Starting Cyclosporine on Day Zero and Mycophenolate on Day + 1 in Unmanipulated Peripheral Blood Haplo Transplant with Cyclophosphamide Post-Transplantation Is Feasible, Abrogate the Severity of Cytokine Release Syndrome and Achieves a Very Low Rate of aGVHD

Abstract

Introduction The use of unmanipulated peripheral blood from haploidentical donors (UPB Haplo) with post transplantation cyclophosphamide (PT-Cy) is often associated with a higher incidence and severity of cytokine release syndrome (CRS) and aGVHD when it is compared with bone marrow source (BM haplo). Recently it has been published (1) a modification of PT-Cy protocol moving the day of administration of cyclosporine (CsA) and mycophenolate (MMF) from day +5 to zero and + 1 and using BM haplo with encouraging results. With the aim to reduce the incidence of CRS and aGVHD we did the same but keeping UPB haplo as a cellular source. Methods and patients The conditioning used was fludarabine 150 mg/m2, melphalan 100-120 mg/m2, and TBI 200-400 cGy or the same but with busulfan 4 mg/kg instead of melphalan, the CsA began on day zero and continuous until d+180, MMF was administered from d+ 1 to d+ 60 and PT-Cy 50 mg/kg on days +3 and +4 (fig 1). After a signed informed consent, 22 patients were transplanted; median age was 31 y (range 18-64), the diagnoseswere: acute lymphoid leukemia 11, acute myeloid leukemia 7, two had lymphoma, 1 myelodysplasia, and another, chronic myeloid leukemia. 50 % were in first remission, 36% in second, and 14% in third or with active disease. Results All of the donors shared 4 out of 8 alleles with the recipient; their median age was 27 y (range 10-52) in 77% of the cases was a sibling, in 18% a child and in 5% a parent, 4 males received cells from female donors. A median of 7.2 × 10(6)/kg (range 3.9-12) of CD34 and 3 × 10(8)/kg of CD3 were infused. The engraftment rate of 21 patients alive at day +30 was 100%, the median time to achieve 500 neutrophil and self-sustained platelets was 15 and 16 days respectively (range 13-22 and 15-29), one patient with mix chimerism had secondary graft failure. The only manifestation of CRS was fever in 8 out of 22 (36%), range of temperature 38.2 to 39 ¼ C, median duration of 2.5 days. With a median follow-up for surviving patients of 9.5 months (range 3- 18) the incidence of aGVHD (GII-IV) was 5 %. Regarding cGVHD, the follow-up is still short, but only 2 out of 17 evaluable cases had extensive disease. Event was defined as death for any cause or relapse; 3 patients died due to an infection and 2 relapsed, the event-free survival at day 100 was 90% and at one year (Kaplan-Meier) 71.8% (fig 2). Conclusion In this series of 22 patients, the administration of CsA on day zero and MMF on day + 1 in the UPB haplo transplant with PT-Cy was feasible and it decreased the severity and incidence of CRS and of aGVHD, even achieving a rate similar to that which has been reported using BMT haplo. The follow-up is still short to draw conclusions regarding the incidence of cGVHD and relapses, but they also seem encouraging. This strategy deserves further assessment with a bigger number of patients and longer follow-up.