Allogeneic Reduced-Intensity Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease: a Single-Center Prospective Trial

Abstract

Purpose: The purpose of this study was to evaluate engraftment and adverse events with a conditioning and prophylactic regimen intended to achieve high rates of engraftment with minimal graft-versus-host disease (GVHD) in allogeneic transplantation for chronic granulomatous disease in a single center.

Methods: Forty patients, 37 male, with chronic granulomatous disease were transplanted. Transplant products were matched sibling peripheral blood stem cells (PBSCs) in four and matched unrelated donor (MUD) bone marrow in three, and one patient received mismatched unrelated PBSCs. Thirty-two patients received MUD PBSCs. All patients received a conditioning regimen of busulfan/alemtuzumab (with low-dose total body irradiation for MUD recipients) with sirolimus graft-versus-host disease prophylaxis.

Results: Engraftment occured in 38/40 recipients (95%). Acute or chronic GVHD occurred in 18 (45%) and 5 (12.5%), respectively, with 6 episodes of grades III-IV and/or steroid refractory GVHD. Overall survival was 33/40 (82.5%) and event-free survival was 30/40 (80%). Successful engraftment was associated with myeloid and NK cell, but not CD3+ chimerism. Myeloid engraftment was greater than 70% in 30/32 recipients at mean follow-up of 3.4 years. Evidence of persistent immunodeficiency was not seen in successful transplants. Attempts to rescue failed or poorly functioning grafts were associated with unacceptable morbidity and mortality.

Conclusions: A reduced-intensity allogeneic transplant protocol based on alemtuzumab and busulfan with sirolimus GVHD prophylaxis produced high rates of successful engraftment and minimal regimen-related toxicity. Prolonged clinical follow-up has confirmed its efficacy in ameliorating CGD-related disease. Outcomes were not acceptable with donor cell infusion rescue of cause with poor graft function.

Keywords: Chronic granulomatous disease; hematopoietic stem cell transplantation; reduced-intensity conditioning.

Conflict of interest statement

Conflict of Interest

The authors declare that they have no conflict of interest.

Figures

Fig. 1

Distribution of PMA-stimulated O2−⋅ production from neutrophils isolated from CGD patients within NIH cohort

Fig. 2

Event-free survival and overall survival

Fig. 3

Myeloid chimerism of 30 patients with engraftment through day 1146. Data sample numbers are consistent with patient designations in Table 1

Fig. 4

CD3+ cell chimerism of 30 patients with engraftment through day 1146. Data sample numbers are consistent with patient designations in Table 1

Fig. 5

Myeloid (M) and CD3+ (C) cell chimerism of five patients with adverse outcomes related to donor cell infusions. Patient 2 had a second transplant which failed. Patient 7 had insufficient cells for analysis at day 30 and died prior to further analysis after day 100. Patient 21 had Evans syndrome with full myeloid chimerism at all points. Patient 24 received a donor cell infusion for persistent cytopenias in the context of ongoing infection but was fully engrafted in both compartments throughout. Patient 25 received a donor cell infusion after day 100 for cytopenias in the context of ongoing infection. Data sample numbers are consistent with patient designations in Table 1