Fludarabine-Based Reduced Intensity Hematopoietic Stem Cell Transplantation (RIST) for Patients Aged 50–70 Years with Acute Lymphoblastic Leukemia (ALL) in Remission: A Study From the ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT)

Although RIST has become more popular for elderly patients with leukemia, its value for ALL patients is still uncertain. To clarify the clinical significance of RIST for elderly patients with ALL in remission and identify prognostic factors for recipients, we retrospectively surveyed ALL patients receiving RIST who were registered in the JSHCT database. Patients and Methods: This study included ALL patients aged ≥ 50 years who received fludarabine-based RIST as the first transplantation between 2000 and 2009. The preparative regimen was classed as fludarabine-based reduced intensity conditioning if it included non-myeloablative chemotherapy (total dose of busulfan ≤ 8 mg/kg or melphalan ≤ 140 mg/m²) with or without total body irradiation (TBI) ≤ 6 Gy. Results: There were 144 patients, including 118 in first complete remission (CR1) and 26 in CR2. Their median age was 59 years (range: 50–70 years), with 71 males and 73 females. Eighty-seven patients had Philadelphia chromosome-positive ALL. Conditioning regimens contained fludarabine combined with melphalan (n=70), busulfan (n=58), or cyclophosphamide (n=16). TBI plus chemotherapy was used in 90 patients. Bone marrow from related or unrelated donors was transplanted in 71 patients, as well as peripheral blood stem cell from related donors in 31 patients and cord blood in 42 patients. Primary graft failure occurred in 7 patients. Granulocyte and platelet engraftment was achieved after a median of 15 and 26 days, respectively. The incidence of grade II-IV and grade III-IV acute GVHD was 37% and 19%, respectively. After a median follow-up of 16 months (range: 1–83 months), 3-year overall survival (OS) was 53%. The cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) at 3 years was 29% and 31% respectively. According to univariate analysis, factors associated with worse 3-year OS included a high leukocyte count (≥ 30,000 /μl) at diagnosis (vs low leukocyte count: 35% vs 61%, p=0.004), CR2 at transplantation (vs CR1: 30% vs 58%, p=0.014), and grade III-IV acute GVHD (vs grade 0-II: 25% vs 63%, p<0.001). CR2 status (vs CR1: 49% vs 25%, p=0.013) and related donors (vs unrelated donors: 40% vs 24%, p=0.037) were significantly correlated with higher 3-year CIR. Adverse factors for NRM were grade III-IV acute GVHD (vs grade 0-II: 62% vs 22%, p<0.001), older patients (vs younger patients: 40% vs 24%, p=0.022), male (vs female: 37% vs 24%, p=0.041), a high leukocyte count (vs low leukocyte count: 45% vs 24%, p=0.010) and unrelated donors (vs related donors: 38% vs 18%, p=0.025). There was no association of the conditioning regimen with the outcome of transplantation. Multivariate analysis showed that a high leukocyte count (hazard ratio (HR), 2.52; 95% confidence interval (CI), 1.42–4.47; p=0.002) was an independent determinant of 3-year OS. Both CR2 status (HR, 3.82; 95% CI, 1.70–8.58; p=0.001) and unrelated donors (HR, 0.40; 95%CI, 0.17–0.90; p=0.027) were also correlated with 3-year CIR, while grade III-IV acute GVHD (HR, 3.97; 95% CI, 1.70–8.76; p<0.001) and a high leukocyte count (HR, 2.59; 95% CI, 1.22–5.52; p=0.014) were independently associated with higher 3-year NRM. Conclusions: This retrospective survey suggested that fludarabine-based RIST is a promising strategy for elderly patients with ALL in remission. Prognostic factors detected in this study might be useful to stratify patients for comparison of RIST with myeloablative hematopoietic stem cell transplantation.

No relevant conflicts of interest to declare.