Marginal zone lymphoma (MZL) is a group of indolent B-cell malignancies that have a natural history that follows a remitting and relapsing course. For systemic disease, available first-line therapies include anti-CD20 antibody as monotherapy with or in combination with chemotherapy (chemoimmunotherapy), with second-line options such as covalent (c) Bruton tyrosine kinase inhibitors (BTKi). However, management of relapsed and refractory (R/R) MZL remains a challenge. Pirtobrutinib, a highly selective, non-covalent BTKi has shown promising efficacy and tolerability in patients with poor-prognosis B-cell malignancies following prior therapy, including cBTKi. Here we report the safety and efficacy of pirtobrutinib in patients with MZL from the phase 1/2 BRUIN study. Endpoints included investigator assessed ORR by Lugano 2014 criteria, DOR, PFS, OS, and safety. Among 36 R/R MZL patients (EMZL: n=6; NMZL: n=17; SMZL: n=13), median age was 68 years (range, 22-83) and median prior lines of therapy were 3 (range, 2-10) including anti-CD-20 antibody (100%), chemotherapy (86%) and cBTKi therapy (72%). The ORR was 55.6% (95% confidence interval [CI], 38.1- 72.1) including 3 (8.3%) complete responses and 17 (47.2%) partial responses. Median DOR was 17.8 months (95%CI, 7.4-non-estimable [NE]), and median PFS was 16.6 months (95%CI, 9.0-22.1). With median follow-up of 32.4 months (IQR, 28.0, 41.3), median OS was NE (95%CI, 29.5-NE). The ORR for patients with prior cBTKi therapy was 53.8% (95%CI, 33.4-73.4). Pirtobrutinib was well-tolerated with dose reductions in 4 patients (11.1%) and permanent discontinuation due to TEAEs in 4 (11.1%). Pirtobrutinib showed promising efficacy and safety in patients with heavily pre-treated R/R MZL, including prior cBTKi. NCT03740529

BACKGROUND:Covalent Bruton tyrosine kinase (BTK) inhibitors have advanced the treatment of Waldenström macroglobulinaemia; however, the occurrence of progression, intolerance, and acquired resistance are not fully understood. We aim to report on the safety and activity of pirtobrutinib (a highly selective, non-covalent BTK inhibitor) in patients with relapsed or refractory Waldenström macroglobulinaemia, including those who received previous covalent BTK inhibitors as part of the phase 1/2 BRUIN trial. METHODS:The BRUIN study was an open-label, multicentre, phase 1/2 trial that enrolled patients with relapsed or refractory B-cell malignancies from 29 sites across eight countries. Patients aged 18 years or older who previously received BTK inhibitor-containing regimens, had an Eastern Cooperative Oncology Group performance status of 0-2, and histologically confirmed Waldenström macroglobulinaemia were eligible. In phase 1, patients received 100-300 mg oral pirtobrutinib once a day in 28-day cycles and the recommended phase 2 dose (RP2D) of 200 mg pirtobrutinib once a day was determined. The phase 2 primary endpoint was antitumour activity of pirtobrutinib based on objective response rate as assessed by an investigator in patients with chronic lymphocytic leukaemia, small lymphocytic leukaemia, or mantle cell lymphoma. In patients with Waldenström macroglobulinaemia, response was evaluated using the Sixth International Workshop on Waldenström Macroglobulinemia (IWWM-6) criteria. BRUIN is registered with ClinicalTrials.gov, NCT03740529 (completed). FINDINGS:BRUIN recruited patients from Aug 12, 2019, to March 14, 2022, and 778 patients received pirtobrutinib. 80 patients had relapsed or refractory Waldenström macroglobulinaemia (n=18 in phase 1 and n=62 in phase 2), with a median age of 68·5 years (IQR 61·0-75·0). 52 (65%) patients were male and 28 (35%) were female. The median number of previous lines of systemic therapy was 3·0 (2·0-5·0). 63 (79%) patients received previous covalent BTK inhibitors. 73 (91%) received 200 mg pirtobrutinib once per day (the RP2D). Using IWWM-6 criteria, the objective response rate was 82·5% (95% CI 72·4-90·1), with one (1·3%) patient reaching complete response, eight (10·0%) reaching very good partial response, 49 (61·3%) reaching partial response, and eight (10·0%) reaching minor response. The median study follow-up was 35·0 months (17·7-47·7). The objective response rate was 81·0% (69·1-89·8) for those who received previous covalent BTK inhibitors and 88·2% (63·6-98·5) for covalent BTK inhibitor-naive patients. Grade 3 or higher treatment-emergent adverse events occurred in 57 (71%) patients, with the most common being neutropenia or neutrophil count decreased (15 [19%]) and anaemia (19 [24%]). Treatment-emergent deaths were reported in five (6%) patients (bacterial sepsis, intracranial haemorrhage, COVID-19 pneumonia, hypertensive cardiomegaly and pneumonia [n=1 each unrelated to treatment], and treatment-related necrotising pneumonia [n=1]). Treatment-emergent adverse events leading to dose reductions occurred in four (5%) patients and pirtobrutinib discontinuation in 12 (15%). INTERPRETATION:Pirtobrutinib was highly active and well tolerated, regardless of previous exposure to covalent BTK inhibitors, and might be a promising new therapeutic option for patients with relapsed or refractory Waldenström macroglobulinaemia, particularly in those previously exposed to covalent BTK inhibitors, for whom durable and effective treatments are needed. FUNDING:Eli Lilly and Company.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase I/II BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with relapsed / refractory B-cell malignancies (clinicaltrials.gov 03740529). 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 AE 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 chronic lymphocytic / small lymphocytic lymphoma (CLL/SLL) and 21 mantle cell lymphoma (MCL) patients intolerant to prior BTKi, overall response rate to pirtobrutinib was 76.9% and 81.0%, respectively. Median progression-free survival for CLL/SLL was 28.4 months but was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

