Despite multiple prospective studies over the past two decades, the role of alloSCT for adult AML-CR1 patients remains ill-defined. A meta-analysis of 5 prospective trials by Yanada et. al.
indicated an overall OS benefit with alloSCT (p=0.04), and meta-regression suggested that the OS benefit may be restricted to poor-risk AML (p=0.12). 5
In addition to the limited number of trials and the use of indirect evidence (meta-regression) to indicate possible cytogenetic subgroup benefit, double counting of alloSCT data from individual studies that reported alloSCT versus autoSCT and consolidation chemotherapy outcomes separately remains an unaddressed source of bias. An ITT donor no-donor analysis offers a better means to address such concerns. Cornelissen et. al.
combined donor no-donor data from four cooperative groups (BGMT, HOVON/SAKK, MRC and EORTC) in a meta-analysis to demonstrate a statistically significant survival benefit to alloSCT; and in cytogenetic subgroup analyses, an OS benefit was documented for intermediate-risk, but not poor-risk AML. 30
The limited number of trials assessed (e.g. omission of EORTC AML8A study) has likely precluded general acceptance of their meta-analysis.
Thus, current recommendations from NCCN, and from the American Society of Blood and Marrow Transplantation (ASBMT), based on literature review and expert consensus, stratify treatment by cytogenetic risk, and state that there is a survival advantage for alloSCT in patients <55 years with poor-risk AML-CR1; that there is insufficient evidence to routinely recommend alloSCT for patients with intermediate-risk AML-CR1; and that there is no survival advantage for alloSCT in good-risk AML-CR1. 4
The direct evidence supporting these recommendations remains limited, as previously discussed. In part, this may be because all clinical trial data has not been systematically assessed. Quantitatively integrating data from all available trials will likely enhance our understanding of the role of alloSCT for AML-CR1. The robustness of any conclusions can be systematically assessed in secondary analyses.
To comprehensively assess the utility of upfront alloSCT for AML-CR1, we therefore undertook a systematic literature review and meta-analysis of published data from clinical trials allocating alloSCT versus non-alloSCT options (consolidation chemotherapy and/or autoSCT) for such patients. We focused on an ITT analysis based on donor availability in order to capture information from all AML patients who were evaluated for upfront alloSCT with a donor search as part of a prospective trial. Prior meta-analyses have shown that survival after autoSCT is equivalent to that with consolidation chemotherapy for AML-CR1 patients, supporting the decision to combine the non-alloSCT treatment options in a single no-donor category. 6, 7, 37
The systematic literature search identified 24 relevant trials comparing alloSCT versus non-alloSCT treatment for AML-CR1, none of which individually reported an alloSCT OS benefit across all cytogenetic risk groups (), possibly owing to limited sample size (power calculations were not routinely described in the study reports). Enrolling patients between 1982 and 2006, the trials are all mature, and further long-term follow-up is unlikely to yield substantially different results. The trials varied with regards to patient eligibility, study trial design, cytogenetic risk classification and specific interventions used (). Importantly however, inter-study heterogeneity was not significant for OS or RFS endpoints, indicating that the impact of study differences was limited.
Summary of clinical trials evaluating alloSCT benefit for AML in CR1: Therapies utilized
We considered the effect, if any, of differences in cytogenetic risk classification between studies. Such differences, if significant, may be anticipated to increase the between-studies heterogeneity for each cytogenetic risk group’s endpoints, which was not observed. This is likely because the various cytogenetic risk classification schemes are fairly similar, although not identical. 30
While we could not assess the impact of such differences directly, individual prospective studies that directly compared cytogenetic risk classifications (SWOG/ECOG, EORTC/GIMEMA, MRC) documented highly concordant effect estimates, independent of the classification schema used. 25, 26
It is therefore unlikely that variability between cytogenetic risk classifications significantly impacted our analysis.
We also considered the role of treatment compliance. This likely disproportionately impacts the alloSCT (donor) arm, as a significant fraction of patients with donors did not receive alloSCT. Such crossover, analyzed on an ITT basis, is anticipated to reduce the observable survival benefit of alloSCT. Typically, the studies reported an alloSCT compliance rate of >60%, which is considered reasonable for such prospective trials (one trial reported an alloSCT compliance rate of 55%, and in a sensitivity analysis, its removal did not impact the overall conclusions). In addition, the impact of salvage alloSCT after AML relapse cannot be estimated, but likely diminishes any observable OS benefit of upfront alloSCT. Further, the inclusion of older trials, some over two decades old, likely also biases against alloSCT, since advances in supportive care (e.g. growth factors; improved anti-infective strategies; better prophylaxis/therapy of graft-versus-host disease) and transplantation methodology (e.g. PBSC) are considered responsible for improvement in alloSCT outcomes.
