INTRODUCTION:Second-generation covalent Bruton tyrosine kinase inhibitors (cBTKi), acalabrutinib and zanubrutinib, are standard-of-care for treatment-naïve adults with chronic lymphocytic leukemia (CLL). However, real-world evidence remains limited. METHODS:This real-world analysis compared acalabrutinib and zanubrutinib using the IntegraConnect PrecisionQ de-identified electronic health record database, representing >3 million cancer patients across 500+ US sites. Patients initiated cBTKi between January 2020 and November 2023, with follow-up through 3 July 2024. RESULTS:This study included 473 patients; 184 zanubrutinib-treated patients matched to 289 acalabrutinib-treated patients by age and sex. Baseline characteristics were similar. Median time to discontinuation (TTD) for acalabrutinib was 29.5 months (95% confidence interval [CI] 21.2, not reached [NR]). Median TTD for zanubrutinib was NR, with significantly longer duration of treatment than acalabrutinib (adjusted hazard ratio [aHR]: 0.50, 95% CI 0.3-0.7; p < .01). The 12-month probability of remaining on treatment with zanubrutinib (83.3%) was higher than acalabrutinib (69.5%). Toxicity-related discontinuation was higher with acalabrutinib (10.7%) than zanubrutinib (5.4%). Median time to next treatment was 42.5 months for acalabrutinib (95% CI 33.2-NR) and NR for zanubrutinib (aHR 0.82; 95% CI 0.5-1.4). CONCLUSION:Zanubrutinib demonstrated longer treatment persistence and fewer discontinuations attributed to toxicity during chart abstraction than acalabrutinib in treatment-naïve CLL.

There is a dearth of head-to-head studies comparing covalent Bruton tyrosine kinase (cBTK) inhibitors in adults with chronic lymphocytic leukemia (CLL). Real-world evidence may complement clinical trial data by assessing relative effectiveness in routine practice. This retrospective observational study used a de-identified Medicare Fee-For-Service database to compare real-world outcomes associated with first-line cBTKi monotherapies in older adults with CLL. Patients aged ≥ 65 years with CLL initiating first-line ibrutinib, acalabrutinib, or zanubrutinib monotherapy between January 1, 2020 and September 30, 2025 were included. Real-world time to treatment discontinuation (rwTTD), time to next treatment (rwTTNT), and overall survival (rwOS) were evaluated using Kaplan–Meier analyses and Cox proportional hazards models. Subgroup analyses were performed by age group. Among 10,523 patients included, 3006 (28.6

ABSTRACT Introduction B‐cell prolymphocytic leukemia (B‐PLL) is a rare, aggressive leukemic B‐cell malignancy historically associated with poor outcomes and recently reclassified in the WHO Fifth Edition but retained as a distinct entity in the ICC. Methods We analyzed 950 patients labeled as B‐PLL in the National Cancer Database (2004–2019), identified using ICD‐O‐3 morphology code 9833/3. Results Median age was 72 years, and 72% received systemic therapy at diagnosis. Median overall survival (OS) was poor (2.8 years) and did not improve over time. Patients initially managed with active surveillance had longer OS (7.8 years). Outcomes varied by age, comorbidity, and facility type. Conclusion Patients historically diagnosed with B‐PLL experience persistently poor outcomes, highlighting the real‐world clinical consequences of diagnostic heterogeneity and evolving disease classifications.

