Sutimlimab is a monoclonal antibody against complement fraction C1s approved for the treatment of hemolytic anemia due to cold agglutinin disease (CAD). Here, we analyzed and report the largest international CAD cohort of sutimlimab-treated patients ever reported to highlight its safety and effectiveness in the real-world setting. We accrued a cohort of 57 CAD patients (median age 73.5 years, 56% females). At baseline, patients had severe to moderate anemia (median Hb 8.9 g/dL) and active hemolysis, with a substantial transfusion burden despite a median of 2 prior therapies, including corticosteroids and rituximab. After sutimlimab initiation, median Hb increased by 2 g/dL within 2 weeks and reached 12 g/dL in 4 weeks, remaining stable up to 24 months. This improvement was paralleled by an early and durable normalization of hemolytic markers. Objective responses were observed in most patients by week 2, with complete responses in approximately 50% by Week 4 and 55%-60% during long-term follow-up. Peripheral cold-induced symptoms did not improve and were associated with reduced response rates. Inadequate reticulocytosis also predicted poorer response and suggests the combination with recombinant erythropoietin. Sutimlimab was generally well tolerated. Infections were the most frequent adverse events (23%); severe infections predominantly occurred in previously rituximab-treated individuals. Hemolytic exacerbations occurred in 16% of cases, mostly due to infections. Thrombotic complications were rare. Overall, sutimlimab demonstrated rapid, durable effectiveness and a favorable safety profile in heavily pretreated real-world CAD patients.

Despite its great promise, implementation of CAR-T therapy-a personalized, logistically complex, and expensive treatment-remains challenging, hampering patient access across and within countries. Since 2018, six products have been centrally approved in Europe (i.e., the European Economic Area; EU-approved) for 15 hematologic malignancy indications. To better understand patient access to EU-approved commercial CAR-T therapy, we evaluated the current status in all 30 countries where EU-approval is valid plus the UK, addressing economic, clinical, and organizational aspects, and identifying challenges and strategies for improvement. A two-step approach was used, complementing data from marketing authorization holders (4/4 responded) with country-specific insights from clinical experts obtained via an online survey (30/31 responded). In August 2024, 26% of the 31 countries had no CAR-T products commercially available, 74% ≥ 1 product for non-Hodgkin lymphoma and leukemia, and 16% ≥ 1 product for multiple myeloma. One-time payment was the most used reimbursement method. Time to access varied significantly, with medians ranging from 0 (France/Germany) to 53 months (Slovakia). The median number of qualified CAR-T centers per 10 million population per country was 5.0 (IQR: 3.0-6.1). In most countries, patient eligibility assessment was decentralized. Costs and logistical complexity were main factors restricting access in countries with and without commercially available products. Proposed solutions included cost reductions, improving reimbursement processes, and increasing healthcare resources. This study shows that patient access to commercial CAR-T therapy in Europe remains limited. Its insights into this multi-faceted problem can guide policy-making, advocacy work, and research to make this transformative treatment accessible to more patients in need.