Primary central nervous system lymphoma (PCNSL) is a rare form of aggressive non-Hodgkin lymphoma. Given its infrequency, there are few randomized trials to guide induction and consolidation strategies, with no consensus on optimal treatment. Most centers will offer high-dose methotrexate-based induction chemotherapy followed by either autologous stem cell transplant, whole-brain radiation, or prolonged chemotherapy. The preferred strategy at our institution has been 6 doses of methotrexate, temozolomide, and rituximab (MTR) induction with methotrexate on day 15 until complete response for induction followed by 6 monthly cycles of MTR. We conducted a retrospective analysis of patients diagnosed with PCNSL at the University of Pennsylvania from 1 April 2008 to 1 October 2024, identifying 153 patients who received this regimen. With a follow-up of 63 months, the median overall survival (OS) in the entire cohort was 65 months, with a median relapse-free survival (RFS) of 36 months. In the cohort of patients who were able to complete 6 months of MTR induction and proceed with MTR consolidation, median OS and RFS were 143 and 122 months, respectively. Although 13% of patients discontinued therapy because of toxicity, there was no treatment-related mortality. These results indicate that prolonged MTR is a safe treatment option and an alternative to intensified consolidation strategies. Further randomized studies are necessary to determine the optimal treatment strategy in newly diagnosed PCNSL.

ABSTRACT:Relapsed/refractory (R/R) follicular lymphoma (FL) is a chronic disease often requiring multiple lines of therapy. Covalent Bruton tyrosine kinase inhibitor (BTKi) monotherapy has resulted in variable response rates, yet patients invariably experience relapse. While newer therapies such as bispecific antibodies and chimeric antigen receptor T-cell (CAR T cell) therapy are available, patient access and eligibility remain challenging. Here, we report the safety and efficacy of pirtobrutinib, a noncovalent (reversible) BTKi monotherapy in a R/R FL cohort from the multicenter phase 1/2 BRUIN study. Key end points included investigator-assessed overall response rate (ORR) per Lugano 2014 criteria, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Among 48 patients with FL, the median age was 64.5 years (range, 37.0-85.0). Patients had received a median of 3 (range, 1-12) prior lines of therapy. The ORR with pirtobrutinib was 52.1% (95% confidence interval [CI], 37.2-66.7), and median DoR was 10.2 months (95% CI, 3.7-25.7). Median PFS was 5.8 months (95% CI, 3.8-8.1), and median OS was not estimable, with a median follow-up of 35.2 months (interquartile range, 31.1-41.8). The estimated DoR, PFS, and OS rates at 24 months were 33.3% (95% CI, 15.9-51.9), 25.6% (95% CI, 13.9-39.1), and 75.1% (95% CI, 59.5-85.4), respectively. Pirtobrutinib was well tolerated, with 2 patients (4.2%) discontinuing treatment due to adverse events (AEs; 1 treatment-related) and 4 patients (8.3%) having dose reductions due to AEs (all treatment related). Pirtobrutinib showed promising efficacy and was well tolerated in this cohort of patients with heavily pretreated R/R FL, warranting further investigation. This trial was registered at www.clinicaltrials.gov as #NCT03740529.

