Fakhri, Bita

Abstract Introduction: Lisocabtagene maraleucel (liso-cel) was approved in the United States for the treatment of CLL in 3/2024 for patients who have received two prior lines of therapy including a covalent BTK inhibitor and a BCL-2 inhibitor. Data regarding outcomes of liso-cel is limited to reports from the registrational TRANSCEND-CLL 004 clinical trial which had strict inclusion and exclusion criteria. This work investigates the real-world efficacy and safety of liso-cel for patients with CLL and its efficacy in specific sub-populations. Methods: This is a multi-institutional retrospective study (Collaborative Assessment of Real-World Evidence of Lisocabtagene Maraleucel in Patients with Relapsed/Refractory CLL/SLL [CARE CAR-T CLL]) of patients with CLL who received commercial liso-cel in the United States. Patients with Richter transformation were excluded. Response was defined by iwCLL criteria. Patients who did not undergo a marrow biopsy but met other criteria for a complete response (CR) were categorized as unconfirmed CR (CRu). CRS and ICANS were graded per ASTCT criteria. Results: A total of 30 patients were identified with a median age of 67 years (range 44 – 80). Twenty of thirty patients (67%) had either del17p and/or mutated TP53, and 8/30 (27%) had complex karyotype (≥ 3 abnormalities) at time of liso-cel infusion. Patients received a median of 6 prior lines of therapy (range 1 - 12), and 24 (80%) were previously treated with chemotherapy. All patients had previous exposure to a covalent BTK inhibitor and a BCL-2 inhibitor. Twenty-seven (90%) of patients had prior exposure to pirtobrutinib. Twenty-nine patients (96.7%) received bridging treatment that was stopped after leukapheresis with 1 patient in CR and 25 patients in PR at time of liso-cel. Eighteen patients (60%) were treated with pirtobrutinib as the last line of treatment prior to liso-cel. Median length of time on pirtobrutinib prior to liso-cel infusion was 4 months (interquartile range [IQR], 2 – 8 months). Twelve (66.7%) patients stopped pirtobrutinib between leukapheresis and lymphodepletion, and 6 continued after liso-cel. Best CR/CRu rate was 60.0% (CR, n = 17/30; CRu, n = 1/30), and best overall response rate (ORR) was 83.3% (25/30) with median time to best response of 30 days (IQR, 28 – 30 days). Of the 18 patients who received pirtobrutinib as their last line of therapy, 13 (72%) achieved a CR/CRu. Meanwhile, of the 12 patients who did not receive pirtobrutinib as their last line of therapy, only 5 (28%) achieved a CR. Measurable residual disease testing (MRD) by flow cytometry was done in 14/30 patients, and 9 patients (64%) had achieved undetectable MRD (uMRD). MRD by next generation sequencing (NGS) was done in 17 patients, and 7 (41%) patients had uMRD. Twenty-seven of 30 patients (90%) were alive at time of data collection. Median follow-up was 3.3 months (IQR, 1.2 – 8.9 months). Twenty-six patients (87%) experienced any grade cytokine release syndrome (CRS), and 3 patients experienced grade 3 CRS (10%). Twelve patients (40%) experienced any grade immune effector cell-associated neurotoxicity syndrome (ICANS), and 4 patients (13%) experienced grade 3 ICANS. There were no grade 4 or 5 CRS or ICANS. One patient experienced grade 3 immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). At day 30, patients had a median absolute neutrophil count of 1.7K/μL (IQR, 0.8 – 3.6K/μL), hemoglobin of 11.7 g/dL (IQR, 8.6 – 13.1 g/dL), and platelet count of 72K/μL (IQR, 29 – 119K/μL). Conclusion: Real-world analysis of liso-cel for patients with relapsed/refractory CLL showed CR and ORR of 60.0% and 83.3%, respectively. Despite having a heavily pre-treated and chemotherapy-exposed population and with over half the patients having high-risk features, these response rates are higher than what was described in the TRANSCEND-CLL 004 clinical trial. These results are limited by the short follow-up period and the variability in response assessment typical of a retrospective study. As we increase our sample size, we will also be interested if the use of the non-covalent BTK inhibitor pirtobrutinib prior to liso-cel is associated with a higher CR rate, mimicking the findings of the sub-cohort analysis of TRANSCEND-CLL 004 where the concurrent use of ibrutinib led to higher CR rates. Further updates and patients from additional collaborators will be presented at the meeting.

