Personalizing AML Treatment Through Mutational Profiling

Understanding the genetics of the disease is opening up treatment options.

Last month, James Fitzgerald celebrated his wedding day. It was an event that he never thought he would see when he was diagnosed with acute myeloid leukemia (AML) six years ago. He was immediately hospitalized, and his liver and kidneys failed within 24 hours. His doctors put him into a medically-induced coma for a week before starting his treatment, which included an intensive combination of chemotherapy and radiation. It was one of the only treatment options for AML at that time.

But that’s changing for AML patients like Fitzgerald. Therapies that target some of the specific molecular genetic changes in AML are being developed, and that’s making mutational profiling more important than ever. That’s good news for Fitzgerald who is currently in remission but is concerned that his disease may one day come back.

“When I was diagnosed, I didn’t know to ask my doctors about the different molecular mutations or whether that would even make a difference in my treatment,” Fitzgerald said. “It was only after my treatment that I started asking questions and learning about the genetics of AML.”

Spot the Difference in AML

Enabled by breakthroughs in genome sequencing and analysis over the past decade, researchers have learned more about the genetics that drive AML. In 2008, an AML patient was the first cancer patient to have her genome sequenced, enabling researchers to discover 10 molecular mutations related to the disease.

Since then, scientists have identified as many as 80 potentially disease-associated mutations in many genes, including NPM1, FLT3-ITD, IDH2, DNTM3A, KIT, IDH1, and CEBPA. They have now found genetic differences between the 34 subgroups of AML, confirming the idea that not every AML case is the same.

This diversity can make treatment a challenge. But scientists and patients are hopeful that a better understanding of these molecular changes will improve outcomes. That’s particularly good news for a disease that has not seen substantial improvements in 20 years.

I hope doctors start learning more about the mutations in AML and start talking with their patients about the genetics of the disease.

The current standard of treatment — an intense combination of chemotherapy — is not particularly easy for patients to tolerate, something Fitzgerald can attest to. Eventually, he received a bone marrow transplant and has been in remission ever since.

“It certainly wasn’t fun,” said Fitzgerald. “I had a 106-degree fever at one point, and I was in the hospital for three months. It was definitely tough for me, but at least I had that option.”

Given the severity of treatment-related adverse events, the standard treatment regimen is often not prescribed for older or unhealthy patients. So while half of AML patients under age 60 years live five years or longer, only up to 15 percent of older patients, who more often cannot receive intense chemotherapy, reach the same milestone.

Mutational Profiling May Help Inform Therapeutic Decisions

Researchers are turning their focus to develop therapies that target the specific molecular mutations that drive AML. A recent analysis of 200 patients showed that more than 99 percent of patients had at least one mutation associated with the disease.

As new targeted therapies are being explored, an understanding of the underlying mutations in each patient becomes increasingly important for doctors and patients to decide on an appropriate treatment plan. The Leukemia & Lymphoma Society is exploring the possibility of bringing a personalized approach to AML treatment through its Beat AML clinical trial. With such initiatives in progress, molecular profiling is on its way to becoming a standard part of disease classification and treatment for AML patients.

“I hope doctors start learning more about the mutations in AML and start talking with their patients about the genetics of the disease,” said Fitzgerald. “I can only hope AML patients don’t have to go through what I faced in my treatment.”

To learn more about how clinical trials are bringing a precision medicine approach to AML, read “Bring Patients Closer to Personalized AML Treatments.”