Relapse, poor survival in leukemia linked to genetic mutations that persist in remission

August 25, 2015, Washington University School of Medicine
Eight in 10 patients with acute myeloid leukemia relapse after remission, and for most of them there's no reliable way to predict relapse. But new research by Timothy J. Ley, MD, and colleagues at Washington University in St. Louis suggests that performing genetic profiling while a patient is in remission can help physicians assess response to treatment and determine whether aggressive, follow-up treatment is necessary. Credit: Mark Katzman

For patients with an often-deadly form of leukemia, new research suggests that lingering cancer-related mutations - detected after initial treatment with chemotherapy - are associated with an increased risk of relapse and poor survival.

Using to study bone marrow samples from patients with (AML), researchers found that those whose cells still carried 30 days after the initiation of were about three times more likely to relapse and die than patients whose bone marrow was cleared of these mutations.

The study, by a team at Washington University School of Medicine in St. Louis, is published Aug. 25 in JAMA.

While the genetic profiling of cancer is not yet routine, such testing typically is performed only at the time of diagnosis to try to pinpoint how aggressive a tumor is and whether it will respond to a particular treatment. The new findings suggest a different approach, one that focuses less on the specific set of mutations present in a patient's tumor at the time of diagnosis and more on whether those mutations are cleared by initial treatment with chemotherapy.

"Most patients diagnosed with AML fall into a gray area when it comes to being able to predict their risk of relapse," said senior author Timothy J. Ley, MD, the Lewis T. and Rosalind B. Apple Professor of Oncology in the Department of Medicine. "About 80 percent of AML patients go into remission with chemotherapy, but most of them eventually will relapse. Unfortunately, we still don't have a definitive test that tells us early on which patients will relapse.

"Such information is important to know because high-risk patients need aggressive, potentially curative therapy with a stem-cell transplant when they are in remission, early in the course of the disease. However, we don't want to transplant patients who are unlikely to relapse following conventional chemotherapy because the transplant procedure is expensive and carries a significant risk of severe side effects and even death."

AML is a cancer of blood-forming cells in the bone marrow. An estimated 19,000 cases of AML will be diagnosed in the United States this year, and some 14,000 will die of the disease.

The current study was retrospective, meaning that the researchers looked at bone marrow samples from patients whose outcomes were already known. The investigators studied leukemic bone marrow samples obtained at diagnosis from 71 AML patients treated at the Siteman Cancer Center? at Barnes-Jewish Hospital and Washington University. Genome sequencing and analysis were performed at the university's McDonnell Genome Institute.

For the 71 bone marrow samples obtained at the time of diagnosis and then sequenced, the specific leukemia-related mutations found in each patient's AML cells were no more informative than standard methods for assessing the risk of relapse.

The researchers then conducted on samples that had been obtained from 50 patients at the time of diagnosis and again 30 days after the initiation of chemotherapy, when they were in remission. Analyzing these samples, the researchers found that 24 patients had persistent mutations in after chemotherapy, even though by standard clinical measures they were in remission. This suggested that at least some leukemia cells had survived the initial therapy. In several cases, these same cells were shown to expand and contribute to relapse.

Those with persistent mutations had a median survival of only 10.5 months, compared with 42 months for the 26 patients whose leukemia mutations had been cleared by initial chemotherapy.

"If our results are confirmed in larger, prospective studies, genetic profiling after initial chemotherapy could help oncologists predict prognosis early in the course of a patient's leukemia and determine whether that patient has responded to the chemotherapy - without having to wait for the cancer to recur," said first author Jeffery M. Klco, MD, PhD, now at St. Jude Children's Research Hospital. "This approach to genetic profiling, which focuses on performing genome sequencing after a patient's initial treatment, also may be useful for other cancers."

In an accompanying editorial, Friederike Pastore, MD, and Ross Levine, MD, of Memorial Sloan Kettering Cancer Center, write: "Although many important questions remain, the findings reported by Klco and colleagues provide critical insights into the role of molecular monitoring in AML and into the dynamics of genetic mutations during AML treatment."

