Myeloablative Conditioning Haploidentical Stem Cell Transplantation (MAC-HAPLO) with Post-Transplant Cyclophosphamide (PTCy) As GvHD Prophylaxis in High Risk Leukemias/Myelosdysplastic Syndromes (MDS): Geth Experience

Introduction: Allogeneic transplantation is the only curative option for patients with high risk leukemias or MDS. Only one third of them have an HLA identical sibling donor and around 60-70% will find an unrelated donor, that´s why haploidentical stem cell transplantation (HAPLO-HSCT) offers a therapeutic option to most of these patients. Myeloablative conditioning (MAC) produce better disease control than reduced intensity conditioning regimens (RIC), but with higher toxicity, rendering long term similar results.

Patients and methods: We retrospectively evaluated the results of our MAC-HAPLO regimens in patients diagnosed with high risk leukemias or MDS (Fludarabine 30 mg/m2 x5 days, Cyclophosphamide14,5 mg/kg x2 days, IV Busulfan 3,2 mg/kg x 3 days (BUX3), or Fludarabine 40 mg/m2 x4 days and IV Busulfan 3,2 mg/kg x 4 days (BUX4)) with GVHD prophylaxis based on PT-CY (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5, performed in GETH centers (Spanish Group for Hematopoietic Transplantation).

Results: From Feb-2012, 65 MAC-HAPLO HSCT have been reported by 14 centers. Median age was 41 years (15-67), 66% were males and all were in advanced disease phase or presented high risk features (AML 47/ALL 8/MDS 5/ Others 5). Previous HSCT had been employed in 12% (autologous in 5, allogeneic in 3), and in 88% the HAPLO-HSCT was their first transplant. Disease status at HAPLO-HSCT was morphologic CR in 80%, but disease persisted in 52% (MRD+ by flow or molecular markers 32%, morphologic disease 20%). Their disease risk index (DRI) was high or very high in 65%, and the comorbidity index (HCT-CI) was higher than 2 in 18%. PBSC was the graft source in 56 (86%), non T-cell depleted in all cases. The haploidentical donor was the patient´s mother (21.5%), father (12%), siblings (43%) or offspring (23%). MAC regimen was BUX3 in 25 (38.5%) and BUX4 in 40 patients (61.5%). Median infused CD34+ cells were 5.31 x10e6/kg (2.75-11.42). There were no graft failures. Median neutrophils engraftment was reached at day +17 (12-29) and platelets >20K at day +26 (11-150). Complete chimerism was obtained at a median of 28 days (13-135) in 60 evaluated patients. Cumulative incidence (CI) of non-relapse mortality (NRM) was 12.5% at day +100 and 19% at 1 year. CI of grade II-IV acute GVHD was 28.5% at day +100, and grade III-IV was 6.5%. CI of chronic GVHD at 2 years was 28%, being extensive in 8% . No differences in acute or chronic GvHD CI were seen when comparing BUX3 against BUX4. After a median follow-up of 17 months (5-50), estimated 24-months event-free survival (EFS) and overall survival (OS) were 58,5% and 60% respectively. CI of relapse or progression was 21%. No significant differences in NRM, EFS, OS and relapse incidence were detected between BUX3 and BUX4. The impact of CR prior to MAC-HAPLO, the DRI or chronic GvHD in the disease control have not been apropiately demostrated probably due to the limited number of events in our series.

Conclusions: IV Busulfan based MAC-HAPLO with PT-CY in the treatment of high risk leukemias and MDS offers good disease control with manageable toxicity, with either BUX3 or BUX4. These efective MAC regimens combined with peripheral blood HAPLO donors could control high risk hematologic diseases in the long term. Severe acute or chronic GvHD are low frecuency events, but relapses persist as the main problem in this patients population.