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.

Background:Richter transformation (RT) occurs in up to 10% of patients with chronic lymphocytic leukemia (CLL), typically presents as an aggressive diffuse large B-cell lymphoma (DLBCL) and is associated with poor survival. RT has no approved standard therapy; and clinical trial enrollment is the preferred first line of therapy. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, that inhibits both wildtype and C481-mutant BTK with equal low nM potency, has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval. Pirtobrutinib demonstrated durable overall response rates (ORR) and was well tolerated in patients (pts) with poor-prognosis B-cell malignancies regardless of prior therapy. Here we provide updated safety and efficacy of pirtobrutinib in RT pts from the phase 1/2 BRUIN trial (NCT03740529). Methods: Pts with previously treated, histologically confirmed RT were eligible in the global, multicenter, phase 1/2 BRUIN study. Pts with untreated RT became eligible after Amendment 10. All but one patient received the recommended phase 2 dose of 200 mg daily. Key endpoints included investigator-assessed ORR, DoR per Lugano 2014 criteria, OS, and safety. A data cut of 05 May 2023 was utilized. To assess clonal relationship, IGH rearrangement studies were done on tissue biopsies with RT involvement, and baseline blood or bone marrow (BM) samples with CLL involvement. Results: Among all pts with RT (N=82) the median age was 67 (range, 26-95) and the median total number of lines of prior systemic therapy was 4 (range, 0-13). Pts with prior treatment had a median of 2 CLL-directed therapies and 2 RT-directed therapies. Eight pts did not have a previous line of RT-directed therapy, and 1 patient received neither RT- nor CLL-directed therapy. Common prior RT- and CLL-directed therapies (RT, CLL) included: chemotherapy (76%, 52%), cBTKi (34%, 62%), anti-CD20 antibody (78%, 66%), BCL2i (38%, 49%), stem cell transplant (SCT; 6%, 7%), and CAR-T (11%, 4%). Of 29 pts with bone marrow screening, 41.4% had CLL alone present in BM, 13.8% had DLBCL present and 24.1% had both CLL and DLBCL present. For 39 pts with available PET data, the median SUVmax was 19.1 (range, 2.6-41.2). For all 82 pts, the ORR was 50.0% (95% CI, 38.7-61.3) including complete (13.4%, n=11) and partial (36.6%, n=30) responses. For 61 pts who received prior cBTKi therapy, the ORR was 45.9% (95% CI 33.1-59.2). Among 28 pts with an RT-directed cBTKi and 51 pts with prior CLL-directed cBTKi, the ORR was 42.9% (95% CI, 24.5-62.8) and 43.1% (95% CI, 29.3-57.8), respectively. In 50 pts who discontinued prior cBTKi due to disease progression, the ORR was 42.0% (95% CI, 28.2-56.8). At median follow-up time of 9.7 months, the median DoR for all 82 RT pts was 7.4 months (95% CI, 3.1-19.1) and the estimated rate at 12 months was 45.9% (95% CI, 28.3-61.8). The median time on treatment for the 41pts who responded to treatment was 8.3 months. Eight pts stopped pirtobrutinib to pursue curative-intent allogeneic SCT and DoR was censored at the last preceding disease assessment. At a median survival follow-up of 18.3 months, the median OS for the entire RT cohort was 12.5 months (95% CI, 6.9-20.5). At 18 months, the OS rate was 44.3% (95% CI, 32.5-55.4). Frequent treatment-emergent adverse events (TEAE) in the RT cohort (n=82) were neutropenia/decreased neutrophil count (29.3%, n=24), fatigue (24.4%, n=20) and diarrhea, dyspnea, thrombocytopenia, and pyrexia (18.3% each, n=15). Common grade ≥3 TEAEs were neutropenia/decreased neutrophil count (23.2%, n=19), thrombocytopenia (11.0%, n=9), plus anemia and sepsis (9.8% each, n=8). Any grade hypertension (3.7%, n=3) or atrial fibrillation (1.2%, n=1) were infrequent. Three pts (3.7%) had treatment-related AEs leading to dose reductions, but no pt had a treatment-related AE leading to pirtobrutinib discontinuation. Analyses of clonality will be presented. Conclusions: Continued follow-up from BRUIN demonstrates encouraging response and OS in pts with RT. Pirtobrutinib remains well-tolerated with low rates of discontinuation and manageable safety profile. While RT remains a challenging diagnosis, pirtobrutinib represents a potential treatment option that warrants further investigation.

