ZUMA-8 (NCT03624036) is the first prospective trial to evaluate the safety of brexucabtagene autoleucel (previously KTE-X19), a CD19-directed autologous CAR T-cell immunotherapy, in patients with R/R CLL. Patients with ≥2 prior lines of therapy (including a BTK inhibitor) underwent leukapheresis, followed by optional bridging therapy, then conditioning chemotherapy (fludarabine/cyclophosphamide) before infusing 1×106 (Cohort 1) or 2×106 (Cohort 2) anti-CD19 CAR T cells/kg. Patients in Cohort 3 (low tumor burden), and Cohort 4A (ibrutinib pre-treated closely to the apheresis) received 1×106 cells/kg. Fifteen patients, median age 63 years (52-79 years), were treated in Cohort 1 (n=6), Cohort 2 (n=3), Cohort 3 (n=3), and Cohort 4A (n=3). Median follow-up was 24.3 months. One DLT was observed in Cohort 3 (n=1 grade 4 cytokine release syndrome). Grade ≥3 neurologic events occurred in 3 patients (20%). Seven of 15 patients responded (ORR 47%, CR 7%), including all 3 patients in cohort 3 (1 with CR). CAR T-cell expansion occurred in 4 patients (27%), with an apparent weak inverse correlation with absolute lymphocyte count (ALC) prior to the apheresis. Brexu-cel did not have any new safety signals in R/R CLL, and CAR T-cell expansion and responses occurred in patients with low tumor burden.

Wiskott-Aldrich Syndrome (WAS) is a rare X-linked disorder, characterized by thrombocytopenia, eczema, recurrent infections, autoimmunity and malignancy. Here we discuss current conservative and definitive approaches to treating WAS, based on recently published evidence. Disease severity in WAS is highly variable. Recent studies confirm that the probability of disease progression depends on the type of genetic variant, supporting early diagnosis and tailored treatment strategies. Milder cases, historically termed X-linked thrombocytopenia (XLT), received supportive care, while severe cases were referred for standard allogeneic hematopoietic cell transplantation (HCT) or gene therapy (GT) in clinical trials. Advances in HCT and GT, together with recent knowledge that even "XLT" patients are at risk for severe immune complications, suggest that most young patients with WAS should be offered a potentially curative approach at diagnosis. Older patients with a small subset of milder variants may be treated conservatively unless they develop life-threatening autoimmune or malignant complications; regular monitoring and proactive management are critical to preventing irreversible complications. We recommend discontinuing the term XLT as it implies a mild and uncomplicated disease, which is not the norm, and instead tailor treatment for all WAS patients to their individual genetic profile, disease severity, and clinical course.

Idecabtagene vicleucel (ide-cel) was the first FDA approved CAR T cell therapy for multiple myeloma. However, as clinical trials are highly selective with stringent eligibility criteria, the objective of this study was to evaluate the safety and effectiveness of standard of care (SOC) ide-cel in the real world. Using the CIBMTR registry we evaluated 821 patients who received SOC ide-cel. Median follow-up was 11.6 months. Median age was 66 years, and the cohort included 31% patients ≥70 years, 15% Black, 7% Hispanic and 77% patients with at least one significant co-morbidity. The median number of prior lines of therapy was 7, 15% patients previously received BCMA-directed therapy, 17% had extramedullary disease and 27% had high-risk cytogenetics. Overall response rate was 73%, and complete response (CR) rate was 25%. Median progression-free survival was 8.8 months. Treatment-related mortality was reported in 6% of patients. Cytokine release syndrome was diagnosed in 80% of patients (grade >=3: 3%). Immune effector cell associated neurotoxicity syndrome was observed in 28% (grade >=3: 5%), with no cases of Parkinsonism reported. Clinically significant infections were seen in 45% of patients. Second primary malignancies were reported in 4%, including 1% myeloid malignancies. This is the largest real-world study of ide-cel CAR-T cell therapy in pts with RRMM. We observed a favorable safety and efficacy profile that mirrors trial experience, even in the setting of significant co-morbidities in 77% of patients, many of which would have made them ineligible for the registrational KarMMa clinical trial.

Acalabrutinib is a Bruton tyrosine kinase inhibitor approved for treatment of chronic lymphocytic leukemia. We present results from ELEVATE-TN (NCT02475681) after 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 IGHV (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 vs 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 1-2. 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 vs chlorambucil-obinutuzumab including in patients with high-risk features.

