Clinical challenges: timely testing for genetic mutations in AML

Acute myeloid leukemia (AML) is a genetically heterogeneous malignant tumor characterized by recurrent gene mutations. Genomic heterogeneity, individual patient variability and recurrent mutations are major obstacles to optimal treatment.

“Genetic knowledge has been increasingly integrated into the diagnosis, prognosis and treatment of AML over the past decade. It is still relatively new, although it has become the standard of care in large centers at the time of diagnosis and remission, ”said John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York. York. The presence of mutations such as IDH1 can help determine a patient’s risk of relapse and whether the risk is high enough to warrant a bone marrow transplant in addition to chemotherapy, he said. MedPage today.

“But while mutations can help in treatment decisions, the meaning of a mutation is not black and white or cut and dry,” he added.

The diverse genetic landscapes of AML patients pose considerable challenges to clinicians even before treatment, including the time it takes to get results of genetic tests defining treatment before optimal treatment can begin.

“A sick patient enters or is transported in a chopper or brought to the clinic on a stretcher. He may need to start anti-AML treatment urgently, but if he has any of the mutations that are impacting treatment, you may not know for 5 to 21 days, “said Mark Levis, MD, PhD, of the Sidney Kimmel Cancer Center at Johns Hopkins Medicine in Baltimore “Testing is labor intensive and time consuming.

And while a polymerase chain reaction (PCR) test for a specific mutation might take a few days, it takes 2 weeks to transform a next-generation sequencing panel (NGS) on multiple variations, he said. declared. MedPage today.

“The problem,” Levis added, “is that standard intensive chemotherapy will almost certainly do harm if the patient has, say, a TP53 mutation.”

These mutations are associated with complex cytogenetic abnormalities, advanced age, drug resistance, decreased response to bone marrow transplantation and poor outcomes, Levis explained. “So the dilemma is, are we waiting to rule this out even though the patient is in desperate need of immediate treatment? “

One way around this problem is to test for the complex karyotype, which most TP53 carriers have and that only takes 2-3 days, he said, noting he’s working “desperately” with science labs, health bureaucracy and MBA consultants to speed things up and get those through. foreground tests. “So if they have a complex karyotype, they might well have a TP53 mutation, and I have to do everything I can to stop the treatment until this is confirmed, ”said Levis.

Then there is the added layer of getting timely authorization from insurers for testing, especially for outpatients, who stay home while awaiting test results. “We don’t want outpatients ending up with big bills for genetic testing that the insurance company won’t allow, so we’re working with the insurance bureaucracy on this,” he said.

Consider the context of elderly patients with AML who are not candidates for standard intensive chemotherapy, continued Lévis. Knowing early on that they mutated FLT3 may lead to the use of a FLT3 inhibitor instead of non-targeted therapy. “But you have to start the inhibitor on day 8 or you missed your opportunity. You can get the PCR results on a mutation in a few days, but the panel takes 2 weeks, so we’re not ordering that,” a- he declared. Explain.

He said that in the absence of formal clinical trials, oncologists are experimenting “on the fly” with the off-label addition. FLT3 inhibition of treatment with azacitidine and venetoclax (Venclexta).

It’s an unorthodox approach, but doctors are trying it all over the country. “I have 80-year-old AML patients in remission and playing golf who would otherwise have died. No matter how chaotic it seems, it’s clear that we are moving forward, ”said Levis.

Aaron Gerds, MD, MS, of the Cleveland Clinic Taussig Cancer Institute, shares Lévis’s frustration over the insurance coverage feud, which can delay the critical diagnostic and prognostic tool of genomic testing.

“The challenge is to achieve universal coverage for genomic profiling. This is something that we are still struggling with,” he said. MedPage today. “This is essential for risk stratification. We need to understand the patient’s prognosis as soon as possible to know whether a transplant will be necessary or not.”

If new patients with AML have mutated FLT3, this is crucial to know in a timely manner in order to obtain insurance clearance to supplement chemotherapy with midostaurin (Rydapt) – a multi-target oral kinase inhibitor – by day 8, as recommended by the RATIFY trial.

“But some won’t get cleared until well past Day 8, Day 10, or even Day 20, and the therapeutic window is lost,” Gerds said. “So in this age of targeted therapy, we can have the treatment, but we don’t get the approval early enough to follow the trial protocols.”

Timely testing is also important in the post-treatment phase, Mascarenhas said, noting that after PCR, NGS provides a superior measure of minimal residual disease and facilitates better treatment decisions.

Studies are underway to determine which mutational profiles will make leukemia cells more sensitive to targeted and gene-specific treatments, he added. “Mutations are heterogeneous and must be viewed in the context of other mutations. We must find how best to induce remission in people at genetic risk and achieve the longest full remission and the best lifesaving therapy for relapsers.”

As trials progress with gene targeting done earlier in treatment and the identification of new targeted treatments for different mutations and ways to better target existing agents, the acceleration of genomic information at diagnosis will become even more. important, said Gerds. “I can foresee a not too distant point in the future when induction therapy for a patient with HDI the mutation may be a HDI inhibitor.”

The big puzzle of AML genetic mutations could potentially be put together by artificial intelligence, Gerds continued. Machine learning can help clarify relationships between recurrent mutations in different populations, determine how to fit them into patient variables, and help clinicians produce compilations based on profiles of therapies that will work best for individuals.

“But that’s a few years away,” he said. “Machine learning is not there yet. Right now we need to create much better databases and better algorithms for better results. Right now the problem is ‘garbage in, garbage out’. . “

Last updated on September 22, 2021

  • Diana Swift is a Toronto-based freelance medical journalist.

Disclosures

Lévis did not disclose any competing interests related to these comments.

Gerds and Mascarenhas had no disclosure regarding their comments.

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