ABSTRACT:The phase 3 CRISTALLO trial compared first-line fixed-duration venetoclax-obinutuzumab (VenO) vs fludarabine, cyclophosphamide, and rituximab (FCR)/bendamustine-rituximab (BR) in patients with chronic lymphocytic leukemia (CLL), using undetectable minimal residual disease (uMRD) as the sole primary end point. Previously untreated patients with a cumulative illness rating scale score ≤6 and creatinine clearance ≥70 mL/min without del(17p)/TP53 mutations were randomized 1:1 to VenO or FCR/BR. The primary end point was uMRD (<10-4) in peripheral blood (PB) using next-generation sequencing at month 15. Key secondary end points included uMRD (<10-4) in PB and bone marrow (BM) at end of treatment (EOT) and progression-free survival (PFS). uMRD at deeper cutoffs were explored. At data cutoff (19 March 2024), 80 patients received VenO, and 86 received FCR/BR. Baseline characteristics were generally balanced across arms. The primary end point was met: 81.3% (VenO) and 54.7% (FCR/BR) achieved uMRD (<10-4) in PB at month 15 (P = .0004). uMRD (<10-4) in PB and BM at EOT was also higher with VenO vs FCR/BR. Short follow-up precluded evaluation of PFS at the first planned interim analysis; however, fewer patients progressed/died with VenO vs FCR/BR (7 vs 13). At month 15, 65.0% (VenO) and 25.6% (FCR/BR) achieved uMRD (<10-6) in PB. The overall safety profile was consistent with the known safety profile of each drug. No patient in the VenO arm was deemed high risk for tumor lysis syndrome (TLS) after obinutuzumab debulking; no clinical TLS occurred. These results confirm and extend the findings from the GAIA-CLL13 trial, validating increased depth of response with VenO vs chemoimmunotherapies. This trial was registered at www.clinicaltrials.gov as NCT04285567.

BACKGROUND:Real-world data are an essential complement to clinical trials. This is particularly true for chronic lymphocytic leukemia, where five first-line options have never been directly compared. METHODS:The authors present the results of a national multicenter real-world study focusing on treatment choices in frontline chronic lymphocytic leukemia (CLL) and the criteria underlying this choice. Patients' medical records were included over a 6-month period in 25 centers. RESULTS:The majority of patients received obinutuzumab and venetoclax, especially those with mutated IGHV status. Patients harboring TP53 alterations were almost all treated with Bruton tyrosine kinase inhibitors, with a preference for zanubrutinib. Patients initiated on continuous Bruton tyrosine kinase inhibitors (BTKi) regimens were significantly older; second-generation BTKi, acalabrutinib and zanubrutinib were mostly prescribed. The most cited choice criteria by physicians were genetic prognostic factors, followed by fixed treatment duration and patient logistics considerations. Multiple correspondence analysis and unsupervised hierarchical clustering analysis allowed to identify two distinct patient profiles: younger patients, mostly with mutated IGHV status, who were mainly treated with combined drug regimens due to their fixed duration, and older patients, largely treated with BTKi because of the possibility of outpatient management. CONCLUSION:This study is the first to report real-world evidence on treatment choice in first-line CLL and highlight two distinct groups of patients.

CAR T cell therapy has recently become a major treatment in hematology for lymphoma and myeloma patients. Following treatment, patients remain at risk of complications, including infections. Here, we report on a -81 year-old female patient who developed late HBV reactivation following CAR T cell.

Background:For chronic lymphocytic leukaemia (CLL) and intermediate risk factors (unmutated IGHV and/or 11q deletion and/or complex karyotype; no TP53 alteration), the best first-line treatment is unclear. We compared an MRD-guided, fixed-duration ibrutinib-venetoclax (IV) regimen to fludarabine-cyclophosphamide-rituximab (FCR) in this population. Methods:The ERADIC randomised, phase 2 trial (NCT04010968), conducted at 35 French hospitals, recruited previously untreated, fit adults with intermediate-risk CLL. Randomisation was 1:1 to: 6x4-weekly cycles of FCR (Months 1-6); or ibrutinib 420 mg/day from Month 1 plus venetoclax (ramp-up to 400 mg/day from Month 4) for a duration depending on the bone marrow measurable residual disease level at Month 9 (if undetectable at a threshold of <0·01% [BM uMRD4] to Month 15; otherwise to Month 27). Primary outcome was the BM uMRD4 rate at Month 27, by assessment oligocentrally (intent-to-treat, worst-case scenario method). Findings:Between 27 September 2019 and 31 January 2021, 120 patients were enrolled (73% male). At Month 27, the BM uMRD4 rate was 37% (22/59; 95% confidence interval [CI] 25, 51) with IV versus 13% (8/61; 95% CI 6, 24) with FCR. The high amount of missing BM MRD data, along with imbalance in missing data between arms, meant that no confirmatory statistics were performed. Best rate of BM uMRD4 plus peripheral blood uMRD5 was 47% (22/47) with IV versus 19% (8/43) with FCR (p = 0·0090). With median 43 months' follow-up, progression-free survival was longer with IV versus FCR (estimated hazard ratio 0·35, 95% CI 0·16, 0·80, p = 0·012). By Month 27, six deaths had occurred (FCR: acute myeloid leukaemia, septic shock, myelodysplastic syndrome; IV: 2 sudden deaths, COVID-19). By the time of follow-up, the most common serious grade 3/4 events were infections and haematological toxicities with FCR, and infections and cardiovascular/metabolic toxicities with IV. Interpretation:Due to the high amount of missing BM MRD data at Month 27, the primary outcome statistical analysis was not deemed feasible. The outcomes reported are secondary and exploratory, and were not been powered for in the study design. A patient profile suitable for an MRD-guided, fixed-duration IV regimen requires consideration of potential toxicities. Funding:Abbvie and Janssen France.