FCARH143, an autologous BCMA-targeted CAR-T therapy which incorporates a fully human BCMA-specific scFv and 4-1BB costimulatory domain, was evaluated in a phase 1 trial (NCT03338972) for relapsed/refractory multiple myeloma (RRMM). Patients were stratified by bone marrow (BM) plasma cell involvement (10-30% or >30%) and received lymphodepleting chemotherapy followed by escalating CAR-T cell doses (50×106 to 450×106). The primary endpoint was safety; secondary endpoints were overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Among 28 enrolled patients, all underwent leukapheresis and successful CAR-T manufacturing, though three (11%) did not proceed to infusion. The 25 treated patients (median age 64 years) had a median of eight prior therapies, 80% were triple-class refractory, and 44% had extramedullary disease (EMD). Cytokine release syndrome (CRS) occurred in 84% (8% grade 3-4, no grade 5), and neurotoxicity in 24% (12% grade 3, no grade 4-5). No treatment-related deaths occurred. At a median follow-up of 67.3 months, treated patients had an ORR of 100%, including a stringent complete response in 64%. Median PFS and overall survival (OS) were 15.5 and 32.1 months, respectively. In an intention-to-treat analysis (median follow-up 69.6 months), the ORR was 89.3%, and OS was 30.2 months. FCARH143 demonstrated potent anti-myeloma activity with a 100% response rate and manageable toxicity, independent of disease burden or cytogenetic risk. Further evaluation in high-risk RRMM is warranted.

Lineage switch (LS), defined as the immunophenotypic transformation of acute leukemia, has emerged as a mechanism of relapse following antigen-targeted immunotherapy which is associated with dismal outcomes. Through an international collaborative effort, we identified cases of LS following a host of antigen-targeted therapies (e.g., CD19, CD22, CD38 and CD7), described how LS was diagnosed, reviewed treatment approaches, and analyzed overall outcomes for this form of post-immunotherapy relapse. Collectively, 75 cases of LS were evaluated, including 53 (70.7%) cases of B-ALL to AML, 17 (22.7%) cases of B-ALL to mixed phenotypic acute leukemia (MPAL)/acute leukemias of ambiguous lineage (ALAL), and 5 (6.7%) cases of rare LS presentation (i.e., T-cell ALL to AML). An additional 10 cases with incomplete changes in immunophenotype, referred to as "lineage drift" were also described. With a primary focus on the 70 cases of LS from B-ALL to AML or MPAL/ALAL, LS emerged at a median of 1.5 months (range, 0-36.5 months) post-immunotherapy, with 81.4% presenting with LS within the first 6 months from the most proximal immunotherapy. While the majority involved KMT2A rearrangements (n=45, 64.3%), other rare cytogenetic and/or molecular alterations were uniquely observed. Treatment outcomes were generally poor with < 40% remission rates. The median overall survival following LS diagnosis was 4.8 months. Outcomes were similarly poor for those with rare immunophenotypes of LS or "lineage drift." This global initiative robustly categorizes lineage changes post-immunotherapy and, through enhanced understanding, establishes a foundation for improving outcomes of LS.

The therapeutic success of first line quadruplet (QUAD) induction therapy and autologous stem cell transplantation (ASCT) has reinvigorated an interest in fixed-duration therapy, yet optimal short-term efficacy endpoint for treatment cessation is unknown. Using data from a phase II clinical trial and a prospective institutional database, we tested the predictive performance of 5 short-term efficacy endpoints among 221 patients who received QUAD+ASCT followed by treatment cessation if minimal residual disease (MRD by next generation sequencing) negative for two consecutive timepoints. Efficacy endpoints tested were IMWG-defined stringent complete response (sCR), MRD<10-5 (single datapoint), MRD<10-6, sustained MRD (S-MRD, two consecutive assessments at least 1 year apart) <10-5and S-MRD<10-6. We built five parallel Cox regression models for each efficacy endpoint with progression free survival (PFS) as the outcome. Best fitting models were determined using Akaike's information criterion (AIC) and Heagerty & Zheng C-index. The best fitting model (AIC 417.2, C-stat 0.757) was based on S-MRD<10-5 (HR=0.23, 95% C.I. 0.11-0.47). Similar results were seen for predicting risk of progression/MRD resurgence among 121 patients undergoing MRD-guided treatment cessation. S-MRD<10-5 is the best predictor of PFS and yields best predictive models for risk of MRD resurgence or progression in the setting of fixed duration therapy. NCT03224507.

Inflammation is increasingly recognized as a critical factor in acute myeloid leukemia (AML) pathogenesis. We performed blood-based proteomic profiling of 251 inflammatory proteins in 543 newly diagnosed AML patients. Using a machine learning model, we derived an eight-protein prognostic score termed Leukemia Inflammatory Risk Score (LIRS). Individual proteins were evaluated in multivariable cox models and model performance was assessed by cumulative concordance index. Findings were validated in internal and external cohorts across two institutions. Blood-based LIRS significantly outperformed the European LeukemiaNet (ELN) 2022 risk model and was independently prognostic of overall survival after accounting for known clinical and molecular prognostic factors. OSMR was uniquely identified as the strongest independent predictor of survival, early mortality, and induction chemotherapy response, and further validated in an independent assay. These blood-based biomarkers could have significant clinical implications for risk stratification and prognostication in patients with newly diagnosed AML.