TP53|General AML

Genetic mutations in AML predicts treatment outcomes: different types of AML should be treated differently

In November 2016, Elihu Estey, M.D., from the University Of Washington Medical Center and the Fred Hutchinson Cancer Research Center, Seattle, published an editorial in the New England Journal of Medicine discussing the heterogeneity of Acute Myeloid Leukemia (AML) driven by genetic mutations and the resulting treatment outcome.

According to Estey, AML is several diseases, characterized by non-random heterogeneity after homogeneous treatment. The author noted that AML can be characterized by different karyotypes and molecular aberrations which results in different treatment outcomes.

To elaborate further, he discussed the findings of a trial recently published by Welch et al., which reported on the effectiveness of repeated 10-day course of decitabine in monthly cycles in 43 patients with unfavorable karyotypes among 116 patients with AML or Myelodysplastic Syndromes (MDS) who received treatment. Higher response rates were reported in patients with unfavorable-risk cytogenetic profiles (29/43 patients [67%]) than patients with intermediate- or favorable-risk cytogenetic profiles (24/71 patients [34%]; P<0.001). The findings of this study also show that 21 patients with TP53 mutations (20 of whom had an unfavorable-risk cytogenetic profile) had an enhanced response to decitabine compared to patients who did not have TP53 mutations but had an unfavorable-risk cytogenetic profile. TP53 mutations associated with unfavorable cytogenetic profile. Welch et al. conclude that patients with unfavorable-risk cytogenetic abnormalities, TP53 mutations, or both, had better clinical responses and robust mutation clearance after decitabine treatment.

In the editorial, Estey highlighted that the data from the Welch et al. study suggests that patients with AML and TP53 mutations, which are readily detected with the use of validated commercial platforms, should receive decitabine for 10-days and so should the far larger group of patients with unfavorable-risk cytogenetic profiles. 

Elihu Estey concluded the editorial by remarking that Welch et al.’s results point to the inevitable replacement of large trials in which homogenous therapy is administered for heterogeneous disease with trials involving smaller subgroups of patients with specific mutations; different types of AML should ideally be treated differently.

References
  1. Estey E. Acute Myeloid Leukemia- many diseases, many treatment. N Engl J Med. 2016 Nov; 375(21):2094–2095. DOI:10.1056/NEJMe1611424
  2. Welch J.S. et al. TP53 and decitabine in Acute Myeloid Leukemia and myelodysplastic syndromes. N Engl J Med. 2016 Nov; 375:2023–2036. DOI: 10.1056/NEJMoa1605949.