|Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials
|Koreth J, Schlek R, Kopecky K J, Honda S, Sierra J, Djulbegovic B J, Wadleigh M, DeAngelo D J, Stone R M, Sakamaki H, Appelbaum F R, Dohner H, Antin J H, Soiffer R J, Cutler C
This generally well-conducted review concluded that allogeneic stem cell transplantation for treating acute myeloid leukaemia had benefits for intermediate risk and poor risk acute myeloid leukaemia. Although the general conclusion seemed reliable, heterogeneity and inconsistencies limited the reliability of the pooled estimates, and smaller numbers of participants in the chemotherapy trials indicated that evidence in this area was weaker than for autologous treatment.
To assess the relapse-free survival and overall survival benefits of allogeneic stem cell transplantation for treating acute myeloid leukaemia.
MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials were searched to March 2009 using reported search terms. References of relevant articles, systematic reviews and meta-analyses, and abstracts of relevant scientific meetings were also searched. International experts were contacted to identify further studies.
Prospective trials of adults with acute myeloid leukaemia in first complete remission that compared allogeneic stem cell transplantation with consolidation chemotherapy, autologous stem cell transplantation, or both, were eligible for inclusion in the review. Trials had to report hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival benefit and/or relapse-free survival benefit on an intention-to-treat donor versus no-donor basis (or provide data to estimate HRs).
The trials included in the review studied populations aged between one year and 60 years with newly diagnosed acute myeloid leukaemia, adequate organ function and no significant concomitant disease. The proportion of patients in first complete remission ranged from 56 per cent to 89 per cent. Trials compared allogeneic stem cell transplantation with autologous stem cell transplantation and/or with consolidation chemotherapy. Some trials also included an observation group. Daunorubicin or idarubicin, with cytarabine, were commonly used as induction therapies.
Two reviewers screened studies for inclusion; this was done independently for the full paper stage only.
Assessment of study quality
Study quality was assessed with regard to the following criteria: the requirement for prospective treatment assignment; reporting of intention-to-treat outcomes; study size; number of participating centres; adequacy of induction chemotherapy; and the proportion of patients allocated allogeneic stem cell transplantation who actually received transplantation. The authors did not state how the validity assessment was performed.
Two reviewers independently extracted HRs and 95% CIs (or data from which they could be calculated). Any disagreements were resolved by consensus. Authors were contacted for missing data.
Methods of synthesis
Meta-analyses were used to pool data using fixed-effect and random-effects models. Heterogeneity was assessed using the Q and I2 statistics. Subgroup/sensitivity analyses were performed in relation to study quality, trials stratifying treatment by cytogenetic risk and trials reporting only relapse-free survival. An outlier study with missing data was excluded. Funnel plots were used to assess publication bias.
Results of the review
Twenty-four trials (n=6,007) were included in the review. Overall the studies were considered to be of good quality. Allogeneic stem cell transplantation adherence was reasonable for most trials. Median follow up ranged from 19 to 142 months. Funnel plots did not show any evidence of publication bias.
Treatment with allogeneic stem cell transplantation reduced the incidence of death or relapse (18 trials, HR 0.80, 95% CI:0.74, 0.86, p<0.01, I2=0%). Subgroup analyses by cytogenetic risk also showed significant benefit for poor risk (14 trials, HR 0.69, 95% CI:0.57, 0.84) and intermediate risk acute myeloid leukaemia (14 trials, HR 0.76, 95% CI: 0.68, 0.85), but not for good risk acute myeloid leukaemia (10 trials). Allogeneic stem cell transplantation treatment also resulted in significant overall survival benefit (15 trials, HR 0.90, 95% CI: 0.82, 0.97, I2=18.5%). Subgroup analyses by cytogenetic risk also showed significant benefit for poor risk (14 trials, HR 0.73, 95% CI: 0.59, 0.90) and intermediate risk acute myeloid leukaemia (14 trials, HR 0.83, 95% CI: 0.74, 0.93), but not for good risk acute myeloid leukaemia (10 trials).
Results from sensitivity analyses were also reported.
Compared with non-allogeneic stem cell transplantation therapies, allogeneic stem cell transplantation has significant relapse-free survival and overall survival benefits for intermediate risk and poor risk acute myeloid leukaemia, but not for good risk acute myeloid leukaemia in first complete remission.
The review addressed a clear question supported by appropriate inclusion criteria. Attempts were made to identify relevant studies by searching three databases and using other methods. It was not clear whether the authors searched for studies published in any language (experts were contacted in non-English speaking countries). The study selection and data extraction processes were conducted in duplicate. No methods were reported for the quality assessment. Study quality assessment was appropriate, as the inclusion criteria precluded inclusion of poorer-quality studies. Meta-analyses using both fixed-effect and random-effects models were used to pool data. Where reported, there was no statistically significant heterogeneity, but there was clinical heterogeneity, particularly between the comparator groups. There was also a number of discrepancies between the forest plots and the text, and the number of studies included in the analyses was unclear, so the reliability of the pooled results was uncertain. The reporting of heterogeneity results was often incomplete or unclear, in both the text and forest plots. This was a generally well-conducted review, and although there is some question over the reliability of the pooled results, the general conclusions seem reliable. However, the smaller numbers of participants in the chemotherapy trials indicated that the evidence in this area was weaker than for autologous treatment; analyses stratified by comparator would have demonstrated this.
Implications of the review for practice and research
Practice: The authors stated that within the general guidelines there remained a need to further individualise the allogeneic stem cell transplantation decision, based on factors such as patient age, comorbidity and the presence of additional molecular lesions.
Research: The authors stated that more systematic reporting of adverse events was required, and that a meta-analysis of individual patient data could provide more complete estimates of RFS and overall survival benefits.
Koreth J, Schlek R, Kopecky K J, Honda S, Sierra J, Djulbegovic B J, Wadleigh M, DeAngelo D J, Stone R M, Sakamaki H, Appelbaum F R, Dohner H, Antin J H, Soiffer R J, Cutler C. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 2009; 301(22): 2349-2361
Subject indexing assigned by NLM
Antineoplastic Agents /therapeutic use; Clinical Trials as Topic; Humans; Leukemia, Myeloid, Acute /mortality /therapy; Remission Induction; Risk Assessment; Stem Cell Transplantation; Survival Analysis; Transplantation, Homologous
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.