Non-relapse mortality (NMR) may turn for the worse overall outcome of conventional myeloablative conditioning (MAC) allo-stem cell transplantation (SCT) for elderly patients and patients with comorbidities. Therefore, allo-SCT using reduced intensity conditioning (RIC) may provide opportunities to obtain a significant clinical effect without the adverse effects of intense myeloablative preparative regimens.
Aims: In this Japanese nationwide survey we reported the outcome of 575 adult acute lymphoblastic leukemia (ALL) patients age at the first transplantation 45 years or more who underwent allo-SCT in CR and analyzed according to the type of conditioning regimen (MAC vs RIC) before allo-SCT registered in the JSHCT database between 2000 and 2009.
The preparative regimen was classed as fludarabine-based RIC if it included non-myeloablative chemotherapy (total dose of busulfan ≤ 9 mg/kg or melphalan ≤ 140 mg/m2) with or without total body irradiation (TBI) ≤ 8 Gy (206 patients). Also, MAC included (total dose of busulfan > 9 mg/kg, melphalan > 140 mg/m2 or cyclophosphamide 120mg/kg) with or without TBI > 8 Gy (369 patients). Their median age was 51 years for MAC and 58 years for RIC (range: 45–70 years), with 280 males (180 vs 100) and 295 females (189 vs 106). There were 310 patients in the first complete remission (CR1) and 55 patients in the second CR (CR2) for MAC and 160 patients and 40 patients for RIC. Bone marrow from related or unrelated donors was transplanted in 343 patients (234 vs 109), as well as peripheral blood stem cell from related donors in 96 (47 vs 49) patients and cord blood in 127 (80 vs 47) patients.
Patients in the RIC group were older (median age, 58 vs 51 years, p<0.0001). The incidence of grade II-IV acute graft-versus-host (GVHD) was 44% of MAC group and 42% of RIC group. There were no statistically differences in one- and three-year overall survival (OS), disease-free survival (DFS) and non-relapse mortality (NRM): 51% vs 53%, 47% vs 39% and 38% vs 36%, respectively. Relapse rate in the RIC conditioning group at 3 years was higher than that in the MAC group (26% vs 15%, p= 0.008). Multivariate analysis showed that CR2 and HLA mismatching were associated with poor OS (p=0.002 and p=0.019, respectively). HLA mismatching was associated with lower rate of relapse (p=0.016) but was associated with higher rate of NRM (p=0.001). RIC was associated with good OS and DFS in patients who received HLA-mismatch transplantation and were aged 55 years or more compared with MAC by multivariate analysis for each event with interaction (HR and 95% CI: 0.35 and 0.15–0.81, p=0.014 for OS and 0.36 and 0.16–0.81, p=0.013 for DFS). Conversely, MAC showed good OS and DFS in patients with HLA matching and aged less than 50 years (HR and 95% CI: 3.88 and 1.60–9.43, p=0.003 for OS and 3.51 and 1.52–8.09, p=0.003 for DFS) (Fig. 1).
This retrospective survey showed that conditioning intensity did not affect OS or DFS for adult ALL patients aged 45–70 years at transplantation. However, patients aged 55 years or more with HLA mismatch transplantation would be candidates for RIC rather than MAC.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.