Therapy-related myeloid neoplasms (t-MN), including myelodysplastic neoplasms (t-MDS) and acute myeloid leukemia (t-AML), have emerged as significant late complications after CAR T cell therapy. We retrospectively analyzed 539 patients with B cell lymphoma treated with CD19 directed CAR T cell therapy across four French centers. Cumulative incidences of t-MN was estimated with relapse or death treated as competing risk. Univariate and propensity score matching (PSM) analyses were conducted to assess risk factors with age and the number of prior treatments as covariates. After a median follow-up of 25 months, the cumulative incidence of t-MN was 4.5% at 2 years. T-MN occurred predominantly as t-MDS (62%) and t-AML (38%) with high cytogenetic risk. Median overall survival after t-MN diagnosis was 4.5 months. In univariate analysis, older age (p < 0.01), higher MCV (p < 0.01), and higher ICANS grade (p = 0.04) were associated with increased risk of t-MN. After PSM, MCV and ICANS grade remained significant risk factors. CAR T cell products with CD28 co-stimulatory domains trended towards higher t-MN risk (p = 0.09). NGS analysis showed that 85.7% of t-MN had pre-existing mutations, most commonly TP53. This study highlights t-MN as a severe late complication of CAR T cell therapy. MCV and ICANS grade were identified as key risk factors.

Introduction Introduction. CART-cell therapy targeting CD19 and B-cell maturation antigen (BCMA) has improved the prognosis of patients (pts) with relapsed/refractory (R/R) non-hodgkin lymphoma (NHL) and multiple myeloma (MM). Upon sustained remission, infections are major causes of morbidity and mortality, some of which are vaccine-preventable. Still, there are limited evidence on vaccine immunogenicity and seroprotection after CAR T-cell therapy. This explains that the vaccination schedule after CAR T-cell is translated from guidelines used in recipients of hematopoietic stem cell transplantation. This study aims to assess humoral vaccine-induced response after vaccination in comparison with baseline in pts with R/R NHL and MM treated with anti-CD19 or anti-BCMA CAR T-cells. Patients and Methods. Pts eligible for the study had a progression-free survival of 6 months or more after CAR T-cells. Pts who had received infusion of immunoglobulins within the past 2 months were excluded. Samples were collected at the time of lymphodepletion and at least six months after CAR T-cell infusion. The seroprotection rate was defined using pre-established cutoffs (or 4 fold increases after vaccination) of IgG-specific antibodies. Post-vaccination titers were obtained at least one month after the final dose was administered. Results From 509 pts treated by CAR T-cell therapy targeting CD19 and BCMA between 2017 and 2024 in a tertiary department of hematology, we retrospectively included 92 pts who were evaluated for seroprotection levels against diphtheria (D), tetanus (T), Haemophilus influenzae (Hib), hepatitis A (HA) and B viruses (HB), the varicella-zoster virus (VZV), and the measles virus (Mv). Median age was 66 (IQR 58-72) and 64 (54-71) year old for MM and NHL pts, respectively. In MM pts, the median number of previous lines was 3 [IQR 3-5], among whom 76% (n=19/25) had received an autologous stem cell transplantation (ASCT). In NHL pts the median number of previous lines was 2 [IQR 1-3], among whom 21% (n=15/68) had received an ASCT. Forty-five pts received a three-dose revaccination schedule with the pediatric combined D, T, acellular Pertussis (aP), HB, inactivated poliovirus (IPV), Hib conjugate vaccine (DTaP-HB-IPV-Hib) and with the pneumococcal (Pc) conjugate vaccine containing 13-valent. Upon lymphodepletion preceding CAR T-cell infusion, MM pts (n = 24) had significantly lower sero-protection rates compared to NHL pts (n=68) against D: 4/23 (17%) vs. 30/60 (50%), T: 8/24 (33%) vs. 57/62 (92%), Hib: 2/24 (8%) vs. 29/61 (48%), VZV: 7/24 (29%) vs. 57/62 (92%), and Mv: 12/24 (50%) vs. 58/62 (94%). There was a trend toward lower HB sero-protection titers in MM pts [4/24 (17%)] compared to NHL pts [23/62 (37%)] (p=0.12). Similar immunization rates were found for HA (52% for both groups). At least 6 months after CAR T-cell infusion, the seroprotection rates of pts against D, T, Hib,VZV and Mv remained similar. In vaccinated pts, the median time from CAR-T cell infusion to first vaccine administration was 7 months (IQR, 6-11). Among pts who were not protected prior to vaccination, the response rates were as follows: 82% for D (14/17), 100% for T (4/4), 26% for Hib (6/23), 52% for HB (14/27), and 12% for pneumococcus (Pc) (3/26). The geometric mean titers (GMTs) increased significantly after revaccination against D (0.08 to 0.49; p =0.001), T (0.35 to 0.61; p =0.015), Pc (8.93 to 14.35; p =0.057), and HB (5.54 to 16.12; p =0.035), but not for Hib (0.30 to 0.81; p =0.104). Among immune factors, we found that pts with detectable circulating B lymphocytes CD20+ (cut off > 64 cells/mL) exhibited significantly higher antibody titers following the D and HB vaccines compared to pts with undetectable B cells (p <0.01 and p<0.01, respectively). Conclusion Pts treated with CAR T-cells retain immunity of prior vaccines. We observed lower sero-protection in MM pts treated by BCMA CAR T-cell compared to NHL pts treated with anti CD19 CAR T-cells, due to prior treatments targeting long-lived plasma cells. Immunization against D, T, Hib, and HB is effective in CAR-T cell recipients at least six months after infusion suggesting that memory B cells can be remobilized. These findings highlight the clinical relevance of implementing early and targeted revaccination strategies to restore protective immunity and prevent severe infections in CAR T-cell recipients.