Patients in the liso-cel plus ibrutinib cohort of the phase 1/2, open-label TRANSCEND CLL 004 study had relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and received liso-cel (50×106 [dose level (DL)1] or 100×106 [DL2] chimeric antigen receptor-positive T cells) with concurrent ibrutinib from enrollment through 90 days after liso-cel infusion or longer per investigator discretion. Primary end point was complete response/remission (CR)/CR with incomplete marrow recovery (CRi) by investigator assessment. Among 56 patients who received ibrutinib plus liso-cel (DL1, n=5; DL2, n=51), median (range) age was 64.5 years (44‒77), 98% had high-risk cytogenetics, 55% had progression on Bruton tyrosine kinase inhibitor and venetoclax failure, and median (range) number of prior therapies was 5 (1‒13). Median (range) follow-up was 24.8 months (3.1‒51.8). At DL2, CR/CRi rate was 45% (95% confidence interval [CI], 31‒60) and overall response rate was 86% (95% CI, 74‒94). Median (95% CI) duration of response was not reached (NR; 28.7‒NR) for patients with CR/CRi and 41.4 months (23.3‒NR) for all responders. Median (95% CI) progression-free survival was 31.4 months (20.1‒NR). In DL1+DL2, most common grade ≥3 treatment-emergent adverse events (TEAE) were neutropenia (52%) and anemia (41%). Cytokine release syndrome was reported in 80% of patients (grade 3, 4%; no grade 4/5), and neurological events in 41% (grade 3/4, 11%; no grade 5). Ibrutinib-related TEAEs were reported in 68% of patients (grade 3/4, 43%; no grade 5). Liso-cel plus ibrutinib demonstrated notable efficacy in patients with relapsed/refractory CLL/SLL with predictable and manageable safety. Clinicaltrials.gov: NCT03331198; NCT03435796.

Over the past decade, treatment recommendations for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) have shifted from traditional chemoimmunotherapy to targeted therapies. Multiple new therapies are commercially available, and in many cases a lack of randomized clinical trial data makes selection of the optimal treatment for each patient challenging. Additionally, many patients continue to receive chemoimmunotherapy in the US, suggesting a gap between guidelines and real-world practice. The Lymphoma Research Foundation convened a workshop comprised of a panel of CLL/SLL experts in the US to develop consensus recommendations for selection and sequencing of therapies for patients with CLL/SLL in the US. Herein, the recommendations are compiled for use as a practical clinical guide for treating providers caring for patients with CLL/SLL, which complement existing guidelines by providing a nuanced discussion relating how our panel of CLL/SLL experts in the US care for patients in a real-world environment.

BACKGROUND:Patients with follicular lymphoma (FL) grade (G) 1-3A who meet treatment criteria are commonly treated with chemo-immunotherapy regimens such as bendamustine plus rituximab (BR) or rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone (RCHOP). Two prospective trials have compared BR to RCHOP-like regimens and showed improved progression free survival with BR in FL G1-2 patients. However, in real-world practice, there is clinical variability in utilization of BR versus RCHOP-like regimens. Additionally, the optimal treatment for patients with FL G3A remains unclear. METHODS:We used a nationwide electronic health record-derived de-identified database to compare outcomes in 2089 patients with FL G1-3A treated with frontline BR versus RCHOP-like regimens. RESULTS:We demonstrated clinical improvement in time to next treatment or death (TTNTD) with BR (median 96 vs. 78 months, HR 1.15, 95% CI 0.986-1.332, P = .086), albeit not statistically significant. No difference in overall survival (OS) was observed. Maintenance rituximab was associated with improved TTNTD and OS. Among G3A patients (N = 304), TTNTD was comparable between the 2 regimens, however OS was significantly improved with RCHOP-like regimens in univariate analysis (median 138 vs. 96 months, HR 0.51, 95% CI 0.313-0.834, P = .007). CONCLUSIONS:In conclusion, this study of real-world patients supports the use of BR and rituximab maintenance for front-line treatment of FL. Further prospective studies are needed to determine the ideal treatment for FL G3A.

BACKGROUND:Bruton's tyrosine kinase inhibitors (BTKi) have prolonged survival in chronic lymphocytic leukemia (CLL), however continuous administration increases toxicity. Little is known about clinical outcomes of patients who discontinue BTKi for reasons other than CLL progression. We aimed to report these outcomes. PATIENTS/METHODS:With the CLL Society, we solicited volunteers with CLL who self-reported BTKi discontinuation for reasons other than CLL progression to participate in a web-based survey. RESULTS:In 170 patients, BTKi was discontinued for toxicity, because CLL was in remission, or personal choice in 62%, 14% and 8%, respectively. When asked how they felt about stopping the BTKi, most were relieved that they may eliminate toxicity (45%), could focus less on CLL (11%), and would not have to pay for the medicine (7%), while 29% experienced anxiety. A statistically significant increase in perceived quality of life (QOL) was observed from prior- versus post-BTKi discontinuation. Of patients who reported that they experienced clinical CLL progression (n = 80), 46% reported that these events did not happen for ≥ 1 year after BTKi discontinuation. Those that were on a BTKi for ≥ 2 years before discontinuation had more time without CLL relapse. CONCLUSIONS:These data provide a unique report of patient experiences. The data suggest that BTKi may be feasible and result in a period of treatment-free remission. The data also indicate that patients are generally relieved when they anticipate BTKi discontinuation and observe significant QOL improvements after BTKi discontinuation. As such, these data should prompt prospective study of time-limited BTKi therapy for CLL.

