Ryan Daniel Cassaday

No chimeric antigen receptor therapy (CAR-T) is currently approved for WM. This study assessed safety and efficacy of CD20-targeted CAR-T in BTKi-refractory, heavily pre-treated WM patients. With a CR/VGPR rate of 80%, this treatment should be evaluated in larger trials. ClinicalTrials.gov number NCT03277729

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.

Relapse in the central nervous system (CNS) is a devastating outcome in acute lymphoblastic leukemia (ALL). Allogeneic hematopoietic cell transplantation (HCT) in ALL is reserved for patients with high-risk and/or relapsed/refractory disease. However, there is a paucity of data describing the incidence and factors associated with post-HCT CNS relapse in the modern era. In this multicenter retrospective study of adults with ALL who underwent first HCT between 2011 and 2021 at Stanford Health Care (SHC) or University of Washington/Fred Hutch Cancer Center (UW/FH), we aimed to describe the incidence of post-HCT CNS relapse, factors associated with post-HCT CNS relapse, and the impact of CNS relapse on overall survival (OS). A total of 636 patients were included. The 1- and 3-year cumulative incidences of CNS relapse after HCT were 3% and 6%, respectively. Absence of CNS involvement prior to HCT, pre-HCT MRD negativity, and receipt of TBI-based conditioning were significantly associated with decreased risk of post-HCT CNS relapse. These three characteristics defined a composite low-risk group that was associated with lower risk of post-HCT relapse [HR = 0.31 (95% CI, 0.15-0.68), p = 0.0032]. Post-HCT CNS relapse was significantly associated with shorter overall survival [HR 7.33 (95% CI, 5.12-10.49), p < 0.0001]; worse outcomes were seen with earlier post-HCT CNS relapse. Future studies will be needed to assess if this low-risk group may benefit from de-escalation of CNS-directed interventions during HCT.

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.

As our approaches to the management of adults with acute lymphoblastic leukemia (ALL) have become more effective, they have introduced new administrative complexities. These include challenges pertaining to medication administration and financial implications of treatment choices. Because approximately half of these patients are typically treated outside of larger referral centers, these difficulties are being passed on to clinicians in settings that rarely encounter this complex disease. Instead of an evidence-focused review on contemporary management of ALL in adults, this article seeks to highlight how some of these important medical advances may be difficult to operationalize outside of high-volume centers. It will also attempt to identify areas in which clinicians and investigators might consider modifying their respective approaches to mitigate how the realities of modern medical care may affect our ability to optimally manage these patients now and in the future.

Brexucabtagene autoleucel (brexu-cel) is a chimeric antigen receptor T (CAR T) cell therapy approved for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We studied the impact of social determinants of health (SDoH) on outcomes of adults with B-ALL receiving brexu-cel. This retrospective analysis included adults (≥18 years) with R/R B-ALL treated with brexu-cel between 2021 and 2023. Cox proportional hazards models evaluated the association of race, ethnicity, and SDoH with progression-free survival (PFS) and overall survival (OS). 189 patients received brexu-cel and 57% were male. 55% were non-Hispanic White, 30% Hispanic, 7% non-Hispanic Black, 6% Asian/Pacific Islander, and 2% other/unknown. 43% were referred from private/community-based practices and 35% lived 50 miles or greater from the CAR T center. Health insurance included public (47%) and private (41%). 31% had a high social deprivation index (SDI, 76–99th percentile). Black race was associated with worse OS (HR 3.48; 95% CI 1.01–12.03). There was no difference in PFS (HR 1.03, 95% CI 0.50–2.10) or OS (HR 1.43; 95% CI 0.56–3.65) in Hispanic patients. Outcomes appear independent of SDoH and SDoH did not impact OS. We observed comparable outcomes to non-Hispanic patients.