Zamtocabtagene autoleucel is an autologous, non-cryopreserved tandem CD20-CD19 directed CAR-T cell therapy produced on the fully automated CliniMACS® Prodigy System in 12 d and showed promising efficacy and safety in a Phase II trial in r/r DLBCL. We report primary analysis results of the pivotal DALY 2-EU trial (NCT04844866), which compares zamto-cel vs standard of care (SoC) as second-line (2L) therapy for r/r LBCL in non-transplant eligible (NTE) pts in a randomized, multicenter study.Adult NTE pts with r/r (≤ 24 m after start of first-line [1L] therapy) LBCL were assigned to receive zamto-cel or SoC (R-GemOx, n=78 or Pola-BR, n=8). Key inclusion criteria were LBCL, ECOG ≤ 2 or one NTE criterion. Pts in the zamto-cel arm started lymphodepletion (fludarabine + cyclophosphamide) during manufacturing, followed by infusion of zamto-cel, target dose 2.5 × 106 CAR-T cells/kg body weight. No chemoimmunotherapy bridging except steroids was allowed. The primary endpoint was event free survival (EFS) by blinded independent review committee comparing zamto-cel vs R-GemOx. Key secondary endpoints included remission rates, progression-free survival (PFS) and overall survival.In total, 168 pts were randomized (N=82 zamto-cel, N=86 SoC). Key baseline characteristics were balanced: 63% male pts, median age 74 y (range 19-87), 85% DLBCL, 57% refractory to 1L therapy, 57% IPI 3-5 pts and 66% stage III-IV. 76 pts (93%) received zamto-cel. Six pts did not receive zamto-cel (2 withdrawals, coronary artery stenosis, pneumonia, worsening condition, progressive disease). Median vein-to-vein time was 15 d (range 14-16). With a median follow-up of 17 m, median EFS was 6.2 m (95% CI 3.8-13.8) for zamto-cel and 2.5 m (95% CI 2.0-3.3) for R-GemOx (HR 0.39; 95% CI 0.27-0.58; p<0.0001) in the ITT population. Median PFS was significantly longer with zamto-cel vs R-GemOx (8.5 m [95% CI 3.8-16.8] vs 3.3 m [95% CI 2.0-3.8]; HR 0.43 [95% CI 0.28-0.65]; p<0.0001). ORR was 72% (61-81%) with a CR rate of 54% for zamto-cel vs 45% (34-57%) ORR and 14% CR rate for R-GemOx. Among all patients treated with zamto-cel in the experimental arm, ORR was 78%, with 58% achieving CR. In the zamto-cel arm, CRS Grade (G) ≥3 was reported in 4 pts (5.3%; 2 pts G3, 1 pt G4, 1 pt G5). Median time to onset of CRS was 2 d (1-14), median duration was 3 d (1-24). One pt (1.3%) had ICANS G3, no G4/5. For CRS, 29 (38%) pts received tocilizumab, 14 (18%) corticosteroids. Persisting neutropenia (≥ 28 d) of G4 was reported in 7 pts (9%). Within 90 d after start of treatment, 8 pts died in each arm; main reason was progression in 4 (50% zamto-cel) and 5 (63% R-GemOx) pts.Zamto-cel demonstrated significant and clinically meaningful superiority over R-GemOx in NTE pts. Zamto-cel was well tolerated in this vulnerable elderly population with low rates of severe CRS/ICANS. This favorable risk/benefit profile suggests the use of zamto-cel as preferred treatment option in 2L NTE pts with r/r LBCL.

Abstract Classic hairy cell leukemia (HCL) is a rare indolent B-cell lymphoproliferative disorder characterized by the driver mutation BRAF V600E. Standard treatment with purine analogs (eg, cladribine) induces long-term remissions, but up to 25% of patients relapse early. Even when targeting BRAF V600E, residual HCL cells frequently persist in the bone marrow (BM). To identify additional biological alterations contributing to HCL persistence, we performed single-cell RNA sequencing of sorted primary HCL cells from long-term vs short-term cladribine responders (ST-R; >10 vs ≤3 years of progression-free survival) at diagnosis and from ST-R at diagnosis vs relapse. We identified a distinct HCL subcluster characterized by increased DUSP1, FOS, and JUND expression that was detected in all patients and persisted or even expanded at relapse. Cancer pathway analysis suggested enhanced tumor microenvironment dependence, as reflected by suppression of the p38 mitogen-activated protein kinase pathway. In the absence of a suitable BRAF V600E-mutated HCL cell line, we validated HAIR-M cells (BRAF D594E) as a bona fide experimental HCL model. The activating BRAF D594E mutation mimics V600E-induced downstream signaling that can be effectively targeted by BRAF inhibitors (BRAFi). HAIR-M coculture with BM stromal cells (BMSC) strongly induced DUSP1 and was accompanied by protection from BRAFi-induced HAIR-M apoptosis. The functional importance of DUSP1 was corroborated by showing that BMSC-induced protection from cell death could be overcome by DUSP1 inhibition. Our results may set the stage for future clinical testing of DUSP1 inhibition to eliminate minimal residual disease and prevent relapse in HCL.