"HSR25-185: A Multicenter Retrospective Study of Treatment and Survival Outcomes of Patients With Secondary CNS Relapsed DLBCL in the Modern Era" published on 28 Mar 2025 by National Comprehensive Cancer Network.

e23279 Background: Bruton tyrosine kinase inhibitors (BTKis)are standard of care in CLL/SLL, but are associated with cardiovascular (CV) toxicities, such as HTN, that can affect treatment dose intensity. These toxicities are especially important in the Medicare population, who are typically elderly with multiple pre-existing CV comorbidities. This real-world study compared the risk of HTN and TTF with acalabrutinib versus ibrutinib monotherapy in treatment-naive Medicare-eligible patients with CLL/SLL. Methods: This retrospective, observational study used electronic medical record data from ONCare Alliance, a network of 32 US community oncology/hematology practices, and consisted of Medicare-eligible patients with treatment-naive CLL/SLL who started acalabrutinib or ibrutinib monotherapy on or between 1/1/2017 and 12/31/2023. The primary endpoint was time to development of new HTN/worsening of pre-existing HTN, defined as the addition of an anti-HTN medication, a dose increase of a current anti-HTN medication, a dose modification/discontinuation of the BTKi due to high blood pressure, or a provider reporting new/worsening HTN. The secondary endpoint was TTF, defined as time from treatment start to discontinuation due to disease progression, drug intolerability, patient/provider choice, or death. Endpoints were evaluated using propensity score-weighted Kaplan-Meier and multivariate Cox proportional hazard regression analyses. Sensitivity analyses tested the stability of the primary endpoint. Results: 166 acalabrutinib- and 173 ibrutinib-treated Medicare-eligible patients aged ≥ 65 years were included. Baseline characteristics were well balanced between acalabrutinib and ibrutinib, with respect to median age (76 vs 75 years), ECOG performance status, and history of HTN (75.9% vs 73.4%). After a median follow-up of 28 months, drug discontinuations due to intolerability were less common with acalabrutinib than ibrutinib (22.9% vs 48.6%; p = 0.001). Acalabrutinib significantly reduced the risk of new/worsening HTN (hazard ratio [HR] 0.22; 95% confidence interval [CI] 0.09–0.53; p = 0.001) and improved TTF (HR 0.44; 95% CI 0.32–0.61; p = 0.001) versus ibrutinib. Other CV events were less common with acalabrutinib than ibrutinib. The sensitivity analyses indicated stability in the primary analysis results. Conclusions: In treatment-naive Medicare-eligible patients with CLL/SLL, acalabrutinib had fewer CV events, a lower risk of new/worsening HTN, fewer discontinuations due to intolerability, and prolonged TTF versus ibrutinib.