PURPOSE:Several chronic lymphocytic leukemia (CLL) studies have demonstrated promising efficacy with the combination of BCL2 and Bruton tyrosine kinase inhibitors; however, patients with CLL with del(17p) and/or TP53 mutation (TP53mut) comprised a small percentage of study populations or were excluded entirely. The purpose of the SEQUOIA Arm D cohort was to evaluate the combination of zanubrutinib + venetoclax in treatment-naïve (TN) patients with CLL/small lymphocytic lymphoma (SLL), in a large population of patients with TP53-aberrant disease. PATIENTS AND METHODS:Arm D is a nonrandomized cohort of patients aged 65 years and older (or 18-64 years with comorbidities). Patients received zanubrutinib from cycle 1 and venetoclax from cycle 4 (ramp-up) to cycle 28, followed by continuous zanubrutinib monotherapy until progressive disease (PD), unacceptable toxicity, or meeting undetectable minimal residual disease (uMRD)-guided stopping criteria. RESULTS:Between November 2019 and July 2022, 114 patients were enrolled: 66 (58%) with TP53-aberrant disease, 47 (41%) without TP53-aberrant disease, and 1 with missing TP53 results. At a median follow-up of 31.2 months, 85 patients (75%) remained on zanubrutinib monotherapy; 29 patients (25%) discontinued zanubrutinib because of adverse event, uMRD-guided stopping criteria, PD, or other. In the intention-to-treat population, 59% of patients achieved peripheral blood uMRD. The 24-month progression-free survival estimate was 92% (95% CI, 85% to 96%). The most common any-grade treatment-emergent AEs (TEAEs) were COVID-19 (54%), diarrhea (41%), contusion (32%), and nausea (30%). The most common grade ≥3 TEAEs were neutropenia (17%), hypertension (10%), diarrhea (6%), and decreased neutrophil count (6%). CONCLUSION:Zanubrutinib + venetoclax demonstrated impressive efficacy and a favorable safety profile in patients with TN CLL/SLL, regardless of the presence of TP53-aberrant disease.

12127 Background: Multidisciplinary follow-up is crucial to manage drug-related problems (DRP) associated with oral anticancer therapies (OAT). However, these approaches might fail to address social vulnerability determinants, such as a low level of health literacy (HL), which can be a barrier to patient education and contributes to inappropriate self-management of medications. This study aims to assess the impact of HL on relative dose intensity (RDI) of OAT and health-related quality of life (HRQoL) in cancer patients followed by Oncoral, a multidisciplinary program consisting in personalized face-to-face consultations with a pharmacist and nurse after each subsequent oncologist consultation, to prevent and correct DRPs. Methods: This prospective cohort study enrolled adult cancer patients who initiated OAT (baseline) from 11/03/2019 to 24/08/2022 and were followed by Oncoral for ≥6 months. HL was assessed at baseline using the HLS-EU16 questionnaire. The primary endpoint was RDI at 6 months, defined as the ratio between the prescribed dose of OAT and the optimal dose to be administered according to Summary of Product Characteristics. A RDI ≥80% was considered satisfactory, based on the literature. The secondary endpoint was the variation in HRQoL from baseline to 6 months of OAT, measured by the EORTC QLQ C30 questionnaire. Results: This study included 182 patients (58.2% male, median [range] age 69 [29-101] years), mostly with hematological malignancies (60.4%, including multiple myeloma 29.7% and chronic lymphocytic leukemia 11.0%) and breast cancer (12.1%). At baseline, the majority (71.8%) lived with a partner, 20.0% had children living at home. Most were retired (67.1%) but 18.2% worked full-time. Household incomes were inferior to French minimum wage for 20.6% of patients, and 20.6% only received elementary education. Mean HL score was 12.1 ± 3.12, 52.7% of patients having a HL score considered sufficient (13-16), 32.4% problematic (9-12) and 14.8% insufficient (0-8). RDI at 6 months was evaluable for 135 patients (74.2%), 68.9% of which maintained a RDI ≥ 80%. Mean RDI was 83.9 ± 20.4%. HL had no influence on 6-month RDI. Variation of HRQoL was evaluable for 114 patients (62.6%). Patients with inadequate HL showed lower emotional (p = 0.02) and cognitive scores (p = 0.03) at baseline. A significant improvement was shown at 6 months for global health status (+9.83 out of 100, p = 0.001), emotional functioning (+10.73, p < 0.001), insomnia (-14.03, p < 0.001), pain (-11.76, p = 0.02) and fatigue (-11.76, p = 0.005), with no difference in other scales. Conclusions: Cancer patients followed by Oncoral globally maintain a 6-month RDI ≥ 80% regardless of HL, with a HRQoL maintained or improving in all dimensions, suggesting that this personalized follow-up benefits to all patients and may limit the impact of social vulnerability.

