HLA-haploidentical hematopoietic stem cell transplantation after removal of α/β+ T cells and of CD19+ B cells in children with leukemia and life-threatening non malignant disorders

Over the last 4 decades, allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an HLA-matched donor, either related or unrelated, has been increasingly used to treat patients affected by several malignant or non-malignant hematological disorders. However, only 25% of the patients who need an allograft have an HLA-identical sibling and a suitable, HLA-compatible, unrelated volunteer can be found for less than 60% of the remaining patients. In the absence of an HLA-matched donor, alternative donor/sources of hematopoietic stem cells such as HLA-haploidentical relatives, are being increasingly used. In the context of great immune genetic disparity between patient and donor, although mature donor T cells present in the graft facilitate T-cell reconstitution, they are responsible for the occurrence of graft-versus-host disease (GvHD), a severe, sometimes fatal, immune complication, which also impairs patient’s immune reconstitution. Strategies to prevent GvHD after HLA-haploidentical allo-HSCT based on either pharmacological immunosupression or T-cell depletion of the graft have been developed. In particular, the physical elimination of T cells from the graft has been demonstrated to be highly effective to prevent both acute and chronic GvHD. However, with T- cell depletion of the graft, the patient cannot benefit from the adoptive transfer of donor-derived, memory T lymphocytes, which are mainly responsible for protection from severe infections during the state of profound immune deficiency that usually lasts for at least 4-6 months after transplantation. Overall, HLA-haploidentical allo-HSCT is associated with an higher incidence of graft rejection, disease relapse and both viral and fungal infections, resulting in high transplantation-related mortality (TRM). Recently, experimental and clinical results brought the light that not only adaptative immunity but also innate immunity, and in particular Natural Killer (NK) cells, influence the patient’s outcome. In view of these considerations, the transplantation of mobilized peripheral blood stem cells (PBSCs) selectively depleted of TCR T-lymphocytes would offers advantages as compared to the use of positively selected CD34+ hematopoietic stem cells because of the presence of other ancillary non-stem cells that might have potential positive effects on the outcome of the transplant, in particular NK and TCR T cells. The role of NK cells in allogeneic HSCT has been first reported to positively affect the outcome of transplantation from an HLA-haploidentical relative in adults with acute myeloid leukemia (AML) and, more recently, in children with high risk acute lymphoblastic leukemias (ALL). Indeed, in patients receiving the graft from a NK alloreactive donor, the probability of 10 leukemia recurrence was particularly low, while the probability of leukemia-free survival (LFS) was found to be at least as good as that of patients transplanted in a similar disease phase from an HLA-matched sibling or unrelated volunteer. Furthermore T cells have been shown to have a potent GvL effect. In their study, Lamb et al. showed that in patients with ALL or AML and transplanted with a partially mismatched TCR T-cell depleted graft, those who have an increased proportion of T cells in their peripheral blood have a better disease-free survival probability, compared with patients showing a normal proportion of these cells. Based on these observations, we propose, in this study, to evaluate the feasibility and safety of infusing a TCR depleted graft, using the CliniMACS system (Mylteni Biotech, Germany), from a partially matched family donor in pediatric patients affected by both malignant and non-malignant hematological disorders