Nonmyeloablative Haploidentical Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide for Pediatric and Young Adult Patients with High-Risk Hematologic Malignancies

Abstract

Lower-intensity conditioning regimens for haploidentical blood or marrow transplantation (BMT) are safe and efficacious for adult patients with hematologic malignancies. We report data for pediatric/young adult patients with high-risk hematologic malignancies (n = 40) treated with nonmyeloablative haploidentical BMT with post-transplantation cyclophosphamide from 2003 to 2015. Patients received a preparative regimen of fludarabine, cyclophosphamide, and total body irradiation. Post-transplantation immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, and tacrolimus. Donor engraftment occurred in 29 of 32 (91%), with median time to engraftment of neutrophils >500/µL of 16 days (range, 13 to 22) and for platelets >20,000/µL without transfusion of 18 days (range, 12 to 62). Cumulative incidences of acute graft-versus-host disease (GVHD) grades II to IV and grades III and IV at day 100 were 33% and 5%, respectively. The cumulative incidence of chronic GVHD was 23%, with 7% moderate-to-severe chronic GVHD, according to National Institutes of Health consensus criteria. Transplantation-related mortality (TRM) at 1 year was 13%. The cumulative incidence of relapse at 2 years was 52%. With a median follow-up of 20 months (range, 3 to 148), 1-year actuarial overall and event-free survival were 56% and 43%, respectively. Thus, we demonstrate excellent rates of engraftment, GVHD, and TRM in pediatric/young adult patients treated with this regimen. This approach is a widely available, safe, and feasible option for pediatric and young adult patients with high-risk hematologic malignancies, including those with a prior history of myeloablative BMT and/or those with comorbidities or organ dysfunction that preclude eligibility for myeloablative BMT.

Keywords: Acute leukemia; Cyclophosphamide; HLA-haploidentical transplantation; Lymphoma; Myelodysplastic syndrome; Nonmyeloablative bone marrow transplantation.

Figure 1

Preparative regimen and graft-versus-host disease prophylaxis. Fludarabine 30 mg/m2 IV days -6 through −2, cyclophosphamide (Cy) 14.5 mg/kg IV days −6 and −5, total body irradiation (TBI) 200 cGy day −1, graft infusion day 0, Cy 50 mg/kg/dose IV days +3 and +4, mycophenolate mofetil (MMF) 15mg/kg/dose PO TID (maximum daily dose 3 gm/d) days +5 through +35, tacrolimus 0.015 mg/kg/dose IV every 12 hours day +5 through either day +60, +90, or day +180, and filgrastim 5 μg/kg/day day +5 through neutrophil recovery.

Figure 2

Cumulative incidences of A. Grades 2 to 4 and grades 3 to 4 acute GVHD; B. Overall chronic GVHD and moderate-severe GVHD; C. relapse; D. transplant-related mortality.

Figure 3

Cumulative incidence of Overall Survival and Event-Free Survival.

Figure 4

Cumulative incidence of Overall Survival, analyzed by sub-groups. A. Age at the time of BMT; B. Prior myeloablative alloBMT; C. Year of BMT; D. MRD status; E. Met eligibility for myeloablation.