HLA-Haploidentical Hematopoietic Cell Transplantation for Treatment of Nonmalignant Diseases Using Nonmyeloablative Conditioning and Post-Transplant Cyclophosphamide

Abstract

Allogeneic hematopoietic cell transplant (HCT) is often the only curative therapy for patients with nonmalignant diseases; however, many patients do not have an HLA-matched donor. Historically, poor survival has been seen after HLA-haploidentical HCT because of poor immune reconstitution, increased infections, graft-versus-host disease (GVHD), and graft failure. Encouraging results have been reported using a nonmyeloablative T cellÀreplete HLA-haploidentical transplant approach in patients with hematologic malignancies. Here we report the outcomes of 23 patients with various nonmalignant diseases using a similar approach. Patients received HLA-haploidentical bone marrow (n = 17) or granulocyte colony-stimulating factorÀmobilized peripheral blood stem cell (n = 6) grafts after conditioning with cyclophosphamide 50 mg/kg, fludarabine 150 mg/m 2 , and 2 or 4 Gy total body irradiation. Postgrafting immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, tacrolimus, § sirolimus. Median patient age at HCT was 10.8 years. Day 100 transplant-related mortality (TRM) was 0%. Two patients died at later time points, 1 from intracranial hemorrhage/disseminated fungal infection in the setting of graft failure and 1 from infection/ GVHD. The estimated probabilities of grades II to IV and III to IV acute GVHD at day 100 and 2-year National Institutes of Health consensus chronic GVHD were 78%, 26%, and 42%, respectively. With a median follow-up of 2.5 years, the 2year overall and event-free rates of survival were 91% and 78%, respectively. These results are encouraging and demonstrate favorable disease-specific lineage engraftment with low TRM in patients with nonmalignant diseases using nonmyeloablative conditioning followed by T cellÀreplete HLA-haploidentical grafts. However, additional strategies are needed for GVHD prevention to make this a viable treatment approach for patients with nonmalignant diseases.

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

“…The highly immunosuppressive properties of alemtuzumab are particularly appealing in the setting of nonmalignant HSCT, where GvHD provides no clinical benefit and relapse of malignancy is not applicable. Indeed, none of our patients developed any signs of acute or chronic GvHD as compared to the relatively high rates of acute and chronic GvHD reported by Mallhi et al using a RIC conditioning without serotherapy [10]. Commonly used pediatric transplantation regimens include alemtuzumab doses of 0.5-1 mg/kg given over 3-5 days [12].…”

“…Recent reports focusing on haploidentical HSCT with PT-Cy in pediatric patients with nonmalignant diseases offer different promising approaches using a variety of conditioning regimens [6][7][8][9][10]. Klein et al reported HSCT of 11 children with nonmalignant disorders showing very good outcomes with limited GvHD, excellent engraftment outcomes and no treatment related mortality using a RIC regimen with fludarabine, melphalan and upfront serotherapy with alemtuzumab [9].…”

“…Klein et al reported HSCT of 11 children with nonmalignant disorders showing very good outcomes with limited GvHD, excellent engraftment outcomes and no treatment related mortality using a RIC regimen with fludarabine, melphalan and upfront serotherapy with alemtuzumab [9]. Another recent report by Mallhi et al of 23 pediatric nonmalignant patients also used a RIC regimen including low dose cyclophosphamide (50 mg/kg), fludarabine and a low dose of total body irradiation (2-4 Gy) and showed favorable outcomes but relatively high rates of GvHD [10]. Kurzay et al used a treosulfanbased myeloablative conditioning regimen with upfront serotherapy and an addition of thiotepa and low dose cyclophosphamide in a recent report of 13 pediatric patients with nonmalignant diseases showing good overall survival, low rate of GvHD and few infectious complications [7].…”

“…The availability, safety profile, effectiveness in reducing GvHD, and low cost of the procedure have contributed to the increasing popularity of this modality all over the world [5]. For pediatric nonmalignant diseases, regimens with PT-Cy for haploidentical HSCT are increasingly adapted as well, and recent reports of haploidentical HSCT with PT-Cy for nonmalignant diseases show feasibility of this approach and promising results [6][7][8][9][10].…”

Considerations in Preparative Regimen Selection to Minimize Rejection in Pediatric Hematopoietic Transplantation in Non-Malignant Diseases

“…A well-established alkylating agent, cyclophosphamide has maintained its role in HSCT due to its highly immunosuppressive properties and the relative resistance of hematopoietic stem cells to this agent even the highest doses (8,10,11). Recent studies have utilized cyclophosphamide post graft infusion to improve the outcomes of haploidentical transplant procedures (12)(13)(14). The success of this strategy has probably entrenched this agent as a major element of transplant therapy.…”