7025 Background: CB-010 is an allogeneic anti-CD19 CAR-T cell therapy derived from healthy donor T cells using CRISPR hybrid RNA-DNA (chRDNA) technology. This technology is used to introduce 3 genome edits: (1) knockout of TRACto eliminate TCR expression and reduce risk of GvHD, (2) insertion of a CD19-specific CAR (scFv FMC63) into the TRAC locus, and (3) knockout of PD-1 to prevent premature CAR-T cell exhaustion and potentially enhance antitumor activity. Methods: ANTLER is a Phase 1 clinical trial (NCT04637763) with a 3+3 dose escalation phase and a dose expansion phase designed to evaluate safety, tolerability, and antitumor activity of CB-010 in patients (pts) with r/r B-NHL and determine RP2D. In dose escalation, pts must have received ≥2 prior lines of chemoimmunotherapy or had primary refractory disease to 1L therapy. Pts received lymphodepletion with sequential cyclophosphamide (60 mg/kg/day x 2 days) and fludarabine (25 mg/m2/day x 5 days) followed by a single CB-010 infusion. Results: 16 pts with r/r B-NHL (10 LBCL, 3 MCL, 2 FL with POD24, 1 MZL) received CB-010 at 40 x 106 CAR-T cells (dose level 1; N=8), 80 x 106 CAR-T cells (dose level 2; N=5), or 120 x 106 CAR-T cells (dose level 3; N=3) during dose escalation. Median age was 66 years (range 55-82). Median time since first diagnosis was 2.4 years (range 0.2-16.4). Median prior lines of therapy was 2 (range 1-8). CB-010 was generally well tolerated. No GvHD was seen. CRS occurred in 7/16 (44%) pts (no CRS grade ≥3). Median time to CRS onset was 3.5 days and median duration was 3 days. ICANS occurred in 4/16 (25%) pts (13% grade ≥3). Median time to ICANS onset was 7.5 days and median duration was 2 days. The 3 most common TEAEs grade ≥3 were thrombocytopenia (11/16; 69%), neutropenia (9/16; 56%), and anemia (8/16; 50%). One grade 3 infection (antecubital cellulitis) occurred unrelated to CB-010. After a single CB-010 infusion, 15/16 (94%) pts achieved an overall response, 11/16 (69%) achieved a CR, and 7/16 (44%) achieved a CR at ≥6 months. Median time to CR was 28 days. Among LBCL pts (n=10), 9 (90%) achieved an overall response, 7 (70%) achieved a CR, and 5 (50%) achieved a CR at ≥6 months. To date,2 pts have completed the 24-month study period with ongoing CR. Peak expansion of CB-010 occurred at days 7-10 post-infusion. T and NK cells recovered rapidly in peripheral blood (<3 weeks) after lymphodepletion, and B cells remained below the limit of quantification beyond 3 months, supporting specific targeting of B cells by CB-010. Conclusions: CB-010 showed a manageable safety profile and promising efficacy for treatment of pts with r/r B-NHL, including aggressive subtypes. The dose escalation phase is complete. Enrollment of 2L LBCL pts in dose expansion is ongoing. Initial dose expansion data at the CB-010 RP2D and translational data will be presented for the first time at the meeting. Clinical trial information: NCT04637763 .

7037 Background: TRANSCEND CLL 004 (NCT03331198) is a phase 1/2, open-label, nonrandomized, multicohort study in adult patients (pt) with R/R chronic lymphocytic leukemia/small lymphocytic lymphoma with liso-cel mono and liso-cel + ibrutinib combo cohorts. Given the study design, we performed PS matching/weighting to adjust for differences in key covariates between cohorts to compare efficacy and safety. Methods: Here, PS is the probability of receiving combo given the covariates and estimated by logistic regression. Covariates were hemoglobin, LDH, number of prior therapies, platelets, prior BTKi + venetoclax exposure, R/R on prior BTKi, and bulky disease for efficacy; and ALC, bulky disease, CRP, ferritin, and number of prior therapies for safety. PS balancing methods were optimal 1:1 matching, average treatment effect for treated pts (ATT) full matching, and ATT inverse probability of treatment weighting (IPTW). Efficacy endpoints were response (CR rate, ORR) and time to event endpoints (DOR, PFS, OS). Safety endpoints were proportions of pts with any-grade (gr)/gr ≥ 3 cytokine release syndrome (CRS) and investigator-identified neurological events (NE). Results: Fifty-one and 88 efficacy-evaluable pts were treated at dose level 2 (100 × 10 6 CAR + T cells) in the combo and mono cohorts, respectively. Before matching/weighting on PS, odds of achieving CR and overall response were statistically significantly higher for combo (Table). DOR did not differ between cohorts. For PFS and OS, HRs were lower with combo vs mono (not statistically significant [NS]). Odds of gr ≥ 3 CRS/NE were lower with combo vs mono (NS). After matching/weighting, odds of CR (except IPTW ATT) and overall response remained statistically significantly higher in combo. HRs for PFS and OS and ORs for gr ≥ 3 CRS/NE were numerically lower with combo vs mono (NS, except IPTW ATT for PFS). HRs for DOR were less but close to HR of 1. Conclusions: The liso-cel + ibrutinib combo demonstrated a trend for better efficacy and safety vs liso-cel mono, with statistically significant differences for CR rate and ORR. Clinical trial information: NCT03331198 . Efficacy and safety outcomes: combo vs mono. No adjustment ATT optimal 1:1 IPTW - ATT CR rate, OR (95% CI) 2.07* (1.01–4.28) 2.40* (1.05–5.66) 2.00(0.89–4.61) ORR, OR (95% CI) 3.96* (1.68–10.51) 3.43* (1.33–9.71) 4.18* (1.63–11.78) DOR, HR (95% CI) 0.98(0.51–1.87) 0.88(0.43–1.78) 0.96(0.50–1.85) PFS, HR (95% CI) 0.62(0.37–1.02) 0.61(0.35–1.05) 0.59* (0.35–0.98) OS, HR (95% CI) 0.70(0.38–1.28) 0.73(0.37–1.43) 0.66(0.36–1.22) CRS, OR (95% CI) 0.63(0.26–1.56) 0.67(0.24–1.84) 0.69(0.24–1.88) Gr ≥ 3 CRS, OR (95% CI) 0.23(0.01–1.35) 0.49(0.02–5.28) 0.26(0.01–1.94) NE, OR (95% CI) 0.84(0.41–1.68) 0.92(0.40–2.08) 1.10(0.48–2.52) Gr ≥ 3 NE, OR (95% CI) 0.56(0.19–1.45) 0.58(0.16–1.89) 0.68(0.19–2.30) *Statistically significant difference at 5% level.

