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.

Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation

“…This indirectly demonstrates the susceptibility of AML to graftversus-tumor effects. In contrast, as observed by other groups of investigators, 10,20,21 current data indicated that grade II acute GVHD had no net impact on LFS/OS because the lower risk of relapse in patient with grade II-IV acute GVHD was offset by a higher NRM, and grade III-IV acute GVHD was associated with worse LFS/OS. Second, current data confirmed an association between chronic GVHD and a lower risk of AML relapse, as observed previously by other groups of investigators, 10,11 but demonstrated that the beneficial effect of chronic GVHD in terms of survival was restricted to patients with limited chronic GVHD, given that extensive chronic GVHD was strongly associated with higher NRM.…”

“…28 Given the close relationship between GVHD and GVL, this study sought to assess the impact of GVHD on outcome in a large and rather homogeneous cohort of AML patients given PBSC after various RIC, and particularly at assessing the impact of GVHD on survival given the divergent results observed in studies containing fewer number of patients. [10][11][12][20][21][22][23][24] Several observations could be drawn from the current findings. First, current study observed a positive impact (that is, lower risk of relapse translating into better LFS) of grade I acute GVHD on transplantation outcomes in patients given RIC allo-SCT for AML.…”

“…[7][8][9][10][11][12][13][14][15][16][17][18][19] The goal of RIC allo-SCT is to harness the GVL effect, 7 while minimizing toxicities and the risk of GVHD. However, this is a delicate balance as a number of prior studies have shown a lower risk of relapse in AML patients who experienced chronic GVHD after RIC allo-SCT compared with those patients who did not, [10][11][12]20,21 while some other studies failed to find such an association. 22,23 A recent analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR) analyzed the impact of GVHD in a cohort of patients with AML or myelodysplastic syndrome given various graft types after RIC conditioning.…”

Achieving stringent CR is essential before reduced-intensity conditioning allogeneic hematopoietic cell transplantation in AML

“…14,15,42 This is particularly applicable for RIC allo-HCT. 11,21,[43][44][45] We observed a reduced risk of relapse in CMV seropositive recipients. Although we did not evaluate CMV reactivation after allo-HCT, CMV reactivation after allo-HCT has been associated with a decreased risk of relapse, 46 possibly due to promotion and persistence of educated natural killer cells.…”

Impact of ABO blood group mismatch in alemtuzumab-based reduced-intensity conditioned haematopoietic SCT

“…32,33 This has been overcome in part by the use of alemtuzumab, an anti-CD52 monoclonal antibody that has significantly reduced the risk of GVHD 34 without affecting risk of relapse or survival, and forms the basis of many modern-day conditioning regimes. 35 We sought to address the impact of ABO mismatch on both transplant outcomes and transfusion requirements in a clearly defined, homogeneous cohort undergoing RIC HSCT with alemtuzumab conditioning.…”