7009 Background: Zanu monotherapy demonstrated superior progression-free survival (PFS) compared with bendamustine + rituximab in patients (pts) without del(17p) at 26.2-month follow-up and sustained PFS benefit at 5-year follow-up. In a single-arm cohort, zanu monotherapy was also shown to be effective in pts with del(17p). Several CLL studies have demonstrated promising efficacy with the combination of B-cell lymphoma 2 + Bruton tyrosine kinase inhibitors; however, pts with del(17p)/ TP53 mutation comprised a small percentage of or were excluded from study populations. Here, we present results in SEQUOIA (NCT03336333) arm D with zanu + ven in pts with or without del(17p) and/or TP53 mutation. Methods: Arm D is a nonrandomized cohort of the SEQUOIA study in pts aged ≥65 years (or 18-64 years with comorbidities). Pts received zanu (160 mg twice daily) + ven (ramp-up to 400 mg once daily) from cycle 4 to cycle 28, followed by continuous zanu monotherapy until progressive disease (PD), unacceptable toxicity, or meeting undetectable minimal residual disease (uMRD)–guided early zanu or ven stopping rules (CR/CRi and uMRD [<1×10 −4 by flow cytometry] in peripheral blood [PB] and bone marrow on 2 consecutive tests ≥12 weeks apart). Efficacy responses were assessed by investigator every 3 cycles until cycle 28, then every 6 cycles with PB MRD assessment. Results: Between Nov 2019 and Jul 2022, 114 pts were enrolled: 66 (58%) with del(17p) and/or TP53 mutation, 47 (41%) without del(17p) and TP53 mutation , and 1 with missing TP53 results. In all pts, median age was 67 years (range, 26-87), 64 (56%) were male, 86 (75%) had unmutated IGHV, and 47 (41%) had complex karyotype (≥3 abnormalities). As of Sept 16, 2024, 85 (75%) remained on treatment. The most common reasons for early discontinuation were reaching the uMRD-guided early stopping rules (zanu: 7%; ven: 7%), adverse events (AEs) (zanu: 8%; ven: 6%), and PD (zanu: 5%; ven: 4%). Six pts died (5 due to non–treatment-related AEs; 1 due to PD). Pts with or without del(17p)/ TP53 mutation achieved similar efficacy responses and best PB uMRD (Table). The most common any-grade treatment-emergent AEs (TEAEs) were COVID-19 (54%), diarrhea (41%), contusion (32%), and nausea (30%). The most common grade ≥3 TEAEs were neutropenia (17%), hypertension (10%), diarrhea (6%), and neutrophil count decreased (6%). Conclusions: SEQUOIA arm D data demonstrate promising efficacy and tolerability of zanu + ven combination treatment in TN CLL/SLL, regardless of del(17p) and/or TP53 mutation status. The safety profile of zanu + ven was consistent with results of prior zanu studies, and no new safety signals were identified. Clinical trial information: NCT03336333 . del(17p)− and TP53 wtn=47 del(17p)+ or TP53 mutn=66 TotalN=114 Median follow-up, mo 30 39 31 24-month PFS rate, % 89 94 92 ORR, n/N (%) 45/46 (98) 65/65 (100) 111/112 (99) CR/CRi, n/N (%) 23/46 (50) 31/65 (48) 55/112 (49) Best PB uMRD, % 60 59 59

In previously untreated, medically fit, patients with chronic lymphocytic leukemia, research is focused on developing fixed-duration strategies to improve long-term outcomes whilst sparing patients from serious toxicities. The ICLL-07 trial evaluated a fixed-duration (15-month) immunochemotherapy approach with a 9 months obinutuzumab-ibrutinib (O+I) induction. Patients (n=10) in complete remission (CR) with low bone marrow (BM) measurable residual disease (MRD <0.01%) continued ibrutinib alone at 420 mg/day for 6 additional months (I arm). All other patients (n=115) received up to 4 cycles of fludarabine-cyclophosphamide-obinutuzumab consolidation together with ibrutinib (I-FCG arm). Primary analysis at month 16 showed that 62.2% (84/135) of all patients enrolled achieved CR with BM MRD <0.01% (Michallet AS, Lancet hematol 2019 ; Blood 2021). Peripheral blood (PB) MRD (low-level [i.e. detectable but <0.01%] or undetectable at a threshold of 10-4), in evaluable patients, was still 92.5% (74/80) at month 40 and 80.6% (50/62) at month 64. No difference in PB MRD status was apparent according to the IGHVlmutational status (Michallet AS, Blood advances 2023). Here follow up with a median of 97 months (Inter quartile range [IQR] 93-102.5) is reported. Progression-free and overall survival rates are at 87 % and 93%, respectively. At last follow up, 92/128 (72%) patients are alive in CR, 8 in PR, 1 in stable disease. Fourteen (11%) patients are progressing, 4 of them receiving treatment (rituximab venetoclax, n=3, or ibrutinib + venetoclax, n=1). Twelve patients died, including 2 from cardiac toxicity during treatment with O+I attributable to I (M6 and M7). The ten other deaths are distributed among 4 infections (3 bacterial pneumonias at M38, M55, M50 and 1 COVID 19 at M49), 1 histiocytic sarcoma (M47), 1 myelodysplasia (MDS; M56) and 1 acute myeloid leukemia (AML; M68). Three deaths were due to progression (n=1, M103) or transformation in Richter large B-cel lymphoma (n=1; M54) or Hodgkin lymphoma (n=1; M23). No second cancer developed in 88% of the patients (104/118). With a median time between treatment initiation and development of a second disease of 72 months (IQR 10.28-97.77), nine patients developed respectively prostate cancer (n=2), kidney cancer (n=1), Merkel cell carcinoma (n=1), choroidal melanoma (n=1), hepatocellular carcinoma (n=1), skin cancer (n=1), MDS (n=1) or AML (n=1). In long-term infectious follow-up, no serious infections (grade 3-4) were observed in 84% (99/118) of the patients, while 10 (8%) developed a grade 3 infection (2 SARS-CoV2, 1 viral gastroenteritis, 2 respiratory syncytial virus, 3 bacterial pneumonias, 1 bronchitis, 1 shingles). These long-term results show excellent survival rates (close to those of a healthy population in the same age range) in patients with first-line CLL regardless of IGHV mutation status, with no increased risk of infection or second cancer.