e23280 Background: Bruton tyrosine kinase inhibitors (BTKis) are standard of care in CLL/SLL. However, BTKis, especially ibrutinib, are associated with CV toxicities that can affect the relative dose intensity and duration of therapy. This real-world analysis compared the frequency of CV adverse events and explored TTNT in treatment-naive patients with CLL/SLL receiving acalabrutinib or ibrutinib monotherapy in US clinical practice. Methods: This retrospective, observational study used electronic medical record data from ONCare Alliance, a network of 32 US community oncology/hematology practices. The study included patients with treatment-naive CLL/SLL initiating either acalabrutinib or ibrutinib monotherapy on or between 1/1/2017 and 12/31/2023. Data collected included patient and disease characteristics, CV medical events of interest (MEOI), and TTNT, calculated as the time from the start of therapy to the next treatment. Endpoints were evaluated using propensity score-weighted Kaplan-Meier analysis and Cox proportional hazards multivariate analysis. A sensitivity analysis was conducted to evaluate the stability of the primary findings. Results: The analysis included 454 patients (227 per treatment group). Baseline characteristics of patients in the acalabrutinib and ibrutinib cohorts were generally well balanced, with respect to median age (72 vs 73 years) and history of hypertension (HTN) (67.8% vs 66.5%). After a median follow-up of 28 months, the proportion of patients with CV MEOI was lower in the acalabrutinib cohort than in the ibrutinib cohort (20.3% vs 45.8%; p < 0.001). The median time to first CV MEOI was not reached (95% confidence interval [CI] 34.5–not reached [NR] months) with acalabrutinib versus 44.8 months (95% CI 8.2–NR) with ibrutinib (hazard ratio 0.47; 95% CI 0.33–0.68; p < 0.001).Specific MEOIs were generally less common with acalabrutinib than with ibrutinib, including new/worsening HTN, atrial fibrillation, clinically significant bleeding events, cardiac arrhythmia, and ventricular arrhythmia. Median TTNT in the acalabrutinib cohort was 48.2 months (95% CI 41.8–NR) and in the ibrutinib cohort was 30.7 months (95% CI 9.8–NR). Conclusions: In this retrospective real-world data analysis comparing acalabrutinib with ibrutinib in the first-line setting, treatment-naive patients with CLL/SLL receiving acalabrutinib had fewer CV safety events and continued to receive treatment for longer than those receiving ibrutinib.