Introduction In the primary analysis of TRANSCEND FL (NCT04245839), an open-label, pivotal study, liso-cel showed high response rates and favorable safety in patients with R/R FL. Objectives To report 3-y follow-up (FU) results in patients with 3L+ FL, including efficacy, safety, and longitudinal safety analyses for key AEs. Methods Eligible patients had R/R FL after ≥ 2 prior lines of combination systemic therapy, including an anti-CD20 antibody and an alkylator. Patients received liso-cel after lymphodepleting chemotherapy (LDC). Bridging therapy was allowed with reconfirmation of PET-positive disease before LDC. The primary endpoint was ORR per independent review committee by PET/CT using Lugano 2014 criteria. Secondary endpoints included CR rate, duration of response, PFS, OS, and safety. Additional post hoc analyses included time to next treatment and efficacy by progression of disease ≤ 24 mo from first-line chemoimmunotherapy (POD24) status (yes vs no) and by prior bendamustine exposure before leukapheresis (yes vs no). Incidences of infections, second primary malignancies (SPM), hypogammaglobulinemia, and grade ≥ 3 cytopenia (overall and by lineage) were assessed over time from Days 1–30, at 3-mo intervals until Month 12, at 6-mo intervals until Month 36, and from Month 36 until end of study. Results At data cutoff (03/31/2025), 107 patients with 3L+ FL received liso-cel and were evaluable for safety; 103 were efficacy evaluable. Median (range) age was 62 y (23–80); 95 (89%) had Ann Arbor stage III/IV disease; 61 (57%) were high risk per FL International Prognostic Index. Fifty-nine patients (55%) had POD24; 69 (64%) were double refractory to anti-CD20 antibody and an alkylator; 65 (61%) had prior bendamustine exposure.Median (range) on-study FU was 41.5 mo (0.3–54.0). Response rates were high overall and regardless of POD24 status or prior bendamustine exposure (Table 1).Treatment-emergent (TE) AE rates were consistent with the primary and 2-y FU analyses. Grade 3 cytokine release syndrome was reported in 1% (no grade 4/5) and grade 3 neurological events in 2% (no grade 4/5). SPMs were reported in 11 patients (10%; 4 additional patients since the 2-y FU analysis; no secondary T-cell malignancies). Grade ≥ 3 infections were reported in 13 (12%) patients, including 7 (7%) in the TE period (≤ 90 d after infusion) and 8 (7%) in the post-TE period (3 more patients since the 2-y analysis). AE incidences over time are shown in Table 2. Conclusion In patients with 3L+ FL, a single infusion of liso-cel demonstrated remarkable efficacy, with durable responses and high 3-y survival rates, regardless of POD24 status or prior bendamustine exposure. No new safety signals were identified. Grade ≥ 3 neutropenia and hypogammaglobulinemia decreased over time and severe infections remained low, further underscoring the favorable long-term safety profile of liso-cel in patients with 3L+ FL.

In the TRANSCEND FL primary analysis, lisocabtagene maraleucel (liso-cel) showed high response rates and favorable safety in patients with relapsed/refractory (R/R) follicular lymphoma (FL). Longer follow-up is needed to assess remission durability and long-term or late-onset toxicities. Here, we report 3-year follow-up results (median [range] on-study follow-up, 41.5 months [0.3‒54.0]) in patients with third-line or later (3L+) FL. Patients had R/R FL after ≥2 prior lines of combination systemic therapy, including an anti-CD20 antibody and an alkylator. A total of 107 patients received liso-cel and 103 were efficacy evaluable, with overall and complete response rates (95% CI) per independent review committee of 97% (92‒99) and 94% (88‒98), respectively. Medians were not reached for all time-to-event outcomes; estimated 36-month (95% CI) rates for duration of response, progression-free survival, time free from next treatment, and overall survival were 70% (60‒78), 68% (58‒76), 75% (70‒80), and 86% (78‒92), respectively. Response rates and 36-month time-to-event rates were consistent in high-risk subgroups, including patients with disease progression within 24 months of starting first-line immunochemotherapy, bulky disease, or double-refractory status. Longitudinal safety analyses showed decreasing grade ≥3 cytopenias and hypogammaglobulinemia (immunoglobulin G <500 mg/dL), with use of supportive care (transfusions, growth factors, intravenous immunoglobulin) mostly limited to the 3 months after infusion, and consistently low incidences of grade ≥3 infections in short- and long-term periods. At 3-year follow-up, a single liso-cel infusion delivered durable efficacy and high survival, including in high-risk subgroups, alongside a favorable long-term safety profile in patients with 3L+ FL. Clinicaltrials.gov: NCT04245839.

