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Originally published as JCO Early Release 10.1200/JCO.2008.16.4293 on June 16 2008 © 2008 American Society of Clinical Oncology.
Molecular Classification of Acute Myeloid Leukemia: Are We There Yet?
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA The treatment of acute myeloid leukemia (AML) has made incremental advances during the last few decades, but the outcomes are still fairly grim. Combination chemotherapy can cure approximately 25% of patients. The strongest prognostic factor remains cytogenetics. Patients with "good-risk" cytogenetics have the relatively favorable outcome of disease-free survival (DFS) of approximately 60%; on the opposite side of the spectrum, patients with "unfavorable" cytogenetics have survival of about 10%.1 The majority of patients fall into the intermediate-risk group, and most of these patients have no abnormal chromosomes at diagnosis. This group comprises approximately 40% of all adult patients, and their DFS is about 25%. Once patients experience relapse, the outcome is especially grim. About half of these patients can be reinduced into a second remission, but conventional chemotherapy will cure few, if any, of these patients. Allogeneic transplantation can cure about 25% of patients placed into a second remission, and fewer if they undergo transplantation in continued relapse. In contrast, transplantation can cure 60% of patients who undergo transplantation in first remission, but the issue remains as to how patients should be selected to undergo transplantation early, and who should get continued chemotherapy with the expectation of a reasonable response. Whereas the cytogenetic risk may help guide that decision for those at the extremes (good or bad risk), what does the clinician do with the considerable number of patients with normal cytogenetics? The promise of using genetics as a deeper approach to understanding the heterogeneity of AML is enormous, but the delivery to the clinic has made slow progress. There are a number of genetic lesions that have been found to be potentially significant in AML. Mutations to the signaling transduction pathway are common in 60% to 70% of AML patients.2,3 The first described were point mutations to the guanine triphosphatase protein RAS (principally n-RAS), that are found in 10% to 20% of AML patients.4,5 Mutations in the upstream receptor tyrosine kinases can be found in more than 40% of patients, including point mutations in fms and kit, but predominately in FLT3, which increase in frequency from 10% in pediatric patients to 40% in elderly AML patients. Mutations in the FLT3 gene have been shown in several studies to be a strong prognostic factor in both pediatric and adult AML.6,7 FLT3 mutations occur in two varieties. The most common is the internal tandem duplication, a head-to-tail duplication of 20 to 300 base pairs in the exons coding for the juxtamembrane region of the molecule. This structural change alters the biology of the FLT3 receptor from normally signaling through ligand-dependent dimerization to that of ligand-independent activation. Tyrosine kinase activation of FLT3 also occurs in 5% to 10% of patients through point mutations in the activating loop of the kinase domain of the molecule.8 There is an emerging complexity of the relationship of FLT3 mutations and prognosis that is an important object lesson. Though in vitro studies suggest that FLT3-ITD and FLT3-ALM mutations similarly alter signal transduction, FLT3-ITD mutations are clearly associated with a poor prognosis, whereas this association is less clear in patients with FLT3 point mutations.7,8 Moreover, not all FLT3-ITD mutations are created equal. Some patients with FLT3-ITD are in a heterozygous state—that is, one mutated, and one wild-type allele. Other patients have clones that are homozygous for the mutated allele. Several studies have demonstrated that the higher the allelic ratio (meaning more mutated v wild-type allele), the worse the prognosis.7,9-11 The prognostic power of FLT3 is increased by combining it with the recently described mutation status of the nucleophosmin (NPM1) gene. Mutations in NPM1 are the most common mutations detected in AML, occurring in 40% of patients.12-14 The combination of a wild-type FLT3 with a mutated NPM provides the best prognosis, whereas the worst prognosis is in patients with the FLT3 mutation and wild-type NPM.14,15 These associations, along with the emerging field of classification using gene expression, where outcome is associated with the expression of tens to thousands of genes,16,17 offer a destination on the long road