Haploidentical Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide Plus Thiotepa Improves Donor Engraftment in Patients with Sickle Cell Anemia: Results of an International Learning Collaborative

Abstract

Curative therapy for individuals with severe sickle cell disease (SCD) who lack an HLA-identical sibling donor has been frustratingly elusive. In with the goal of improving engraftment while minimizing transplantation-related morbidity, a multi-institutional learning collaborative was developed in the context of a Phase II clinical trial of nonmyeloablative, related HLA-haploidentical (haplo) bone marrow transplantation (BMT) with post-transplantation cyclophosphamide. All eligible participants had hemoglobin SS, and 89% (16 of 18) had an identifiable donor. The median patient age was 20.9 years (IQR, 12.1 to 26.0 years), and the most common indication for transplantation was overt stroke (in 69%; 11 of 16). In the first 3 patients, the conditioning regimen consisted of antithymocyte globulin, fludarabine, cyclophosphamide, and low-dose total body irradiation. Graft-versus-host disease (GVHD) prophylaxis included post-transplantation cyclophosphamide, mycophenolate mofetil, and sirolimus. Primary graft rejection occurred in 2 of the 3 patients (67%), which triggered the study-stopping rule. To reduce graft rejection risk, thiotepa was added to the conditioning regimen, and then 15 patients (including 2 with previous graft rejection) underwent haplo-BMT with this thiotepa-augmented conditioning regimen. At a median followup of 13.3 months (interquartile range [IQR], 3.8 to 23.1 months), 93% (14 of 15) had >95% stable donor engraftment at 6 months, with 100% overall survival. The median time to neutrophil engraftment (>500) was 22 days (IQR, 19 to 27 days), and that for platelet engraftment (>50 x 10 9/L ) was 28 days (IQR, 27 days to not reached). Two patients had grade III-IV acute GVHD, 1 patient had mild chronic GVHD, and 86% of patients (6 of 7) were off immunosuppression therapy by 1-year post-transplantation. Our data suggest that haplo-BMT with post-transplantation cyclophosphamide and thiotepa improves donor engraftment without significantly increasing morbidity or mortality and could dramatically expand curative options for individuals with SCD.

Haploidentical bone marrow transplant with posttransplant cyclophosphamide for sickle cell disease

“…Initial approaches using a combination of recipient immunoablation with conditioning chemotherapy and total body irradiation appear too toxic. Notably, patients in the de la Fuente et al study had more comorbidities at baseline, namely moyamoya, cerebrovascular infarcts, and acute chest syndrome, compared with those in the Bolanos-Meade et al study [30,31]. Nonmyeloablative haplo-HCT appears to address these limiting factors.…”

“…To improve enrollment of transplant-eligible individuals with sickle cell disease and improve generalizability of findings, an international team-based learning collaboration was established between centers in the United States, United Kingdom, and France 7 [30]. With a focus on haplo-HCT, the group hypothesized that nonmyeloablative conditioning with the addition of thiotepa followed by infusion of marrow allografts and PTCy-based GvHD prophylaxis regimen would reduce graft rejection and improve transplantrelated outcomes (Figure 2).…”

“…The Phase II study was conducted by de la Fuente et al [30] with the primary end point being 1-year event-free survival, which included primary or secondary graft rejection, stroke, or death (Table 1). Eighteen patients with a median age of 20.9 years were included, the first three of whom received the Johns Hopkins platform, the remaining 15 received thiotepa for conditioning due to graft rejection seen in 66% (2/3) initial patients.…”

Improvement in processing speed following haploidentical bone marrow transplant with posttransplant cytoxan in children and adolescents with sickle cell disease

“…A select cohort of patients underwent reduced intensity conditioning haplo‐BMT with posttransplant cytoxan for SCD as part of an international learning collaborative. Only participants with pre‐ and posttransplant cognitive assessments were included in analyses . The transplant data base and electronic patient records were used to assess baseline demographics and transplant‐related outcomes.…”

“…The transplant data base and electronic patient records were used to assess baseline demographics and transplant‐related outcomes. All patients received a common conditioning regimen of fludarabine, cytoxan, thiotepa, and rabbit antithymocyte globulin along with 200 cGy total body irradiation followed by infusion of unmanipulated bone marrow grafts from related haploidentical donors that were at least 5/10 human leukocyte antigen matched . Graft‐versus‐host‐disease prophylaxis included posttransplant cytoxan along with sirolimus and mycophenolate mofetil .…”