Haploidentical BMT with a Post-Infusion of Stem Cells Cyclophosphamide Approach Is Feasible and Leads to a High Rate of Donor Engraftment in Haemoglobinopathies Allowing Universal Application of Transplantation

Introduction: BMT is the only proven curative treatment available for haemoglobinopathies. However, the number of patients who can benefit is seriously restricted by the lack of HLA-matched related donors not suffering from the condition and the limited number of unrelated donors available for the ethnic groups in which these conditions are prevalent. In order to expand the donor pool, haploidentical transplantation with a post-infusion of stem cells cyclophosphamide approach has been developed for young adults, but whilst well tolerated it has resulted in relatively high rates of rejection and the need for a prolonged period of immunosuppression¹.

Materials (or patients) and methods: 16 consecutive related haploidentical transplants (13 for sickle cell disease and 3 for β halassaemia major) were performed at St. Mary's Hospital, London, from June 2013 to May 2015. The donor was a parent in 15 cases and a sibling in one case. The median age was 10 years of age (range 3 to 18). All patients lacked a suitable HLA-matched related donor and an unrelated search had not identified a 10/10 or 9/10 donor. Endogenous haemopoieis was suppressed with hypertransfusions, hydroxycarbamide 30 mg/kg and azathioprine 3 mg/kg for at least two months pre-transplantation. The conditioning included fludarabine 150 mg/m², thiotepa 10 mg/kg was added, cyclophosphamide 29 mg/kg, TBI 2 Gy and ATG (Thymoglobulin) 4.5 mg/kg. GvHD prophylaxis was provided with cyclophosphamide 50 mg/kg on days +3 and +4, MMF and sirolimus. The median survival was 8.19 months post-transplantation (1.28-22.96) and half of the patients are >150 days post-transplantation and have completed all treatment. The source of stem cells was G-CSF primed bone marrow in all cases, aiming ≥8 x 10⁸ TNC/kg [median 9.97 x 10⁸ TNC/kg (2.35-20.5), 3.88 x 10⁶ CD34+/kg (1.12-9.21)].

Results: All patients engrafted, though one patient subsequently suffered secondary graft failure following macrophage activation syndrome and died. The median neutrophil engraftment was 17 days (range 16 to 29). The median platelet engraftment >50 x10⁹/L was 32 days (range 20 to 64). All 15 surviving patients are cured from the manifestations of the original disease. One patient suffered VOD following autologous rescue with limited conditioning for secondary graft failure. Infectious complications occurred at a higher rate than seen for related transplants for the same conditions at our institution. Acute GvHD ≥ grade II occurred in two patients (12.5%, skin and gut GvHD respectively) responding to treatment with MSC and one patient was treated for chronic GvHD (6.3%). The median time to cessation of immunosuppression was 124 days (108-189). All patients but one achieved ≥90% donor fraction both in whole blood and T cells at day +180, with only such patient requiring continuation of immunosuppression (day +28: 93.3% patients ≥95% donor and 6.7% patients ≥90-94% in whole blood, and 73.3% patients ≥95% donor, 13.3% patients ≥90-94%, 6.7% donor ≥50-89% and 6.7% donor <50% in T cells, n=15; day +180: 70% patients ≥95% donor, 20% patients ≥90-94% and 10% patients ≥50-89% in whole blood, and 80% patients ≥95% donor, 10% patients ≥90-94% and 10% donor <50% in T cells, n=10).

Conclusion: Related haploidentical transplantation providing sufficient myelosuppression to avoid rejection is feasible, leading to outcomes which approach the results for related transplantation and allowing all patients with haemoglobinopathies requiring a transplant to benefit fromm such treatment.

References: 1. Bolaños-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, Brodsky RA. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood. 2012 Nov 22;120(22):4285-91.