Novel Assay May Further Individualize Treatment for AML

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(ChemotherapyAdvisor) – Information provided by BH3 profiling, an assay of mitochondrial apoptotic function, can “potentially be exploited” to personalize therapy for patients with acute myelogenous leukemia (AML), according to an article in the October 12 issue of Cell.

This includes application of BCL-2 antagonists, allogeneic bone marrow transplant, and conventional chemotherapy, noted Anthony Letai, MD, PhD, of Harvard Medical School and Dana-Farber Cancer Institute, Boston, MA, senior author.

“Rather than taking a genetic approach favored by many, we took a functional approach to ask how differential mitochondrial readiness for apoptosis (‘priming') might explain individual variation in clinical behavior,” the authors wrote.

This rationale is based on observations over the past 4 decades that have shown since the introduction of effective chemotherapy regimens for AML, some patients respond to chemotherapy and others do not; those relapsing after initial response are unlikely to be cured by chemotherapy alone; there is an unexplained therapeutic index for induction chemotherapy; and allogeneic transplant is necessary to rescue those who have relapsed or are poor risk.

“Our results suggest that differences in pretreatment mitochondrial priming, as measured by BH3 profiling, provide a biological explanation for these heretofore unexplained clinical observations,” they wrote.

For example, differential priming between malignant myeloblasts and normal hematopoietic stem cells supports a mitochondrial basis to the therapeutic index for chemotherapy, with BH3 profiling identifying “BCL-2 inhibition as a targeted strategy likely to have a useful therapeutic index. BH3 profiling refines predictive information provided by conventional biomarkers currently in use and thus may itself have utility as a clinical predictive biomarker.”

Knowing whether a patient is likely to have a complete response to chemotherapy is useful in personalizing chemotherapy decisions, even when bone marrow transplant is not a consideration. “In elderly patients with AML, chemotherapy can be very toxic with an increased risk of fatal complications,” said Dr. Letai. “Our data suggest that applying our assay in addition to conventional indicators yields a much better predictive tool."

The investigators plan to confirm their results and test the assay's performance prospectively in clinical trials “to see if we can use it to do a better job of assigning individualized therapy in AML.”

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