4-Log Ex-Vivo T-Lymphocyte Depleted Myeloablative HLA-Matched Sibling Transplants; a Platform for Adoptive Immunotherapy
Authors: Battiwalla Minoo , McIver Zachariah A. , Haggerty Janice , Koklanaris Eleftheria K. , Chawla Kamna , Superata Jeanine , Childs Richard , Kurlander Roger , Stroncek David , Khuu Hanh , Citrin Deborah , Sabatino Marianna , Leitman Susan , Barrett A. John 
Published: October 2019

Abstract
Abstract 2091

Allogeneic hematopoietic stem cell transplantation (HSCT) strategies must serve as platforms for adoptive cellular immunotherapy if the graft-versus-leukemia (GVL) effect is to be fully exploited. In sequential clinical trials at the National Institutes of Health we have used ex-vivo T cell depletion to develop an HSCT with minimal graft versus host disease (GvHD) prophylaxis followed by elective donor lymphocyte infusion on day 90. T-cell depletion creates the lymphodepleted environment for preferential homeostatic expansion of adoptively infused cells, while minimization of post-transplant immunosuppression promotes expansion of the adoptively transfused cells. Since non-engraftment is a limiting complication with extreme T lymphocyte depletion and reduced GvHD prophylaxis, we measured lineage-specific chimerism and clinical outcomes utilizing our optimized approach. Thirty-six patients with hematologic malignancies underwent allogeneic HSCT with a graft from their HLA-identical siblings. The median age was 43 years (range 16–68), 50% were males. Transplant indications were AML(17), ALL (7), MDS (6), CML (2), CLL (2), NHL (1) and CMMoL (1). 50% were standard risk and 50% were high risk. Subjects received myeloablative conditioning regimen with cyclophosphamide (60 mg/kg/dose × 2), fludarabine (25 mg/m2/dose × 5) and total body irradiation (12 Gy divided in 8 fractions, with lung shielding to 6 Gy). Subjects 55 years of age and older received 4 Gy divided in 8 fractions without lung shielding. G-CSF mobilized peripheral blood stem cells from the donor were CD34+ selected by the Miltenyi CliniMacs system, with infusion of a target CD34+ dose of 6 × 106/kg (range 3 to 10 × 106/kg) and a fixed CD3+ dose of 5 × 104/kg. Low-dose cyclosporine till day 21 was the sole GVHD prophylaxis. Delayed lymphocyte add back (5 × 106 CD3+/kg) was given at day 90 in the absence of significant GvHD. CD3+ and myeloid chimerism analysis were performed sequentially on peripheral blood with early lymphocyte add back in cases with falling chimerism. Day 200 overall survival (the primary study endpoint) was 84%. One patient, who was postpartum, failed to engraft and required a second transplant. 34/36 subjects achieved complete donor (>95%) myeloid chimerism by day 14 and the median time to complete donor CD3+ chimerism was 45 days. The incidence of acute GVHD grade II, III and IV were 23%, 2.9% and 0%, respectively. The incidence of chronic GVHD was 34.3%. At a median follow up of 3.7 years, Kaplan-Meier estimates of relapse, nonrelapse mortality and overall survival were 32%, 31% and 46% respectively. In conclusion, transplants utilizing this approach have acceptable engraftment and clinical outcomes and may serve as an ideal platform for adoptive cellular immunotherapy.

Disclosures:
No relevant conflicts of interest to declare.