7009 Background: Zanu monotherapy demonstrated superior progression-free survival (PFS) compared with bendamustine + rituximab in patients (pts) without del(17p) at 26.2-month follow-up and sustained PFS benefit at 5-year follow-up. In a single-arm cohort, zanu monotherapy was also shown to be effective in pts with del(17p). Several CLL studies have demonstrated promising efficacy with the combination of B-cell lymphoma 2 + Bruton tyrosine kinase inhibitors; however, pts with del(17p)/ TP53 mutation comprised a small percentage of or were excluded from study populations. Here, we present results in SEQUOIA (NCT03336333) arm D with zanu + ven in pts with or without del(17p) and/or TP53 mutation. Methods: Arm D is a nonrandomized cohort of the SEQUOIA study in pts aged ≥65 years (or 18-64 years with comorbidities). Pts received zanu (160 mg twice daily) + ven (ramp-up to 400 mg once daily) from cycle 4 to cycle 28, followed by continuous zanu monotherapy until progressive disease (PD), unacceptable toxicity, or meeting undetectable minimal residual disease (uMRD)–guided early zanu or ven stopping rules (CR/CRi and uMRD [<1×10 −4 by flow cytometry] in peripheral blood [PB] and bone marrow on 2 consecutive tests ≥12 weeks apart). Efficacy responses were assessed by investigator every 3 cycles until cycle 28, then every 6 cycles with PB MRD assessment. Results: Between Nov 2019 and Jul 2022, 114 pts were enrolled: 66 (58%) with del(17p) and/or TP53 mutation, 47 (41%) without del(17p) and TP53 mutation , and 1 with missing TP53 results. In all pts, median age was 67 years (range, 26-87), 64 (56%) were male, 86 (75%) had unmutated IGHV, and 47 (41%) had complex karyotype (≥3 abnormalities). As of Sept 16, 2024, 85 (75%) remained on treatment. The most common reasons for early discontinuation were reaching the uMRD-guided early stopping rules (zanu: 7%; ven: 7%), adverse events (AEs) (zanu: 8%; ven: 6%), and PD (zanu: 5%; ven: 4%). Six pts died (5 due to non–treatment-related AEs; 1 due to PD). Pts with or without del(17p)/ TP53 mutation achieved similar efficacy responses and best PB uMRD (Table). The most common any-grade treatment-emergent AEs (TEAEs) were COVID-19 (54%), diarrhea (41%), contusion (32%), and nausea (30%). The most common grade ≥3 TEAEs were neutropenia (17%), hypertension (10%), diarrhea (6%), and neutrophil count decreased (6%). Conclusions: SEQUOIA arm D data demonstrate promising efficacy and tolerability of zanu + ven combination treatment in TN CLL/SLL, regardless of del(17p) and/or TP53 mutation status. The safety profile of zanu + ven was consistent with results of prior zanu studies, and no new safety signals were identified. Clinical trial information: NCT03336333 . del(17p)− and TP53 wtn=47 del(17p)+ or TP53 mutn=66 TotalN=114 Median follow-up, mo 30 39 31 24-month PFS rate, % 89 94 92 ORR, n/N (%) 45/46 (98) 65/65 (100) 111/112 (99) CR/CRi, n/N (%) 23/46 (50) 31/65 (48) 55/112 (49) Best PB uMRD, % 60 59 59