Introduction: A major advance in the care of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the development of Bruton tyrosine kinase inhibitors (BTKis). Ibrutinib was the first BTKi to be approved and has demonstrated sustained progression-free survival over 8 years of follow-up in treatment-naïve patients with CLL/SLL (Barr et al. 2022). However, there is concern about the tolerability of ibrutinib, which is characterized by hypertension (HTN) and major adverse cardiovascular events (MACE). Acalabrutinib is a second generation BTKi that has also demonstrated durable disease response but with a potentially improved safety profile versus ibrutinib. Acalabrutinib has not been compared with ibrutinib in treatment-naïve patients with CLL/SLL in a randomized trial. This real-world analysis compared the risk of HTN and time to treatment failure (TTF) with acalabrutinib versus ibrutinib monotherapy in treatment-naïve patients with CLL/SLL. Methods: This retrospective, observational study used electronic medical record data from ONCare Alliance, a network of 29 community oncology/hematology practices across the United States. The study included patients with treatment-naïve CLL/SLL initiating either acalabrutinib or ibrutinib monotherapy on or between January 1, 2017 and December 31, 2023. The primary endpoint was time to the development of new HTN/worsening of pre-existing HTN. New/worsening HTN was defined as the addition of an anti-HTN medication, an increase in the dose of a current anti-HTN medication, a dose modification or discontinuation of the BTKi due to elevated blood pressure, or a provider statement reporting new/worsening HTN. The secondary endpoint was TTF, defined as time from treatment initiation to discontinuation due to disease progression, drug intolerability, patient/provider choice, or death. Data collection included patient and disease characteristics, comorbidities, history of prior HTN and MACE, and Eastern Cooperative Oncology Group performance status (ECOG PS). The primary and secondary endpoints were evaluated using multivariate Cox proportional hazard regression analysis. To control for selection bias, propensity scores were used to weight the comparative multivariate analyses. Sensitivity analyses evaluated primary and secondary endpoints in scenarios without propensity score weighting, using different applications of the propensity scores, excluding non-responders and excluding patients without a history of HTN. Results: The analysis included 454 patients (227 per treatment group). Baseline characteristics of patients in the acalabrutinib and ibrutinib groups were well balanced with respect to median age (72 vs 73 years), ECOG PS, median Charlson comorbidity score (3 vs 3), median systolic (130 vs 127 mmHg) and diastolic (72 vs 71 mmHg) blood pressure (BP), and history of HTN (67.8% vs 66.5%). After a median follow-up of 18 months, drug discontinuations due to intolerability were more common with ibrutinib versus acalabrutinib (47.1% vs 20.3%; p < 0.001). Median time to new/worsening HTN was not reached (NR) with acalabrutinib or ibrutinib, and median TTF was NR with acalabrutinib and 16.1 months with ibrutinib. After a propensity score weighted Cox proportional hazard analysis versus ibrutinib, acalabrutinib was associated with a significantly lower risk of new/worsening HTN (hazard ratio [HR]: 0.21, 95% confidence interval [CI]: 0.10-0.43; p < 0.001) and a longer TTF (HR: 0.42, 95% CI: 0.31-0.56; p < 0.001). Sensitivity analyses were consistent with the primary analyses. High baseline systolic BP (HR: 1.03; p < 0.001), presence of B symptoms (HR: 2.23, p = 0.007), and a history of valvular heart disease (HR: 3.11, p = 0.039) increased the risk of new/worsening HTN. Older age (HR: 1.03, p < 0.001), high comorbidity burden based on the Charlson comorbidity score (HR: 1.09, p = 0.039), history of atrial fibrillation (HR: 1.51, p = 0.023), and ECOG PS ≥ 2 (HR: 1.48, p = 0.05) increased the risk of treatment failure. Conclusions: In treatment-naïve patients with CLL/SLL, acalabrutinib monotherapy was associated with a lower rate of new/worsening HTN, fewer discontinuations due to intolerability, and a prolonged TTF versus ibrutinib, even after statistical adjustments to reduce potential selection bias.