Background Primary CNS lymphoma (PCNSL) is a rare and aggressive non-Hodgkin lymphoma with increasing incidence in the US particularly among elderly (PMID 26511214). Though initial response rates to regimens containing high-dose methotrexate (HD-MTX) can be upwards of 65%, 5 year overall survival (OS) is less than 30% (PMID 23873804). Aggressive consolidation strategies including whole brain radiation therapy (WBRT) and chemoimmunotherapy (CI) followed by autologous stem cell transplant (auto-SCT) can be toxic for older patients. Extended courses of HD-MTX are well tolerated and have favorable outcomes (PMID 36672475). Here we present our institutional experience. Methods We identified 156 patients with PCNSL from Jan 1, 1997 to Aug 30, 2023. Demographics, diagnostic work up, treatment and outcomes were reviewed retrospectively. Results 156 patients with PCNSL were identified with a median follow up of 26.9 months (2-200 mo). 52.6% were female (82/156). 85.9% identified as non-Hispanic white (134/156), 7.0% Asian (11/156), 6.4% African-American (10/156) and 0.6% Hispanic (1/156). The median age at diagnosis was 63 with a range of 20 to 85 years. Most had an ECOG PS of between 0-1 (69.9%, 109/157) at diagnosis. The most common histology was DLBCL (91.0%, 142/156), then HGBCL (2.6%, 4/156), MZL (1.3%. 2/156), plasmablastic lymphoma (0.6%, 1/156) and PTCL (0.6%, 1/157). Non-germinal center B-cell (GCB) was the more common subtype in those with DLBCL (80.2%, 81/101) though we identified 20 cases of GCB PCNSL. 13 cases of DLBCL were EBV+ thought to be driven by immunodeficiency secondary to HIV (6.7%, 9/134), dermatomyositis or lupus. In terms of treatment, 85.9% (135/156) were treated with a HD-MTX containing induction regimen. The most frequently used regimen was MTX-rituximab-temozolomide (MTR) in 83.0% of cases (112/135) based on CALBG 50202 then MTX-R (8.9%, 12/135), MTX alone (6.7%, 9/135), R-MTX-procarbazine-vincristine (0.7%, 1/135) and MTX-ibrutinib (0.7%, 1/135). Mean MTX dose was 5 g/m2 (2-8g/m2). Overall response rate to a HD-MTX induction regimen was 83.0% with 66.7% of patients in CR and 16.3% in PR. Of the 135 patients who received HD-MTX based induction, 44.4% (60/135) received consolidation with MTX-based maintenance regimen, most receiving (91.7%, 55/60) MTR. The median number of cycles of HD-MTX was 6 (2-8 cycles). Those who did not receive MTX-based maintenance were treated with Rituximab-etoposide/ara-C (5.9%, 8/135), brain radiation (5.9%, 8/135), temozolomide maintenance (4.4%, 6/135), HD-chemotherapy followed by auto-SCT (3.0%, 4/136) or other treatments (ibrutinib, lenalidomide). 34.1% (46/135) of patients did not receive consolidation due to disease progression (52.2%, 24/46), patient preference (13.1%, 6/46), MTX toxicity (10.9%, 5/46), death (10.9%, 5/46) or they were lost to follow up. 57% (77/135) of patients undergoing MTX induction had no major adverse events (AE). The most common AEs were AKI (22.2%, 30/135) and transaminitis (8.1%, 11/135). 83.3% (25/30) of patients with AKIs required MTX dose reduction and less commonly discontinuation of the drug (36.7%, 11/30). Dose reduction due to transaminitis was required less frequently (7/11, 63.6%) as was drug discontinuation (1/11, 9.1%). Among all patients, median OS was 11.6 mo (95% CI 6.5-18.5). 2 and 5 year OS rates were 62% and 45.5%, respectively. In patients who received at least 4 doses of HD-MTX induction without consolidation, median OS was 16.3 mo (95% CI 9.0-32.7). 2 and 5 year OS rates were 35.5% and 17.6%, respectively. In patients who completed HD-MTX induction and consolidation, median OS was 41.3 mo (95% CI 23.9-71.2). 2 and 5 year OS rates were 90.7% and 76.2% respectively. These data are comparable to reported survival outcomes after chemoimmunotherapy and auto-SCT. Cause of death included complications from lymphoma (72.7%, 64/88), unrelated solid tumor and pneumonia. Conclusion The majority of patients at our institution received HD-MTX induction followed by maintenance. In patients with response and who were able to tolerate treatment, long term remissions of >5 years were attainable. Though recent studies have shown improved survival in patients receiving HD-MTX based combination CI followed by auto-HSCT, non-relapse morbidity and mortality remain high, especially in the elderly population. These data show favorable outcomes with the use of MTX-based induction and consolidation.

