Scientists develop marker for treatment response in acute myeloid leukemia

With the combination of the drugs Venetoclax and 5-Azacitidine, a new, effective, and potentially more effective alternative to chemotherapy for AML has been available for several years. But for some patients, the drug combination doesn’t work. Doctors and scientists from the German Cancer Research Center, the Heidelberg Institute for Stem Cells HI-STEM and the University Hospital Heidelberg have developed a marker for treatment response: only when leukemia stem cells express a specific combination of cell death-inhibiting proteins do patients respond to them. The new treatment.

Acute myeloid leukemia (AML) is the most common and most aggressive type of leukemia in adults. Until recently, high-dose chemotherapy was only available to treat disease. But for about half of those affected, especially the elderly or frail, this painful treatment is out of the question.

Venetoclax has been approved for several years. The survival of AML cells depends on specific proteins that inhibit apoptosis – programmed cell death. Venetoclax specifically blocks the anti-apoptotic protein BCL-2, which leukemia cells use to protect themselves from cell death, thus keeping AML in check. The combination of Venetoclax and the epigenetic drug 5-Azacitidine (Ven/Aza) is relatively well tolerated and has significantly improved the treatment of patients for whom high-dose chemotherapy is not an option.

Therefore, it is currently being investigated whether this drug combination would also be suitable for so-called first-line therapy in younger or otherwise fit AML patients, which would spare them the need for high-dose chemotherapy. However, not every acute myelogenous leukemia patient responds to combination drugs. In some cases, leukemia cells are resistant from the start. “So far, there are no prognostic indicators that can reliably predict the response to Venetoclax,” says Andreas Tromp, Head of Department at the German Cancer Research Center (DKFZ) and Director of HI-STEM in Heidelberg.

In collaboration with colleagues from Heidelberg University Hospital, Aleksandr Waklawischek, Inoue-Maia Lipa and Simon Reynders in Tromp’s team investigated the characteristics of blood and bone marrow samples from VEN/Aza-treated AML patients that correlate with treatment response. The researchers found that a small group of cells that display the characteristics of leukemia stem cells are responsible for the response to treatment. If these cells express a specific combination of proteins in the BCL-2 family, the Ven/Aza combination can induce apoptosis in leukemia stem cells, stopping AML.

BCL-2, a known inhibitor of apoptosis, is a member of a family of proteins involved in the regulation of apoptosis. The Heidelberg research team found that it is not only the amount of BCL-2 in leukemia stem cells that determines the Ven/Aza response, but what is important is the quantitative ratio of specific BCL-2 family members. Based on this observation, they derived a so-called “MAC score” (“Medians of Apoptosis Combinatorial Score”), which expresses the ratio of the amount of BCL-2, BCL-xL and MCL-1 proteins in AML stem cells and can be determined by flow cytometry. cellular. The higher the score, the longer the treatment success will last.

We can thus offer an inexpensive test that gives reliable information after only a few hours whether AML responds to Ven/Aza and thus whether high-dose stress chemotherapy can be avoided. “

Andreas Trump, study leader

The test can be performed in any well-equipped hematology laboratory to determine the best possible form of treatment for patients with leukemia. Together with Carsten Müller-Tidow at Heidelberg University Hospital V, the findings will be further evaluated in future clinical studies before the test can find its way into the routine care of patients with AML.


Journal reference:

Waclawiczek, A., et al. (2023). BCL-2 family combinatorial expression in acute myeloid leukemia stem cells predicts clinical response to Azacitidine/Venetoclax. Cancer discovery.

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