Abstract Background: Undetectable minimal residual disease (uMRD) at the end of first-line (1L) treatment (tx) with 12-cycles (C) of venetoclax (ven) + obinutuzumab (obin) is associated with prolonged survival for patients (pts) with chronic lymphocytic leukemia (CLL, Al Sawaf et al. Blood 2024). We hypothesized that MRD may be used to guide ven tx duration for CLL pts treated with 1L ven + obin. Methods In this ongoing phase II, multicenter investigator-initiated study, pts receive ven + obin for 1L tx of CLL/small lymphocytic lymphoma (NCT04447768). Eligible pts have a CIRS score of ≤ 6 and require 1L tx per iwCLL 2018 criteria. Pts receive 6 x 28-day C of obin and initiate ven on C1D22. Ven duration is dependent on peripheral blood (PB) MRD status measured by ClonoSeq next generation sequencing. At C7, pts undergo MRD testing. Pts uMRD6 (<10-6 sensitivity) at both C7 and C9 dc ven after 9C and enter treatment free observation (TFO). Pts with detectable MRD6 (dMRD6) at C7 undergo repeat testing at C12; if uMRD5 (<10-5) pts dc ven after 12C. Pts dMRD5 at C12 continue ven for an additional 12C (24C total) prior to TFO. The primary study endpoint is 36-month PFS; the unpromising rate is set at 82% and will be tested by a nonparametric survival estimate (Kaplan-Meier) along with Greenwood's formula. RNA sequencing (RNAseq) was performed pre-tx on patient bone marrow (or PB if inaspirable) samples. Unsupervised clustering using machine learning (ML) based on consensus nonnegative matrix factorization was applied to the most variable genes to identify patient clusters. Clusters were then biologically characterized by gene signature scoring using xCell algorithm and assessed for association with uMRD6 at C7 using a Fisher exact test. Results Baseline characteristics of the 100 pts who initiated tx include: median age 58 (range 34-81); 71% male, 90% White, 3% Black and 2% Asian, 5% unknown; 49% IGHV unmutated, 16% TP53 mutation, 8% del17p (previously reported, Roeker et al. ASH 2024). 3 pts stopped tx prior to C7. 51 pts were uMRD6 at C7 and C9 and completed 9C ven. 46 pts were dMRD6 at C7; 6 pts stopped tx outside of meeting protocol requirements and are included in intention-to-treat (IIT) analyses. 32 pts were uMRD5 at C12 and dc ven after 12C. 8 pts were dMRD5 at C12: 5 continued ven per protocol (3 completed 24C ven, 2 ongoing tx as of 15 May 2025 data cut-off), 2 stopped ven outside of protocol requirements (included in ITT analyses), and 1 pt withdrew consent. At a median follow-up of 35 months, the 36-month PFS rate is 90% (95% CI: 84%, 97%). 36-month OS is 94% (95% CI: 89%, 99%). Landmark PFS analyses from EOT were performed for pts who dc ven after 9C due to uMRD6 (24-month PFS 92%, 95% CI: 85, 100%, n=51) and pts who dc ven after 12C due to uMRD5 (24-month PFS 96%, 95% CI: 89%, 100%, n=32). For pts dc ven after 9C due to uMRD6 (n=51), PB MRD at 12C after EOT was: 59% uMRD6, 12% uMRD5, 4% uMRD4, 8% dMRD4 and 18% unknown. For pts dc ven after 12C due to uMRD5 status (n=32), PB MRD at 12C following EOT was: 9% uMRD6, 31% uMRD5, 9% uMRD4, 25% dMRD4 and 25% unknown. Of the 5 pts with PD, 3 pts have had Richter Transformation to diffuse large B-cell lymphoma (all uMRD6 at C7 / 9). Two pts with PD have not met iwCLL tx criteria and remain in TFO. Five pts have died (suicide, West Nile encephalitis, COVID-19, complications of glioblastoma and RT DLBCL). Five C12 dMRD5 pts who continued ven have reached C18, with only 1 of 5 converting to uMRD5 in PB. However, all 5 maintained uMRD4 (<10-4). Of 3 pts that completed 24C ven (2 ongoing tx), 1 pt had deepening of response to uMRD5 at C24, and 2 pts had rising MRD on ven (dMRD4 at C24). To investigate patient heterogeneity at baseline and its relationship to uMRD, we clustered patient RNAseq samples into two clusters using artificial intelligence/ML based unsupervised clustering. The clusters associated with uMRD6 at C7 (Fisher exact test p=0.038), and patients in the cluster with significantly higher immunosuppressive cells such as T-regulatory cells and M2 macrophages were less likely to be uMRD6 at C7. Conclusions At a median follow-up of 35 months, the estimated 36-month PFS rate is 90%. RNAseq transcriptomic analyses identified that patients with enriched immunosuppressive cells were less likely to be uMRD6 at C7. Additional follow-up is required to confirm the durability of this MRD-guided ven + obin tx strategy.

