Haploidentical stem cell transplantation with post-transplant cyclophosphamide for osteopetrosis and other nonmalignant diseases

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for a variety of nonmalignant disorders including osteopetrosis, bone marrow failures, and immune deficiencies. Haploidentical HSCT is a readily available option in the absence of a matched donor, but engraftment failure and other post-transplant complications are a concern. Post-transplant cyclophosphamide (PT-Cy) regimens are gaining popularity and recent reports show promising results. We report our experience with nine pediatric patients with nonmalignant diseases who were transplanted from a haploidentical donor with PT-Cy. From 2015 to 2019, nine children with nonmalignant diseases underwent haploidentical HSCT with PT-Cy, two as a second transplant and seven as primary grafts after upfront serotherapy and busulfan-based myeloablative conditioning. Patient's diseases included osteopetrosis (n = 5), congenital amegakaryocytic thrombocytopenia (n = 2), hemophagocytic lymphohistiocytosis (n = 1), and Wiskott Aldrich syndrome (n = 1). Two patients failed to engraft following upfront PT-Cy transplants, one was salvaged with a second PT-Cy transplant, and the other with a CD34+ selected graft. None of the patients suffered from graft-versus-host disease. Three patients died from early posttransplant infectious complications and six patients are alive and well. In conclusion, haploidentical HSCT with PT-Cy is a feasible option for pediatric patients with nonmalignant diseases lacking a matched donor.

How we approach malignant infantile osteopetrosis

“…Out of five MIOP patients, three patients survived and are alive and well. Of note, none of the patients developed any signs of graft‐versus‐host disease (GvHD) 40 . In our experience, outcomes of HSCT from unrelated donors, including donors with a one locus mismatch, are promising, with high rates of engraftment and overall survival 41 .…”

“…Out of five MIOP patients, three patients survived and are alive and well. Of note, none of the patients developed any signs of graft-versus-host disease (GvHD) 40.…”

The Impact of Graft-Versus-Host Disease on Survival in Children with Non-Malignant Disorders Receiving Allogeneic Hematopoietic Cell Transplant

“…Post-transplant cyclophosphamide use results in excellent outcomes and significant reduction in grade III/IV GVHD; however, higher risk of graft failure in pediatric non-malignant conditions and hemoglobinopathies, and post-transplant late effects related to high dose chemotherapy warrant caution when using this method of GVHD prophylaxis in children with NMD. (20,21) Literature indicates that alpha beta CD3+/CD19+ cell depleted haploidentical HCT resulted in excellent survival, low GVHD rates, and good immune reconstitution, and this method is emerging as a promising strategy for GVHD prevention in children with NMD. (13) However, some investigators feel that significant myeloablation, required for T-cell depleted transplants, is a disadvantage of this approach.…”

Autosomal recessive osteopetrosis: mechanisms and treatments

“…Alternatively, T-cell depletion in the graft prior to haploidentical infusion reduces graft versus host disease (GvHD) but causes delayed immune recovery, making patients more susceptible to infections ( Bertaina et al, 2017 ). For these reasons, in vivo T-cell depletion has been developed and successfully employed, using post-transplant cyclophosphamide unmanipulated HSCT in osteopetrotic patients ( Even-Or et al, 2021 ). Depletion of both donor and recipient alloreactive cells promotes engraftment and decreases risk of GvHD ( Even-Or and Stepensky, 2021 ).…”

“…For these reasons, in vivo T-cell depletion has been developed and successfully employed, using post-transplant cyclophosphamide unmanipulated HSCT in osteopetrotic patients ( Even-Or et al, 2021 ). Depletion of both donor and recipient alloreactive cells promotes engraftment and decreases risk of GvHD ( Even-Or and Stepensky, 2021 ).…”