Dana-Farber / Brigham and Women's Cancer Center

Defining Predictors of Success to Tailor Therapy for Patients with Leukemia

Anthony Letai, MD, PhD

Researchers at Dana-Farber/Brigham and Women’s Cancer Center have developed a novel predictive biomarker for success in treatment for leukemia. This assay is able to determine which patients who initially respond to chemotherapy for acute myelogenous leukemia (AML) will continue in remission with standard chemotherapy alone and which patients are likely to relapse and may benefit from an allogeneic bone marrow transplantation.

  Mitochondrial priming
 
Mitochondrial priming of AML versus hematopoietic stem cells determines the chemotherapeutic index.

Anthony Letai, MD, PhD, a medical oncologist in the Center for Hematologic Oncology at Dana-Farber/Brigham and Women’s Cancer Center, is senior author of the study, which was supported by the National Institutes of Health (NIH), Gabrielle’s Angel Foundation, and the Leukemia and Lymphoma Society and published in Cell (Cell. 2012 Oct 12;151(2):344-55.). The study uses a functional approach to determine how differential mitochondrial readiness for apoptosis, known as mitochondrial priming, may explain individual variation in clinical response to treatment.

“Oncologists currently predict outcome by assessing pathological features and the presence of certain mutations,” said Dr. Letai. “These indicators, however, do not explain patients' differing responses to treatment.”

The researchers found that mitochondrial priming is a determinant of initial response to induction chemotherapy, relapse after remission, and need for allogeneic bone marrow transplantation. Using BH3 profiling on stored AML cell samples, they were able to determine the degree to which mitochondria were primed for apoptosis. BH3 profiling exposes mitochondria in cancer cells to BH3 molecules, which mimic protein death signals. If the mitochondrial membrane is rapidly and easily disrupted during this process, the cells are considered to be highly primed for apoptosis and likely to respond well to chemotherapy. If the mitochondria strongly resist the disruption, the leukemia cells are less likely to respond to chemotherapy. Normal hematopoietic stem cells were found to be less primed to apoptosis than leukemia cells that were readily destroyed by chemotherapy. Cells from AML patients who had responded poorly to chemotherapy were even less primed than normal hematopoietic stem cells to apoptosis.

  priming of normal hematopoietic stem cells
 
The priming of normal hematopoietic stem cells is compared with priming of cured, relapse, and no clinical response patients.

"Our data suggest that applying our assay, in addition to conventional indicators, yields a much better predictive tool," said Dr. Letai. “The information gleaned from this biomarker will help us tailor treatments for patients based on their likelihood to respond, as well as avoid toxic effects of aggressive therapies where they may not be warranted.”

Through BH3 profiling, researchers in the study also found that AML cells, compared with normal hematopoietic stem cells, are more dependent on molecular signals generated by the BCL-2 protein for survival. Experimental drugs that inhibit BCL-2 are being tested in clinical trials and may provide a potential way to better prime leukemia cells for apoptosis.

Dr. Letai and his team are planning to initiate validation studies of the biomarker approach in 2013 and expect prospective clinical trials to open in 2014. Using an independent set of patients, validation studies will assess the test’s accuracy in determining which young patients with AML who achieve complete remission in induction chemotherapy should receive bone marrow transplantation or consolidation chemotherapy, as well as the best initial therapy for AML patients over the age of 60.

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