Abstract Background: Covalent Bruton tyrosine kinase inhibitors (cBTKi) have dramatically changed the treatment (tx) landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), especially in the first-line setting. However, cBTKi resistance or intolerance eventually occurs. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits BTK with low nM potency throughout the daily dosing interval. Pirtobrutinib demonstrated safety and efficacy in the phase 1/2 BRUIN study among patients (pts) with R/R CLL/SLL, including pts previously treated with a BTKi. Pirtobrutinib is approved for treating CLL in adults in the EU after prior tx with a BTKi, and in the USA for adults with CLL/SLL who have received at least 2 prior lines of therapy, including a BTKi and a BCL-2i. Here, we report the final results from the phase 1/2 BRUIN study (NCT03740529) with more than 5 years (yrs) follow-up (f/u), focusing on efficacy and safety of pirtobrutinib in pts with CLL/SLL in the post-cBTKi setting. Methods: Pts with prior cBTKi-exposed CLL/SLL were eligible for tx with pirtobrutinib. Endpoints included overall response rate (ORR) per 2018 iwCLL criteria, ORR including partial response with lymphocytosis (PR-L), duration of response (DOR), and progression-free survival (PFS), assessed by independent review committee (IRC; presented herein) and investigator, overall survival (OS), and safety. Data cut was 27 January 2025, providing a median study f/u of 34.1 months (mos; range, 0.5-69.8). Results: Among the 282 pts with CLL/SLL who were cBTKi-exposed and treated with pirtobrutinib, of which 84.4% (238/282) received 200 mg as the starting dose, the median age was 69 yrs (range, 36-88). The median number of prior therapies was 4 (range, 1-11), with 45.4% of pts having received prior BCL2i, and 77.0% having discontinued prior cBTKi due to progressive disease (PD), 19.5% due to toxicity, and 3.5% due to other reasons/missing. High-risk features were frequent: unmutated IGHV in 85.8% (193/225), mutated TP53 in 40.4% (99/245), and del(17p) in 29.2% (59/202). The ORR was 72.3% (95% CI, 66.7-77.5). ORR including PR-L was 81.6% (95% CI, 76.5-85.9), which was consistent across subgroups including BCL2i-exposed (80.5%; 95% CI, 72.5-86.9), BCL2i-naive (82.5%; 95% CI, 75.5-88.1), unmutated IGHV (82.9%; 95% CI, 6.8-87.9), del(17p) (88.1%; 95% CI, 77.1-95.1), and prior cBTKi discontinuation due to PD (79.7%; 95% CI, 73.8, 84.9) or toxicity (87.5%; 95% CI, 76.8-94.4). The median DOR was 18.4 mos (95% CI, 14.82-20.27), with 36-mos DOR rate of 28.0% (21.6-34.7). The median PFS was 18.7 mos (95% CI, 16.6-21.8) among all pts and the 36-mos PFS rate was 25.0% (95% CI, 19.4-31.0) with 44 mos of f/u. Further, the median PFS was 22.3 mos (95% CI, 19.3-27.6) for BCL2i-naive pts, and 15.9 mos (95% CI, 13.6-17.5) for BCL2i-exposed pts; 16.6 mos (95% CI, 13.8-19.4) among those who discontinued prior cBTKi therapy due to PD, and not estimable (NE) (95% CI, 25.2-NE) in those who discontinued due to toxicity. Among all pts with CLL/SLL, with a median f/u of 46.5 mos, the median OS was NE (95% CI, 47.8-NE), with the 36-mos OS rate of 62.0% (95% CI, 55.8-67.7). Median time on pirtobrutinib was 20.0 mos (range, 0.2-69.8), and 43 (15.2%) pts were still on tx at data cutoff. The most frequent TEAEs, regardless of attribution, were fatigue (38.7%), neutropenia/neutrophil count decreased (35.8%), diarrhea (30.5%), cough (29.8%), COVID-19 (28.4%), and contusion (27.7%). The most frequent grade ≥3 TEAEs were infection (36.5%) and neutropenia/neutrophil count decreased (29.8%). Low rates of grade ≥3 TEAE of hypertension (5.3%), hemorrhage/hematoma (2.5%), and atrial fibrillation/flutter (2.1%) were observed. Grade 5 TEAEs, regardless of attribution, occurred in 35 (12.4%) pts. Overall, 11 (3.9%) pts had a TRAE leading to a dose reduction, and 9 (3.2%) pts had a TRAE leading to pirtobrutinib discontinuation. Conclusion: In heavily pretreated R/R post-cBTKi CLL/SLL pts, pirtobrutinib continues to show favorable and durable efficacy. Pirtobrutinib is well-tolerated, with low rates of hypertension, hemorrhage/hematoma, and atrial fibrillation/flutter, which can be frequently observed with cBTKi. Additionally, dose reductions/discontinuations due to pirtobrutinib TRAEs were low. No new pirtobrutinib safety signals were identified with more than 5 yrs of f/u.

