Study Identifies Gene-Mutation Combinations That Predict AML Outcomes in Older Patients

April 09, 2018
Bloomfield Eisfeld

Columbus, Ohio – A new study led by researchers at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James) has identified combinations of gene mutations that predict whether an older person with acute myeloid leukemia (AML) might achieve complete remission when treated with standard chemotherapy.

The researchers analyzed the AML cells of 423 patients age 60 and older for mutations in 80 cancer- or leukemia-associated genes. They then used that mutation information to classify the patients into groups that had a good, poor or intermediate outcome after treatment with standard chemotherapy.

Overall, the study, published in the journal Leukemia, highlighted the extremely poor outcome of AML patients aged 60 years and older with current treatment approaches. However, the authors found specific mutation combinations that associated with patient survival, some of which were different than those known to be associated with outcome in younger AML patients.

“This study is important,” said study leader Clara D. Bloomfield, MD, Distinguished University Professor and Ohio State University Cancer Scholar and Senior Adviser and the William Greenville Pace III Endowed Chair in Cancer Research, “because the majority of research in AML is done in patients under age 60, even though the majority of AML patients are of older age.” Bloomfield also noted that the findings might refine the classification of older AML patients who are to be treated with chemotherapy.

“We found that the number and types of chromosome changes and gene mutations are different in older AML patients compared with younger patients, along with the significance of some of those abnormalities,” Bloomfield says. “So it’s important that we evaluate older AML patients separately from younger patients.”

First author and OSUCCC – James researcher Ann-Kathrin Eisfeld, MD, a member of Ohio State’s Internal Medicine/Physician-Scientist Training Program, noted that the favorable complete response rate of the good-risk group did not lead to better overall survival, however.

Of patients in the good-risk group, 82 percent experienced relapse of their disease, as did patients in the intermediate-risk group. “And those groups did only slightly better than the poor-risk group, where 93 percent of patients relapsed,” Eisfeld says. “This tells us that once patients are in remission they probably require additional or different treatment than chemotherapy alone to extend remission or potentially cure those patients.”

Among other findings, they showed that the “good risk” group of patients was not only driven by the beneficial influence of NPM1 mutations, but was additionally altered by coexisting mutations in other genes.

“Our findings suggest that older AML patients should be tested for additional gene mutations before receiving standard chemotherapy,” Eisfeld says. 

Some 19,500 people are expected to be diagnosed with AML in 2018, and the majority of them will be age 60 or over. Of those older patients, only 5 to 15 percent will be cured of their leukemia following standard chemotherapy versus about 40 percent of adult patients under age 60.

For this study, Bloomfield, Eisfeld and their colleagues used next-generation sequencing to analyze the cancer genomes of older AML patients that were treated with standard therapy.

Key findings include:

  • Mutation testing is important for the identification of the small group of older patients who have an excellent chance to achieve a complete remission when treated with standard induction chemotherapy
  • Complete response rates of patients with mutated NPM1 varied from 50-95 percent, depending on the presence or absence of specific co-existing mutations.
  • Patterns of coexisting mutations also revealed higher rates of three-year disease-free survival.

Funding from the National Cancer Institute of the National Institutes of Health (grants CA180821, CA180882, CA003927, CA047545, CA101140, CA140158, CA180850, CA180861, CA180866, CA180867, CA196171, CA197734, CA189850 and CA016058), the Coleman Leukemia Research Foundation, the National Comprehensive Cancer Network Foundation Young Investigator Award, the Alliance for Clinical Trials in Oncology Scholar Award, The D. Warren Brown Foundation, and the Pelotonia Fellowship Program supported this research.

Other researchers involved in this study were Jessica Kohlschmidt, Krzysztof Mrózek, James S. Blachly, Christopher J. Walker, Deedra Nicolet, Shelley Orwick, Sophia E. Maharry, Albert de la Chapelle and John C. Byrd, The Ohio State University; Andrew J. Carroll, University of Alabama at Birmingham; Richard M. Stone, Dana-Farber/Partners CancerCare; Eunice S. Wang, Roswell Park Cancer Institute; Jonathan E. Kolitz, Hofstra Northwell School of Medicine; and Bayard L. Powell, Wake Forest University.

About the OSUCCC – James

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 45 National Cancer Institute-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials on novel anticancer drugs. As the cancer program’s 306-bed adult patient-care component, The James is one of the top cancer hospitals in the nation as ranked by U.S. News & World Report and has achieved Magnet designation, the highest honor an organization can receive for quality patient care and professional nursing practice. At 21 floors with more than 1.1 million square feet, The James is a transformational facility that fosters collaboration and integration of cancer research and clinical cancer care.

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