Prospective PhaseⅡ Study of Reduced Toxicity Conditioning Consisted of High Dose-Cytarabine, Fludarabine, Cyclophosphamide +/- Total Body Irradiation Followed By Allogeneic Stem Cell Transplantation

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-SCT) using reduced intensity conditioning (RIC) has been widely applied to elderly or frail patients who are not eligible for conventional conditioning regimen. However, benefit provided by reduced toxicity has been often offset by increased incidence of relapse. So far, the optimal conditioning for those patients has not been established. Here, to investigate whether addition of high dose cytarabine (AraC) to RIC regimen consisting of fludarabine (Flu) and cyclophosphamide (Cy) +/- total body irradiation (TBI) can be available for elderly or frail recipients, phase II study has been designed.

Methods: This study was conducted from April 2011 to December 2015. The protocol was approved by each institutional review board (Trial identifier: UMIN000007281). Patients aged from 55 to 70, or patients who have some organ damage or a history of SCT aged from 20 to 54 with hematologic malignancies were enrolled after obtaining written informed consent. Bone marrow (BM), peripheral blood (PB), or cord blood (CB) was used as stem cell sources. Pretransplant conditioning regimen consisted of 30 mg/m² of Flu for 5 days (total 150 mg/m²), 4 g/m² of AraC for 2-4 days (divided by 2 daily, total 8-16 g/m²) and 50mg/kg of Cy for a day. Four gray of TBI was used for all CB transplant recipients, whereas 2 gray of TBI was used in other stem cell sources except a matched related donor according to each institutional policy. Calcineurine inhibitors (cyclosporine or tacrolimus) and short term methotrexate were used as GVHD prophylaxis. Donor cell engraftment and 60 day-survival were assessed as a primary end point to evaluate feasibility of this protocol.

Results: Thirty nine patients including 7 recipients with a history of SCT were enrolled. Median age was 61 (28-69), 21 were male, and 18 were female. Nineteen were acute myeloid leukemia, 11 myelodysplastic syndrome, 6 malignant lymphoma and 3 acute lymphoblastic leukemia. Donors were 4 matched related PB, 8 matched unrelated BM, 5 1-Ag/allele-mismatched unrelated BM, and 22 ≤2-Ag-mismatched CB. Thirty seven (94.9%) patients have passed 60-day-point post-transplant. In 38 (97.4%) recipients, engraftment was obtained, a patient died before engraftment due to sepsis caused by enterococcus faecium (male CB recipient, 55y, day15). Median neutrophil recovery to over 500/μl was obtained on day 19 (16-38). Fourteen blood stream infections (13 bacteremias and 1 candidemia) judged as grade 3 toxicity and 2 cases (1 sepsis and 1 endotoxemia ) of grade 4 toxicity were observed within 60 days post-transplant. There were 2 deaths of post-engraftment due to cerebral bleeding (1 female CB recipient, 64y, day 46) and GVHD (1 male CB recipient, 60y, day 77) within 100 days. Although no relapse was observed up to day 60, 7 relapses were observed up to 1 year. Overall survival and disease-free survival were estimated to be 82.1% and 73.8 % at 1 year post-transplant, respectively.

Conclusions: RIC using Flu/high dose AraC /Cy +/- TBI was well tolerated with acceptable low toxicities and was sufficient to allow donor cell-engraftment post allo-SCT for elderly or frail patients with hematologic malignancies. Longer follow up and another prospective study enrolling more patients are required to evaluate the eventual survival benefit by reducing relapse.