Background: Venetoclax + an anti-CD20 antibody has shown deep remissions and long-term immune recovery in patients (pts) with relapsed/refractory CLL (Kater et al. Hemasphere 2024). Immunological effects of this combination in 1L CLL are not fully characterized. The CRISTALLO Phase III trial compared the efficacy and safety of fixed duration (FD) VenO vs fludarabine-cyclophosphamide-rituximab/bendamustine-rituximab (FCR/BR) in fit pts with treatment (Tx)-naïve CLL (Sharman et al. ASH 2024). Immune dynamics during and after VenO Tx and correlation of immune recovery patterns with minimal residual disease (MRD) status were explored. Methods: Pts were randomized 1:1 to VenO or FCR/BR. The primary endpoint was undetectable MRD (uMRD; <10-4) rate at Month 15 in peripheral blood (PB). Key secondary endpoints included progression-free survival. Immune profiling was performed at baseline, during Tx, and every 3 months (mos) up to 48 mos post-Tx in pts stratified by MRD status at Month 15 (<10-4) in PB. A flow cytometry panel was developed to identify non-malignant B cells (CD3/CD24/CD56-CD19+ and excluding CD19+CD20dim/negCD5+CD23+CD79bdim/neg) vs CLL cells (CD19+CD20dim/negCD5+CD23+CD79bdim/neg) in PB. Serial measurements included lymphocyte subsets (CD4+/CD8+ T cells and NK cells), immunoglobulin (Ig) levels (IgG, IgA, IgM), and detailed B-cell compartment analysis. Results: Overall, 80 and 86 pts were randomized to VenO and FCR/BR, respectively; 81.3% (VenO) and 54.7% (FCR/BR) achieved uMRD at Month 15. Non-malignant B-cell and CLL cell profiling was performed for 80 pts at baseline and on-Tx in the VenO arm, and 84 pts at baseline in the FCR/BR arm. Lymphocyte subsets (n=72) and Ig profiles (n=77) were assessed pre- and post-VenO up to 48 mos follow-up (FU). At baseline, no significant differences in levels of CLL cells, non-malignant B cells, CD4+ T cells, CD8+ T cells, NK cells, and Igs were observed between Tx arms in both uMRD and MRD+ groups. Analysis of CD19+ cells (capturing CLL and non-malignant B cells) during VenO Tx showed a marked depletion at 12 mos FU. In the uMRD group, CLL cells remained suppressed up to 36 mos FU (median: 3.9 CLL cells/µL). In contrast, in the MRD+ group, CLL cells were not fully depleted at 12 mos FU (median: 28.9 CLL cells/µL) and rebounded rapidly, showing a 10-fold increase by 18 mos FU (median: 315.1 CLL cells/µL). Non-malignant B cells were relatively less depleted with Tx vs CLL cells (median: 66.9 and 51.8 cells/µL in the uMRD and MRD+ groups, respectively). Notably, the MRD+ group showed a faster recovery of non-malignant B cells over time, with median counts rising to 373.3 cells/µL at 24 mos FU vs 127.9 cells/µL in the uMRD group. However, recovery was partial and did not return to baseline in the uMRD group (1127.7 cells/µL). Similar to B-cell recovery kinetics, NK cells showed gradual immune reconstitution after transient depletion at 6 mos FU in the VenO arm. However, recovery of CD4+ and CD8+ T cell counts was delayed and did not return to baseline by 48 mos FU, irrespective of MRD status. Ig levels, including IgG, IgM, and IgA, showed a significant but transient decline after VenO Tx, with the lowest levels seen at 3 mos FU, followed by signs of recovery from 9 mos FU. IgM levels were 0.22 g/L at baseline (n=63), 0.14 g/L at 3 mos FU (n=13), 0.19 g/L at 12 mos FU (n=55), 0.315 g/L at 24 mos FU (n=48), and 0.335 g/L at 36 mos FU (n=28), mirroring non-malignant B-cell recovery patterns. Consistent with the facilitated non-malignant B-cell recovery in the MRD+ group, median IgG, IgA, and IgM levels were all numerically higher in the MRD+ vs the uMRD group across all time points. Additional assessment on the impact of Igs on grade ≥3 infection will be presented. At final data cutoff (19 Mar 2025; median FU: 41 mos), fewer pts had progressed/died with VenO vs FCR/BR (14 vs18; p=0.399). There were no new deaths since the primary analysis and no new safety signals were identified with VenO. Conclusions: CRISTALLO demonstrated that FD VenO causes differential effects on malignant and non-malignant B-cell populations, with sustained CLL cell depletion in pts achieving uMRD alongside B-cell recovery, delayed T-cell recovery and effective Ig reconstitution. Findings extend previous observations and confirm that immune reconstitution can occur while maintaining deep remissions. Furthermore, final analysis results continue to support the efficacy and safety of FD VenO.

ABSTRACT:Acalabrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia. We present results from ELEVATE-TN after a median follow-up of 74.5 months. Overall, 535 patients were randomized (acalabrutinib-obinutuzumab, n = 179; acalabrutinib, n = 179; chlorambucil-obinutuzumab, n = 177). Median age was 70 years, 63.0% had unmutated immunoglobulin heavy chain variable region gene (uIGHV), 13.6% had del(17p) and/or mutated TP53, and 17% had complex karyotype (CK; ≥3 chromosomal abnormalities). Median progression-free survival (PFS) was not reached (NR) for acalabrutinib-obinutuzumab and acalabrutinib vs 27.8 months for chlorambucil-obinutuzumab (both P < .0001); estimated 72-month overall PFS rates were 78.0%, 61.5%, and 17.2%, respectively. Acalabrutinib-obinutuzumab resulted in improved PFS vs acalabrutinib monotherapy (hazard ratio [HR], 0.58; P = .0229). Patients with uIGHV, del(17p) and/or mutated TP53, or CK had significantly improved PFS with acalabrutinib ± obinutuzumab vs chlorambucil-obinutuzumab (P < .0001, P ≤ .0009, and P < .0001 for both acalabrutinib-containing arms, respectively). Median overall survival (OS) was NR for all treatments, with significantly longer OS for acalabrutinib-obinutuzumab than chlorambucil-obinutuzumab (HR, 0.62; P = .0349). Estimated 72-month OS rates were 83.9%, 75.5%, and 74.7% for acalabrutinib-obinutuzumab, acalabrutinib, and chlorambucil-obinutuzumab, respectively. Adverse events (AEs) occurring after >4 years were mostly grade 1 to 2. Rates of AEs, serious AEs, and events of clinical interest were similar between acalabrutinib-containing arms and consistent with the known safety profiles of acalabrutinib and obinutuzumab. Efficacy and safety of acalabrutinib-containing arms were maintained, with longer PFS in both acalabrutinib arms than chlorambucil-obinutuzumab including in patients with high-risk features. This trial was registered at www.ClinicalTrials.gov as #NCT02475681.