Pastore and Levine call for next steps to include the development of assays to detect residual disease after AML treatment, and the formulation of therapeutic regimens to target such residual disease, with the goal of improving outcomes for patients with AML.

Ley added: "These findings build on studies performed more than a decade ago that suggested the failure to clear leukemia cells bearing chromosomal abnormalities was associated with increased risk of relapse. But that technology was applicable only for the subset of patients with abnormal chromosomes, while genome sequencing can detect mutations in virtually all patients and is much more sensitive and specific. This new approach gives us a way to think about how to use genomics to evaluate the risk of relapse for nearly all AML ."

Explore further: Scientists aim at a genetically lethal strain of leukemia

More information: JAMA, doi:10.1001/jama.2015.9643
JAMA, doi:10.1001/jama.2015.9452

Related Stories

Scientists aim at a genetically lethal strain of leukemia

July 17, 2015
Researchers at UR Medicine's Wilmot Cancer Institute have developed what they believe to be the first mouse model to investigate why a certain subset of acute myeloid leukemia (AML) patients responds particularly poorly to ...

Genetic errors linked to aging underlie leukemia that develops after cancer treatment

December 8, 2014
For a small percentage of cancer patients, treatment aimed at curing the disease leads to a form of leukemia with a poor prognosis. Conventional thinking goes that chemotherapy and radiation therapy induce a barrage of damaging ...

Compound that could prevent acute blood cancer relapse identified

April 17, 2013
Researchers from the RIKEN Center for Integrative Medical Sciences in Japan report today that they have identified a compound that could be used as a new treatment to prevent relapse in acute myeloid leukemia patients.

Calculating leukemia progression

August 4, 2015
A new computational study published in the International Journal of Bioinformatics Research and Applications has shown how mutations that give rise to drug resistance occur in a form of cancer known as acute myeloid leukemia ...

Temple and Fox Chase Cancer Center testing drug for cancer and bone marrow disorders

August 18, 2015
Temple University Hospital and Fox Chase Cancer Center are the only two sites in Philadelphia that participated in an international phase I, randomized clinical trial which tested the drug guadecitabine (SGI-110) in Myelodysplastic ...

New tool determines leukemia cells' 'readiness to die,' may guide clinical care

October 11, 2012
Researchers at Dana-Farber Cancer Institute have developed a novel method for determining how ready acute myeloid leukemia (AML) cells are to die, a discovery that may help cancer specialists to choose treatments option more ...

Recommended for you

Compound in citrus oil could reduce dry mouth in head, neck cancer patients

May 21, 2018
A compound found in citrus oils could help alleviate dry mouth caused by radiation therapy in head and neck cancer patients, according to a new study by researchers at the Stanford University School of Medicine.

Scientists reveal likely cause of childhood leukaemia

May 21, 2018
A major new analysis reveals for the first time the likely cause of most cases of childhood leukaemia, following more than a century of controversy about its origins.

Bladder cancer model could pave the way for better drug efficacy studies

May 21, 2018
Understanding that not all bladder cancers are the same, researchers at the University of North Carolina Lineberger Comprehensive Cancer Center have created a tool that may help them to uncover why only a fraction of patients ...

Ice cream funds research showing new strategy against thyroid cancer

May 21, 2018
Anaplastic thyroid cancer is almost uniformly fatal, with an average lifespan of about 5 months after diagnosis. And standard treatment for the condition includes 7 weeks of radiation, often along with chemotherapy.

MR spectroscopy imaging reveals effects of targeted treatment of mutant IDH1 gliomas

May 18, 2018
Using a novel imaging method, a Massachusetts General Hospital (MGH) research team is investigating the mechanisms behind a potential targeted treatment for a subtype of the deadly brains tumors called gliomas. In their report ...

Particle shows promise to prevent the spread of triple-negative breast cancer

May 18, 2018
USC researchers have pinpointed a remedy to prevent the spread of triple-negative breast cancer. Metastatic breast cancer is a leading cause of death for women. The findings appear today in Nature Communications.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.