trip from bench to bedside. New technology and more gene discoveries yield more and more potential candidates to be tested. Predictably, clinicians and scientists are left to say, "Are we there yet?" Two articles in this issue of Journal of Clinical Oncology merge onto this road, further refining the genetic risk of AML based on gene mutations. Paschka et al18 studied the impact of WT1 mutations in adult AML with normal cytogenetics. WT1 was originally described as a tumor suppressor associated with Wilms’ tumor, but has been shown to be a transcription factor with cell-context–dependent oncogenic properties.19 WT1 is overexpressed in more than 70% of AML patients, and in some acute lymphoblastic leukemia and myeloid blast crisis chronic myelogenous leukemia.20,21 Indeed, some investigators have advocated the use of WT1 expression as a marker of prognosis and residual disease in AML.22 Mutations in WT1 exon 7 and 9 have been previously reported.21,23 In the Paschka et al article, the investigators studied 196 patients, analyzing not only for WT1 mutations, but also FLT3, NPM, and CEBPA mutations, as well as ERG expression, all of which have been associated with prognosis in AML.24-26 WT1 mutations were found in 11% of patients, and although patients with mutations had similar rates of complete remission compared with patients without WT1 mutations, the relapse and progression-free survival was remarkably different. Patients with WT1 mutations had a 3-year DFS of only 13%, whereas patients without WT1 mutations had a DFS of 50%. This impact of WT1 was preserved when adjusted for the mutation status of the other potential prognostic factors noted above. The clinical implication is that patients with WT1 mutations would benefit from aggressive consolidation, for example, allogeneic or autologous transplantation. The article by Neubauer et al27 studies the prognostic significance of RAS mutations in adult AML, investigating the possibility that RAS mutations have a differential effect based on cytarabine dose, as is seen with the t(8;21) and inv(16) translocations.28 Patients (N = 185) enrolled onto a study that randomly assigned patients to low-, standard-, or high-dose cytarabine consolidation were retrospectively tested for RAS mutations (though it is not clear whether these are n-, k-, and h-RAS mutations or a subset of these three); 18% of patients were found to have RAS mutations at diagnosis. Overall there was no effect of RAS mutations on outcome. However, in the subset of those receiving high-dose cytarabine, patients with RAS mutations had fewer relapses compared with patients with wild-type RAS. Thus, the cumulative incidence of relapse was 45% for patients with RAS mutations, compared with 68% in wild-type RAS patients. Moreover, among RAS mutants, the relapse rate was far lower in patients receiving high-dose compared with low-dose cytarabine. The clinical implication is that patients with RAS mutations will benefit from consolidation with high-dose cytarabine. Both articles have some limitations, but nothing that undermines the main message of the studies. In the article by Paschka et al, one wonders how WT1 mutations correlated with WT1 expression, and how using this and the FLT3 allelic ratio would have changed the multivariate results. In the article by Neubauer et al, would mutated RAS still have significance when correcting for cytogenetic status, or mutations in other key genes? And in both articles, what was the percentage of blasts in the diagnostic samples that harbored WT1 and RAS mutations? The percentage of mutations of RAS and FLT3, for example, are quite variable at presentation, and one wonders if the association of mutation and outcome is different in patients in whom the mutation is dominant, as opposed to a minority of the leukemia cells. It is clear that the mutation detection should be a part of most, if not all, clinical trials, as should soon be a part of routine clinical practice. The road ahead to genetic stratification still has its obstacles (and, if one considers the current grant funding situation, there is little money to pay the tolls). First, only a few specialized laboratories have invested in testing the breadth of relevant mutations. Second, it is clear that the relevance of mutations must be taken in the context of the type of mutation (eg, FLT3-ITD v ALM), other mutations (eg, FLT3-ITD and NPM1), and the particular therapy. This is problematic for clinical investigators, though it ironically adds job security to those interested in the intersection of genetics and clinical medicine. Nonetheless, for those heckling in the back, wondering when on earth we'll get there, patience, please: I think I see a sign up ahead. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on June 16, 2008 REFERENCES 1. Byrd JC, Mrozek K, Dodge RK, et al: Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8461). Blood 100:4325-4336, 2002 2. Meshinchi S, Stirewalt DL, Alonzo TA, et al: Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood 102:1474-1479, 2003 3. Stirewalt DL, Kopecky KJ, Meshinchi S, et al: FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 97:3589-3595, 2001 4. Neubauer A, Dodge RK, George SL, et al: Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia. Blood 83:1603-1611, 1994 5. Radich JP, Kopecky KJ, Willman CL, et al: N-ras mutations in adult de novo acute myelogenous leukemia: Prevalence and clinical significance. Blood 76:801-807, 1990 6. Kottaridis PD, Gale RE, Frew ME, et al: The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: Analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98:1752-1759, 2001 7. Meshinchi S, Alonzo TA, Stirewalt DL, et al: Clinical implications of FLT3 mutations in pediatric AML. Blood 108:3654-3661, 2006 8. Yamamoto Y, Kiyoi H, Nakano Y, et al: Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 97:2434-2439, 2001 9. Gale RE, Green C, Allen C, et al: The impact of FLT3 internal tandem duplication mutant level, number, size and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 111:2776-2784, 2008 10. Thiede C, Steudel C, Mohr B, et al: Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: Association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99:4326-4335, 2002 11. Whitman SP, Archer KJ, Feng L, et al: Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: A cancer and leukemia group B study. Cancer Res 61:7233-7239, 2001 12. Döhner K, Schlenk RF, Habdank M, et al: Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: Interaction with other gene mutations. Blood 106:3740-3746, 2005 13. Falini B, Mecucci C, Tiacci E, et al: Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352:254-266, 2005 14. Schnittger S, Schoch C, Kern W, et al: Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 106:3733-3739, 2005 15. Thiede C, Koch S, Creutzig E, et al: Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 107:4011-4020, 2006 16. Bullinger L, Dohner K, Bair E, et al: Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med 350:1605-1616, 2004 17. Wilson CS, Davidson GS, Martin SB, et al: Gene expression profiling of adult acute myeloid leukemia identifies novel biologic clusters for risk classification and outcome prediction. Blood 108:685-696, 2006 18. Paschka P, Marcucci G, Ruppert AS, et al: Wilms’ tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: A Cancer and Leukemia Group B Study. J Clin Oncol 26:4595-4602, 2008 19. Yang L, Han Y, Suarez Saiz F, et al: A tumor suppressor and oncogene: The WT1 story. Leukemia 21:868-876, 2007[Medline] 20. Bergmann L, Miething C, Maurer U, et al: High levels of Wilms’ tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood 90:1217-1225, 1997 21. King-Underwood L, Pritchard-Jones K: Wilms’ tumor (WT1) gene mutations occur mainly in acute myeloid leukemia and may confer drug resistance. Blood 91:2961-2968, 1998 22. Weisser M, Kern W, Rauhut S, et al: Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia. Leukemia 19:1416-1423, 2005[CrossRef][Medline] 23. Summers K, Stevens J, Kakkas I, et al: Wilms’ tumor 1 mutations are associated with FLT3-ITD and failure of standard induction chemotherapy in patients with normal karyotype AML. Leukemia 21:550-551; aut, 2007[CrossRef][Medline] 24. Fröhling S, Schlenk RF, Stolze I, et al: CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: Prognostic relevance and analysis of cooperating mutations. J Clin Oncol 22:624-633, 2004 25. Marcucci G, Baldus CD, Ruppert AS, et al: Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: A Cancer and Leukemia Group B study. J Clin Oncol 23:9234-9242, 2005 26. Marcucci G, Mrózek K, Ruppert AS, 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 23:5705-5717, 2005 27. Neubauer A, Maharry K, Mrózek K, et al: Patients with acute myeloid leukemia and RAS mutations benefit most from postremission treatment with high-dose cytarabine: A Cancer and Leukemia Group B study. J Clin Oncol 26:4603-4609, 2008 28. Byrd JC, Ruppert AS, Mrozek K, et al: Repetitive cycles of high-dose cytarabine benefit patients with acute myeloid leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): Results from CALGB 8461. J Clin Oncol 22:1087-1094, 2004 Related Articles
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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