Hernandez‐Ilizaliturri, Francisco J.

Background: Despite the efficacy of covalent (c) Bruton tyrosine kinase inhibitors (BTKi) in R/R MCL, disease relapse arises through evolution of resistance mechanisms or development of cBTKi intolerance. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable oral pharmacology that enables continuous BTK inhibition throughout the daily dosing interval regardless of the intrinsic rate of BTK turnover. Pirtobrutinib is the first BTKi to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated R/R MCL and was well-tolerated with a low frequency of treatment discontinuation due to toxicity (Wang et al., JCO, 2023). Pirtobrutinib is approved in the USA to treat relapsed or refractory MCL after at least two lines of systemic therapy including a prior cBTKi. Here, we report updated results of pirtobrutinib therapy in all patients (pts), including those with biologically high-risk R/R MCL with a median survival follow-up of 24.2 months (range, 18.2-29.8). Methods: Pts with R/R MCL received pirtobrutinib monotherapy in the multicenter Phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in all cBTKi pre-treated pts, as well as in cBTKi treatment-naïve pts. Key endpoints included overall response rate (ORR) as assessed by independent review committee per Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Pts were included across the dose escalation range and expansion (25-300 mg/day) with 93% (n=141) receiving at least one dose of 200 mg/day, the FDA-approved dose. A data cut of 05 May 2023 was utilized. Results: Among all 152 pts with R/R MCL who received a prior cBTKi, the median age was 70 years (range, 46-88), and 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. Median prior lines of therapy were 3 (range, 1-9), including an anti-CD20 antibody (96.7%), chemotherapy (90.1%), immunomodulator (17.1%), stem cell transplant (21.7%), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%), and PI3K inhibitor (3.9%). Among pts with high-risk biomarker data available, 30/60 (50%) had TP53 mutations and 45/63 (71%) had a Ki-67 index of ≥30%. The ORR for cBTKi pre-treated pts was 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (n=24) and 33.6% partial responses (n=51), whilst cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2). The ORR among 128 pts who had discontinued a prior cBTKi due to PD and 21 pts who had discontinued for toxicity/other reasons was 43.0% and 90.5%, respectively. Among the 75 responding cBTKi pre-treated pts, the median DOR was 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The 18- and 24-month DOR rates were 51.9% (95% CI, 37-64.8) and 38.9% (95% CI, 22.7-54.8), respectively. ORR and DOR by high-risk subgroups (including blastoid/pleomorphic variants, Ki-67 index ≥30%, and TP53 mutations) are shown in Table 1. The 18- and 24-month DOR rates among 12 responding cBTKi naïve pts were both 90.0% (95% CI, 47.3-98.5). The median PFS and OS for cBTKi pre-treated pts was 5.6 months (95% CI, 5.3-9.2), and 23.5 months (95% CI, 17.1-NE), respectively. In the MCL cohort (n=166), the most frequent treatment-emergent adverse events (TEAEs) were fatigue (31.9%), diarrhea (22.3%), and dyspnea (17.5%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%) and the rate of Grade ≥3 infections was (19.9%). Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. Overall, 8 pts (5%) had treatment-related AEs leading to dose reductions and 5 (3%) had treatment-related AEs leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. High ORRs were observed in pts who had PD on a prior cBTKi, and in pts with high-risk disease features including blastoid/pleomorphic variants, elevated Ki-67 index, and TP53 mutations.

Novel targeted therapies (small molecule inhibitors, antibody–drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton’s tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.

Abstract Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.

ImportanceSystematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking.ObjectiveTo assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022.ExposureTreatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19.Main Outcomes and MeasuresMain outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up.ResultsOf 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13).Conclusions and RelevanceIn this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19–related thromboembolism in patients with cancer.

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.

Abstract This global phase 3 study compared lisocabtagene maraleucel (liso-cel) with a standard of care (SOC) as second-line therapy for primary refractory or early relapsed (≤12 months) large B-cell lymphoma (LBCL). Adults eligible for autologous stem cell transplantation (ASCT; N = 184) were randomly assigned in a 1:1 ratio to liso-cel (100 × 106 chimeric antigen receptor–positive T cells) or SOC (3 cycles of platinum-based immunochemotherapy followed by high-dose chemotherapy and ASCT in responders). The primary end point was event-free survival (EFS). In this primary analysis with a 17.5-month median follow-up, median EFS was not reached (NR) for liso-cel vs 2.4 months for SOC. Complete response (CR) rate was 74% for liso-cel vs 43% for SOC (P < .0001) and median progression-free survival (PFS) was NR for liso-cel vs 6.2 months for SOC (hazard ratio [HR] = 0.400; P < .0001). Median overall survival (OS) was NR for liso-cel vs 29.9 months for SOC (HR = 0.724; P = .0987). When adjusted for crossover from SOC to liso-cel, 18-month OS rates were 73% for liso-cel and 54% for SOC (HR = 0.415). Grade 3 cytokine release syndrome and neurological events occurred in 1% and 4% of patients in the liso-cel arm, respectively (no grade 4 or 5 events). These data show significant improvements in EFS, CR rate, and PFS for liso-cel compared with SOC and support liso-cel as a preferred second-line treatment compared with SOC in patients with primary refractory or early relapsed LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03575351.