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Stratifying Risk in AML

Presence of leukemia cell mutations correlated with treatment outcomes in patients with karyotypically normal acute myelogenous leukemia.

Cytogenetic abnormalities are powerful positive and negative predictors of clinical and therapeutic responses in adults with acute myelogenous leukemia (AML). However, nearly half of all patients have leukemia cells with normal karyotypes, and clinical outcomes among these patients are highly heterogeneous. As small mutations that occur commonly in individual leukemia-cell genes are not detectable in gross karyotype analyses, investigators from the German-Austrian AML Study Group performed a retrospective analysis of mutation frequency in five specific genes — NPM1, FLT3 (including internal tandem duplication [ITD] or tyrosine kinase domain mutation [TKD]), CEBPA, MLL, and NRAS — and correlated the DNA findings with treatment response.

A total of 872 AML patients (age range, 16–60) with normal leukemia-cell karyotypes (by both standard cytogenetic methods and fluorescence in situ hybridization [FISH] translocation analysis), were identified from four multicenter European trials. All patients received double-induction chemotherapy regimens followed by consolidation with high-dose cytarabine. Patients with suitable donors were referred for allogeneic stem-cell transplantation, whereas the remainder received consolidation chemotherapy only or autologous transplantation. Transplant-related mortality for allogeneic transplant was 21%.

Only about half the patients were assessable for all the mutations, and 21% were not analyzable for any mutation. NPM1 mutations were identified in 53% of assessable patients, and FLT3 mutations were identified in 42%; CEBPA, MLL, and NRAS mutations each were found in fewer than 13%. In multivariable analyses, the presence of a CEBPA mutation or an NPM1 mutation without FLT3-ITD was a favorable marker and was significantly correlated with complete remission after induction chemotherapy. Among the group with favorable NPM1 mutations, no benefit was found for allogeneic stem-cell transplantation, although benefit was demonstrated for patients with unfavorable mutations who received allogeneic transplants. Another group of researchers reported on further refinement of the FLT3 mutation analysis by generating a gene-expression signature for this same cohort.

Comment: Therapeutic progress and better clinical outcomes have been realized for hematologic malignancies such as lymphoma and myeloma, and we’re beginning to see developments in AML as well. Recent progress in biomarkers and new therapeutic approaches are improving outcomes for younger patients, and older patients likely will benefit from these advances. Patients with specific AML subtypes, such as acute promyelocytic leukemia, have benefited dramatically from incorporation of all-trans retinoic acid into induction therapies, and we likely will move beyond the traditional "7+3" induction and standard consolidation regimens for most AML patients soon. The refinement of clinically useful molecular biomarkers that can be analyzed by standard cytogenetics and FISH has enhanced our ability to risk-stratify patients, and the current report further advances this capability by incorporating genotyping for patients with normal karyotypes. Interestingly, specific FAB subtypes of AML did not correlate with study endpoints, which suggests that mutational genotyping, in conjunction with standard karyotype and FISH, is of great value for both prognostic and therapeutic stratification. Prospective verification of these results and development of novel therapeutics targeted at these mutations hold promise for improving response and survival for AML patients.

— Michael E. Williams, MD

Published in Journal Watch Oncology and Hematology May 13, 2008

Citation(s):

Schlenk RF et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008 May 1; 358:1909.

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• Medline abstract (Free)

Bullinger L et al. An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML. Blood 2008 May 1; 111:4490.

• Original article (Subscription may be required)
• Medline abstract (Free)