Conditioning Regimens Prior to Allogeneic Stem-Cell Transplantation (SCT) In Acute Leukemia: The Role Of Dose Intensity

Abstract

Allogeneic SCT with both myeloablative and reduced-intensity conditioning (RIC) is effective therapy in acute leukemia. To better define the role of dose intensity in SCT, we retrospectively analyzed SCT outcomes in 356 consecutive adult patients (pts) with MDS/AML (n = 277) and ALL (n = 79) given SCT over an 8-year period in a single institution. The median age was 51 (range, 17–75). The donors were HLA-matched siblings (n = 191), matched unrelated (n = 139) and alternative (n = 26). Pts meeting standard eligibility criteria were routinely given myeloablative conditioning (MAC, Cy/TBI or BuCy, n = 141). Pts non-eligible for MAC were given either RIC (fludarabine and reduced doses of busulfan or melphalan, n = 116) or modified myeloablative conditioning (modMAC, fludarabine with myeloablative doses of busulfan or treosulfan, n = 99). Disease status at SCT was CR1/ CR2 (n = 176), previously untreated or untreated relapse (n = 63) and chemo-refractory (n = 117). With a median follow-up of 30 months (range 1–103), 159 pts are alive and 197 died; 75 of treatment-related causes and 122 of relapse. The estimated 5-yr overall survival (OS) in this relatively high-risk pt group was 34% (95%CI, 27–41). The status of disease at SCT was the most important factor predicting OS; 48, 31 and 16% for pts in CR, untreated or chemo-refractory leukemia, respectively (p<0.001). Multivariable analysis (MVA) identified SCT not in CR, SCT from unrelated and alternative donors as adverse prognostic signs with hazard ratios (HR) of 2.7, 1.5, and 2.2, respectively. The conditioning regimen used was not a significant factor in the whole pt group with 5-yr OS of 38, 35 and 31% after MAC, modMAC and RIC, respectively (p = NS). However, RIC was associated with reduced OS in 2 subgroups. Among pts with MDS/AML given SCT not in CR, 5-yr OS was 34, 24 and 13% after MAC, modMAC and RIC, respectively (p = 0.03) with HR of 1.6 for RIC in MVA. In the group of ALL pts, MVA identified RIC and SCT not in CR1 as adverse prognostic signs with HR of 2.0 (p = 0.04) and 2.0 (p = 0.03), respectively. In conclusion, MAC should still be considered the standard of care for SCT in acute leukemia in eligible pts. RIC is associated with inferior outcome in pts with ALL and pts not in CR at SCT. Randomized studies are needed to determine the role of RIC in MDS/AML pts in CR at SCT. The novel modMAC regimens are relatively well tolerated even in pts not eligible for MAC and may be more effective than standard RIC in refractory disease.