Paper Details

ABSTRACT

Background:?Relapse of B-ALL after CART19 occurs in up to 50% of children, adolescents and young adults (CAYA) and is associated with a reported median overall survival (OS) of 12 months (mos). Factors associated with outcomes and optimal salvage approaches are unknown. The only established curative therapy is hematopoietic cell transplant (HCT), but the ability to bridge to HCT is also uncertain. To address these knowledge gaps, we sought to define survival outcomes by post-CART19 relapse leukemia immunophenotype, identify clinical factors associated with survival, establish salvage therapy response rates, and ascertain rates of subsequent HCT.

Methods: We conducted a retrospective review of CAYA <30 years (y) who achieved a CART19 induced measurable residual disease-negative (MRD-) complete remission (CR) by flow cytometry and experienced a subsequent relapse without interval therapy. The primary endpoint was OS from post-CART19 relapse. Clinical factors associated with OS were identified with multivariable Cox models. Secondary endpoints were: 1) Event-free survival (EFS), defined as time to treatment failure (failure to achieve MRD- CR within 6 mos of post-CART19 relapse), subsequent relapse, or death; 2) Salvage therapy response rates; and 3) OS, EFS, and non-relapse mortality (NRM) among patients who underwent HCT.

Results: Of 425 patients treated with experimental CART19 products across 10 clinical trials or with commercial tisagenlecleucel at Children’s Hospital of Philadelphia from 2012-2025, 390 (92%) achieved MRD-negative CR, of whom 136 (35%) relapsed without interval therapy at a median of 7.5 mos (range 1.4-101) from infusion (CD19+ n=61; CD19- n=65; myeloid lineage switch n=7; unknown n=3).

With a median follow-up of 67 mos from post-CART19 relapse, median OS was 15 mos (95% CI 10-32). For patients with CD19+ relapse, 3y OS was 50% (95% CI 39-65) vs 32% (95% CI 22-47) for CD19- relapse. Lineage switch was uniformly fatal at a median of 3.1 mos (range 1.1-20) from relapse. In multivariable analysis, Black race (HR 3.04, P=0.003), receipt of CART19 in ≥3rd relapse (HR 3.84, P=0.02), relapse <6 mos from CART19 (HR 3.62, P<.001) and lineage switch (HR 5.67, P<.001) were associated with worse OS, and age ≥16 years with improved OS (HR 0.52, P=0.027). CD19- B-ALL, disease burden pre-CART19, and prior HCT were not independently associated with post-relapse OS. 

Among 136 CAYA with post-CART19 relapse, 120 (88%) received salvage therapy. EFS at 3y was 27% (95% CI 20-37) overall, 32% (95% CI 22-47) for CD19+, and 26% (95% CI 16-41) for CD19- relapse. In total, 58/120 (48%) patients achieved flow MRD- CR with 1st salvage attempt. Morphologic CR and flow MRD- CR rates to specific 1st salvage therapies were: Cytotoxic chemotherapy (n=47), 47%/26%; inotuzumab (n=34), 95%/71%; alternative CART19 (n=15), 73%/67%; CART22 (n=9), 78%/78%. Twenty-seven additional patients obtained MRD- CR with a median of 1 further line of salvage therapy (range 1-4). Altogether, among 85 patients who achieved MRD- CR, the most frequent regimens that resulted in MRD- CR were: Inotuzumab (33%), CART22 or CART19/22 (15%), alternative CART19 (14%), cytotoxic chemotherapy (14%) and blinatumomab (7%).

At time of post-CART19 relapse, intended definitive therapy was HCT for 71 (59%), alternative CART for 33 (28%), or other/undecided for 16 (13%). Of 71 intended for HCT, 52 (73%) successfully underwent HCT while 19 (27%) did not reach a transplantable CR. Including those not initially intending transplant, 69 patients underwent HCT following post-CART19 relapse (1st HCT, n=49; 2nd HCT, n=20). With a median follow-up of 65 mos from HCT, 3y outcomes for 1st and 2nd HCT, respectively, were: OS, 64% (95% CI 52-79) and 41% (95% CI 23-71); EFS, 60% (95% CI 48-76) and 26% (95% CI 12-57); and NRM, 14% (95% CI 6-26) and 20% (95% CI 6-40). 

Conclusions: This study represents the largest analysis to date of detailed post-CART19 relapse outcomes in CAYA with B-ALL. Despite overall poor long-term survival, nearly 2/3 of patients achieved another MRD- CR, a subset of whom remained in durable remissions.  Inotuzumab and newer CART approaches induced the greatest CR rates. Nearly 3/4 of patients intended for HCT to treat relapse successfully underwent transplant with generally favorable post-HCT outcomes. These findings help shape risk-stratification, guide selection of salvage therapy, and inform decisions about consolidative HCT after initial CART19-induced CR.