Allogeneic Hematopoietic Stem Cell Transplantation Using Fludarabine/Melphalan and Low-Dose Total Body Irradiation: A Single Center Analysis

Background: Indications for allogeneic hematopoietic stem cell transplantation (allo-HCT) with reduced-intensity conditioning (RIC) have expanded widely for elderly patients and those with comorbidities. However, the optimal RIC regimen remains uncertain. A combination of fludarabine phosphate (Flu) and melphalan (Mel) is widely used in RIC regimen with comparable results to that of fludarabine phosphate and busulfan. In our hospital, Flu/Mel and low-dose total body irradiation (Flu/Mel/TBI) is mainly used in RIC regimen. We analyzed safety and efficacy in allo-HCT patients with Flu/Mel/TBI.

Methods: This study was a retrospective analysis of patients with hematopoietic malignancies who received their first allo-HCT with Flu/Mel/TBI from between January 2005 to December 2015. Patients were included for Flu/Mel/TBI treatment for elderly, those with a recent fungal infection or organ dysfunction. Flu/Mel/TBI consists of intravenous Flu (125-150 mg/m²), Mel (140 mg/m²), and TBI (2-4 Gy). GVHD prophylaxis consists of tacrolimus and short-term methotrexate with or without low-dose anti-thymocyte globulin (ATG). The primary end point was non-relapse mortality (NRM) on day 100. As the secondary end point, we verified the effects about Flu/Mel/TBI for patients with non-remission.

Results: From January 2005 to December 2015, 168 patients received conditioning regimens with Flu/Mel/TBI. The median age was 59 years (16-71 years). Hematopoietic malignancies consisted of acute myeloid leukemia (AML) (n=74), myelodysplastic syndrome (MDS) (n=63), acute lymphoblastic leukemia (ALL) (n=12), malignant lymphoma (ML) (n=10), chronic myeloid leukemia (CML) (n=5), adult T-cell leukemia (ATL) (n=2), acute myeloid/NK cell leukemia (n=1), and chronic active Epstein-Barr virus infection (CAEBV) (n=1). Twenty-eight donors were HLA matched siblings, 6 were mismatched siblings, and 2 were haplo-identical donors. Of these, 55 had matched unrelated bone marrow donors, and 47 had 1-allele mismatched unrelated donors and 30 cord blood donors. With regard to disease status at allo-HCT, 44 patients (26.0%) were in remission and 124 patients (74.0%) were non-remission. Forty-nine patients were administered low-dose ATG. The median observation period of survivors was 2021 days (758-4660 days). Neutrophil engraftment was achieved in 89.3%. Median neutrophil recovery to over 500/µl was obtained on day 19 (11-87). Cumulative incidence of NRM at day 100 was 17.4%. Early death, defined as death before day 100, from allo-HCT occurred in 32 patients. Three patients had early relapse. Causes for NRM were infection in 15 patients (8 pneumonia, 7 sepsis), acute cardiac failure in 3 patients, cerebral hemorrhage in 2 patients, thrombotic microangiopathy in 2 patients, acute GVHD in 1 patient, hemophagocytic syndrome in 1 patient, and 5 other causes. NRM rates at day 100 by disease status at allo-HCT showed no significant differences (remission: 15.9% vs non-remission: 17.9%, p=0.15). Overall survival (OS) and disease-free survival (DFS) at 2 years were 50.6% and 43.5%, respectively. Survival rates with regard to disease status showed significant differences. Patients in remission had a 2-year OS of 65.9%, whereas patients in non-remission had a 2-year OS of 45.2% (p=0.031). Patients in remission had a 2-year DFS of 59.1%, whereas patients in non-remission had a 2-year DFS of 37.9% (p=0.016). Cumulative incidences of grade 2-4 and 3-4 acute GVHD were 30.7% and 17.1%, respectively. Cumulative incidence of relapse at 2 years was 29.8%.

Conclusion: The current study proved that disease status at allo-HCT were mainly in non-remission. In such a situation, RIC using Flu/Mel/TBI was well tolerated with relatively low NRM, and was sufficient to allow engraftment for elderly or frail patients with hematopoietic malignancies.