Background: Cold agglutinin disease (CAD) and cold agglutinin syndrome (CAS) are cold antibody driven autoimmune hemolytic anemias, characterized by hemolysis via the classical complement pathway; CAS, unlike CAD, is typically linked to an underlying condition.CADENCE is the first global, prospective registry for patients with CAD or CAS, and collects data on over 400 patients to better characterize the long-term clinical and patient-reported outcomes. The CADENCE registry documents real-world treatment patterns and regimens, including a sutimlimab-treated cohort, in patients with CAD/CAS. Sutimlimab is a humanized monoclonal antibody that selectively inhibits the classical complement pathway by inactivating C1s; it is the first approved treatment for CAD. Aims: This analysis focuses on the sutimlimab cohort, with the aim of describing the long-term safety of sutimlimab in patients with CAD in a real-world setting. Methods: Between 12 December 2019 and 4 February 2025, 442 patients were enrolled in the registry; all patients were ≥18 years of age. Of these, 63 were treated with sutimlimab, including 58 diagnosed with CAD, 4 with CAS, and 1 patient for whom diagnosis information was not provided during the reporting period. Patient enrollment in the study is now complete. Results: Atotal of 63 patients were included in the sutimlimab cohort across the US (n=24), Germany (n=20), Japan (n=7), Italy (n=6), Austria (n=2), Spain (n=2), and France (n=2). The mean (SD) age of patients treated with sutimlimab was 72.7 (8.8) years at the time of enrollment and the percentage of female patients was 76.2%. At data cut-off, the mean (SD) and median (Q1; Q3) sutimlimab treatment duration was 25.1 (18.7) and 22.7 (10.4; 32.6) months, respectively. In the sutimlimab cohort, a total of 159 adverse events (AEs) were reported in 33 (52.4%) patients, including 156 AEs in 31 (53.4%) patients with CAD and 3 AEs in 2 (50%) patients with CAS. AEs considered related to sutimlimab by the investigator were reported in a total of 6 patients (9.5%), including 5 AEs in 5 (8.6%) patients with CAD and 1 AE in 1 (25.0%) patient with CAS. A total of 37 serious adverse events (SAEs) were reported in 11 (17.5%) patients; 36 SAEs were reported in 10 (17.2%) patients with CAD, and 1 SAE was reported in 1 (25.0%) patient with CAS. The SAE experienced by the patient with CAS (chest pain/stable angina) was a suspected unexpected SAE and considered related to sutimlimab. Furthermore, 1 death was reported in a patient with CAD (SAE of low right lung pneumonia) unrelated to sutimlimab. Adverse events of special interest (AESIs) were observed within the sutimlimab cohort in patients diagnosed with CAD, including 3 patients who experienced serious infections (sepsis, urinary tract infection, positive Gram-negative rods blood culture [klebsiella], cellulitis, and bilateral pneumonia), 2 patients who experienced arterial hypertension (reported as non-serious), and 3 patients with concomitant use of rituximab; none of of these AESIs were considered related to sutimlimab. Non-serious AESIs of acrocyanosis were reported in 8 patients; 2 were considered possibly related to sutimlimab. Other AESIs monitored during this reporting period were thromboembolic events, autoimmune disorders (including systemic lupus erythematosus), hypersensitivity reactions and anaphylaxis, and meningococcal infection, none of which were observed in this cohort of patients. Conclusion: After a mean treatment duration of over 2 years, no new safety concerns were identified in this updated analysis of CADENCE registry patients with CAD and CAS chronically treated with sutimlimab. Safety findings are consistent with earlier clinical trial data and continue to support the long-term safety profile of sutimlimab in patients with CAD. Final follow-up results are expected from the CADENCE registry in 2031 and will further inform the understanding of the long-term safety and efficacy of sutimlimab. CADENCE adds to the growing body of evidence supporting the role of sutimlimab in continued classical complement pathway inhibition in patients with CAD.