Introduction: Zanubrutinib, a next-generation irreversible Bruton tyrosine kinase (BTK) inhibitor, was formulated with improved selectivity to BTK to reduce the off-target effects associated with earlier generation BTK inhibitors. In the global, randomized, open-label, phase 3 ALPINE trial (NCT03734016), zanubrutinib demonstrated superior efficacy and a better safety profile compared with ibrutinib as treatment for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). As low health-related quality of life (HRQoL) in patients with CLL/SLL is associated with the manifestation of disease and worsens with increased disease severity, the purpose of this post hoc analysis was to assess progression-free survival (PFS) in patients with low baseline health status scores who were subsequently treated with zanubrutinib or ibrutinib monotherapy in the ALPINE trial. Methods: Patients enrolled in ALPINE completed the EuroQoL EQ-5D-5L at baseline (before the first dose of study drug), at cycle 1, and then at every third cycle. The EQ-5D-5L is a generic evaluation of overall health status that incorporates a visual analog scale (EQ-VAS) for patients to rate their general health “today” on a scale from 0 (the worst health one can imagine) to 100 (the best health one can imagine). Low HRQoL was operationalized as scores below the median of the baseline EQ-VAS. The relative efficacy (investigator-assessed PFS) of zanubrutinib versus ibrutinib was examined using a log-rank test (and Kaplan-Meier plot) as well as a Cox proportional hazards (CPH) model. The CPH model included effects for treatment and baseline EQ-VAS score. Results: Of 630 patients, 315 (158 randomized to zanubrutinib; 157 randomized to ibrutinib) scored below the median of 77.50 on the baseline EQ-VAS. Patients with low HRQoL scores who were treated with zanubrutinib had a significantly longer median PFS than those treated with ibrutinib (66 occurrences of disease progression or death at a median of 48.95 months vs 85 occurrences at a median of 38.77 months; P=0.0053). The associated CPH model-derived hazard ratio (HR) for treatment was 0.617 (95% confidence interval [CI]: 0.445–0.855; P=0.0037). The baseline EQ-VAS score effect was not significant (HR=0.993 [95% CI: 0.982–1.005; P=0.2377]). Conclusions: In the ALPINE trial, when only patients with low HRQoL at baseline were included in the analysis, PFS was significantly longer among those who received zanubrutinib than among those who received ibrutinib. The magnitude of this effect (HR=0.62) was consistent with what was reported in prespecified interim analyses of the full intention-to-treat population at a median follow-up of 29.6 months (HR=0.65). This finding suggests that the efficacy of zanubrutinib is maintained in patients with relapsed/refractory CLL/SLL with greater disease severity and symptoms that impact their overall health state.

Background Carfilzomib (K), a next-generation proteasome inhibitor, has proven strong efficacy in Multiple Myeloma (MM), and has demonstrated clinical superiority to bortezomib in the ENDEAVOR study in relapsed/refractory (RR) setting. Moreover, its selective action directed against 20S proteasome leads to much lower peripheral neuropathy incidence, although caution must be accorded to cardio-vascular toxicity. However, K is not approved at diagnosis, making its use restricted to subsequent lines of therapy. In this single center retrospective study, we aimed to describe our utilization of K-based combinations in RRMM patients, to report efficacy and tolerability, and to provide guidance in routine practice. Methods Demographic, safety and efficacy data from RRMM patients having received K-based combinations, apart from clinical trials or bridging therapy to CAR T-cells therapy, in the 2018-2024 period were retrospectively collected. Response evaluation was based on the IMWG criteria. Univariate and multivariate analysis were performed to assess any predictive value of age, cytogenetics, number of previous lines of therapy, bortezomib and/or lenalidomide refractoriness, and cardiovascular medical history for progression-free survival (PFS) and overall survival (OS). Results Data from 78 patients were collected. Median age was 62 years (46 - 83). Fifty-seven percent were male. Median time between diagnosis of MM and initiation of K was 49.2 months (27.3 – 79.8). Cytogenetics were available in 73% of patients. Eight (13%) and 9 (15%) of all patients harboured t(4;14) and 17p deletion respectively. The median number of previous lines was 2 (range 1 - 9) and 74% had received more than 1 previous therapy. All patients had been exposed to IMiDs (lenalidomide, pomalidomide, thalidomide), 89% to proteasome inhibitors (bortezomib, carfilzomib, ixazomib), and 64% to anti-CD38 monoclonal antibodies (daratumumab, isatuximab). Cardiovascular medical history was documented in 44 (54%) of patients, mostly hypertension (36%). Coronary artery disease was infrequent (n = 6, 7.4%). Before initiation or K, 28 (36%) patients had cardiac evaluation before initiation of K with cardiac echography in 28 patients. K-based combinations were as followed: Kd in 62%, Daratumumab-Kd in 26 %, KRd in 3.7 %. Most patients (67 %) received K in a weekly schedule. In almost half of responding patients, K infusions were spaced to bi-monthly or monthly schedule, after at least 6 cycles of treatment. Overall response rate (ORR) (≥ PR) was 51%, comprising 26% VGPR; and 14% of patients had a stable disease. Median PFS was 6.7 (5.6 - 9.2) months, while median duration of response was 13.8 (0.25 - 48) months. Median overall survival (OS) was 16.6 (13 - 36.8) months. In PFS univariate and multivariate analysis, we did not identify predictive response factors. As for OS, we identified known prognostic factors such as 17p deletion (HR 2.97, p = 0.02), and bortezomib refractoriness (HR 2.94, p = 0.02). In our cohort, toxicity profile was favourable, with only 19 (23.5%) patients having presented cardiovascular adverse event (CTCAE grade 1 to 4), mostly hypertension (n = 14, 17.3%). Heart failure and coronaropathy were both observed in only 2 (2.5%) patients. No thrombotic microangiopathy occurred. Finally, 9% (n=7) of drug discontinuation due to toxicity was reported, due to asthenia or digestive discomfort but not cardiovascular events. Conclusion This real-life retrospective study showed favourable benefit/toxicity profile of K-based combinations in RRMM patients with a PFS of 16.6 months and an ORR of 51%. Initial weekly dosing of K followed by spacing out infusions in responding patients led to better tolerance. Currently, K-based combinations also represent interesting options as bridging therapy to CAR T-cells therapies.