Background: The primary analysis of the phase 1/2, single-arm, multicenter TRANSCEND CLL 004 (NCT03331198) study with a median follow-up of 21.1 mo showed that a single administration of liso-cel achieved rapid, deep, and durable responses and a manageable safety profile in pts with heavily pretreated, high-risk R/R CLL/SLL, including those with progression on a previous Bruton tyrosine kinase inhibitor (BTKi) and venetoclax failure (primary efficacy analysis set [PEAS]; Siddiqi T, et al. Lancet 2023). With 5 mo of additional follow-up (median of 23.5 mo), liso-cel continued to demonstrate durable CR/CR with incomplete marrow recovery (CRi) and high undetectable MRD (uMRD; 10−4 by next-generation sequencing) rates with no new safety signals. Median duration of response (DOR) was 35.3 mo (95% CI, 12.4-not reached [NR]), and median OS was 30.3 mo (95% CI, 15.0-NR) (Siddiqi T, et al. Blood 2023). Here, we report updated results from TRANSCEND CLL 004 with 16 mo of additional follow-up since primary analysis and a median on-study follow-up of 23.8 mo (range, 0.4-59.6). Methods: Pts must have received ≥ 2 prior lines of therapy (LOTs), including a BTKi (full population). Eligible pts received liso-cel at a target dose of either 50 × 106 (dose level [DL] 1) or 100 × 106 (DL2) CAR+ T cells after lymphodepleting chemotherapy. The primary endpoint was CR/CRi per independent review committee in the PEAS at DL2. Key secondary endpoints were ORR and blood uMRD rate. All pts who received liso-cel and completed or discontinued early from the study were asked to enroll in a separate long-term follow-up (LTFU) study (NCT03435796) assessing safety and OS for up to 15 y after liso-cel. Results: As of the data cutoff (01/12/2024), 118 of 137 leukapheresed pts received liso-cel (safety set), 97 (DL1, n = 9; DL2, n = 88) were efficacy evaluable, and 54 (DL1, n = 4; DL2, n = 50) were in the PEAS. A total of 22 pts were ongoing in TRANSCEND CLL 004, and 19 of 60 eligible pts enrolled to the LTFU study. In the safety set, pts had a median age of 65 y (range, 49-82), and 83% had high-risk cytogenetic markers (del[17p], 42%; TP53 mutation, 47%; unmutated immunoglobulin heavy-chain variable gene, 47%). Median prior LOTs was 5 (range, 2-14); 86% of pts had prior chemoimmunotherapy. In the PEAS at DL2, CR/CRi rate remained at 20%, ORR at 44%, blood uMRD rate at 64%, and marrow uMRD rate at 60%. Median DOR was NR (95% CI, 12.4-NR), with a median follow-up of 31.7 mo (95% CI, 21.3-35.5). Estimated 36-mo DOR rate was 61% (95% CI, 30-81). Median (95% CI) DOR was NR in pts with CR/CRi. Median (95% CI) PFS was 11.9 mo (5.7-26.2) overall, 26.2 mo (11.9-NR) in pts with blood uMRD, and 2.8 mo (0.8-3.2) in pts with detectable blood MRD. Median OS, including 19 pts in the LTFU, was 43.2 mo (95% CI, 14.5-NR). Efficacy outcomes were similar in the full population at DL2. A subgroup of 23 pts who had only prior BTKi exposure and were venetoclax naïve was less heavily pretreated, with a median of 3 prior LOTs (range, 2-11); all pts had prior chemoimmunotherapy. In the efficacy-evaluable pts of this subgroup at DL2 (n = 18), the CR/CRi rate was 22%; ORR was 61%; and median (95% CI) DOR was NR (17.1-NR), PFS was NR (18.0-NR), and OS was 52.2 mo (26.9-NR). In the safety set, rates of any-grade/grade ≥ 3 cytokine release syndrome (85%/8%), any-grade/grade ≥ 3 neurological events (45%/19%), prolonged cytopenia (grade ≥ 3 at Day 30 after liso-cel infusion [54%]), grade ≥ 3 infections (18%), and second primary malignancy (9%) remained the same as previously reported (Siddiqi T, et al. Blood 2023); most pts with prolonged cytopenia had resolution to grade ≤ 2 by Month 3. Forty-six (34%) of 137 leukapheresed pts died after CAR T cell infusion, including 1 additional pt since the previous report with an unknown cause of death at ~14.5 mo after infusion. Persistence of the liso-cel transgene was detected up to 48 months after liso-cel infusion (2/5 evaluable pts at DL2 at Month 48). Conclusions: In this updated follow-up, liso-cel continued to demonstrate durable responses with an extended median OS of 43.2 mo in pts with R/R CLL/SLL. The safety results were similar to those previously reported with no new safety signals. These data confirm the sustained clinical benefit and favorable benefit-to-risk profile of a single treatment of liso-cel in pts with R/R CLL/SLL.

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 beta 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.