Favorable Outcomes in Pediatric R/R-ALL Following Immunotherapy with CAR-T and UCB Combined to TCR_αβ-Depleted Haplo-HSCT

Background and aim:

TCRαβ-depleted HLA-haploidentical stem cell transplantation(TCD Haplo-HSCT) represents a promising curative option for children with relapsed and refractory acute lymphoblastic leukemia (R/R-ALL). However, disease recurrence remains the primary cause of treatment failure. We developed a novel approach using chimeric antigen receptor modified T (CAR-T) cells and umbilical cord blood (UCB) in addition to TCD Haplo-HSCT to decrease relapse risk and improve transplant outcomes.

Patients and method:

Between December 1, 2020 and July 1, 2024 , 50 children with R/R-ALL (median age 7 years; range 1-17 yeas) were treated with CAR-T treatment followed by TCRαβ-depleted haplo-HSCT. The male: female was 24:26. Forty-six B-ALL patients received single CD19-CAR-T infusion, single CD22-CAR-T infusion, or CD19/CD22-CAR-T sequential infusion. Four T-ALL patients received CD7-CAR-T treatment. The median time from CAR-T treatment to haplo-HSCT was 43 days (range, 23-380 days). All children were given a fully myeloablative preparative regimen. The conditioning consisted of Cyclophosphamide (1 × 50 mg/kg, days -10, -3 to -2), Fludarabine (1 × 40 mg/m², days -7 to -4), Thiotepa (2 × 5 mg/kg, day -4), Bu ( total 90 mg/m², days -7 to -5) , and Anti-human T lymphocyte immunoglobulin (ATG-F) (1 × 15 mg/kg，days -9 to -8 ) or Anti-thymocyte globulin (ATG) (5 mg/kg total, days -9 to -8 ). TCRαβ-depleted grafts contained a median of 30.3 (range, 13.9-114.3)×10⁶ CD34⁺cells/kg, 111.6 (range, 34.9-323.6)×10⁶ NK-cells/kg, and 34.3 (range, 12.3-142.4)×10⁶ TCRγδ⁺T-cells/kg. No patient received any post-HSCT GVHD prophylaxis. Seventeen patients received additional UCB. Unmanipulated prophylactic haplo-DLI was administered monthly at an escalating dose of 1.0 (range, 0.3-2.7)×10⁵ CD3⁺T-cells/kg , starting from a median of day +55 (range, 41-217）after transplantation.

Results:

With a median follow-up of 612 (range, 16-1292) days, the median time to neutrophil and platelet engraftment was 14 (range, 11-27) and 9 (range, 6-36) days, respectively. Three children experienced primary graft failure, two children were rescued after re-conditioning and a secondary haplo-HSCT. Final engraftment was achieved in 49/50 patients. Four patients died, the cumulative incidence of translate related mortality (TRM) was 8%, whereas one patient relapsed 10 month after transplantation (still alive), resulting in a 2% cumulative incidence of relapse. The overall survival (OS) and leukemia-free survival (LFS) was 92% and 90%, respectively. In comparing haplo-HSCT with UCB versus haplo-HSCT without UCB, the cumulative incidence of OS, LFS, relapse and TRM at 12-months was 100% vs. 87.9% (P=0.151), 100% vs. 84.8% (P=0.135), 0% vs. 3% (P=0.678) and 0% vs.12.1% (P=0.151). Forty-six patients received monthly escalating doses of haplo-DLI. Thirteen patients developed grade I-II aGVHD (15 cases in grade I, 4 cases in grade II), and one patient developed grade IV GVHD (skin-only). Four patients developed cGVHD. The cumulative incidence of II-IV aGVHD and cGVHD was 10% and 8%, respectively.

Summary:

These data confirm that TCRαβ-depleted haplo-HSCT is a suitable therapeutic option for children with R/R-ALL. The approach combining TCD haplo-HSCT with CAR-T +/- UCB appeared to result in less TRM, less relapse and favorable OS.

No relevant conflicts of interest to declare.