Postremission therapy for acute myeloid leukemia (AML) generally includes either consolidation with chemotherapy used in induction, or intensification using non–cross-resistant agents. Of approximately 60% of patients younger than 55 years who attain first remission with standard induction therapy, projected disease-free survival (DFS) rates range from 20% to 40%. Allogeneic transplantation performed in first remission can provide long-term DFS approximating 65% in young adults with histocompatible sibling grafts, with inferior outcomes observed in patients with advanced age (< 30 years), advanced disease, or infusion of unrelated adult or partially matched donors. Unrelated umbilical cord blood (UCB) has therefore been explored as a potential alternative graft source for AML patients lacking a sibling donor. However, low nucleated cell doses contained in a single UCB unit have limited its widespread use, particularly in adults, and initial reports of high-risk patients enrolled in phase 1 trials demonstrated inferior survival rates compared with conventional grafts.1
In this issue, Ooi and colleagues at the University of Tokyo (page 489) report clinical outcomes in 18 adults with de novo AML, of whom 14 were beyond first remission. These patients were treated with fully ablative total body irradiation (TBI)–based conditioning and infusion of allogeneic unrelated cord blood transplantation. The median age of the patients in this series was 43 years. No patient had a related or unrelated bone marrow donor available at the time of cord blood transplantation. Each patient received a single UCB unit thawed and infused without prior ex vivo expansion. Median cryopreserved UCB graft nucleated cell dose was 2.5 × 107/kg. Of these 18 adult patients, 17 demonstrated sustained donor engraftment, and median day to absolute neutrophil count of 0.5 × 109/L was 23 days. In the 17 patients demonstrating myeloid reconstitution, chimerism analyses confirmed full donor engraftment. On day 27, 1 patient died with organ toxicity, and 3 patients relapsed within the first 2 years after transplantation. The remaining 14 patients are alive and free of disease for up to 48 months of follow-up, and probability of DFS at 2 years was 76.6%. Further observations outlined in this issue parallel those reported in other adult patient series, that use of unrelated cord blood has been associated with a low incidence of severe acute and chronic graft-versus-host disease (GVHD). The majority (17) of these patients received standard cyclosporine + methotrexate as GVHD prophylaxis. One patient demonstrated severe (< grade II) acute GVHD and 3 patients demonstrated extensive chronic GVHD. All patients who are alive and disease-free received cord blood grafts containing more than 2 × 107 nucleated cells per kilogram, attributable in part to the shorter stature of these Japanese patients (median weight, 55.2 kg). These results confirm the importance of cord blood graft cell dose in determining optimal engraftment rates and survival in adults.
Recent advances in AML pathophysiology and proposed new therapeutic strategies include the following: identification of overexpressed differentiation antigens as targets of graft-versus-leukemia effect,2 fms-related tyrosine kinase 3 (Flt3) mutations, and antibody-targeted chemotherapy with immunoconjugates of calicheamicin (gemtuzumab ozogamicin). Despite these advances, a large proportion of patients treated for AML succumb either to the disease or to complications related to its treatment. As outlined by the study reported by Ooi et al, the use of banked unrelated cord blood as an alternative allogeneic graft source results in durable remissions for adults with de novo AML, elicits low rates of severe GVHD, and is associated with acceptable survival rates. Further studies are warranted to determine the impact of improved HLA matching and higher graft cell dose threshold (< 2 × 107/kg) on unrelated donor UCB stem cell transplantation outcomes in adults with AML.
- Copyright © 2004 by The American Society of Hematology