSD, and Abbvie. Travel support: Kite/Gilead. Jake Shortt: Consultancy: BMS, Otsuka, Pfizer, and Astellas. Speaker's Bureau: Mundipharma and Novartis. Research funding: Astex. Dipti Talaulikar: Consultancy/Advisory/Honoraria: Roche, Janssen, Beigene, Novartis, Amgen, Antengene, CSL, EUSA, BMS, and Takeda. Research funding: Roche, Janssen, and Takeda. Tara Cochrane: Research funding: Beigene. Advisory: Janssen Cilag. Eliza A. Hawkes: Consultancy/Advisory: AstraZeneca, Janssen Oncology, Merck Sharpe & Dohme, Gilead Sciences, Bristol Myers Squibb, Novartis, Beigene, Link Healthcare, and Regeneron. Speaker's Bureau: Roche/Genentech, Regeneron, and Abbvie. Research funding: AstraZeneca, Celgene, Merck KGaA, Janssen‐Cilag, Gilead Sciences, Mundipharma, Bristol‐Myers Squibb, and Roche/Genentech. Travel: AstraZeneca., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment., Methods: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs)., Results: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy., Conclusions: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Diffuse large B-cell lymphoma (DLBCL) may be cured with anti-CD20 based chemoimmunotherapy in the majority of cases, however, relapsed/refractory disease occurs in 30-40% patients, and despite significant recent therapeutic advances, continues to represent an unmet clinical need. Bispecific antibodies represent a novel class of therapy currently in development for relapsed/refractory B-cell lymphoma. This review discusses the background clinical need, mechanism of action, and clinical data including efficacy and toxicity for bispecific antibodies in DLBCL, focusing on the most advanced class in development; CD20 targeting T-cell engaging antibodies. Emerging possibilities for future use of bispecific antibodies is also discussed, including novel and cytotoxic combination regimens in relapsed and first-line settings.

Polatuzumab vedotin (Pola) is an approved therapy in combination with rituximab and bendamustine for relapsed or refractory diffuse large B-cell lymphoma (RR-DLBCL) based on positive results of the landmark phase II randomised G029365 trial. However, trial results for many approved novel therapies in RR-DLBCL have not been replicated in routine care cohorts, as RR-DLBCL patient populations are heterogeneous and trial eligibility is increasingly restrictive. We evaluated outcomes from pola ± bendamustine and rituximab in patients with RR-DLBCL enrolled in a compassionate access program with no alternative treatment options identified via the Australasian Lymphoma and Related Diseases Registry according to their eligibility for the original phase II published study. Of 58 eligible patients, 74% met the criteria deeming them ineligible for the G029365 original study at the time of pola's commencement. Median progression-free survival and overall survival in our cohort were 2.3 and 3.5 months, respectively. In contrast to the landmark trial cohort, more of our patients ceased therapy prior to completion, the majority due to progressive disease and only 8/58 received any subsequent treatment. Dismal outcomes in this Australian real-world population demonstrate trial eligibility is challenging to meet, and newer treatments can be difficult to deliver in routine care. Clinically applicable results from therapeutic studies require trial cohorts to reflect representative clinical populations wherever possible, and more research is required to address the benefit of novel agents in the increasing majority who are ineligible for modern studies., Competing Interests: Briony Shaw, Eliza Chung, Edward Yoo, Rory Bennett, Callum Birks, Jock Simpson, Sumita Ratnasingam, Tasman Armytage, Denise Lee, Colm Keane, Stephanie Wallwork all declare no conflicts of interest. Anna Johnston: Consulting or advisory role, honoraria: Merck Sharpe & Dohme, Roche, Link, BeiGene, Sanofi, EUSA Pharma, Novartis, Chan Y Cheah: Consulting or advisory role, honoraria: Roche, Janssen, Gilead, AstraZenecca, Lilly, TG therapeutics, BeiGene, Novartis, Menarini, Dizal, AbbVie, Genmab, Bristol Myers Quibb; Research funding: Bristol Myers Quibb, Roche, AbbVie, Merck Sharpe & Dohme, Lilly, Nada Hamad: Honoraria: Roche, Janssen, Gilead, AstraZenecca, BeiGene, Novartis, AbbVie, Genmab, Bristol Myers Quibb, Takeda, Jazz Pharmaceuticals, Incyte, Pfizer, Mallinckrodt Pharmaceuticals, Terumo, Allison Barraclough: Honoraria: Roche, Gilead, Novartis, BeiGene, Matthew Ku: Roche, Antengene, Genor BioPharma, Nicholas Viiala: Honoraria and advisory board: Novartis, Tara Cochrane: Consulting or advisory role: Janssen; Honoraria: Celgene (in 2019); Research funding: BeiGene, Geoffrey Chong: Research funding: Bristol Myers Quibb, Merck, AstraZeneca, Pharmacyclics, Regeneron, Hutchmed, Bayer, Incyte, Amgen, Kate Manos: Advisory/honoraria: AbbVie; Research funding: Roche, Stephen Opat: Honoraria: AbbVie, BeiGene, AstraZeneca, Bristol Myers Quibb, CSL Behring, Gilead, Janssen, Merck, Roche, Takeda; Research funding: AbbVie, BeiGene, AstraZeneca, CSL Behring, Gilead, Janssen, Merck, PharmaCytics, Roche, Takeda, Eliza A. Hawkes: Consulting or advisory role: Roche, Merck Sharpe & Dohme, AstraZeneca, Gilead, Antengene, Novartis, Regeneron, Janssen, Specialised Therapeutics; Research funding: Roche, Bristol Myers Squibb, Merck KGaA, AstraZeneca, Merck, (© 2024 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Abstract: CD19-directed chimeric antigen receptor T cells (CAR-T) achieve high response rates in patients with relapsed/refractory mantle cell lymphoma (MCL). However, their use is associated with significant toxicity, relapse concern, and unclear broad tractability. Preclinical and clinical data support a beneficial synergistic effect of ibrutinib on apheresis product fitness, CAR-T expansion, and toxicity. We evaluated the combination of time-limited ibrutinib and CTL019 CAR-T in 20 patients with MCL in the phase 2 TARMAC study. Ibrutinib commenced before leukapheresis and continued through CAR-T manufacture for a minimum of 6 months after CAR-T administration. The median prior lines of therapy was 2; 50% of patients were previously exposed to a Bruton tyrosine kinase inhibitor (BTKi). The primary end point was 4-month postinfusion complete response (CR) rate, and secondary end points included safety and subgroup analysis based on TP53 aberrancy. The primary end point was met; 80% of patients demonstrated CR, with 70% and 40% demonstrating measurable residual disease negativity by flow cytometry and molecular methods, respectively. At 13-month median follow-up, the estimated 12-month progression-free survival was 75% and overall survival 100%. Fifteen patients (75%) developed cytokine release syndrome; 12 (55%) with grade 1 to 2 and 3 (20%) with grade 3. Reversible grade 1 to 2 neurotoxicity was observed in 2 patients (10%). Efficacy was preserved irrespective of prior BTKi exposure or TP53 mutation. Deep responses correlated with robust CAR-T expansion and a less exhausted baseline T-cell phenotype. Overall, the safety and efficacy of the combination of BTKi and T-cell redirecting immunotherapy appears promising and merits further exploration. This trial was registered at www.ClinicalTrials.gov as #NCT04234061., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication., Patients and Methods: Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti-CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts)., Results: Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, -1.5 to 4.4; all-pts) and 1.4% (95% CI, -1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup., Conclusion: In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.