Abstract Background: Despite the efficacy of covalent Bruton tyrosine kinase inhibitors (cBTKi) in R/R MCL, patients (pts) ultimately discontinue treatment due to intolerance or development of resistance and disease relapse. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits BTK with low nM potency throughout the daily dosing interval. Pirtobrutinib was safe and effective in the phase 1/2 BRUIN study in pts with R/R B-cell malignancies, including those previously treated with a BTKi. Pirtobrutinib is approved in the EU for adults with R/R MCL after prior treatment with a BTKi (EMA Conditional Approval, Oct 2023), and in the USA for adults with R/R MCL after ≥ 2 lines of systemic therapy, including a BTKi (FDA Accelerated Approval, Jan 2023).Here, we report the final results from the phase 1/2 BRUIN study (NCT03740529), with a follow-up period of up to 5 yrs, focusing on the efficacy and safety of pirtobrutinib in all R/R MCL pts. Methods: Pts with R/R MCL who received ≥1 prior lines of therapy (including BTKi) were eligible for treatment with pirtobrutinib monotherapy. Key endpoints included overall response rate (ORR), duration of response (DOR) and progression-free survival (PFS), all assessed by independent review committee (IRC) per Lugano 2014 criteria (presented here) and investigator, overall survival (OS), and safety. Pts were included across the range of doses evaluated in dose escalation and expansion (25-300 mg/day). A data cutoff on 27 January 2025 was utilized, with a median study follow-up of 17.5 months (range, 0.5-69.6). Results: Among the 166 pts with R/R MCL, 153 (92%) received the pirtobrutinib approved dose of 200 mg/day, 152 (92%) had received prior cBTKi, of which 128 (84.2%) discontinued any prior cBTKi due to progressive disease (PD), and 15 (9.9%) due to toxicity. The cBTKi-pre-treated pts had a median age of 70 yrs (range, 46-88), 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. The median number of prior lines of therapy was 3 (range 1-9), with most pts having received a prior anti-CD20 antibody (96.7%) and chemotherapy (90.1%). Additional prior therapies included hematopoietic stem cell transplantation (21.7%; 19.7% auto and 4.6% allo), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%). As of the data cutoff, 11 (7.2%) pts who received a prior cBTKi and 6 (42.9%) cBTKi naïve pts remained on treatment. The cBTKi pre-treated pts had an ORR of 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (CR) (n=24) and 33.6% partial responses (PR) (n=51). The 75 responding pretreated pts had a median DOR of 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The ORR among 128 pts who had discontinued any prior cBTKi due to PD and 15 pts who discontinued due to toxicity was 43.0% and 93.3%, respectively. The median PFS and OS for cBTKi pre-treated pts were 5.6 months (95% CI, 5.3-9.2) and 23.9 months (95% CI, 17.3-51.5), respectively. Fourteen pts (9.2%) were censored for PFS due to subsequent anticancer therapy without documented PD, including 8 pts who received CAR-T. The cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2), including 50.0% CR (n=7) and 35.7% PR (n=5). The 12 responding naïve pts had a median DOR of 42.7 months (95% CI, 25.8-NE) at a median follow-up of 43 months. The median PFS and OS in the cBTKi naïve pts were 44.6 months (95% CI, 16.7-NE) and not reached (95% CI, 33.5-NE), respectively. Among all R/R MCL pts (n=166), the most frequent treatment-emergent adverse events (TEAE), regardless of attribution, were fatigue (31.9%), diarrhea (22.9%), anemia (18.1%), and dyspnea (18.1%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%), and the rate of Grade ≥3 infections was 21.1%. Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. In total, 13 (7.8%) pts had a fatal TEAE, with 4 (2.4%) classified as infections. Overall, 8 pts (4.8%) had treatment-related AE leading to dose reductions, and 6 (3.6%) had treatment-related AE leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate efficacy in pts with heavily pre-treated R/R MCL including both those who previously received a cBTKi and those who were BTKi-naïve. The safety profile of pirtobrutinib remained favorable with a low-rate of dose reductions/discontinuations due to drug-related toxicity. No new safety signals were identified after up to 5 yrs of follow-up.

Abstract Background: Venetoclax (VEN)+obinutuzumab (VO) is an effective therapy for CLL/SLL requiring regular monitoring for tumor lysis syndrome (TLS) during VEN ramp-up. The CLL14 trial of VO reported no TLS during VEN ramp-up; however, there are limited real-world data on monitoring practices and TLS outcomes for different dose levels and monitoring timepoints. This study assessed VEN initiation prophylaxis and monitoring outcomes for patients (pts) with CLL/SLL starting VO in first line (1L) in an outpatient, real-world setting. Methods This interim analysis relied onretrospective observational data from 4 US sites of the CLL Collaborative Study of Real-World Evidence (CORE). Adult pts with CLL/SLL were eligible if they: (1) started VO per-label outside of a clinical trial in 1L, or immediately after exposure in 1L to agents with different mechanisms of action (i.e., BTKi, anti-CD20 only) of <30 days; (2) prior to VEN start, had either (i) low physician-determined tumor burden (TB) (i.e., all lymph nodes [LN] <5 cm and ALC <25 x 109/L), or (ii) medium physician-determined TB (i.e., any LN ≥5-<10 cm or ALC ≥25 x 109/L) with creatinine clearance ≥80 mL/min; (3) had no strong CYP3A inhibitors or prophylactic rasburicase from 3 days prior to VEN start until end of VEN ramp-up; and (4) had VEN ramp-up in an outpatient setting. TB-related labs/imaging was assessed from 2 months prior to obinutuzumab initiation (i.e., index date) until VEN start. VEN characteristics (i.e., dosing, duration), prophylaxis measures (i.e., antihyperuricemics and IV hydration), and TLS-related monitoring and management (i.e., lab results and interventions received) were collected per ramp-up week and TLS monitoring timepoint. Results Of 128 pts in CORE who initiated VO in any line, 72 pts met inclusion criteria (low TB: 57 [79.2%]; medium TB: 15 [20.8%]). Median (IQR) age was 62 (56.0, 68.5) years, 58.3% were male, and 81.9% had ECOG grade ≤1. Among pts tested, 7/68 (10.3%) had del(17p)/TP53 mutation and 43/66 (65.2%) had unmutated IGHV. Median (IQR) time from index to VEN start was 23.0 (22.0, 30.0) days. Most pts completed ramp-up (98.6% [71/72]) and followed a per-label regular dosing schedule (93.1% [67/72]). Prior to VEN ramp-up, all pts received prophylactic antihyperuricemics (allopurinol: 71 [98.6%]; febuxostat: 2 [2.8%]) and prophylactic hydration. In the 2 days prior to a dose escalation for at least 1 week of ramp-up, prophylactic IV hydration was reported for 27 (37.5%) pts based on physician determination. One pt stopped VEN after week 2 due to neutropenia (grade 3+). During ramp-up (median [IQR] of 9 [8, 12] blood tests per pt), no lab or clinical TLS was