Seymour, John F.

The mature splenic B‐cell lymphomas are an enigmatic group of lymphoid neoplasms that have long caused significant difficulty for the practicing pathologist due to overlapping diagnostic features among entities and the decreasing availability of splenic tissue for assessment. While some entities have highly characteristic and specific clinicopathological features (e.g. hairy cell leukaemia), others are substantially more difficult to recognise (e.g. splenic diffuse red pulp lymphoma). At the same time, classification systems have been evolving, resulting in multiple changes to the boundaries among these entities and even the existence of some entities in their own right. Moreover, unbiased multi‐omic interrogation (whole genome/transcriptome sequencing, methylome) of the splenic B‐cell lymphomas over the past decade has given us significant insights into the underling biology of these neoplasms. We present a clinicopathological perspective on the historical, current and future state of the diagnosis and classification of splenic B‐cell lymphomas integrating multi‐omic data and highlighting areas of focus for the field in order to continue to strive to improve patient outcomes through accurate diagnosis.

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.

Introduction: BTK inhibitors (BTKis) are approved for chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Disease that progresses on BTKis often has BTK mutations that lead to treatment (tx) resistance; novel BTK-targeting agents that overcome BTKi resistance are needed. BGB-16673 is a heterobifunctional small molecule that binds to BTK and E3 ligase, resulting in BTK degradation via ubiquitination. In preclinical models, BGB-16673 degraded wild-type (WT) BTK and known covalent and noncovalent BTKi-resistant mutant proteins, leading to tumor suppression. Methods: Pts with R/R CLL, WM, MCL, MZL, non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or Richter transformation (RT) were eligible for this open-label, first-in-human, phase 1 trial (BGB-16673-101; NCT05006716). Pts must have received ≥2 prior therapies (≥1 for RT) and have an ECOG performance status of 0-2 and adequate end-organ function. In the US and Australia, pts must have received a covalent BTKi (cBTKi) if approved for their disease. BGB-16673 was dosed daily by mouth in 28-day cycles. Escalation using a Bayesian optimal interval design with 6 dose levels (50-600 mg once daily) is planned. Primary objectives are to assess safety/tolerability and establish the maximum tolerated dose (MTD) and recommended phase 2 dose. Key secondary objectives are to assess pharmacokinetics, pharmacodynamics (PD), and preliminary antitumor activity. Safety was assessed according to CTCAE v5.0 (all pts) and iwCLL hematologic toxicity criteria (pts with CLL). Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks. Response was assessed per Lugano criteria for all except CLL (iwCLL 2018 criteria) and WM (iwWM-6 criteria). Results: As of May 26, 2023, 26 pts (10 CLL, 4 MCL, 2 MZL, 4 WM, 4 FL, 1 DLBCL, 1 RT) were enrolled at 5 dose levels (50 mg, 4; 100 mg, 9; 200 mg, 9; 350 mg, 3; 500 mg, 1). Median age was 70.5 y (range, 25-83). Median number of prior therapies was 3.5 (range, 2-9), including cBTKis (n=21; 10 CLL, 4 WM, 4 MCL, 1 MZL, 1 RT, 1 DLBCL), BCL2 inhibitors (n=12; 9 CLL, 2 WM, 1 RT), and noncovalent BTKis (ncBTKis; n=4; 2 CLL, 1 WM, 1 FL). In CLL, del17p/ TP53 mutation (n=8) and unmutated IGHV (n=7) were frequent. Median follow-up was 3.5 mo (range, 0.2-13.9). MTD was not reached. Treatment-emergent AEs (TEAEs) were reported by 88.5% of pts (grade [gr] ≥3, 46.2%; serious, 38.5%). The most common TEAEs were contusion (30.8%; no gr ≥3), pyrexia (23.1%; no gr ≥3), neutropenia/neutrophil count decreased (23.1%; gr ≥3, 15.4%), and lipase increased (23.1%; gr ≥3, 3.8%; all transient and asymptomatic). No hypertension or atrial fibrillation was observed. One pt died from sepsis with possible disease progression. No discontinuations due to AEs occurred. Two pts had dose reductions due to TEAEs (gr 3 hematuria with urinary tract infection and recurrent urothelial carcinoma and gr 2 arthralgia). One DLT occurred in 1 pt at 200 mg (gr 3 maculopapular rash on day 27; after 5-day dose hold, assigned dose was recommenced with persistent gr 1 rash). BGB-16673 exposure increased in a dose-dependent manner. At steady state with doses ≥50 mg daily, BGB-16673 exposure exceeded the calculated half maximal degradation concentration for WT and cysteine 481-mutated BTK for the dosing interval. Preliminary PD data showed deep, sustained reductions in BTK protein levels in peripheral blood and tumor tissue, even at the lowest dose. Most CLL pts experienced lymphocytosis during the first 3 cycles of tx. Twenty of 26 pts (77%) remain on therapy (discontinuation: 4 progressive disease, 2 withdrawal). Of 18 response-evaluable pts, 12 (67%) responded (5/6 CLL, 1/3 MCL, 2/2 MZL, 3/4 WM, 1/2 FL, 0/1 DLBCL; 1 CR in MCL, all others had PR; Figure), including pts who received a cBTKi (n=10) and an ncBTKi (n=2). Responses started at the lowest dose level. All responders remain in response, the longest responder remaining on tx for 60 weeks. Conclusions: Preliminary data from this ongoing, first-in-human study of the novel BTK degrader BGB-16673 demonstrate a tolerable safety profile and clinical responses in heavily pretreated pts with B-cell malignancies, including those with BTKi-resistant disease. Substantial reductions in BTK protein levels in peripheral blood and tumor tissue were also observed, demonstrating proof-of-concept of a strong, on-target effect.

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.

Abstract ELEVATE-RR demonstrated noninferior progression-free survival and lower incidence of key adverse events (AEs) with acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia. We further characterize AEs of acalabrutinib and ibrutinib via post hoc analysis. Overall and exposure-adjusted incidence rate was assessed for common Bruton tyrosine kinase inhibitor–associated AEs and for selected events of clinical interest (ECIs). AE burden scores based on previously published methodology were calculated for AEs overall and selected ECIs. Safety analyses included 529 patients (acalabrutinib, n = 266; ibrutinib, n = 263). Among common AEs, incidences of any-grade diarrhea, arthralgia, urinary tract infection, back pain, muscle spasms, and dyspepsia were higher with ibrutinib, with 1.5- to 4.1-fold higher exposure-adjusted incidence rates. Incidences of headache and cough were higher with acalabrutinib, with 1.6- and 1.2-fold higher exposure-adjusted incidence rate, respectively. Among ECIs, incidences of any-grade atrial fibrillation/flutter, hypertension, and bleeding were higher with ibrutinib, as were exposure-adjusted incidence rates (2.0-, 2.8-, and 1.6-fold, respectively); incidences of cardiac events overall (the Medical Dictionary for Regulatory Activities system organ class) and infections were similar between arms. Rate of discontinuation because of AEs was lower for acalabrutinib (hazard ratio, 0.62; 95% confidence interval, 0.41-0.93). AE burden score was higher for ibrutinib vs acalabrutinib overall and for the ECIs atrial fibrillation/flutter, hypertension, and bleeding. A limitation of this analysis is its open-label study design, which may influence the reporting of more subjective AEs. Overall, event-based analyses and AE burden scores demonstrated higher AE burden overall and specifically for atrial fibrillation, hypertension, and hemorrhage with ibrutinib vs acalabrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02477696.

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.