Disease Overview: Marginal zone lymphomas (MZL) are collectively the second most common type of indolent lymphoma., Diagnosis: Three subtypes of MZL are recognized: splenic, extranodal, and nodal. The diagnosis is secured following biopsy of an involved nodal or extranodal site demonstrating a clonal B-cell infiltrate with CD5 and CD10 negative immunophenotype most common. Some cases will features IgM paraprotein, but MYD88 L256P mutations are less frequent than in Waldenstrom macroglobulinemia. Prognostication Several prognostic models have been developed, including the MALT-IPI and the MZL-IPI. The latter is broadly applicable across MZL subtypes and incorporates elevated serum LDH, anemia, lymphopenia, thrombocytopenia and nodal or disseminated subtypes as independent predictors of outcome., Treatment: We discuss suggested approach to therapy for both early and advanced-stage disease, with reference to chemo-immunotherapy, radiotherapy, and emerging treatments in relapsed/refractory disease such as BTK inhibitors., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

As part of a phase 1 or 2 study, this single-arm expansion cohort established the efficacy and safety of mosunetuzumab monotherapy in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (received ≥2 previous lines of therapy). Intravenous mosunetuzumab was administered with cycle (C) 1 step-up dosing for cytokine release syndrome (CRS) mitigation: C1 day (D) 1: 1 mg; C1D8 2 mg; C1D15 and C2D1: 60 mg; C3 + D1: 30 mg. Hospitalization was not mandatory. Patients with complete response (CR) completed treatment after C8; those with partial response or stable disease continued treatment for a total of 17 cycles. The primary end point was CR rate (best response), assessed against a historical control CR rate (20%) by independent review facility. Eighty-eight patients (73.9% de novo DLBCL; 26.1% transformed follicular lymphoma) were enrolled; all had received previous anthracycline and anti-CD20 therapy. Overall response and CR rates were 42.0% (95% confidence interval [CI], 31.6-53.1) and 23.9% (95% CI, 15.4-34.1), respectively; CR rate did not reach statistical significance vs the historical control (P = .36). Median time to first response was 1.4 months. Median progression-free survival was 3.2 months (95% CI, 2.2-5.3). The CR rate in 26 patients who received previous chimeric antigen receptor T-cell (CAR-T) therapy was 12%. CRS was one of the most common adverse events (26.1% of patients); predominantly grade 1 to 2 and primarily in C1. Four patients (4.5%) discontinued mosunetuzumab owing to adverse events. Mosunetuzumab demonstrated notable efficacy and a manageable safety profile in patients with R/R DLBCL, including those previously treated with CAR-Ts. This trial was registered at www.clinicaltrials.gov as #NCT02500407., (© 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.)

