KIR Favorable Mismatched Haplo Transplant and KIR Polymorphism in ALL/AML/MDS Allo-HCT Children

Allogeneic hematopoietic stem cell transplantation (HCT) using matched related and unrelated donors is well-accepted therapy for children with subtypes of high-risk acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). For the 40-50% of children who do not have matched donors available, HCT approaches have varied by center and regional preferences. HCT physicians in France and North America tend to use human leukocyte antigen (HLA)-mismatched umbilical cord blood (UCB), while those in many large centers in Germany, parts of Asia, and selected US centers favor HLA-haploidentical donors. Both approaches have improved significantly through the years for a variety of reasons, including better supportive care, cell processing techniques that now deliver more consistently high-quality products, understanding of the importance of cell dose, and key modifications of preparative and immunosuppressive regimens. Both stem cell sources offer distinct advantages and disadvantages. T-cell-depleted haploidentical approaches with killer-cell immunoglobulin-like receptor (KIR) mismatches have been shown to lead to less relapse in patients with AML13 and, in some studies, children with ALL as well. Disadvantages to this approach have been vulnerability to viral infection and the requirement for an ex vivo T-cell depletion procedure that is currently under IND. Cord blood is readily available and is permissive of some degree of HLA mismatch, but current studies show no advantage in survival compared with matched unrelated donors. Recently, a randomized study of one vs. two UCB units based on a hypothesis of decreased relapse incidence with two units resulted in equivalent outcomes in both arms. Neutrophil engraftment and immune recovery after UCB transplantation is relatively slow, leading to a higher risk of transplant-related mortality; in addition, larger patients require two cord units, dramatically increasing the cost of stem cell procurement. No direct comparisons of these two stem cell sources (haploidentical vs. UCB) have been performed in pediatric patients. Recently, investigators at St. Jude Children's Research Hospital published excellent outcomes using haploidentical donors with grafts depleted for CD3+ cells by an ex vivo Miltenyi CliniMACS system. Their recent cohort of AML and ALL patients treated without total body irradiation (TBI) had a 5-year survival of 88±15% in 19 consecutive patients, with 17 surviving long-term and disease-free and only 2 patients died of progressive leukemia. These results compared favorably with the 5-year survival of 70±38% for transplantations using matched siblings and 61±17% for matched unrelated donors treated with identical leukemia protocols with indications for transplantation defined a priori. These preliminary results suggest that a strategy of using favorable KIR-mismatched haploidentical transplantation may lead to a better outcome than other alternative donor approaches without the side effects of TBI. This protocol is a phase II trial seeking to establish the feasibility and preliminary outcomes with this approach in a multi-institutional setting. In addition to KIR-HLA matching, KIR allele polymorphism may also affect transplant outcomes.Recent data from St. Jude showed that in 312 pediatric HCTs, the patients who received a donor graft containing the functionally stronger KIR2DL1 allele with arginine at amino acid position 245 (KIR2DL1-R245) had better survival (p=0.0028) and a lower relapse rate (p=0.022) than those who received a donor graft that contained only the functionally weaker KIR2DL1 allele with cysteine at the same position (KIR2DL1-C245). Patients who received a KIR2DL1-R245-positive graft with an HLA-C receptor-ligand mismatch had the best survival (p=0.00004) and lowest risk of leukemia relapse (p=0.005). Thus, both KIR-HLA matching and KIR allele polymorphism have prognostic value. We will attempt to prospectively confirm these results in this multicenter trial.