Reduced Intensity Conditioning Regimen with a Variety of Stem Cell Grafts Is Well Tolerated, and Results in Timely and Sustained Donor Engraftment in Patients with a Diversity of Nonmalignant Diseases

Abstract

<h3>Objectives</h3> To evaluate engraftment, acute graft-versus-host disease (aGVHD), and overall survival of a reduced intensity conditioning regimen. <h3>Methods</h3> From 2011 to 2019, 69 patients (table 1) with nonmalignant conditions (figure 1) underwent hematopoietic cell transplantation (HCT) following a novel reduced intensity conditioning regimen of dose-adjusted alemtuzumab (0.2-2.2 mg/kg), hydroxyurea (30 mg/kg/day), fludarabine (150 mg/m2), melphalan (140 mg/m2) and thiotepa (200 mg/m2) with GVHD prophylaxis of tacrolimus and mycophenolate mofetil. Forty-nine (71%) were enrolled on clinical trial NCT01962415. Grafts were unmanipulated, with the exception of 5 mismatched and/or PBSC grafts that were ex-vivo T-cell depleted. All patients were recipients of their first HCT, except for a patient with relapsed hematophagocytic lymphohistiocytosis, who received second transplant more than 7 years from the first. <h3>Results</h3> Donor neutrophil engraftment occurred in 68 of 69 patients at a median of 14 days (range 9-33) and platelet engraftment (>50K) occurred in 68 of 69 patients at a median of 37 days (range 14-105). Sustained donor chimerism was excellent (figure 2). There was 1 case of primary graft failure (GF) and 4 cases of secondary GF; 4 of 5 patients successfully underwent a second transplant using busulfan-based reduced toxicity conditioning. Patients endured minimal organ toxicity with one case of venoocclusive disease after first HCT which responded to defibrotide, no cases of hemorrhagic cystitis or pericardial effusions, no need for dialysis, and no persistent organ toxicity or failure. Fifteen (22%) developed grade II-IV aGVHD and 6 (9%) developed grade III aGVHD. There was no grade IV aGVHD, no therapy-refractory GVHD, or death due to GVHD. With an average follow up of 5 years (range 97 days-8 years), the overall survival of this cohort is 91%. <h3>Conclusion</h3> This regimen has demonstrated safety and efficacy with a low rate of severe GVHD for 28 unique nonmalignant conditions, including inborn errors of metabolism, immunodeficiencies, and transfusion-dependent anemias.