TP53|General AML

Decitabine and TP53 mutations in Acute Myeloid Leukemia and Myelodysplastic Syndromes

TP53 mutation in Acute Myeloid Leukemia (AML) is associated with low blast and white blood cell (WBC) counts. This mutation in AML patients is also linked with inferior outcomes compared with Wild Type (WT)-P53. At present, different therapies are required to tackle this patient group as conventional chemotherapy has resulted in poor outcomes.

Decitabine is a novel chemotherapeutic agent. It is a DNA hypomethylating agent licensed in the EU for AML and the US for Myelodysplastic Syndromes (MDS). However, the molecular determinants of clinical responses with this therapy still need to be characterized.

John S. Welch, M.D., et al. conducted a single-institution trial of 84 adult patients with AML or MDS treated with decitabine to identify somatic mutations and their relationships to clinical responses. An extension trial of 32 patients was also performed. This study was published in the New England Journal of Medicine in November 2016.

The key findings were:

  • 53/116 patients (46%) had bone marrow blast clearance (<5% blasts).
  • Patients with TP53 mutations had higher response rates (21/21 [100%]) compared to patients with WT-TP53 (32/78 [41%]; P<0.001).
  • Patients with an unfavorable-risk cytogenetic profile had higher response rates (29/43 patients [67%]) than patients with intermediate- or favorable-risk cytogenetic profile (24/71 patients [34%]; P<0.001).

In summary, the authors report that these findings demonstrated that decitabine was able to produce clinical responses in AML/MDS patients with unfavorable cytogenetic profiles. This study also provides promising results for the difficult to treat TP53 mutation patients group. The novel agent similarly demonstrated favorable but transient clinical efficacy in these patients.

This study was registered at ClinicalTrials.gov NCT01687400.

 Abstract

Background

The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear.

Methods

We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols.

Results

Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles.

Conclusions

Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400.)

References
  1. Welch J.S. et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med. 2016 November 24; 375:2023–2036. DOI: 10.1056/NEJMoa1605949.