Our primary finding is that the totality of the prospective trial data indicates statistically significant RFS and OS benefit for alloSCT in adult AML-CR1. This conclusion is supported by a variety of sensitivity and subgroup analyses as reported above. Additionally, our analyses indicate that alloSCT benefit likely varies by AML cytogenetic risk. We document significant RFS and OS benefit for alloSCT in intermediate- and poor-risk AML, and a lack of significant RFS or OS benefit for good-risk AML. With regards comparative absolute survival, anticipating 5-year OS rates in the control (non-alloSCT) arm of 45% and 20% for intermediate- and poor-risk AML respectively, patients assigned alloSCT in CR1 would likely experience OS rates of 54% and 42% for intermediate- and poor-risk AML respectively.
There are limitations to our analysis. We are aware of relevant studies that have not yet been reported (e.g. UK MRC AML 12/15; GOELAM2). 38–40
As a meta-analysis of the published literature, we extracted summary statistics (HR) from individual studies to determine combined estimates. Dependence on published articles limits the level of detail that can be captured regarding sub-groups that may have greater or lesser benefit from alloSCT. We could not assess outcomes for clinically relevant subgroups other than cytogenetic risk. For instance, patient age is a likely relevant factor, and some, though not all, studies have indicated improved alloSCT outcomes in younger adults. 26, 29, 30
The median patient age in most trials in this report is in the 30s, and while the age eligibility was up to age 60 years in individual studies, it remains unclear if older eligible patients obtained an equivalent benefit.
With regards treatment toxicity, we have summarized available TRM data for individual studies (). However, the variable and limited data reported precluded a more formal analysis, and highlights the need for more systematic reporting of this important endpoint in the future. We also note that while patients in this analysis predominantly had de-novo AML, eligibility criteria in some studies permitted enrollment of patients with prior MDS or therapy-related AML. Finally, the impact of comorbidities could not be assessed, since trial eligibility criteria disbarred entry to such patients. Nonetheless, for treatment outside of the research setting, it has significant impact on alloSCT outcomes in AML. 41, 42
A meta-analysis of individual patient data from the relevant clinical trials is a way to obtain more complete estimates of OS and RFS benefit with alloSCT; and to assess the impact of additional factors like patient age. A broad overview of transplant for AML-CR1 utilizing individual patient data is currently being conducted by the Acute Leukemia Stem Cell Transplant Trialists’ Collaborative Group. Nonetheless, our quantitative analysis of data from 24 trials comprising 6,007 prospectively assigned patients provides the most complete estimate of alloSCT benefit available. It enables an informed assessment of the role of upfront alloSCT for adult AML patients in CR1.
Cytogenetic and molecular risk profiling in AML is an evolving field, and can further stratify outcomes within a known cytogenetic risk group. For instance, Schlenk et. al.
from the German Austrian AML Study Group (AMLSG) reported that for patients with cytogenetically normal AML (who would be classified as intermediate-risk), alloSCT was beneficial for those with either a FLT3 internal tandem duplication (FLT3-ITD), or in the absence of FLT3-ITD, for those without mutations in NPM1 and CEBPA; while for the subgroup with mutations in NPM1 and without FLT3-ITD there was no apparent benefit to having a matched sibling. 31
However, such novel genetic lesions, as well as whole genome analyses, RNA and microRNA profiles that have the potential to further refine AML risk, are not in routine clinical use. 43, 44
The dilemma of how to best treat adult AML-CR1 patients with a known cytogenetic risk profile therefore remains. While enrollment in therapeutic trials is to be encouraged, our findings provide evidence to guide clinical decision-making and future trial design. We find evidence to support treatment based on AML cytogenetic risk. We conclude that alloSCT does not provide significant benefit for good-risk AML in CR1; and that alloSCT offers significant RFS and OS benefits for intermediate- and poor-risk AML in CR1. However, within these general guidelines, there remains a need to further individualize the alloSCT decision, based on factors like patient age, comorbidity, and the presence of additional molecular lesions.