Haploidentical Hematopoietic Stem Cell Transplantation (Haplo-SCT) with Pre-Transplant Immunosuppression and Post-Transplant Cyclophosphamide (Post-Cy) in Severe Thalassemia: A Novel Approach Transplant for Nonmalignant Diseases

Background

Currently, the thalassemia free survival rate after hematopoietic stem cell transplant (HSCT) is about 80-90% with either matched sibling or unrelated donor. However, the probability to find a suitable door is only 25-50%. Since most of these patients (pts) could not find the potential donor, we would like to investigate the haplo-SCT in thalassemia.

Patients and Methods

Between Jan 2013 and October 2014, 15 thalassemia patients (pts) underwent haplo-SCT. Eight subjects were male and 7 were female. The median age was 16 yrs (range; 2-22). Eleven of 15 received stem cells from mother and 4 from father. Twelve of 15 were high risk class 3. These high risk class 3 also received hydroxyurea  20 mg/kg/d for at least 3 months prior to HSCT. All pts received 2 courses of pre-transplant immunosuppression (PTIS) consisting of fludarabine (Flu) 40 mg/m²/d together with dexamethasone (dex) 25 mg/m²/d for 5 days. After 2 courses of PTIS, all pts received a reduced-toxicity conditioning regimen consisting of thymoglobulin 1.5 mg/kg/d (d-11 to d-9), Flu 35 mg/m²/d i.v. (-7 to -2) each dose immediately followed by busulfan (Bu) 130  mg/m²once daily i.v. (d-7 to d -4) for pts  > 10 years and 0.95-1.2 mg/kg every 6 hr (d-7 tod-4) for pts < 10 yrs. GVHD prophylaxis consisted of cyclophosphamide (Cy) 50 mg/kg/d (d +3 to d+4). Tacrolimus was given for 6 months to 1 yr started together with mycophenolate mofetil on d+5, the latter was quickly tapered after 2 months. T-cell repleted peripheral blood stem cells were given to all pts targeting a CD34+ dose of 7-10 x 10⁶ cells/kg.

Results

Fourteen of 15 were engrafted with full donor chimerism (100%) while one pt suffered graft failure. However, this pt received second transplant on day +30 with minimal conditioning regimen and additional PBSC, after which she achieved full donor chimerism. The median time to neutrophil engraftment was 18 days (range; 14 -22). Six pts had acute GVHD gr I, 3 grade II and1 gr III. Only one had limited chronic GVHD. At this time, all 15 pts survive thalassemia-free and have sustained full donor chimerism (100%). The thalassemia free survival and overall survival rates are 100%. The median follow up time was 12 months (range 4-22).

Conclusion       

Haplo-SCT for high risk thalassemia pts with our novel approach is safe, and should be considered as a modality to secure thalassemia-free survival with a low risk of graft rejection and treatment-related mortality. With this result, our Haplo-SCT in thalassemia pts has favorable outcome as related and unrelated HSCT (Thalassemia free survival rate > 90%). In view of our results, we suggest that all thalassemia pts even those with high risk class 3 features should be offered the chance for cure with HSCT.