Risk Factors and Outcome of Children with Relapsed/Refractory Acute Leukemia after T-Cell-Rich Haploidentical Hematopoietic Cell Transplantation

Background: T-cell rich (TCR) HLA-haploidentical SCT (haplo-SCT) is a form of T-cell therapy that has a high degree of efficacy in hematologic malignancies. Previously we reported the safety profile assessing GVHD prophylaxis that was conducted with anti-human thymocyte immunoglobulin (ATG), tacrolimus, methotrexate (MTX) and prednisolone (PSL) in unmanipulated haplo-SCT (Clin Transplant 2010, Transfus Med 2014). We evaluated efficacy and toxicity of TCR haplo-SCT in children with very high risk refractory/relapsed acute leukemia (VHR-R/R AL).

Methods: VHR-R/R AL were defined as: relapse after SCT, very early or early relapse, induction failure(2 or more) and relapse of risk factor with MLL rearrangement, Ph+, Mo7 and 5q-. From Aug 2000 to April 2014, consecutive 38 patients (pts) with VHR-R/R AL who underwent TCR-haplo-SCT were included. The median age of pts was 8.2(0.3-19.1) years old. The diagnosis included ALL (n=27), AML (n=8), M/NKL (n=3). The disease status at TCR-haplo-SCT were 18 in CR (positive MRD: 8 pts), 20 in non-CR. HLA disparities were 2/8 in 1pt, 3/8 in 9 pts, 4/8 in 28 pts. Donors included fathers (n=21), mothers (n=14), and siblings (n=3). Thirty one pts received myeloablative conditioning (TBI based: 20 pts, Bu based: 11 pts) and 34 pts of them received ATG (rabbit, thymoglobulin 2.5mg/kg) containing regimen. The GVHD prophylaxis was conducted with tacrolimus, MTX and PSL. Thirty four pts received peripheral blood stem cells and 4 pts received BM.

Results: Neutrophil engraftment (defined as >0.5x10⁹/L) was 95% with a median day of 13 (range, 10-15). With a median 1640 days follow-up (range, 320-5510 days) in pts without events, the actuarial 3-year overall survival (OS) and disease-free survival (DFS) were 57% and 39%, respectively. On competing-risk analysis, 1-year cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 71% and 63%, respectively; 3-year cumulative incidences of relapse and non-relapse mortality (NRM) were 40% and 20%. On univariate analysis, 3-year OS in pts with acute GVHD vs. without acute GVHD were 70% vs. 22% (p=.0006), in pts CR vs. non-CR at TCR-SCT were 83% vs. 32% (p=.007), in pts infused CD3 cell doses >=5 x 10⁸/kg vs. <5 x 10⁸/kg were 83% vs. 25% (p=.005), according to age at TCR-SCT <9 vs. >=9 were 79% vs. 34% (.008), respectively. In contrast, the occurrence of acute GVHD had no significant difference in infused CD3 cell doses.

Conclusions: These data suggest that TCR haplo-SCT following low-dose ATG containing conditioning combined with our GVHD prophylaxis is well tolerated, facilitates engraftment, and has significant anti-leukemic activity, particularly in pediatric patients with refractory/ relapsed population.