Molecular Tests Discriminate Prognosis in Normal Karyotype AML
Abstract & Commentary
By Andrew Artz, MD, Division of Hematology/Oncology, University of Chicago, Chicago, IL. Dr. Artz reports no financial relationship to this field of study.
Synopsis: Mutations in several genes may refine prognosis in normal karyotype AML. The mutational status of the fms-related tyrosine kinase gene (FLT3), the CCAAT/enhancer binding protein gene (CEPBA), the mixed lineage leukemia gene (MLL) and neuroblastoma RAS viral oncogene homolog (NRAS) were evaluated in 663 normal karyotype AML patients under 60 years of age. Favorable prognostic groups included mutations for NPM1 mutations without a FLT-3 ITD, CEBPA, and MLL. Allogeneic transplant appeared beneficial in the largest prognostically unfavorable groups having with an FLT-3 ITD.
Source: R. Schlenk, et al. for the German-Austrian Acute Myeloid Leukemia Study Group. N Engl J Med. 2008;358:1909-1918.
The initial karyotype in acute myeloid leukemia powerfully predicts outcome and is the primary method used to risk-stratify treatment approaches.1 Approximately 50% of adult AML patients on treatment protocols have a normal karyotype and are considered to have an "intermediate" prognosis of 35 to 45% 5 year survival.2,3 The optimal choice of post-induction therapy should patients achieve complete remission is controversial, particularly whether or not to purse an allogeneic or autologous transplant. Importantly, these studies typically exclude AML in adults over 60 years of age, where the karyotype is often abnormal.
Increasing attention has been devoted to biologically and prognostically refining normal karyotype AML by identifying somatic mutations in the leukemic clone.4 Prognostically favorable mutations include the transcription factor for CCAAT/enhancer-binding protein alpha (CEBPA) and nucleophosmin 1 gene (NPM1).5 Independent prognostic value of mutations in the neuroblastoma RAS viral oncogene homolog gene (NRAS) has not been clearly demonstrated.6 Mutations in the mixed-lineage leukemia gene (MLL)7 and internal tandem duplications in the fms-like tyrosine kinase 3 (FLT-3 ITD) appear to confer an adverse prognosis8 whereas FLT3 mutations in the tyrosine kinase domain (TKD) may not.
Schlenk and colleagues analyzed the frequency and association with treatment outcomes in the FLT3 gene (either the ITD or TKD mutations) and mutations in CEBPA, MLL, NPM1, and NRAS genes. The authors used cryopreserved blood and marrow samples from 1919 patients aged 16 to 60 years of age treated within a German-Austrian study group between 1993 and 2004, focusing on the 45% having a normal pre-treatment karyotype. Patients received standard induction therapy. Those having an HLA-matched sibling underwent a myeloablative transplant for consolidation. For those without a sibling donor, they were randomized to chemotherapy consolidation or an autologous transplant. The four year overall survival was 43% and 76% achieved a complete remission. Compared to patients who underwent either chemotherapy or autologous transplant in remission, the 27% of patients with a matched sibling donor, most of whom underwent allogeneic transplant, had reduced relapse rates but similar overall similar due to 21% mortality related to allogeneic transplant.
Mutations were found for NPM1 in 53%, for FLT3-TKD in 11%, for CEBPA in 13%, for MLL-PTD in 7%, and for NRAS in 13%. Internal tandem duplications were present in FLT3 in 31% (FLT-3 ITD). In multivariable analysis, NPM1 without FLT3-ITD and mutant CEBPA were favorable prognostic factors for achieving remission. Similarly, these two groups also had favorable overall survival of around 60%. Allogeneic transplant did not appear to benefit such patients. However, in the prognostically unfavorable group without NPM or CEBPA mutations, the presence of a donor improved overall survival, suggesting a benefit from allogeneic transplant (HR = 0.61, 95% CI, 0.40 to 0.94).
