Meta-Analysis of Transplant for AML in CR1
Meta-Analysis of Transplant for AML in CR1
Abstract & Commentary
By Andrew S. Artz, MD, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships relevant to this field of study.
Synopsis: Allogeneic hematopoietic cell transplantation (alloHCT) is recommended for consolidation among poor-risk AML patients in CR1, but controversy remains for intermediate-risk disease. Koreth et al performed a meta-analysis of clinical trials among HCT eligible subjects that were "genetically randomized": subjects having an HLA-matched sibling donor underwent alloHCT consolidation in CR1, and those without a donor underwent consolidation treatment with chemotherapy or an autologous HCT. Among 24 trials enrolling 6,007 patients, 3,638 were analyzed by cytogenetic risk group. AlloHCT for AML in CR1 compared to consolidation or autologous HCT led to significantly improved overall survival for intermediate-risk disease (HR 0.76; 95% CI, 0-68-0.85) and poor-risk AML (HR, 0.69; 95% CI, 057-0.84). For good-risk AML in CR1, survival did not differ (HR, 1.06; 95% CI, 0.82 - 0.97). Relapse-free survival showed similar results. AlloHCT consolidation improved relapse-free and overall survival for AML in CR1 with intermediate- and poor-risk cytogenetics but not for good-risk disease.
Source: Koreth J, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission. systematic review and meta-analysis of prospective clinical trials. JAMA. 2009;301:2349-2361.
The role of allogeneic hematopoietic cell transplantation (alloHCT) for acute myeloid leukemia (AML) remains controversial. Although potentially curative for AML, alloHCT entails toxicity that often precludes application to older and less fit individuals. For AML in younger adults, first complete remission (CR1) can be achieved in around 70% of patients, but relapse remains problematic. The initial karyotype in AML powerfully predicts outcome, and is the primary method used to risk-stratify treatment approaches.1 Most consensus panels suggest patients with AML in CR1, with a good risk karyotype (e.g., inversion 16, translocation 8;21), should pursue chemotherapy consolidation, whereas the presence of high-risk cytogenetic abnormalities should prompt consideration of alloHCT in eligible subjects with a donor. The benefit of alloHCT for intermediate-risk AML, the largest category, is controversial.
In this meta-analysis, Koreth et al reviewed clinical trials of allogeneic HCT for AML in CR1 across cytogenetic risk groups compared to chemotherapy and/or autoHCT. Such trials typically employ "genetic randomization" where patients with a Human Leukocyte Antigen (HLA)-matched sibling donor are offered alloHCT, while others are offered consolidation chemotherapy and/or autologous HCT. The review revealed 24 studies that met inclusion criteria of being high quality and reporting the appropriate data. Eighteen studies reported on relapse-free survival (RFS) and 15 detailed overall survival (OS). Begg funnel plots showed a systemic distribution indicating no evidence of publication bias. Outcomes were assessed by intention to treat so that patients having a matched sibling donor were analyzed in the alloHCT group even if they did not proceed to alloHCT.
Stratified by cytogenetic risk group, alloHCT for AML in CR1 had no RFS benefit for good-risk patients (HR: 1.06, 95% CI, 0.80-1.42), but did reveal a statistically significant benefit for intermediate risk patients (HR: 0.76, 95% CI, 0.68-0.85) and poor-risk patients (HR: 0.69, 95% CI, 0.57-0.84). As expected, when examining both intermediate- and/or poor-risk patients together, alloHCT improved RFS.
A combined estimate showed a significant OS benefit for alloHCT across all cytogenetic-risk groups for AML in CR (p < 0.01). Among the six studies reporting OS stratified by intermediate- and poor-risk karyotype, alloHCT afforded improved OS (HR: 0.87, 95% CI, 0.80-0.94). OS was not improved for alloHCT among good-risk AML in CR1 (HR: 1.07, 95% CI 0.83-1.38, p = 0.59). In contrast, alloHCT led to improved OS for patients having intermediate-risk (HR: 0.83, 95% CI 0.74-0.93, p < 0.01) or poor-risk AML (HR: 0.73, 95% CI, 0.59- 0.90, p < 0.01). When different modeling techniques were adopted, results did not change.
