Allogeneic Stem-Cell Transplantation in Patients with AML and MDS Using Myeloablative Versus Reduced-Intensity Doses of Intravenous Busulfan : The Role of Dose Intensity.

Allogeneic stem cell transplantation (SCT) is a potentially curative approach in patients (pts) with AML and MDS. Intravenous busulfan (Busulfex, ivBu) was shown to reduce treatment-related mortality (TRM) and improve outcome after standard ablative conditioning. Reduced-intensity regimens allows SCT in pts not eligible for standard conditioning. It is not yet well established what are the dose intensities of ivBu predicting of better outcome in different settings. Eighty-six pts were included in this analysis; median age 50 years (range, 18–69). Seventy-one had AML; 31 of them had secondary AML following prior MDS (n=19) or prior chemotherapy (n=12, including 6 prior autologous SCT), and 15 had MDS (all with excess of blasts). The donors were HLA-matched siblings (n=42), 1-Ag mismatched relatives (n=6) or matched-unrelated (n=38). Thirty-six pts were in first or second remission at the time of SCT, or with less than 10% marrow blasts, 32 were chemo-refractory, and 18 had untreated MDS or relapsed AML and > 10% marrow blasts. Forty-two pts had myeloablative conditioning with ivBu (12.8 mg/kg) and cyclophosphamide. Forty-four pts considered not eligible for myeloablative therapy due to advanced age, comorbidities or extensive prior therapy were given fludarabine and reduced intensity doses of ivBu (6.4–12.8 mg/kg). With a median follow-up of 13 months, the 1-year overall (OS) and disease-free survival (DFS) rates of all pts were 47% and 44%, respectively. The cumulative incidence of TRM was relatively low at 17% and relapse rate was 40%. The most important predictive factor for survival in multivariant analysis was chemo-refractory disease at SCT (HR 3.2, p=0.001). Age, gender, secondary AML/MDS, donor type and conditioning regimen used were not significant. In particular there was no difference in survival between pts given different doses of ivBu. The OS and DFS of pts given 12.8 mg/kg (Bu16) (with cyclophosphamide or fludarabine) were 47% and 45%, compared with 50% and 45% in pts given 6.4–9.6 mg/kg (Bu8–12). Pts given Bu16 had higher risk of TRM (21% vs 7%) and lower relapse rate (33% vs 50%), not reaching statistical significance. However, the conditioning regimen had a significant influence when only pts with chemo-refractory disease were analyzed. OS, DFS, TRM and relapse rates were 39%, 38%, 26%, and 36% in pts given Bu16 compared with 0% (p=0.06), 0% (p=0.06), 19% (p=NS), and 81% (p=0.03) after Bu8–12, respectively. ivBu dose intensity did not influence outcome in chemo-sensitive disease. Pts previously untreated with > 10% marrow blasts had similar outcome to pts with chemo-sensitive disease if given Bu16, but similar to refractory disease if given Bu8–12. In conclusion, ivBu containing regimens are well tolerated with relatively low TRM rates, in particular in chemo-sensitive disease, and after reduced intensity conditioning. Busulfan dose intensity is not predictive of outcome in chemo-sensitive disease. However, pts with chemo-refractory or untreated disease could only be salvaged if given myeloablative doses of ivBu. Pts considered not eligible for standard ablative conditioning tolerated fludarabine and myeloablative doses of ivBu relatively well, and could be salvaged with this regimen even when treated for chemo-refractory disease. TRM remains acceptable even in these high-risk settings. Randomized studies will be needed to further determine the best dose-intensity in each setting.