Decitabine Effective in High-Risk AML, MDS

Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) with unfavorable risk cytogenetic profiles, TP53 mutations, or both had good clinical response and robust mutation clearance when administrated serial 10-day cycles of decitabine, according to the results of a single-institution study published in the New England Journal of Medicine.

According to John S. Welch, MD, PhD, of Washington University School of Medicine in St. Louis, and colleagues, the trial was designed to identify markers that might help predict response or resistance to single-agent decitabine.

“Decitabine as a single agent is not a cure for anyone with these diseases: the rapid selection of resistant subclones by decitabine and the incomplete clearance of leukemia-specific mutations (even in patients who have a response) explain why remissions are generally short-lived,” Welch and colleagues wrote. “However, the use of decitabine may be an important way to induce clinical remissions in patients with AML who have TP53 mutations and who have disease that is notoriously resistant to induction therapy with standard cytotoxic chemotherapy.”

The study included 84 patients with AML or MDS. Patients were given decitabine 20 mg/m² per day for 10 days in monthly cycles. Patients underwent two types of testing: 67 patients had enhanced exome or gene-panel sequencing and 54 patients had serial sequencing at multiple time points to evaluate patterns of mutation clearance. In addition, there was an extension cohort of 32 patients who received decitabine in different protocols.

Of the 116 total patients, a little less than one-half (46%) of patients had bone marrow blast clearance defined as < 5% blasts.

Patients with unfavorable-risk cytogenetic profile had a response rate of 67%. This was significantly higher than that seen in patients with intermediate-risk or favorable risk-cytogenetic profiles (34%; P < .001). Additionally, those patients with TP53 mutations had a response rate of 100% compared with 41% in patients with wild-type TP53 (P < .001).

“TP53 mutations form the nexus of the worst prognostic group in AML and MDS,” the researchers wrote. “These data suggest an alternative upfront strategy for the treatment of this group of ultra-high-risk patients that will need to be verified in prospective trials.”

Of the 54 patients who had serial sequencing, the researchers found that only two gene mutations (TP53 and SF3B1) had consistent, rapid reduction in variant allele frequency to levels of < 5%. In addition, bone marrow blast clearance often preceded mutation reduction and mutation clearance was never complete, they noted.

The researchers also looked at samples from 20 patients with bone marrow blast clearance after day 28 of cycle 2.

“In these patients, we were able to detect leukemia-specific mutations during morphologic remission. This indicated that decitabine leads only to incomplete clearance of disease,” the researchers wrote.

Among the patients who had gene-panel sequencing, 14 had TP53 mutations. Of those, 14 of 14 had blast clearance with decitabine and 17 of 46 with wild-type TP53 had blast clearance (P < .001).

Welch and colleagues noted that previous studies have shown that patients with unfavorable risk profiles and TP53 mutations who are treated with cytotoxic chemotherapy have poor outcomes. However, in this study, neither of these factors was associated with a lower rate of overall survival than the rate seen in patients with intermediate-risk cytogenetic profiles.

In an editorial that accompanied the study, Elihu Estey, MD, from the University of Washington Medical Center in Seattle, wrote that the results of this trial indicate that “patients with AML and TP53 mutations, which are readily detectable with the use of validated commercial platforms, should receive decitabine for 10 days, as might the far larger group of patients with unfavorable-risk cytogenetic profiles.”

In addition, Dr. Estey wrote that the trial “points to inevitable, rational replacement of large trials in which homogeneous therapy is administered for a heterogeneous disease by smaller, subgroup-specific trials.”