Factors Impacting Overall and Event Free Survival Following Post-CAR T-cell Consolidative Hematopoietic Stem Cell Transplant.

Abstract

BACKGROUND\nHematopoietic stem cell transplant (HSCT) may be used to consolidate CAR T-cell (CAR) therapy induced remissions for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), but little is known about the factors impacting overall (OS) and event free survival (EFS) for post-CAR HSCT.\n\n\nOBJECTIVE\nThe primary objective was identification of factors associated with OS and EFS for consolidative HSCT following CAR induced complete remission (CR) in transplant naïve patients. Secondary objectives included evaluation of OS/EFS, relapse free survival (RFS) and cumulative incidence of relapse for all patients who proceeded to HSCT, stratified by first and second HSCT, as well as the tolerability of HSCT following CAR induced remission.\n\n\nSTUDY DESIGN\nThis was a retrospective review of children and young adults enrolled on one of three CAR T-cell trials at the NCI targeting CD19, CD22, and CD19/22 (NCT01593696, NCT02315612, NCT03448393) who proceeded directly to HSCT following CAR T-cell therapy.\n\n\nRESULTS\nFrom 7/2012 to 2/2021, 46 children and young adults with pre-B ALL went directly to HSCT following CAR therapy. Of these patients, 74% (34/46) proceeded to a first HSCT with a median follow-up of 50.8 months. Transplant naïve patients were heavily pre-treated prior to CAR T-cell therapy (median\u202f=\u202f3.5 lines therapy; range, 1-12) with significant prior immunotherapy exposure (blinatumomab, inotuzumab, and/or CAR therapy) in patients receiving CD22 or CD19/22 constructs (88%, 15/17). Twelve patients (35%) had primary refractory disease, and the median time from CAR infusion to transplant was 54.5 days (range, 42-127). The median OS following first HSCT was 72.2 months (95% CI, 16.9-not estimable [NE]) with a median EFS of 36.9 months (95% CI, 5.2-NE). At 12 and 24 months, the OS was 76.0% (95% CI: 57.6-87.2%) and 60.7% (95% CI: 40.8-75.8%) with an EFS of 64.6% (95% CI: 46.1-78.1%) and 50.9% (95% CI: 32.6-66.6%), respectively. The individual factors associated with both decreased OS and EFS in univariate analyses for post-consolidative HSCT in transplant naïve patients included: ≥5 prior lines of therapy (Not Reached [NR] vs 12.4 mo, p=0.014; NR vs 4.8 mo, p=0.063), prior blinatumomab (NR vs 16.9 mo, p=0.0038; NR vs 4.4 mo, p=0.0025), prior inotuzumab (NR vs 11.5 mo, p=0.044; 36.9 mo vs 2.7 mo, p=0.0054) and ≥ 5% blasts (M2/M3 marrow) pre-CAR (NR vs 17 mo, p=0.019; NR vs 12.2 mo, p=0.035). Primary refractory disease was associated with improved OS/EFS post-HSCT (NR vs 21.9 mo, p=0.075; NR vs 12.2 mo, p=0.024).\n\n\nCONCLUSION\nExtensive prior therapy, particularly immunotherapy, and high disease burden each individually adversely impact OS/EFS following post-CAR consolidative HSCT in transplant naïve patients, primarily due to relapse. Despite this, HSCT remained an important treatment modality in long-term cure. Earlier implementation of HSCT prior to having multiply relapsed disease and incorporation of post-HSCT risk mitigation strategies in patients identified to be at high-risk of post-HSCT relapse may improve outcomes.