Kaitlyn C. Dykes

Brexucabtagene-autoleucel (brexu-cel) produces high rates of measurable residual disease-negative (MRD-) complete response (CR) in adults with Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL); however, subsequent relapses remain frequent. It is unclear whether maintenance with tyrosine kinase inhibitors (TKIs) can enhance remission durability. We evaluated outcomes among adults with relapsed/refractory Ph+ ALL who received commercial brexu-cel and achieved MRD- CR across 19 U.S. institutions. Considering TKI maintenance as a time-varying covariate, we analyzed outcomes based on receipt of subsequent TKI maintenance versus no maintenance. Patients receiving consolidative transplantation or non-TKI maintenance were excluded. Fifty-one patients were included: 20 received TKI maintenance and 31 received no maintenance. The use of TKI maintenance was associated with a significantly lower 1-year cumulative incidence of relapse (HR 0.12; 95% CI, 0.02-0.88; p=0.037) which translated into improved progression-free survival (PFS, HR 0.19; 95% CI, 0.04-0.85; p=0.029) and a trend towards improved overall survival (OS, HR 0.34; 95% CI, 0.07-1.62; p=0.18). There was no difference in non-relapse mortality (NRM, HR 0.83; 95% CI, 0.12-5.87; p=0.85). This real-world analysis supports the administration of TKI maintenance in Ph+ ALL following achievement of MRD- CR with brexu-cel as a strategy to improve PFS following chimeric antigen receptor T cell therapy.

The use of chimeric antigen receptor (CAR) T cell therapy is increasing in adult B-cell acute lymphoblastic leukemia (B-ALL), with three commercially available CD19 CAR T cell products. Several key clinical questions related to best practices for CAR T cell administration in this population exist, and limited prospective randomized trials have been conducted to fill these knowledge gaps. Thus, to help guide clinical practice, we conducted a modified Delphi study to develop and validate consensus recommendations on the administration of commercially available CAR T cell therapy for adults with B-ALL. Consensus panelists (n= 9) included Principal Investigators (PIs) from Real World Outcomes Collaborative of CAR T Cell Therapy in Adult ALL (ROCCA) consortium sites and were selected based on expertise and CAR T center volume. Final panel consensus recommendations were distributed for rating by the remaining PIs from ROCCA consortium sites, which served as the validation group (n=27). Consensus topics included patient selection, bridging and pre-CAR T leukemia staging, lymphodepletion and CAR T treatment setting, specific toxicity prevention and management, post-CAR T response assessment and disease monitoring, and the role of consolidation and/or maintenance therapies following CAR T cell therapy. Initially, 58 recommendation statements were evaluated for consensus. After two panel meetings, a total of 34 statements achieved consensus rating among the expert panel. After rating by the validation group, all but one recommendation statement continued to meet consensus, for a total of 33 consensus recommendation statements on the administration of CAR T cell therapy in adult B-ALL.

In a real-world analysis of brexucabtagene autoleucel recipients with relapsed/refractory B-cell acute lymphoblastic leukemia (N = 278), lack of response to prior blinatumomab correlates with significantly worse following chimeric antigen receptor T-cell therapy outcomes.

Chimeric antigen receptor (CAR) T-cell (CAR-T) treatment for B-cell acute lymphoblastic leukemia (ALL) induces high initial response rates, but most patients relapse. Low disease burden (often defined as <5% blasts in the bone marrow) is associated with better outcomes. CAR HEMATOTOX (HT) is a score using prelymphodepletion hematologic and inflammatory parameters to predict outcomes in lymphoma. Here, we assess its prognostic utility in a large multicenter adult B-cell ALL cohort. Patients who received brexucabtagene autoleucel across 33 centers in North America were included as part of the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium. An independent cohort of 61 patients with ALL treated with an investigational CD19 CAR-T therapy at 1 center was also described. Among 199 ROCCA consortium patients, 43 (22%) patients with HTlow scores had lower rates of delayed neutrophil recovery than those with HThigh scores (26% vs 52%, P = .002) and fewer severe infections (2.5% vs 18.8%, P = .011). They also had higher response rates, overall survival (OS), and event-free survival (EFS), as well as lower nonrelapse mortality and cumulative incidence of relapse. The survival differences remained significant after multivariable adjustment for disease burden and other covariates. In the investigational cohort of 61 patients, patients with HTlow scores had improved OS and EFS, as well as higher peak CAR-T expansion. In summary, CAR HT score is a prognostic factor independent of disease burden in adult ALL. HTlow score is associated with superior outcomes after CD19 CAR-Ts and higher CAR-T expansion in a single-center cohort. These trials were registered at www.clinicaltrials.gov as #NCT01044069 and #NCT01860937.