Grade (G) 3B follicular lymphoma (FL) is a rare FL subtype which exists on a histological continuum between 'lowgrade' (Grade 1, 2 and 3A FL) and diffuse large B-cell lymphoma (DLBCL) appearing to share features with each. Clinical characteristics and outcomes are poorly understood due to lack of adequate representation in prospective trials and large-scale analyses. We analyzed 157 G3BFL cases from 18 international centers, and two comparator groups; G3AFL (n=302) and DLBCL (n=548). Composite histology with DLBCL or low-grade FL occurred in approximately half of the G3BFL cases. With a median of 5 years follow-up, the overall survival and progression-free survival of G3BFL patients was better than that of DLBCL patients (P<0.001 and P<0.001, respectively); however, G3BFL patients were younger (P<0.001) with better performance status (P<0.001), less extranodal disease (P<0.001) and more frequently had normal lactate dehydrogenase (P<0.001) at baseline. The overall and progression-free survival of patients with G3BFL and G3AFL were similar (P=0.83 and P=0.80, respectively). After frontline immunochemotherapy, 24% of G3BFL relapsed; relapse rates were 63% in the DLBCL cohort and 19% in the low-grade FL cohort. Eight percent of relapses occurred beyond 5 years. In this G3BFL cohort, the revised International Prognostic Index successfully delineated risk groups, but the Follicular Lymphoma International Prognostic Index did not. We conclude that patients with immunochemotherapy-treated G3BFL have similar survival outcomes to those with G3AFL, yet a favorable baseline profile and distinctly superior prognosis compared to patients with DLBCL.

Time to progression of disease (POD) after first-line (1L) therapy is prognostic in mantle cell lymphoma (MCL), although studies have included a broad range of 1L, second-line (2L), and subsequent lines of therapy. The purpose of this study was to evaluate the factors predicting outcomes in patients with relapsed/refractory (R/R) MCL exclusively initiating 2L Bruton's tyrosine kinase inhibitors (BTKis) after 1L rituximab-containing therapy. Patients were accrued from 8 international centers (7 main, 1 validation cohort). Multivariable models evaluating the association between time to POD and clinical/pathologic factors were constructed and converted into nomograms and prognostic indexes predicting outcomes in this population. A total of 360 patients were included, including 160 in the main cohort and 200 in the validation cohort. Time to POD, Ki67 ≥ 30%, and MCL International Prognostic Index (MIPI) were associated with progression-free survival (PFS2) and overall survival (OS2) from the start of 2L BTKis. C-indexes were consistently ≥0.68 in both cohorts. Web/application-based calculators based on nomograms and prognostic indexes to estimate PFS2 and OS2 were constructed. The 2L BTKi MIPI identifies 3 groups with distinct 2-year PFS2, including high risk (14%), intermediate risk (50%), and low risk (64%). Time to POD, Ki67, and MIPI are associated with survival outcomes in patients with R/R MCL receiving 2L BTKis. Simple clinical models incorporating these variables may assist in planning for alternative therapies such as chimeric antigen receptor T-cell therapy, allogeneic stem cell transplantation, or novel agents with alternative mechanisms of action., (© 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: Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated mantle-cell lymphoma (MCL), a population with poor prognosis., Methods: Patients with cBTKi pretreated relapsed/refractory (R/R) MCL received pirtobrutinib monotherapy in a multicenter phase I/II trial (BRUIN; ClinicalTrials.gov identifier: NCT03740529). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary end point was overall response rate (ORR). Secondary end points included duration of response (DOR) and safety., Results: The median patient age was 70 years (range, 46-87), the median prior lines of therapy was 3 (range, 1-8), 82.2% had discontinued a prior cBTKi because of disease progression, and 77.8% had intermediate- or high-risk simplified MCL International Prognostic Index score. The ORR was 57.8% (95% CI, 46.9 to 68.1), including 20.0% complete responses (n = 18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5 to not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n = 164), the most common treatment-emergent adverse events (TEAEs) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAEs of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib because of a treatment-related adverse event., Conclusion: Pirtobrutinib is a first-in-class novel noncovalent (reversible) BTKi and the first BTKi of any kind to demonstrate durable efficacy after prior cBTKi therapy in heavily pretreated R/R MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation because of toxicity.