AML Recurrence Linked to Persistent Preleukemic Clones

Nancy A. Melville

June 13, 2016

COPENHAGEN, Denmark ― Even after chemotherapy for acute myeloid leukemia (AML) has pushed the patient into remission, there remain some preleukemic genetic mutations. New research shows that these persistent preleukemic clones are most common in older people and are linked to shorter overall survival, a finding that potentially offers critical clues as to why AML outcomes are particularly unfavorable in the elderly.

"Our study is the first to show a very clear-cut association between older age and mutation persistence during remission," Klaus H. Metzeler, MD, of the University of Munich, Germany, told Medscape Medical News.

"More than a third of patients had persisting mutations, and those with persisting mutations had significantly shorter remission-free and overall survival," he said.

Previous studies have shown that AML can originate in preleukemic clones. Just last year, a study in JAMA showed that persisting leukemia-associated genetic mutations could be detected in nearly half of day-30 postchemotherapy samples.

In the new study, presented here at the European Hematology Association (EHA) 2016 Congress, Dr Metzeler and colleagues looked at a larger sample of 107 patients who had been uniformly treated as part of the German, multicenter, phase 3 AMLCG-2008 trial.

Dr Metzler noted that most of these 107 patients had de novo AML (90%); 5% had secondary AML, and the remaining 5% had therapy-related AML. These patients, whose median age was 53 years, had received intensive induction chemotherapy and had reached either complete remission or complete remission with incomplete blood count recovery.

The researchers used multiplexed amplicon sequencing to conduct mutation analyses of 68 genes known to be altered in leukemias. They evaluated sample pairs of driver mutations taken at the time of leukemia diagnosis and after chemotherapy, when the patient was in remission.

Persisting mutations were found in 36% of patients; no persisting mutations were found in the remaining 64%.

The most common mutations were for DNMT3A (62%), TET2 (69%), SRSF2 (63%), and ASXL1 (42%).

Patients who had one or more persisting mutations while in remission were older (median age, 63 years) than those without the mutations (median age, 48 years; P < .001). The persistence of one or more driver mutations in patients whose disease was in remission was also associated with shorter median relapse-free survival (14.3 vs 58.0 months; P = .009) as well as shorter overall survival (median, 39.6 vs >72 months; P = .005).

"While this association does not establish causality, our data suggest that more frequent persistence of preleukemic clones might be one reason for the worse outcomes observed in elderly AML patients," Dr Metzeler said.

He noted that preliminary data suggest a possible key role for stem cell transplant in eliminating persisting mutations. The outcomes of patients with and without persisting mutations appear to be similar after the patients undergo allotransplant, he noted, but he added that exactly why this is the case is not well understood.

"At the moment, it certainly is too early to suggest that all patients with persisting mutations should be transplanted," Dr Metzeler said.

"However, I would discuss the elevated risk of recurrence associated with a persisting preleukemic clone, especially with those patients who are potential candidates for an allogeneic transplant.

"In my view, it would be prudent to closely monitor such patients, including regular flow-based and/or molecular MRD assessments, to detect impending relapse and initiate salvage treatment," Dr Metzeler added. "However, mutation persistence often affects older patients who may not be good transplant candidates, so other approaches are needed."

The findings raise intriguing questions about the potential for future targeted approaches, Dr Metzeler added.

"It is an exciting question whether novel targeted agents, such as inhibitors of mutant IDH1/IDH2, demethylating agents, or immunotherapeutic approaches, can be used to reduce or eliminate persisting preleukemic clones, and whether this results in a decreased risk of AML relapse," he said.

"This question clearly needs to be addressed in clinical trials," he added.

"Highly Important" Findings

In commenting on the study, Andreas Engert, MD, professor of internal medicine, hematology, and oncology at the University Clinic of Cologne, Germany, agreed that the findings, though preliminary, are highly important.

"We treat patients with chemotherapy, and some will relapse, and we will have no idea why they relapse, so for the first time, this study begins to give us clues as to the reasons why this subset will relapse," he said.

"Now we know this group exists, and we can begin to ask questions regarding why it is that they relapse ― does it have to do with the immune systems in these patients (for instance)?

"So it's the first step in what's going to be a long journey, but it's a very important step," Dr Engert said.

The authors have disclosed no relevant financial relationships. Dr Engert has relationships with Takeda/Millennium, Novartis, Affimed, BMS, and Merck.

European Hematology Association (EHA) 2016 Congress: Abstract S145. Presented June 10, 2016.

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