Effects of the Order of Administration of Total Body Irradiation and Cyclophosphamide on the Outcome of Allogeneic Hematopoietic Cell Transplantation

Background and objectives: Total body irradiation (TBI) combined with cyclophosphamide (CY) is one of the most common myeloablative conditioning regimens used in allogeneic hematopoietic stem-cell transplantation (HSCT) for treating hematological malignancies. However, it remains unclear whether the order of administrating TBI and CY has an effect on the outcome in clinical transplantation. The aim of this study is to clarify the effects of the order of TBI and CY administration on the outcome of allogeneic HSCT.

Patients and Methods: We retrospectively investigated the clinical outcome of 504 adult patients with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), and myelodysplastic syndrome who received allogeneic HSCT with myeloablative conditioning regimens consisting of TBI and CY at the transplant centers participating in the Kanto Study Group on Cell Therapy between January 2001 and August 2012. Patients were divided into two groups based on the order in which TBI and CY were administered. The outcome of HSCT and incidences of acute and chronic GVHD, sinusoidal obstruction syndrome / veno-occlusive disease, and idiopathic pneumonia were compared between the two groups.Patients who underwent HSCT during the first or second remission of acute leukemia or refractory anemia of myelodysplastic syndrome were considered as having standard-risk disease. All other conditions were considered as high-risk disease.

Results: A total of 218 patients received CY before TBI (CY-TBI) and 286 received CY after TBI (TBI-CY). AML was more common in the CY-TBI group (62.8%) compared with the TBI-CY group (51.0%), and ALL was less common in the CY-TBI group (25.7%) compared with the TBI-CY group (37.8%; P = 0.013). High-risk disease was more frequent in the CY-TBI group (38.5%) compared with the TBI-CY group (23.4%; P < 0.001). The proportion of unrelated bone marrow (54.6% vs. 43.4%) and cord blood transplantation (22.9% vs. 17.8) were higher among patients in the CY-TBI group than in the TBI-CY group (P = 0.0014). TBI was administered at a dose of 12 Gy in 212 patients (97.2%) in the CY-TBI group and 266 patients (93.0%) in the TBI-CY group (P = 0.013). More patients received TBI administered in six fractions in the CY-TBI group (72.9%) than in the TBI-CY group (53.1%; P < 0.001). Female to female transplantation was lower in the CY-TBI (13.3%) group compared with the TBI-CY group (24.1%; P = 0.023). Age, gender, GVHD prophylaxis, and blood mismatch were not significantly different between the two groups.

The order in which TBI and CY was administered did not affect the incidence of grades II–IV acute GVHD (45.3% vs. 49.3% at day 100; P = 0.28) and chronic GVHD (36.0% vs. 43.8% at 2 years; P = 0.10), overall survival (52.4% vs. 53.4% at 5 years; P = 0.44), disease-free survival (50.5% vs. 51.5% at 5 years; P = 0.58), relapse rate (30.2% vs. 31.8% at 5 years; P = 0.96) and non-relapse mortality (19.3% vs. 16.7% at 5 years; P = 0.52) in the two groups (CY-TBI and TBI-CY, respectively) by univariate analysis. Moreover, the cumulative incidences of sinusoidal obstruction syndrome / veno-occlusive disease (4.1% vs. 3.8%; P = 0.81) and idiopathic pneumonia were comparable (3.1% vs. 3.4%; P = 0.87) between the two groups (CY-TBI and TBI-CY, respectively).

Conclusions: This study demonstrates that the order of administration of TBI and CY does not have an effect on the outcome of allogeneic HSCT. Further studies are warranted to confirm this result.