Impact of low-dose TBI on outcomes of reduced intensity conditioning allogeneic hematopoietic stem cell transplantation for AML

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for patients with advanced hematologic malignancy, including those with AML. 1 However, allo-HSCT after conventional myeloablative conditioning (MAC) may be associated with a high rate of transplant-related complications. Reduced intensity conditioning (RIC) was developed with the purpose of reducing regimen-related toxicity. 2,3 RIC is increasingly used for allo-HSCT for AML patients who are otherwise considered unfit for MAC.The primary objective of low-dose TBI in RIC is inhibition of the host immune response to facilitate engraftment. 4,5 Several studies have suggested that the addition of low-dose TBI to the conditioning regimen improved outcomes of transplantation. 6,7 However, favorable outcomes of non-TBI-based RIC transplantation were also reported. 8 Thus, the impact of low-dose TBI on outcomes after allo-HSCT remains controversial, and it is unknown whether the addition of low-dose TBI to RIC is beneficial for AML patients. Therefore, we conducted a retrospective analysis to elucidate the clinical impact of low-dose TBI on outcomes after allo-HSCT from a HLA-matched-related donor in the setting of fludarabine-based RIC.Clinical data were collected from the registry database of the Japan Society for Hematopoietic Cell Transplantation. Patients with AML (excluding acute promyelocytic leukemia) aged 16 years or older who underwent fludarabine-based RIC allo-HSCT from an HLA-matched-related donor between January 2000 and December 2012 were extracted from the database. Patients who underwent two or more HSCT were excluded. We retrospectively analyzed the clinical impact of low-dose TBI on outcomes after RIC allo-HSCT. Overall survival (OS), relapse, nonrelapse mortality (NRM) and hematological recovery of patients who received low-dose TBI as a part of fludarabine-based RIC (TBI group) were compared with those of patients who did not receive TBI (non-TBI group). Low-dose TBI was defined as ⩽ 4 Gy, as previously reported. 9 Fludarabine-based RIC was defined as RIC containing fludarabine 120-180 mg/m 2 . Definitions of RIC other than TBI were as follows: oral busulfan o9 mg/kg (or IV injection in equivalent doses) or melphalan ⩽ 140 mg/m 2 . 10 Cytogenetic subgroups were classified according to the Southwest Oncology Group (SWOG) definition. 11 Neutrophil engraftment was defined as the continuous achievement of neutrophil counts 500 × 10 6 /l or higher. Platelet recovery was also defined as continuous achievement of neutrophil counts 50 × 10 9 /l or higher without transfusion. This study was approved by the Institutional Review Board of the Kanagawa Cancer Center. Table 1 shows patients characteristics. Of the 409 patients, 108 patients were in the TBI group and 301 patients were in the non-TBI group. A higher proportion of patients underwent bone marrow transplantation (BMT) (P o 0.001) and received cyclosporine for GvHD prophylaxis (P = 0.006) in the TBI group. The proportion of male patients (P = 0.07) and patients who un...

Clinical significance of low-dose total body irradiation in HLA-mismatched reduced-intensity stem cell transplantation

“…In addition, the benefit of low-dose TBI on neutrophil engraftment was not observed in patients at high risk for graft rejection such as those with two or more HLA mismatches in the HVG direction and those with highrisk disease. Similar results have been previously reported in HLA-matched related RICT [7] and HLA-matched unrelated/ HLA-mismatched RICT [4]. These results suggest that HLAmismatched RICT excluding cord blood transplantation did not always require low-dose TBI to prevent rejection in current clinical practice.…”

“…Previous studies showed that incorporation of low-dose TBI to conditioning regimens reduced the incidence of graft failure in cord blood transplantation [4,5] and SCT in patients with aplastic anemia [6]. Conversely, the addition of low-dose TBI to RIC did not improve neutrophil and platelet engraftment in HLA-matched related SCT [7]. Additionally, administration of low-dose TBI in addition to RIC was not associated with prompt neutrophil engraftment after HLAmatched unrelated or HLA-mismatched unrelated bone marrow transplantation (BMT) [4].…”

“…Regarding clinical outcomes other than engraftment, low-dose TBI was reported to improve survival, thereby compensating the risk of relapse in fludarabine (Flu)/ busulfan (Bu) regimen [8]. In contrast, in SCT from HLAmatched related donor, the addition of low-dose TBI to RIC did not have any impact on nonrelapse mortality (NRM), relapse, or overall survival (OS) [7]. However, the clinical benefit of low-dose TBI in reduced-intensity conditioning SCT (RICT) was not sufficiently evaluated in a large cohort.…”

Comparative Effectiveness of Busulfan and Fludarabine versus Fludarabine and 400 cGy Total Body Irradiation Conditioning Regimens for Acute Myeloid Leukemia/Myelodysplastic Syndrome

“…This has resulted in similar OS between these approaches [5,10]. Similar to our analysis, a retrospective report from the Japan Society for Hematopoietic Cell Transplantation also observed no difference in survival or NRM when comparing lowdose TBI (≤400 cGy) and fludarabine with non-TBI approaches, including busulfan-and melphalan-based regimens [23]. A retrospective comparison of RIC versus myeloablative conditioning from French investigators reported significantly lower NRM for RIC but similar adjusted relapse rate and OS [24].…”

National survey on total-body irradiation prior to reduced-intensity stem cell transplantation in Japan: The Japanese Radiation Oncology Study Group

“…Although reduced-intensity stem cell transplantation (RIST) is thought to induce GVL effects via the use of immunosuppressive drugs, a shortened schedule of TBI is sometimes added to the conditioning regimen in clinical practice. A retrospective analysis of the database of the Japan Society for Hematopoietic Cell Transplantation [1] indicated that adjunctive TBI–RIST did not improve outcomes. Conversely, other reports concluded that TBI–RIST led to significantly better outcomes [2, 3].…”