Pre-transplant CAR T-cell therapy is associated with inferior survival and increased non-relapse mortality in pediatric B-ALL: A single-center retrospective analysis Free

Introduction The curative potential of hematopoietic stem cell transplantation (HSCT) in pediatric patients with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) is greatest when minimal residual disease (MRD)-negative remission is achieved prior to transplant. Chimeric antigen receptor T-cell (CAR T) therapy offers a novel path to remission for chemotherapy-refractory patients, many of whom proceed to consolidative HSCT. While toxicities of HSCT and CAR T-cell therapy are increasingly well-described, data on outcomes when both modalities are used sequentially remain limited. We compared survival and transplant-related toxicity in pediatric patients with B-ALL who received CAR T therapy prior to HSCT versus those who did not.

Methods This retrospective study included patients age 0-25 years who underwent first allogeneic HSCT for B-ALL at Stanford Medicine Children's Health from October 1, 2017 to May 31, 2024. Outcomes were compared between patients who received CAR T therapy pre-HSCT (CAR T group) and those who did not (HSCT-only group). Overall survival (OS) and disease-free survival (DFS) were analyzed using Cox proportional hazard models; graft-versus-host-disease (GvHD)-free relapse-free survival (GRFS) and non-relapse mortality (NRM) were analyzed using Fine & Gray subdistribution hazard models.

Results Among 74 patients, 38 (51%) received CAR T therapy prior to HSCT. Both groups had similar age at diagnosis (median 12.3y), age at transplant (14.9y), and male predominance (58%). The CAR T group had higher proportion of patients with Hispanic/Latino ethnicity (74% vs 43%, p=0.06) and trisomy 21 (8% vs 0%, p=0.08). Risk profiles were similar: 77% were NCI high risk and 22% had unfavorable cytogenetics. CAR T patients had more prior therapy (3.4 vs 2.9 lines, p=0.04), were more often transplanted in ≥CR3 (34% vs 6%, p=0.009), and had higher frequency of primary refractory disease (39.5% vs 25%) and CNS relapse (63% vs 43%). All patients were MRD-negative by flow cytometry pre-HSCT; 78% had undetectable clones by next-generation sequencing (NGS). Donor characteristics, graft source, and GvHD prophylaxis were similar between groups. Sixty percent of patients received T-cell depleted haploidentical peripheral blood stem cell grafts. Median Lansky/Karnofsky score was 90 and comorbidity index (HCT-CI) was 0 in both groups.

Survival Two- and five-year OS for the full cohort were 81.5% and 76.6%, respectively; GRFS at 2 years was 73.6%. The CAR T group had significantly worse OS (p=0.0051), DFS (p=0.0047), and GRFS (p=0.01) compared to the HSCT-only group (2y OS 66.9% vs 94.4%; 5y OS 60.2% vs 90.3%; 2y DFS 66.2% vs 91.6%; 5y DFS 58.9% vs 91.6%; 2y GRFS 64.1% vs 83.2%). One-year NRM was higher in the CAR T group (16.8% vs 2.9%, p=0.01).

In univariate analysis, CAR T was associated with inferior OS (HR 4.82, 95% CI 1.46-15.92), DFS (HR 4.73, 1.46-15.32), and increased NRM (SHR 5.41, 1.25-23.35). Primary refractory disease also predicted worse OS (HR 4, 1.39-11.48) and DFS (HR 4.62, 1.65-12.95). Fungal infection significantly impacted all survival outcomes.

Unexpectedly, outcomes stratified by remission status showed the poorest OS and DFS in CR1 patients (p=0.019 and p=0.038), driven by CAR T recipients in CR1 (2y OS 27.7%, p<0.001).

Toxicity Grade 2-4 aGvHD occurred in 27% of patients; grade 3-4 in 11%. Moderate-to-severe cGvHD occurred in 10% overall. Severe aGvHD (15.8% vs 5.6%) and immune-mediated complications (36.8% vs 19.4%) were more frequent in CAR T patients, but differences were not significant. Grade 3 viral infections were significantly more common in CAR T patients (26% vs 6%, p=0.025), and this association persisted even after adjusting for donor type (HR 6.4, 1.25-32.83, p=0.026).

Immune Reconstitution Median time to CD4 >200/µL was 182 days, similar between groups. CAR T patients had earlier mitogen recovery (232d vs 362d, p=0.001), but delayed B-cell recovery (time to final IVIG 212d vs 82d, p=0.02).

ConclusionPre-HSCT CAR T therapy is increasingly used in pediatric r/r B-ALL; yet, in this cohort, it was associated with significantly worse survival due to higher rates of relapse and NRM. Outcomes were especially poor in those requiring CAR T to achieve first remission. CAR T recipients were more prone to serious viral infections and immune complications post HSCT. These findings highlight the need to better risk-stratify pre-HSCT CAR T recipients and enhance supportive care during HSCT.