Abstract Introduction Fixed-duration treatment (tx) is emerging as a key therapeutic strategy for tx-naive (TN) CLL. However, high risk patients (pts) including those with del(17p)/TP53 mutations (mut) and/or unmutated IGHV (uIGHV) genes often experience earlier disease progression and poorer outcomes. The optimal tx duration for these high-risk subgroups remains unclear. Arm D of the SEQUOIA study (NCT03336333) evaluated zanubrutinib (zanu) + venetoclax (ven) in TN CLL/SLL, in pts with del(17p) and/or TP53mut and without (w/o) both. At a median follow-up (FU) of 31 months (mo), the combination (combo) of zanu+ven in the total Arm D population demonstrated a 24-mo progression-free survival (PFS) rate of 92% and a manageable safety profile (Shadman et al. JCO 2025). Here, we report updated results at a median FU of 38.5mo. Methods: Arm D is a nonrandomized cohort enrolling pts aged ≥65yrs, or 18-64yrs with comorbidities. Pts received zanu (160 mg BID) + ven (ramp-up to 400 mg QD) from cycle 4-28, followed by zanu until progressive disease (PD), unacceptable toxicity, or meeting undetectable minimal residual disease (uMRD)–guided early zanu or ven stopping criteria (complete response/complete response with incomplete hematopoietic recovery and uMRD [<1×10−4 by flow cytometry] in peripheral blood (PB) and bone marrow on two consecutive tests ≥12 weeks apart). Efficacy was assessed every 3 cycles through cycle 28, and every 6 cycles thereafter, with PB-MRD at each timepoint. Results: Between Nov 2019-Jul 2022, 114 pts were enrolled: 66 (58%) with del(17p) and/or TP53mut, 47 (41%) w/o, and one with missing TP53 results. Median age was 67yrs (range, 26-87), 64 (56%) were male, 86 (75%) had uIGHV, and 47 (41%) and 26 (23%) had complex karyotype defined as ≥3 or ≥5 abnormalities, respectively. As of April 30, 2025, median FU was 38.5mo overall, 46.5mo in pts with del(17p) and/or TP53mut, and 36.9mo in pts w/o. In total, 13 pts (5 with del(17p) and/or TP53mut and 8 w/o) have completed zanu and/or ven treatment early per uMRD-guided stopping criteria; of these, eight remain progression-free with sustained uMRD, three (all with del(17p) and/or TP53mut) experienced PD, and two withdrew from the study. At data cutoff, 78 pts (68%) remained on zanu and all pts completed or discontinued ven. PFS was 87% at 36mo overall, 87% at both 36 and 42mo in pts with del(17p) and/or TP53mut, and 89% in those w/o at 36mo. PFS at 36mos was 87% in pts with uIGHV and 87.5% in those with mutated IGHV (mIGHV). The best PB-uMRD rate was 60% overall and 59% and 62% in pts with del(17p) and/or TP53mut and w/o, respectively. After 15 cycles (3 cycles zanu lead-in + 12 cycles of zanu+ven), uMRD rates were 15% and 40% in pts with del(17p) and/or TP53mut and w/o, respectively, and 23% and 33% in pts with uIGHV and mIGHV, respectively. After 27 cycles (3 cycles zanu lead-in + 24 cycles of zanu+ven), uMRD rates were 38% and 36% in pts with del(17p) and/or TP53mut and w/o, and 40% and 29% in those with uIGHV and mIGHV, respectively. A total of 42 pts (24 with del(17p) and/or TP53mut; 18 w/o) completed zanu+ven combo and had uMRD and continued zanu monotherapy. uMRD was maintained in 22/24 pts with del(17p) and/or TP53mut and in all 18 pts w/o at 18mo and 12mo post zanu+ven combo period, respectively. Of the 42 pts described above, 33 had uIGHV, eight had mIGHV and one had unknown IGHV. All eight pts with mIGHV sustained uMRD status at 12mo after zanu+ven combo period and 31/33 pts with uIGHV sustained uMRD status at 18mo after zanu+ven combo period. Overall, safety results were consistent with previous data. The most common Grade ≥3 adverse events (AEs) were neutropenia/neutrophil count decreased (24%), hypertension (9%), and diarrhea (6%). Key Grade ≥3 AEs of interest included infections (12%, no opportunistic infections), hemorrhage (3%), atrial fibrillation/flutter (2%) and other malignancies (5%). Tx-emergent AEs leading to death occurred in five pts (none were tx-related), with no new events reported at this FU. Conclusions: With extended FU of SEQUOIA Arm D, zanu+ven combo demonstrated robust efficacy and a manageable safety profile in TN CLL/SLL. Durable MRD responses were maintained across genomic subgroups, including those with high-risk features. These data support the potential benefit of this regimen in TN CLL/SLL regardless of del(17p), TP53 mutation, or IGHV status.

Richter transformation (RT) is an aggressive lymphoma occurring in patients with chronic lymphocytic leukaemia. Here we investigated the anti-CD3/anti-CD19 T-cell-engager blinatumomab after R-CHOP (i.e. rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with untreated RT of diffuse large B-cell lymphoma histology (NCT03931642). In this multicentre phase 2 study, patients without complete response (CR) after two cycles of R-CHOP were eligible to receive an 8-week blinatumomab induction via continuous vein infusion with stepwise dosing until 112 μg/day. The primary endpoint was the CR rate after blinatumomab induction and secondary endpoint included safety, response duration, progression-free and overall survival. Thirty-nine patients started the first cycle of R-CHOP, 25 of whom received blinatumomab. After blinatumomab induction, five (20%) patients achieved CR, four (16%) achieved partial response, and six (24%) were stable. Considering the entire strategy, the overall response rate in the full-analysis-set was 46% (n = 18), with CR in 14 (36%) patients. The most common treatment-emergent adverse events of all grades in the blinatumomab-safety-set included fever (36%), anaemia (24%), and lymphopaenia (24%). Cytokine release syndrome (grade 1/2) was observed in 16% and neurotoxicity in 20% of patients. Blinatumomab demonstrated encouraging anti-tumour activity (the trial met its primary endpoint) and acceptable toxicity in patients with RT.