Supplementary Fig. S1. Preclinical evaluation and characterization of YTB323 and CTL*019 for Donor 2 and 3; Supplementary Fig. S2. Differential gene expression of CTL*019 cells versus YTB323 cells (preclinical); Supplementary Fig. S3. Preclinical validation of YTB323; Supplementary Fig. S4. Dose-dependent expansion (Cmax and AUC0-21d) of YTB323 and CTL*019 in NSG mice with NALM6; Supplementary Fig. S5. CD4:CD8 ratio comparison of leukapheresis and cell products of YTB323 and tisagenlecleucel; Supplementary Fig. S6. Stemness and memory differentiation gene signatures are retained or enriched for in YTB323 final product; Supplementary Fig. S7. Differential gene expression of tisagenlecleucel versus YTB323 final product; Supplementary Fig. S8. Naive/TSCM cells and a naive stem-like gene signature correlate with higher expansion and a better response; Supplementary Fig. S9. T-cell subset and checkpoint inhibitor analysis by flow cytometry on PBMCs collected post-YTB323 infusion; Supplementary Fig. S10. Pre-clinical T-cell gating strategies.

ABSTRACT:Tisagenlecleucel is a CD19-directed autologous chimeric antigen receptor (CAR) T-cell therapy. Quantitative polymerase chain reaction assays are highly sensitive in defining in vivo kinetics by measuring CAR transgene in peripheral blood. This study aimed to identify clinically meaningful CAR T-cell blood levels that correlated with response/relapse. In pediatric/young adult patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), maximum CAR T-cell blood levels were higher in patients with ongoing complete remission and in patients with CD19- relapse relative to those with CD19+ relapse. In adult patients with R/R diffuse large B-cell lymphoma (DLBCL), no apparent association between in vivo kinetics and response was noted, with a wide range of transgene levels at relapse. In B-ALL, patients with B-cell aplasia sustained >6 months had higher CAR T-cell expansion relative to those with early B-cell recovery (BCR) (<6 months after infusion); however, a definitive cutoff for BCR-associated expansion level could not be identified. In most patients with B-ALL, BCR >6 months maintained favorable responses. However, early BCR could not be confirmed as a potential indicator of relapse due to high censoring from transplant, following presumed risk of relapse. However, allografting in these patients may potentially mitigate the poor prognosis related to early BCR. In DLBCL, BCR was not associated with relapse. These findings suggest that blood CAR transgene levels may be associated with long-term responses; however, they lack robust predictive potential for relapses. As reported earlier, next-generation sequencing for minimal residual disease appears to be a reliable biomarker predictive of relapse for B-ALL.

Supplementary Table S1. Bridging chemotherapies by ATC class and preferred term (safety set); Supplementary Table S2. Lymphodepleting chemotherapies (safety set); Supplementary Table S3. Cytokine release syndrome following YTB323 infusion; Supplementary Table S4. Neurological adverse reactions following YTB323 infusion; Supplementary Table S5. Summary of cellular kinetic parameters in peripheral blood by flow cytometry for YTB323 at DL1 and DL2; Supplementary Table S6. Summary of cellular kinetic parameters in peripheral blood by flow cytometry and qPCR for YTB323 at DL1 and DL2.