reported. Of 21 (29.2%) pts who received an intervention following a lab assessment, most had low TB at VEN start (16 [76.2%]). All interventions were either prophylactic or non-TLS-related. Following a lab assessment for at least 1 week of ramp-up, prophylactic IV or escalated oral hydration intervention was reported in 17/21 pts (81.0%) based on physician determination (e.g., to manage impaired baseline renal function in those with low TB, patient request, or institutional practice) (IV hydration: 15 pts; escalated oral hydration: 2 pts). By per-label monitoring timepoints, hydration intervention was given prophylactically following pre-dose lab tests for 7 pts (across weeks 1-5), 6-8 hours post-dose for 5 pts (weeks 1-2), and 24 hours post-dose for 10 pts (weeks 1-2). By per-label monitoring timepoints, other non-TLS-related interventions (i.e., blood transfusion for anemia, insulin for hyperglycemia, and potassium for non-TLS-related hypokalemia) were given following pre-dose lab tests for 2 pts (weeks 1-5) and 24 hours post-dose for 4 pts (weeks 1-2). Conclusion Consistent with the CLL14 trial, no TLS was reported in this real-world, interim analysis of pts with mostly low TB and good renal function at 1L VO initation. All interventions during VEN ramp-up were prophylactic or non-TLS-related, with prophylactic hydration commonly given based on physician preference. These results suggest that VO initiation is manageable in an outpatient setting. Consideration should be given for simplified monitoring requirements including potential removal of 6-8 hour post-dose lab in this population and be further explored in prospective studies. Data collection for this study is ongoing to further contextualize real-world VEN initiation prophylaxis and monitoring outcomes in a larger cohort.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent’s toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

Abstract Although Bruton tyrosine kinase inhibitors (BTKis) are generally well tolerated and less toxic than chemotherapy alternatives used to treat lymphoid malignancies, BTKis like ibrutinib have the potential to cause new or worsening hypertension (HTN). Little is known about the optimal treatment of BTKi-associated HTN. Randomly selected patients with lymphoid malignancies on a BTKi and antihypertensive drug(s) and with at least 3 months of follow-up data were sorted into 2 groups: those diagnosed with HTN before BTKi initiation (prior-HTN), and those diagnosed with HTN after BTKi initiation (de novo HTN). Generalized estimating equations assessed associations between time varying mean arterial pressures (MAPs) and individual anti-HTN drug categories. Of 196 patients included in the study, 118 had prior-HTN, and 78 developed de novo HTN. Statistically significant mean MAP reductions were observed in patients with prior-HTN who took β blockers (BBs) with hydrochlorothiazide (HCTZ), (−5.05 mmHg; 95% confidence interval [CI], 10.0 to −0.0596; P = .047), and patients diagnosed with de novo HTN who took either an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) with HCTZ (−5.47 mmHg; 95% CI, 10.9 to −0.001; P = .05). These regimens also correlated with the greatest percentages of normotensive MAPs. Treatment of HTN in patients taking a BTKi is challenging and may require multiple antihypertensives. Patients with prior-HTN appear to benefit from combination regimens with BBs and HCTZ, whereas patients with de novo HTN appear to benefit from ACEi/ARBs with HCTZ. These results should be confirmed in prospective studies.

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.

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody–drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1–mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.