Commentary
AlloHCT employs chemotherapy and/or radiotherapy to eradicate residual leukemia, followed by an HLA-matched donor that both rescues from marrow aplasia and may induce immunologic tumor control through a graft-versus-leukemia effect. Nevertheless, the toxicities of alloHCT must be weighed against improved leukemia control. Multiple studies have assessed the benefit of alloHCT for AML in CR1 using "genetic randomization." Patients who are alloHCT-eligible, generally meaning younger adults, undergo alloHCT if an HLA-matched sibling is available. If not, standard consolidation with either chemotherapy alone or an autologous transplant follows. The presenting karyotype of AML enables prognostic stratification, and can be broadly divided into good-risk, intermediate-risk, or poor-risk disease.1 The available data suggest alloHCT is preferred for poor-risk AML in CR1 but, for intermediate-risk disease, the largest category of AML, the data are unclear.2,3
In this meta-analysis, a review of the published literature revealed 24 trials between 1982 and 2006 comparing alloHCT to non-alloHCT for AML in CR1. The non-alloHCT arms included both autologous HCT and chemotherapy-alone consolidation. Koreth et al found that alloHCT improved relapse-free survival (RFS) and overall survival compared to non-alloHCT consolidation. When stratified by cytogenetic risk category, alloHCT improved RFS and OS for intermediate-risk and poor-risk AML, leading to a 30%-50% improvement in survival. For good-risk AML, alloHCT showed no statistical difference in outcomes.
Several methodological limitations exist in this genetic randomization scheme. First, patients without a donor may not proceed to alloHCT. Second, patients without a matched sibling donor could deviate from the protocol and receive an unrelated donor HCT or receive a salvage alloHCT upon disease relapse. In this intent-to-treat analysis, such problems reduce the observed benefit. Thus, the improved outcome from alloHCT may actually be underestimated. Additional limitations of this analysis are germane. Inferences from these data should be done carefully, as numerous advances in diagnosis and treatment have occurred over the 25 years covered in this meta-analysis. The trials analyzed were comprised of younger adults, with a median age in their 30s, using myeloablative HCT regimens. AML is primarily a disease of older adults and, in the modern era, reduced intensity conditioning regimens and better supportive care have combined to enable older and less fit adults to proceed to alloHCT. Definitive conclusions about older adults cannot be drawn from this analysis. Historically, using an unrelated donor led to worse outcomes compared to a matched sibling donor. Molecular methods for HLA typing and other advances have reduced this gap. Thus, an unrelated donor HCT could also be considered for intermediate- and poor-risk AML in CR1, absent a matched sibling donor.
Molecular profiling to refine risk-stratification of normal karotype AML has been a major advance. Prognostically favorable mutations include the transcription factor for CCAAT/enhancer-binding protein alpha (CEBPA) and nucleophosmin 1 gene (NPM1).4 Internal tandem duplications in the fms-like tyrosine kinase 3 (FLT-3 ITD) confer an adverse prognosis.5 In a large donor vs. no donor study, Schlenk et al confirmed the benefit of alloHCT among molecular-stratified AML in CR1 having a normal karotype. AlloHCT improved survival for FLT-3 ITD but not among patients having NPM1 or CEBPA mutations without a FLT-3 ITD.6
This meta-analysis strongly reinforces the recommendation for alloHCT for AML in CR1 for patients having poor-risk disease and a matched sibling donor. In addition, alloHCT for intermediate-risk disease must be considered. The data further illustrate the importance of performing baseline metaphase cytogenetics and, when available, molecular testing for common somatic mutations in newly diagnosed AML. In addition, because of the time required to identify HLA-matched donors, HLA typing of the patient and siblings, and possibly unrelated donors when no siblings are available, should be considered early for HCT-eligible patients with AML having intermediate- or poor-risk cytogenetics.
References
1. Grimwade D, et al. The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood. 1998;92:2322-2333.
2. Yanada M, et al. Efficacy of allogeneic hematopoietic stem cell transplantation depends on cytogenetic risk for acute myeloid leukemia in first disease remission: A metaanalysis. Cancer. 2005;103:1652-1658.
3. Cornelissen JJ, et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood. 2007;109: 3658-3666.
4. Dohner K, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: Interaction with other gene mutations. Blood. 2005;106:3740-3746.
5. Yanada M, et al. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005;19:1345-1349.
6. Schlenk RF, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909-1918.
Allogeneic hematopoietic cell transplantation (alloHCT) is recommended for consolidation among poor-risk AML patients in CR1, but controversy remains for intermediate-risk disease.Subscribe Now for Access
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