ABSTRACT:Patient-reported outcomes (PROs) give direct insights into the treatment's impact on patient's life and complement clinical outcomes. However, since the advent of chimeric antigen receptor T-cell therapy (CAR-T), PROs have been underreported. Particularly, little is known about long-term health-related quality of life (HRQoL) and dimensions such as mental- and social well-being, working life, and financial burden. Therefore, we evaluated multidimensional PROs in a cross-sectional study among European patients who received CAR-T for hematologic malignancies. Patients completed validated questionnaires (EQ-5D-5L/EORTC-QLQ-C30/PCL-5/modified-iPCQ) and ad hoc items on treatment experiences, unmet care needs, and HRQoL. The survey was available online (January-October 2023) in 7 languages. Outcomes were compared with the European general population, a matched CAR-T-naive cohort with hematologic malignancies and across subgroups, using established thresholds for clinically important differences/problems and regression models. From 10 European countries, 389 patients participated (>1 year post-CAR-T: 56%). Mean EQ-VAS was 73.1 (standard deviation, 18.5). HRQoL was similar or better than reference cohorts, except for role-, social-, and cognitive-functioning. Physical-functioning problems were most frequently reported (41%), particularly by women, older individuals, and those who experienced neurotoxicity. The latter subgroup also reported more cognitive- and social-functioning problems. Anxiety regarding disease recurrence (76%), infections (66%) and long-term side effects (59%) was common. Among working-age patients, 72% could continue paid work after CAR-T. Younger patients (32%) reported more financial difficulties than older patients (9%). This study shows favorable general HRQoL after CAR-T compared with reference cohorts. However, a notable proportion of patients experienced problems in physical-, mental- and social well-being. We identified high-risk subgroups and care needs that should be addressed during follow-up.

Sutimlimab has demonstrated high efficacy in increasing hemoglobin levels and reducing markers of hemolysis in patients with cold agglutinin disease (CAD) in clinical trials. However, data on its real-world use are limited. We evaluated 54 patients treated with Sutimlimab through post-trial access or compassionate use programs in Austria, France, Germany, Italy, Japan, Spain, UK, and Australia. Past medical history, CAD treatments and laboratory parameters were collected at baseline and at weeks 2, 4, 8, 12, 16, and 24, and at months 12, 18, 24, after starting sutimlimab. Response was classified as partial (Hb >10 g/dL), complete (>12 g/dL), or no response. The median age was 66 years (range 45-88) and 31 (57%) patients were females. The direct antiglobulin test (DAT) was positive for C3 alone in 35 patients, for IgG and C3 in 8, and for IgM and C3 in 10. The median CA titer was 1:1,024 (range, 1:4 to >1:25,000). CAD bone marrow infiltrate was observed in 23 patients. Prior CAD treatments (median 3, 1-4) included corticosteroids (31), rituximab (40), and rituximab–bendamustine (12). Pre-Sutimlimab complications included 8 G≥ 3 infections and 12 thrombotic events. The median number of RBC transfusions in the 6 months pre-Sutimlimab was 2 (0–18). At baseline, median Hb was 8.4 g/dL (2.9–10.8), LDH 1.6× ULN (0.8–3.6), unconjugated bilirubin 1.9 mg/dL (0.8–7.49), and reticulocytes 107×10⁹/L (10–340). Sutimlimab was administered as monotherapy (n=42) or in combination with erythropoietin (8), corticosteroids (2), or both (2). The median follow-up was 28 months (6–81). Hb increased over time: +2.0 g/dL at 2 weeks, +2.7 g/dL at 4 weeks, and +3 g/dL at 8 weeks, followed by sustained levels up to 24 months. Overall response rates (PR + CR) were 78%, 75%, 84%, 85%, 86%, 80%, 77%, 84%, and 85% at the respective timepoints. An additional 14% of patients showed an Hb increase at week 2 and 18% at week 4. All but 7 patients became transfusion-independent. Sutimlimab was discontinued in 2 patients due to lack of response, in 1 due to overt Waldenström's macroglobulinemia, and in 7 based on their own decision with maintenance of good CAD control; 13 patients had an infection (G3 in 7, 1 H. influenzae pneumonia), 1 thrombosis (DVT of basilic vein), and 8 hemolytic exacerbations. At the last follow up only one patient had died due to progressive WM with sepsis. Sutimlimab confirmed to be an effective treatment in improving anemia and resolving transfusion dependence in more than 70% patients in the real world.