AbstractClinical 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.

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.

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.

Patients with Epstein-Barr virus (EBV)-positive post-transplant lymphoproliferative disease (EBV+ PTLD) in whom initial treatment fails have few options and historically low median overall survival (OS) of 0.7 months following allogeneic hematopoietic cell transplant (HCT) and 4.1 months following solid organ transplant (SOT). Tabelecleucel is an off-the-shelf, allogeneic EBV-specific cytotoxic T-lymphocyte immunotherapy for EBV+ PTLD. Previous single-center experience showed responses in patients with EBV+ PTLD following HCT or SOT. We now report outcomes from a multicenter expanded access protocol (NCT02822495) in HCT (n = 14) and SOT (n = 12) recipients treated with tabelecleucel for EBV+ PTLD that was relapsed/refractory to rituximab ± chemotherapy. The investigator-assessed objective response rate was 65.4% overall (including 38.5% with a complete and 26.9% with a partial response), 50.0% in HCT, and 83.3% in SOT. The estimated 1- and 2-year OS rates (95% CI) were both 70.0% (46.5, 84.7) overall, both 61.5% (30.8, 81.8) in HCT, and both 81.5% (43.5, 95.1) in SOT (median follow-up: 8.2, 2.8, and 22.5 months, respectively). Patients responding to tabelecleucel had higher 1- and 2-year OS rates (94.1%) than non-responders (0%). Treatment was well tolerated with no reports of tumor flare, cytokine release syndrome, or rejection of marrow and SOT. Results demonstrate clinically meaningful outcomes across a broad population treated with tabelecleucel, indicating a potentially transformative and accessible treatment advance for relapsed/refractory EBV+ PTLD following HCT or SOT.

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.

Context Early lines of therapy for CLL/SLL patients often use targeted single-agent options such as BTKis. Despite their efficacy, cBTKis have low oral bioavailability and a short half-life that may lead to suboptimal BTK target coverage. Pirtobrutinib has demonstrated promising efficacy and safety in R/R CLL/SLL patients, but outcomes in BTKi-naïve CLL/SLL patients treated with pirtobrutinib have not been reported to date. Objective We report outcomes of BTKi-naïve patients with R/R CLL/SLL from the phase 1/2 BRUIN study (NCT03740529). Design Patients with R/R BTKi-naïve CLL/SLL received pirtobrutinib. Key endpoints included ORR, including PR-L as assessed by an IRC and investigator per 2018 iwCLL response criteria, PFS, and safety. Data cutoff was May 5, 2023. Results This analysis included 35 patients with R/R BTKi-naïve CLL/SLL treated with pirtobrutinib. Median age was 67 years (range, 38-81), 51.4% were male, and 94.3% had ECOG PS 0-1. Median number of prior therapies was 2 (range, 1-8). Of patients with available data, 20/25 (80.0%) had unmutated IGHV, and 10/27 (37.0%) had TP53 mutation and/or del(17p). Median ToT was 28.8 months, and median ToS was 31.5 months. IRC-assessed ORR was 88.6% (95%CI, 73.3-96.8), with 1 (2.9%) CR and 30 (85.7%) PR. ORR including PR-L was 91.4% (95%CI, 76.9-98.2) with 1 patient (2.9%) achieving PR-L. Investigator-assessed ORR was 85.7% (95%CI, 69.7-95.2), and including PR-L (n=3, 8.6%), was 94.3% (95%CI, 80.8-99.3). 24-month PFS rates by IRC and investigator assessments were 74.7% (95%CI, 55.7-86.5) and 81.8% (95%CI, 63.9-91.4), respectively (median follow-up, 28.1 months). The most frequent TEAEs, regardless of attribution, were COVID-19 (45.7%), neutropenia (including neutropenia and neutrophil count decreased, 42.9%) and diarrhea (31.4%); most frequent grade ≥3 TEAEs were infection (45.7%; 25.7% excluding COVID-19) and neutropenia (including neutropenia and neutrophil count decreased, 34.3%). Grade ≥3 TEAEs of hypertension (8.6%), hemorrhage/hematoma (2.9%), and atrial fibrillation/flutter (2.9%) were observed. TEAEs led to pirtobrutinib dose reduction in 5 patients (14.3%) and discontinuation in 2 (5.7%). Two patients (5.7%) died, both due to COVID-19 infection considered by the investigator to be unrelated to pirtobrutinib. Conclusion Pirtobrutinib demonstrated promising efficacy in patients with R/R BTKi-naïve CLL/SLL and was well tolerated with a low rate of discontinuation. Acknowledgement Originally presented at EHA 2023.