We conducted a prospective randomized clinical trial to investigate the combination of posttransplant cyclophosphamide (PTCy) and abatacept (Aba) for graft-versus-host disease (GVHD) prophylaxis. Patients with hematologic malignancies undergoing an allogeneic transplant from an 8/8 matched related or unrelated donor were randomized 1:1 to tacrolimus and methotrexate (standard-of-care arm [SOC]) or PTCy on days +3 and +4, followed by Aba on an extended schedule: days +5, +14, and +28, and every 4 weeks up to day +168 (PTCy+Aba). All patients received peripherally collected stem cells. The primary end point was moderate and severe chronic GVHD at 1 year. Following US Food and Drug Administration approval of Aba for GVHD prophylaxis leading to change in institutional SOC, the trial was amended to enroll only on the PTCy+Aba arm. A total of 25 patients enrolled on PTCy+Aba, and 15 on SOC. The trial met its primary end point: Kaplan-Meier estimates of moderate and severe chronic GVHD were 0% on the PTCy+Aba and 65.8% on the SOC arm (P < .0001). GVHD-free, relapse-free survival (GRFS) was 62.5% on PTCy+Aba and 24.1% on SOC (P = .010). There were no treatment-related deaths on PTCy+Aba and 2 on SOC. Overall survival (PTCy+Aba, 92%; SOC, 80%; P = .28), disease-free survival (PCTy+Aba, 68%; SOC, 92.9%; P = .105), and infection rates at 1 year were similar. Grade 3/4 acute GVHD rate was 4.2% on PTCy+Aba and 21.4% on SOC (P = .092). PTCy+Aba preserved regulatory T-cell proliferation and increased CD16+CD56dim cytotoxic natural killer cells. In conclusion, PTCy+Aba is well tolerated and associated with reduced chronic GVHD and improved GRFS. This trial was registered at www.ClinicalTrials.gov as #NCT03680092.

Patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) with central nervous system (CNS) involvement (CNS B-ALL) have poor outcomes and were frequently excluded from CD19-targeting chimeric antigen receptor (CAR) T-cell clinical trials. The efficacy and safety of brexucabtagene autoleucel (brexu-cel) in adults with R/R B-ALL was established by the ZUMA-3 trial, which excluded patients with advanced or symptomatic CNS involvement. In this retrospective multicenter analysis, we investigated the safety and efficacy of brexu-cel in patients with CNS B-ALL using data from the ROCCA (Real-World Outcomes Collaborative for CAR T in ALL) consortium. Of 189 patients who received infusion, 31 had CNS-2 (presence of blasts in cerebrospinal fluid with 5 WBCs per μL and/or clinical signs/symptoms) disease before apheresis and are the focus of this report. The median age was 46.5 years (range, 24-76), and 58.1% were male. Most (87.1%) received bridging therapy. After brexu-cel, 21 of 24 patients with CNS restaging (87.5%) achieved CNS-1. Additionally, 28 of 30 evaluable patients achieved marrow complete remission; 25 were measurable residual disease negative. No statistically significant differences were seen in progression-free survival or overall survival after brexu-cel among patients with or without CNS involvement. Similarly, grade 3/4 immune effector cell–associated neurotoxicity syndrome occurred similarly in patients with (35.5%) and without (30%) CNS disease. In conclusion, our data suggest that brexu-cel results in high response rates in patients with CNS B-ALL, with toxicity comparable with that in patients without CNS involvement.

Antibody-based immunotherapies are a class of therapeutics under active investigation in clinical trials for the treatment of acute myeloid leukemia (AML). Our review provides a comprehensive examination of trials published to date, focusing on recurrent challenges and promising aspects of antibody-based therapeutics. We described antibody-based immunotherapies for AML, specifically, an overview of the most prominent antigen targets in published clinical trials investigating monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor therapies. Manuscripts and abstracts describing clinical trials investigating antibody-based therapies for AML published through December 2024, identified by searching Google Scholar and PubMed were included. Antibody-based immunotherapies for AML have encountered limitations, including imperfect target antigens with significant associated toxicity such as myelosuppression, in addition to challenges specific to the AML patient population. The majority of trials have targeted CD33, CD123, CD371 (CLL1/Clec12), and CD47. For successful implementation of antibody-based therapeutics in AML treatment future directions require creative applications of antibody-based therapeutics specifically engineered to minimize limiting toxicities and tailoring of therapies for this unique patient population.

The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO exposed). InO-exposed patients were more heavily pretreated (P = .02) and frequently had active marrow disease before apheresis (P = .03). Response rate and toxicity profile after brexu-cel were comparable for InO-exposed and InO-naïve patients; however, consolidation therapy after brexu-cel response was used at a higher rate in InO-naïve patients (P = .005). With a median follow-up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS; P = .013) and overall survival (OS; P = .006) in univariate analyses; however, prior InO exposure did not influence PFS (hazard ratio, 1.20; 95% confidence interval, 0.71-2.03) in multivariate models. Within InO-exposed patients, InO responders had superior PFS (P = .002) and OS (P < .0001) relative to InO-refractory patients. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (P = .51) and OS (P = .86) for patients receiving InO as bridging therapy or before apheresis. In conclusion, although InO exposure was associated with inferior survival outcomes after brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively affects brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.