Introduction: Most adult patients (pts) with r/r B-ALL die due to disease complications, indicating a need for more effective therapies. Rapcabtagene autoleucel is an innovative autologous next-generation CD19-directed chimeric antigen receptor (CAR)-T cell therapy that is rapidly manufactured using the T-Charge™ platform. Here we present safety and efficacy data for rapcabtagene autoleucel in adults with r/r B-ALL in a phase 1, multicenter study (NCT03960840). Methods: Eligible pts were ≥18 y of age, had CD19-positive r/r B-ALL, morphologic disease in the bone marrow, ECOG 0-1, and ≥1 of the following: prior allogeneic hematopoietic stem-cell transplantation (alloHSCT), ≥2 prior therapeutic lines, primary refractory disease, relapse within 12 mo of first remission, or Philadelphia chromosome-positive B-ALL with failure/intolerance of ≥2 different tyrosine kinase inhibitors. Pts received single-infusion rapcabtagene autoleucel at targeted dose level (DL) DL1 (2.5×106 CAR+ cells), DL2 (5×106 CAR+ cells), DL3 (7.5×106 CAR+ cells), or DL4 (12.5×106 CAR+ cells). Primary endpoints characterized safety and dose-limiting toxicities (DLTs) to identify a recommended dose. Secondary endpoints assessed antitumor activity and included best overall response (BOR) of complete remission (CR)/CR with incomplete blood count recovery (CRi) by month 3, and duration of response (DOR). Results: As of February 20, 2025 (data cutoff), 41 adult pts with r/r B-ALL were enrolled and 35 (85%) received rapcabtagene autoleucel: 10 at DL1, 6 at DL2, 12 at DL3, 6 at DL4, and 1 assigned to DL3 who actually received 18.9×106 CAR+ cells. Median age was 41.0 y, 91% received ≥2 prior lines of therapy (range 1-10), and 66% had prior alloHSCT. Sixteen pts (46%) were previously treated with blinatumomab and 13 pts (37%) with inotuzumab. Median (range) time from most recent relapse/progression to infusion was 2.3 (1.0-7.6) mo. Pts were followed for a median 27.7 (18.9-49.5) mo post infusion. All pts experienced ≥1 adverse event (AE) of any grade (Gr), and 94% had a Gr ≥3 event. DLTs were experienced by 2/10 pts at DL1 (1 pt: Gr 5 cytokine release syndrome [CRS]; 1 pt: Gr 4 neurotoxicity, Gr 3 CRS, Gr 4 bone marrow failure), 1/6 pts at DL2 (Gr 4 CRS and Gr 4 ICANS), 1/12 pts at DL3 (Gr 4 neutropenia) and 0/6 pts at DL4. CRS occurred in 30 pts (86%). Gr ≥3 CRS was reported in 8 pts (23%): 3/10, 3/6, 2/12, and 0/6 pts at DL1, DL2, DL3 and DL4; 1 pt (3%) at DL1 experienced Gr 5 CRS. CRS management included tocilizumab (70%), siltuximab (10%), corticosteroids (40%), tocilizumab plus corticosteroids (37%), and anakinra (7%). Median time to CRS onset was 8 (2-15) d and time to resolution was 6 (4-8) d. Two pts experienced Gr 2 hemophagocytic lymphohistiocytosis (1 DL1, 1 DL4); both cases resolved. ICANS was reported in 9 pts (25.7%): 2, 3, 3, and 1 pts at DL1, DL2, DL3 and DL4. Gr 3/4 ICANS was reported in 5 pts (14%): 1, 1, 2, and 1 pts at DL1, DL2, DL3 and DL4. Median times to onset and resolution of ICANS were 13 (4-35) d and 5 (1-not estimable) d, respectively. Seven pts received supportive measures for ICANS, including dexamethasone (5 pts, 71%) and anakinra (3 pts, 43%). Gr 4 cytopenias were observed in all pts post baseline. All cytopenias occurring within 4 weeks of infusion had resolved by 6 mo, except for 1 case of lymphopenia at DL4. BOR of CR/CRi by 3 mo was achieved in 70% (40% CR; 30% CRi), 100% (50% CR; 50% CRi), 92% (50% CR; 42% CRi), and 83.3% (67% CR; 17% CRi) of pts at DL1, DL2, DL3 and DL4. Among pts with a measurable residual disease (MRD) status available by month 3, 6/9 (67%) at DL1, 3/3 (100%) at DL2, 8/9 (89%) at DL3, and 1/2 (50%) at DL4 achieved MRD-negativity. Median DOR was 5.3 mo for DL1 and 10.8 mo for DL2 and not reached for DL3 or DL4. Cellular expansion was higher at DL2 (geometric mean 139,000 copies/μg DNA), DL3 (55,300 copies/μg), and DL4 (68,300 copies/μg) compared with DL1 (20,900 copies/μg). Median time to last detectable CAR19 transgene concentration was 91, 226, 57, and 181 days for DL1, DL2, DL3, and DL4. Conclusions: Phase 1 results with long follow-up suggest rapcabtagene autoleucel is active with high cellular expansion, durable efficacy for DL2–DL4, and a manageable safety profile in adult pts with r/r B-ALL. DL3—at which 92% of pts achieved BOR of CR/CRi by 3 mo, with median DOR not reached after 22 mo median follow-up—exhibited an acceptable balance of safety, efficacy, and cellular expansion.

