Development of an Alpha/Beta T-Cell Depleted Allogeneic Stem Cell Transplantation Protocol Form Matched Related and Unrelated Donor Grafts in Patients with Poor Risk Leukemia

Abstract

▪Introduction: The outcome of allo-SCT in patients with poor risk leukemia is still hampered by GVHD and relapse. The innate immune system has been reported to contribute to tumor control, with lower incidence of GVHD. Specific depletion of αβ T- cells – key players in the development of GVHD – will render NK cells and γδ T cells within the allograft. Recently reported results have shown the great promise of this approach in haploindentical transplantations. Within this study, we aim to extend αβT- cell depleted allo-SCT to patients with a MRD or MUD.Methods: Patients with either ‘poor-risk’ or ‘very poor-risk’ leukemia were included in this phase I study. Either HLA matched siblings (MRD) or fully matched HLA matched (10/10) unrelated donors (MUD) were eligible. abT-cell reduction was performed by negative selection with anti-abTCR antibodies in combination with magnetic microbeads, using the automated CliniMACS device (Miltenyi Biotec, Bergisch Gladbach, Germany). The maximal contamination with αβT-cells for all dose levels was 5x105/kg. Three conditioning regimens have been investigated (I): fludarabine 120 mg/m2 + cyclophosfamide 4800 mg/m2, (II): fludarabine 120 mg/m2 + busilvex AUC=90 and (III): ATG (Genzyme®) 4 mg/m2 + fludarabine 120 mg/m2 + busilvex AUC=90 followed by αβT- cell depleted grafts from matched related or unrelated donors. Within cohort II and III, no additional immune suppression was given after allo-SCT.Results: Products for 14 patients have been successfully processed and used for αβT-cell depleted allo-SCT between 2011 and 2013. A ~4 log depletion of αβT-cells has been observed in the product with a recovery of ~75% of CD34+ cells. In cohort I and cohort II, 60% and 25% primary graft failures were observed, whereas in cohort III primary engraftment (chimerism > 95%) was observed in all patients. The combination of ATG/fludarabine/busilvex was well tolerated with a hematological recovery of within 3 weeks. In all 14 patients immune reconstitution primarily consisted of innate cells (NK cells and γδ T cells) the first 6 months post transplantation. In addition, no increase in CMV or EBV reactivations has been observed so far under the profound “innate control”.Conclusion: ATG Busulfan Fludarabine is a low toxicity platform for abTCR-depleted transplantations, resulting in a swift reconstitution of innate cells (NK cells and γδ T cells) the first 6 months post transplantation. This transplantation strategy can serve as a tool for future immunological interventions such as a low dose DLI or genetically modified T cells. DisclosuresNo relevant conflicts of interest to declare.