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Blood Cancer Patients With TP53 Mutations Demonstrate Enhanced Response to Decitabine

NEW YORK (GenomeWeb) – Aggressive forms of acute myeloid leukemia marked by TP53 mutations or unfavorable cytogenetic patterns appear more apt to respond to a relatively mild chemotherapy, decitabine, according to a study published today in the New England Journal of Medicine.

Researchers from Washington University, the University of Chicago, and Massachusetts General Hospital tracked treatment response in more than 100 individuals who received decitabine treatment for AML or myelodysplastic syndrome (MDS), a blood condition that can progress to AML.

With help from exome or gene panel sequencing on 67 patients, they saw enhanced decitabine response in patients with TP53 mutations and/or cytogenetic patterns that typically don't bode well for conventional chemotherapy response. All told, some 67 percent of patients with traditionally risky cytogenetic profiles responded to the drug, as did 100 percent of individuals with verified TP53 mutations.

"With standard aggressive chemotherapy, we only see about 20 to 30 percent of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies," senior author Timothy Ley, an oncology researcher at Washington University, said in a statement.

Though Ley cautioned that the results need to be verified in larger trials, he added that results so far hint that TP53 mutations can predict decitabine response, "potentially prolonging survival in this ultra high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates."

Decitabine was approved for treating MDS a decade ago. Because it is less toxic than conventional chemotherapy, it is sometimes used to treat AML in elderly patients who may not tolerate standard treatment well. Older individuals are also more prone to having forms of AML involving TP53 mutation, which is usually linked to poorer outcomes.

To search for molecular features associated with decitabine response, the researchers used Illumina HiSeq 2000 or 2500 instruments to sequence protein-coding sequences captured with Nimblegen reagents for 28 individuals with AML and 11 individuals with MDS. They also did gene-panel sequencing on another 51 individuals with AML and nine MDS patients, focusing on either eight or 264 genes. A subset of individuals were followed over time with serial gene-panel sequencing.

Across all 116 patients, TP53 mutations showed the most pronounced ties to decitabine response. The mutations tended to coincide with unfavorable cytogenetic patterns — those found in individuals with poor response to standard cytotoxic chemotherapy.

When it came to decitabine response, though, the researchers found that some 67 percent of patients with unfavorable cytogenetic profiles responded to that treatment. On the other hand, decitabine response was detected in only about one-third of individuals in the cytogenetically intermediate- or favorable-risk groups. All of the individuals with known TP53 mutations responded to decitabine, while the response rate was just 41 percent for those with wild-type forms of the gene.

In its analysis, the team saw overall survival times of 11.6 months, on average, in individuals with the unfavorable cytogenetics compared to 10 months in the other cytogenetic groups. For those with TP53 mutations, the overall survival time was 12.7 months — slightly shorter than the 15.4 months survival reported for the wild-type TP53 group.

The investigators noted that though the treatment responses were not durable, it was promising that short-term treatment with decitabine appeared to close the gap between outcomes for those with or without TP53 mutations.

"[N]o one was cured with this drug," Ley explained. "But patients who responded to decitabine lived longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or two and with a good quality of life, because the chemotherapy is not too toxic."

The study provides a "comprehensive mutational analysis that helps us figure out which patients are likely to benefit," added co-author Amanda Cashen, an oncology researcher at Washington University, in a statement. "This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations."

In an editorial published in NEJM, University of Washington and Fred Hutchinson Cancer Research Center researcher Elihu Estey discussed the findings in more detail, noting that the study "points to inevitable, rational replacement of large trials in which homogeneous therapy is administered for a heterogeneous disease by smaller, sub-group specific trials."