Sibling donor transplantation in first remission has been used for many years as a primary approach to treatment of AML, with survival rates of 60% to 70% reported from many centers and cooperative groups.2,3,5,6
Improvements in risk stratification on the basis of genetic abnormalities in leukemic blasts and more effective chemotherapy protocols now allow the identification of subgroups of children with AML for whom transplantation is deemed unnecessary in first remission because cure with chemotherapy is equally likely.2
In parallel with interest in limiting use of transplantation in children with a good prognosis, there is increased interest in investigating whether unrelated donor transplantation can improve outcomes for children with particularly poor prognoses, such as those with primary induction failure and those who relapse after a first remission.11,19,20
In this study, we have explored outcomes in a large group of children receiving unrelated donor transplantations facilitated by the NMDP in the United States to determine how successful this therapy is in rescuing children for whom chemotherapy has been ineffective and to identify risk factors that predict a good outcome after transplantation.
The majority of children included in this study underwent transplantation in second remission. Overall, outcomes were encouraging, with almost half of the children receiving transplantation in second complete remission surviving 5 years later and significant numbers of survivors among the children with refractory disease receiving transplantation. In the current report, the only risk factor that predicted relapse, overall survival, and leukemia-free survival was disease status at the time of transplantation, with children who underwent transplantation in second complete remission having superior outcomes to children who underwent transplantation in relapse or with primary refractory disease. Despite this, 28% of children who underwent transplantation in relapse and 17% of children who underwent transplantation with primary induction failure were alive 5 years after transplantation, suggesting that transplantation can cure at least some children with the most resistant disease. It is perhaps surprising that length of first complete remission did not predict outcome in our study. This may be a reflection of the demographics of the patients, the majority of whom had experienced relapse early, with first complete remission of less than 12 months, limiting statistical power to look at this risk factor.
Children receiving transplantation in remission clearly had a superior outcome to those who underwent transplantation in relapse. It is commonly debated whether it is preferable to perform transplantation in children identified in early relapse immediately or to pursue reinduction chemotherapy and attempt to achieve a second remission before performing transplantation. Although our data show better disease control in children who underwent transplantation in remission, these patients had chemotherapy-sensitive disease and would, therefore, be expected to have better outcomes. Importantly, 76% of the patients who underwent transplantation in relapse had received chemotherapy but did not achieve remission; however, these patients had a 5-year probability of overall survival of 28%. This result suggests that transplantation is worthwhile in this group of particularly difficult patients. Our data are unable to definitively answer the question of the efficacy of immediate transplantation without an attempt at reinduction because there were only 22 such patients in this study. However, the 5-year leukemia-free survival rate was 25% in this group, which is similar to the rate in the group for whom reinduction was attempted. Most of the 22 patients reported good performance scores (90 to 100) despite a high tumor burden; nine patients had peripheral blasts, 10 patients had marrow blast counts of more than 10%, and three patients had marrow blast counts of 5% to 10%. We did not observe differences in leukemia-free survival rates after transplantation for patients in first relapse and second relapse, but there were only 24 patients in the latter group, and our inability to observe differences may be explained by the relatively small number of patients (5-year leukemia-free survival rates of 19% and 22%, respectively).
The importance of adverse cytogenetics was challenging to assess in this group. Our analysis failed to show a significant effect of intermediate- or poor-risk cytogenetics on leukemia recurrence, leukemia-free survival, or overall survival. This may be explained by the fact that patients with recurrent leukemia have high-risk disease, and consequently, the relevance of cytogenetics is limited by the relatively small sample size of approximately 260 patients. Data on cytogenetics were not available for approximately 23% of patients, which is a limitation that occurs when using data reported to an observational database and when transplantations are performed over a 10-year period because cytogenetic testing was not routinely performed during the early years. We adjusted for this limitation by stratifying all analysis of risk factors for transplantation outcome by cytogenetic risk group given the prognostic importance of cytogenetics for this disease.
Almost one third of grafts in this study were T-cell depleted. Although T-cell depletion reduced acute GVHD rates, treatment-related mortality was unchanged, as were leukemia-free and overall survival and relapse, indicating a neutral effect of T-cell depletion on overall outcome. As reported by others, we did not observe lower chronic GVHD rates after T-cell–depleted transplantations.21
Age and WBC count at diagnosis were not associated with transplantation outcome after a first relapse. This is similar to observations by Webb et al11
on outcome for children with relapsed AML after treatment on the Medical Research Council AML 10 trial at diagnosis. We did not observe a graft-versus-leukemia effect in our cohort. This may be explained by the inclusion of patients who received T-cell–depleted grafts (38% of patients) and patients with high tumor burden (47% of patients underwent transplantation in relapse or primary induction failure).
This study represents the largest series of children receiving unrelated donor bone marrow transplantation for AML currently in the literature. The strengths of the study are its large size and high-quality audited data. The limitations of the study are its retrospective nature, the heterogeneity inevitable in registry studies describing aggregate outcomes of transplantations performed at multiple centers, and our inability to compare transplantation outcomes to those after chemotherapy alone in a similar group of patients. We did not observe a significant correlation between year of transplantation, HLA mismatch, and survival, and this may be explained by the relatively few patients who received allele-matched bone marrow grafts in this report. Larger studies in unrelated donor bone marrow transplantation clearly demonstrate the negative effect of HLA mismatch on survival, and matching between donor and recipient using allele-level typing at HLA-A, HLA-B, HLA-C, and DRB1 represents the current standard of care.22
Despite these limitations, these data indicate that unrelated donor bone marrow transplantation is an effective therapy for a significant proportion of children with recurrent or refractory AML who are unlikely to be cured with chemotherapy alone.