Commentary
The initial karyotype for adult AML patients under the age of 60 years is the strongest prognostic factor for outcome and guides post-remission therapy. For those having unfavorable cytogenetics, allogeneic transplant is generally recommended should the patient be a suitable candidate and have a donor. Approximately half of patients will have a normal karyotype and fall into an intermediate risk category with an overall survival of 35-45%.
The past 5 years have witnessed a rapid increase in knowledge about somatic mutations in AML that further discriminate prognosis, especially among the heterogeneous group having a normal karyotype. This large analysis of four consecutive cooperative group studies within a German-Austrian treatment consortium of patients 16 to 60 years of age clarifies the frequency and prognostic relevance of mutations in the FLT3 gene (either the ITD or TKD) and in CEBPA, MLL, NPM1, and NRAS genes. NMP1 and FLT-3 mutations are relatively frequent, confirming what others have reported. The independent influence of these mutations has been less well understood. The authors found that mutations in NPM1 without FLT3-ITD or CEBPA mutations conferred a favorable prognosis with higher complete remission rates and better overall survival. Specifically, 4-year survival was around 60%, similar to survival in studies among the good prognostic cytogenetic groups of inversion 16 or translocation 8;21.9 A poor prognostic group clearly emerged from patients with a FLT3-ITD genotype or lacking the favorable mutations of NPM1 and CEBPA with a 4 year survival of 24% to 33%. In prior reports, the FLT-3 ITD has consistently been associated with higher relapse and poor survival; however, the impact of FLT-3 TKD mutations is controversial.10 In this study, NPM1 mutations appeared to mitigate the prognosis of TKD FLT-3 mutations. In the presence of the NPM1 mutant genotype and FLT-3 TKD mutations, the prognosis was favorable. However, the prognosis was unfavorable in the presence of a mutated FLT-3 TKD without an NPM1 mutation.
The "genetic randomization" for allogeneic transplant was revealing. Patients having a donor underwent allogeneic transplant and those without were assigned to either chemotherapy consolidation or an autologous transplant. Thus, patients having a sibling donor were in effect randomized to allogeneic transplant. Using this method, patients in the favorable prognostic risk groups did not benefit from allogeneic transplant. However, patients who underwent allogeneic transplant in the unfavorable categories of FLT-3 ITD or lacking NPM1 or CEPBA mutations had improved survival.
The implications of these and other data identifying new prognostic subcategories of AML are immense. First, risk adapted approaches can be appropriately tailored based upon accurate prognostic categorization. These data suggest that AML with a normal karyotype and prognostically favorable mutation category (eg, NPM1 or CEPBA mutation without a FLT-3 ITD), standard chemotherapy consolidation may be reasonable. Although the unfavorable prognostic categories require further clarification, the data are quite consistent that the presence of an internal tandem duplication in FLT-3 confers a poor prognosis. Allogeneic or possibly autologous transplant should be considered. Finally, the biologic mutations may also represent therapeutic targets. For example, numerous drugs are being tested that may inhibit FLT-3 tyrosine kinase.
Unfortunately, data for mutations are sparse for adults 60 years and over with AML, an age at which the majority of cases occur. The inadequate existing data for such patients make it unlikely that favorable prognostic groups will soon be identified.
Community oncologists who treat AML are now faced with the practical implications of these emerging data. First, testing for molecular mutations is already available and may quickly become the standard of care. Mutational testing at least for FLT-3 ITD, and possibly NPM1 and CEPBA seem reasonable, if and when available. As with all rapidly emerging diagnostic tests, concerns will exist around the reliability and validity of clinically available testing since these studies originate from research laboratories. Clinicians also need to interpret these tests appropriately and consider transplant referral for high-risk patients. For transplant eligible patients, HLA testing of the patient and siblings while awaiting the results of cytogenetics and molecular testing is probably prudent to avoid subsequent delays. In conclusion, molecular genetic testing for somatic mutations in younger AML patients who have a normal karyotype has prognostic importance and may quickly become the standard of care.
References
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9. Marcucci G, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol. 2005;23:5705-5717.
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