Allogeneic hematopoietic stem cell transplantation for the treatment of high-risk acute myelogenous leukemia and myelodysplastic syndrome using reduced-intensity conditioning with fludarabine and melphalan

Abstract

Reduced-intensity conditioning has extended the use of allogeneic hematopoietic stem cell transplantation (HSCT) to patients otherwise not eligible for this treatment due to older age or frailty. One hundred twelve acute myelogenous leukemia/myelodysplastic syndromes patients received fludarabine and melphalan (FM) conditioning with allogeneic HSCT. Most patients (73%) were not in remission. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini-methotrexate. Median age was 55 years (range, 22-74). Donors were related (53%) and unrelated (47%). Median follow-up of surviving patients (n = 43) was 29.4 months (range, 13.1-87.7). The complete remission (CR) rate was 82%. Estimates of 2-year survival were 66%, 40%, and 23% for patients in CR, with active disease without and with circulating blasts at HSCT, respectively. In multivariate analysis, survival was negatively influenced by active disease at HSCT and development of grade II-IV acute GVHD. Presence of circulating blasts at HSCT negatively influenced freedom from disease progression. Incidence of nonrelapse mortality (NRM) was significantly higher for patients with active disease, but was not influenced by patient age. Patients in CR had a day-100 and 2-year NRM of 0% and 20%, respectively. Use of unrelated donors increased the risk of NRM only among patients with active disease. FM and HSCT elicited long-term disease control in a significant fraction of this high-risk cohort.

Figure 1

(A) Patients in complete remission at transplantation: survival, cumulative incidence of disease relapse, and nonrelapse mortality, showed by melphalan dose in the conditioning regimen (solid line, fludarabine [F] and melphalan [M] 100 mg/m²; tight dashed line, FM180 mg/m²; spaced dashed line, FM140 mg/m²). Patients receiving FM100 in complete remission were older than those treated with FM140 or FM180 (59 versus 43 years, P = .002). Most patients in the FM100 subgroup were in first remission, while recipients of FM140 or FM180 were mostly in second remission. Differences in outcomes were not statistically significant. (B) Patients with active disease at transplantation: survival, cumulative incidence of disease relapse, and nonrelapse mortality showed by melphalan dose (tight dashed line, FM180 mg/m²; spaced dashed line, FM 140 mg/m²). Differences in outcomes were not statistically significant.

Figure 2

Cumulative incidence of disease progression by disease status at transplantation.

Figure 3

Overall survival by disease status at transplantation. Kaplan-Meier estimates of overall survival of all patients, as a function of disease status at transplantation. Estimates of 2-year overall survival were 66% for those in remission, 40% for patients with active disease without circulating blasts, and 23% for those with circulating blasts. P = .0007 for the overall comparison. Compared to patients in remission, patients with active disease at transplantation had worse survival (P = .02, for the comparison with patients with circulating blasts, and P = .06, for patients without circulating blasts). Among patients with active disease, presence of peripheral blood blasts was associated with worse survival (P = .06).

Figure 4

Cumulative incidence of nonrelapse mortality was higher for patients transplanted with active disease.