Outcome and immune reconstitution of children and young adults with acute leukemia after alfa/beta T-cell and B-cell depleted HLA-Haploidentical transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children/young adults with acute leukemia (AL) either relapsed or at high-risk of treatment failure and in urgent need of an allograft. A novel method of graft manipulation based on the selective, negative depletion of αβ T and B cells has been recently developed. In the present study, enrolled and analyzed are 111 children with AL, with a median age of 10 years (range 0.9-22.2) transplanted between September 2011 and May 2018. Eighty-two (74%) and 29 (26%) patients had acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML), respectively; all children were transplanted in complete morphological remission and received a fully myeloablative preparative regimen. The donor was mainly chosen according to immunological criteria, giving priority to NK-cell alloreactivity, KIR B haplotype, higher B-content score and size of NK alloreactive subset. They received Anti-Thymocyte Globulin (ATG) prior to HSCT to prevent GvHD and no patient was given any post-transplant pharmacological GvHD prophylaxis. With a median follow-up 47 months (range: 2 months – 7.7 years), the 5-year probability of overall survival was above 70% for both AML and ALL patients. The cumulative incidence of grade I-II acute GvHD was 25% (95% confidence interval, CI, 17-33), with skin GvHD being the most frequent organ involved, and no patient developed grade III/IV aGvHD. Four out of 91 patients at risk developed chronic GvHD, in all cases of limited severity, with a cumulative incidence of 5%. Six patients died for transplant-related complications, this resulting into a 5-year cumulative incidence of transplant-related mortality (TRM) of 6% (95% CI, 2-11) while the 5-year cumulative incidence of relapse was 24% (95% CI, 16-33) at a median time of 186 days (range 60-1012) after transplantation. The 5-year probability of LFS in children with ALL and AML was 69% (95% CI, 57-79) and 73% (95% CI, 52-86), respectively., and the use of total body irradiation (TBI) during the preparative regimen was associated with better patient’s outcome, since it protected against the risk of leukemia recurrence [18% (95% CI, 10-28) vs. 45% (95% CI, 22-66) in patients who did or did not receive TBI, respectively, p<0.01]. The median CD3+ cell count on day +90, +180 and +360 were 247, 659 and 1380/mcl, respectively. This study confirms that αβ T- and B-cell depleted haplo-HSCT is an effective option for patients in need of an urgent allograft and lacking an HLA-identical donor. While TRM is impressively low, the main cause of treatment failure is leukemia recurrence, whose incidence could be lowered by the use of TBI during the conditioning regimen. The remarkably low risk of chronic GvHD renders the approach attractive also in terms of patient’s quality of life.