Objectives: Bruton tyrosine kinase inhibitors (BTKi) are associated with an increased risk of bleeding events. Pirtobrutinib, a non-covalent (reversible) BTKi FDA approved for treatment of R/R MCL after 2 lines of therapy including a BTKi, demonstrated efficacy and tolerability across multiple B-cell malignancies. The incidence of bleeding events in pts treated with pirtobrutinib and concomitant antithrombotic therapy have not been specifically reported. We analyze bleeding events in pts from BRUIN who received pirtobrutinib with antithrombotic therapy. Material and methods: Pts with B-cell malignancies (317 CLL, 166 MCL, 290 other) who enrolled in the open-label, multicenter Phase 1/2 BRUIN study (NCT03740529) were analyzed. Concomitant antithrombotic therapy (direct factor XA inhibitors, heparin anticoagulants, platelet aggregation inhibitors) at time of enrolment was permitted (excluding warfarin). Pirtobrutinib was administered once daily in 28-day cycles) until disease progression or discontinuation due to toxicity. Common Terminology Criteria for Adverse Events V5.0 were used to determine grade and type of bleeding events. Descriptive analyses were performed. Results: As of 29 July 2022, 773 pts received at least 1 pirtobrutinib dose of pirtobrutinib monotherapy, including 216 with concomitant antithrombotic therapy (median age: 72 years [IQR 65-77]and the proportion who were ≥75 years: 34%). Median time on pirtobrutinib with and without antithrombotic therapy was 10.6 (IQR 4.0-19.9) and 9.3 months (IQR 3.1-17.3). Any-grade bleeding events were reported in 44.9% (97/216) pts with antithrombotic therapy vs 32.5% (181/557) without. Most bleeding events (>90%) in both groups were grade ≤2. The most common bleeding events (≥3%) in pts with antithrombotic therapy were contusion (22.7%), hematuria (5.6%), epistaxis (5.1%), petechiae (3.7%), and hematoma (3.2%). Of the 6 (2.8%) pts on antithrombotic therapy with a grade3 bleeding event, 2 (0.9%) were deemed related to pirtobrutinib by investigators: an upper GI bleeding with anemia and a hemarthrosis from a knee injury (1each). Grade≥3 bleeding events occurred in 11 (2%) pts not taking antithrombotics. Any-grade hemorrhage/hematoma occurred in 13/79 (16.5%) pts who received direct factor XA inhibitors, 10/39 (25.6%) who received heparins and 18/112 (16.1%) who received platelet aggregation inhibitors (some received >1 class). Among pts with antithrombotic therapy, median time to onset of any-grade bleeding event was 8.1 weeks (IQR 2.6-24) and median duration of a bleeding event was 2.1 weeks (IQR 0.6-4.3). Among pts who received antithrombotic therapy, bleeding events required dose interruption of pirtobrutinib in 5 pts (2.3%) and no bleeding events led to dose reduction or permanent discontinuation of pirtobrutinib. Conclusion and discussion: Concomitant antithrombotic therapy with pirtobrutinib was associated with an increased rate of bleeding events relative to pirtobrutinib alone, though most events were grade ≤2. High-grade bleeding events were infrequent (<2%). This supports the safety of pirtobrutinib administration in pts requiring antithrombotic therapies. Previously presented at EHA 2023.