Reduced Intensity Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Pediatric Inherited Immune Deficiencies and Bone Marrow Failure Syndromes

Orly R Klein, Samantha Bapty, Howard M Lederman, M Elizabeth M Younger, Elias T Zambidis, Richard J Jones, Kenneth R Cooke, Heather J Symons, Orly R Klein, Samantha Bapty, Howard M Lederman, M Elizabeth M Younger, Elias T Zambidis, Richard J Jones, Kenneth R Cooke, Heather J Symons

Abstract

Purpose: Allogeneic bone marrow transplantation (alloBMT) is the only cure for many primary immune deficiency disorders (PIDD), primary immune regulatory disorders (PIRD), and inherited bone marrow failure syndromes (IBMFS).

Methods: We report the results of 25 patients who underwent alloBMT using reduced intensity conditioning (RIC), alternative donors, and post-transplantation cyclophosphamide (PTCy). In an attempt to reduce regimen-related toxicities, we removed low-dose TBI from the prep and added mycophenolate mofetil and tacrolimus for graft-versus-host disease (GVHD) prophylaxis for all donor types in the latter 14 patients. Donors were haploidentical related (n = 14), matched unrelated (n = 9), or mismatched unrelated (n = 2). The median age was 9 years (range 5 months-21 years).

Results: With a median follow-up of 26 months (range 7 months-9 years), the 2-year overall survival is 92%. There were two deaths, one from infection, and one from complications after a second myeloablative BMT. Three patients developed secondary graft failure, one at 2 years and two at >3 years, successfully treated with CD34 cell boost in one or second BMT in two. The remaining 20 patients have full or stable mixed donor chimerism and are disease-free. The incidence of mixed chimerism is increased since removing TBI from the prep. The 6-month cumulative incidence of grade II acute GVHD is 17%, with no grade III-IV. The 1-year cumulative incidence of chronic GVHD is 14%, with severe of 5%.

Conclusion: This alloBMT platform using alternative donors, RIC, and PTCy is associated with excellent rates of engraftment and low rates of GVHD and non-relapse mortality, and offers a curative option for patients with PIDD, PIRD, and IBMFS.

Trial registration: ClinicalTrials.gov Identifier: NCT04232085.

Keywords: Blood and marrow transplantation; alternative donor; inherited bone marrow failure disorders; post-transplant cyclophosphamide; primary immune deficiency disorders; primary immune regulatory disorders.

Conflict of interest statement

K.R.C. serves on the Speaker Bureau and Advisory Board for Jazz pharmaceuticals and received a research grant from Jazz pharmaceuticals; he is on an investigator-initiated trial of post-transplant therapy for solid tumors that is supported in part by Bristol Meyers Squibb. H.J.S. is on the Speaker Bureau for Jazz pharmaceuticals and is on an investigator-initiated trial of post-transplant therapy for solid tumors that is supported in part by Bristol Meyers Squibb. None of these are in direct conflict with the manuscript.

Figures

Fig. 1
Fig. 1
Preparatory regimen and GVHD prophylaxis. Prep includes alemtuzumab, fludarabine, and melphalan. GVHD prophylaxis includes cyclophosphamide, tacrolimus, and mycophenolate mofetil. Cy, cyclophosphamide; GCSF, granulocyte colony stimulating factor; MMF, mycophenolate mofetil
Fig. 2
Fig. 2
Absolute lymphocyte count (ALC) values and median. The individual values for absolute lymphocyte count (ALC) are shown for days 30, 60, 180, and 365. The median ALC at each time point were 0.38 × 109/L (range 0.02–1.14 × 109/L), 0.60 (range 0.18–2.22 × 109/L), 0.95 (range 0.14–2.10) × 109/L, and 1.76 × 109/L (range 0.37–4.35 × 109/L), respectively. The total number of patients at each time point is n = 26, n = 25, n = 24, and n = 18, respectively
Fig. 3
Fig. 3
Chimerism in whole blood and CD3+ compartment. Chimerism for all patients, n = 25 (A), chemotherapy + total body irradiation, n = 8 (B), Chemotherapy-only, n = 18 (C), IBMFS patients, n = 5 (D), PIDD/PIRD, n = 20 patients (E), and CGD patients, n = 11 (F). Graphs show percent of patients with full chimerism (defined as > 95%), high-level mixed (defined as 50–95%), low-level mixed (defined as < 50% but detectable), none detected, or not measured
Fig. 4
Fig. 4
Disease-free survival (DFS)/overall survival (OS) and event-free survival (EFS). Disease-free survival/overall survival and event-free survival for all patients. OS and DFS are the same at 2 years; three patients who developed secondary graft failure were successfully treated

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