Fixed-duration venetoclax-rituximab (VenR) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) in the phase 3 MURANO trial (NCT02005471) resulted in superior progression-free survival (PFS) and overall survival (OS) vs bendamustine-rituximab (BR). We report the final analyses of MURANO (median 7 years follow-up). Patients were randomized to VenR (venetoclax 400 mg daily for 2 years plus monthly rituximab for 6 months; n = 194) or BR (6 months; n = 195). In a substudy, patients with progressive disease (PD) received VenR as retreatment or crossover from BR. At the final data cut (3 August 2022), median PFS with VenR was 54.7 vs 17.0 months with BR. Seven-year PFS with VenR was 23.0%. Seven-year OS was 69.6% and 51.0%, respectively. Among VenR-treated patients with undetectable (u) minimal residual disease (MRD) and no PD at end of treatment (EOT) (n = 83), median PFS from EOT was 52.5 vs 18.0 months in patients with MRD at EOT (n = 35; P < 0.0001). Fourteen patients had enduring uMRD. Three distinct mutations in BCL2 in four patients were identified. In the substudy, 25 patients were retreated with VenR and nine patients crossed over to VenR; median PFS was 23 and 27 months, and best overall response rate was 72% and 89%, respectively. At the end of combination treatment, following retreatment or crossover, eight and six patients achieved uMRD, respectively. No new safety findings were observed. Overall, these final MURANO analyses support consideration of fixed-duration VenR therapy for patients with relapsed/refractory CLL.

Supplementary Data containing the statistical analysis plan, Supplemental Figures 1-6 and Supplemental Tables 1 and 2

Constitutively active NOTCH2 signaling is a hallmark in chronic lymphocytic leukemia (CLL). The precise underlying defect remains obscure. Here we show that the mRNA sequence coding for the NOTCH2 negative regulatory region (NRR) is consistently deleted in CLL cells. The most common NOTCH2ΔNRR-DEL2 deletion is associated with two intronic single nucleotide variations (SNVs) which either create (CTTAT, G>A for rs2453058) or destroy (CTCGT, A>G for rs5025718) a putative splicing branch point sequence (BPS). Phylogenetic analysis demonstrates that rs2453058 is part of an ancient NOTCH2 gene variant (*1A01) which is associated with type 2 diabetes mellitus (T2DM) and is two times more frequent in Europeans than in East Asians, resembling the differences in CLL incidence. In contrast, rs5025718 belongs to a recent NOTCH2 variant (*1a4) that dominates the world outside Africa. Nanopore sequencing indicates that somatic reciprocal crossing over between rs2453058 (*1A01) and rs5025718 (*1a4) leads to recombined NOTCH2 alleles with altered BPS patterns in NOTCH2*1A01/*1a4 CLL cases. This would explain the loss of the NRR domain by aberrant pre-mRNA splicing and consequently the NOTCH2 gain-of-function phenotype. Together, our findings suggest that somatic recombination of inherited NOTCH2 variants might be relevant to CLL etiology and may at least partly explain its geographical clustering.