Heidelberg – With the combination of the drugs venetoclax and 5-azacitidine, a new, effective and more tolerable alternative to chemotherapy for the treatment of AML has been available for several years. But for some patients, the drug combination does not work. Doctors and scientists from the German Cancer Research Center, the Heidelberg Stem Cell Institute HI-STEM* and the Heidelberg University Hospital have now developed a marker for therapy response: patients only respond to the new therapy if the leukemia stem cells express a specific combination of cell death-inhibiting proteins at.
Acute myeloid leukemia (AML) is the most common and very aggressive form of blood cancer in adults. Until recently, only high-dose chemotherapy was available to treat the disease. But for about half of those affected, especially the elderly or frail people, this stressful treatment is out of the question.
The active ingredient venetoclax has been approved for several years. The survival of AML cells depends on certain proteins that suppress programmed cell death – apoptosis. Venetoclax specifically inhibits the anti-apoptotic protein BCL-2, which leukemia cells use to protect themselves from cell death, thereby keeping AML in check. A combination of venetoclax and the epigenetic drug 5-azacitidine (Ven/Aza) has significantly improved the treatment of patients for whom high-dose chemotherapy is not an option – and is comparatively well tolerated.
It is therefore currently being examined whether this combination of active ingredients is also suitable as a so-called first-line treatment for younger or physically fit AML patients, thereby sparing them high-dose chemotherapy. However, not every AML patient responds to the drug combination. In some cases, the leukemia cells are resistant from the start. “Until now there have been no predictive markers that can reliably predict a response to venetoclax,” says Andreas Trumpp, head of department at the German Cancer Research Center (DKFZ) and director of the stem cell institute HI-STEM in Heidelberg.
Together with colleagues from the Heidelberg University Hospital, Alexander Waclawiczek, Aino-Maija Leppä and Simon Renders in the Trumpp team were now looking for characteristics in blood and bone marrow samples from AML patients treated with Ven/Aza that correlate with the response to the therapy. The researchers realized that a small population of cells that exhibit characteristics of leukemia stem cells is responsible for the response to therapy. If these cells express a certain combination of proteins of the BCL-2 family, the Ven/Aza combination can induce programmed cell death in the leukemia stem cells and thus arrest AML.
BCL-2, a known inhibitor of apoptosis, is a member of a family of proteins involved in the regulation of programmed cell death. The Heidelberg research team discovered that it is not just the amount of BCL-2 in the leukemia stem cells that determines the Ven/Aza response, but that the amount of certain members of the BCL-2 family is important. From this they derived the so-called “MAC score” (“Mediators of Apoptosis Combinatorial Score”), which expresses the quantitative ratio of the proteins BCL-2, BCL-xL and MCL-1 in the AML stem cells and can be determined by flow cytometry . The higher the score, the longer the treatment success lasted.
“We can thus provide an inexpensive test that provides reliable information after just a few hours as to whether AML responds to Ven/Aza and thus the stressful high-dose chemotherapy can be avoided,” says study leader Andreas Trumpp. The test can be used by anyone well-equipped hematology laboratory to determine the best possible course of treatment for leukemia patients.” The results are to be further evaluated in prospective clinical studies together with Carsten Müller-Tidow at the Heidelberg University Hospital V before the test can be used in the routine care of AML patients.
Alexander Waclawiczek, Aino-Maija Leppä, Simon Renders, Karolin Stumpf, Cecilia Reyneri, Barbara Betz, Maike Janssen, Rabia Shahswar, Elisa Donato, Darja Karpova Vera Thiel, Julia M. Unglaub, Susanna Grabowski, Stefanie Gryzik, Lisa Vierbaum, Richard F Schlenk, Christoph Röllig, Michael Hundemer, Caroline Pabst, Michael Heuser, Simon Raffel, Carsten Müller-Tidow, Tim Saue and Andreas Trumpp: Combinatorial BCL-2 family expression in Acute Myeloid Leukemia Stem Cells predicts clinical response to Azacitidine/Venetoclax
Cancer Discovery 2023, DOI:
*The Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) gGmbH was founded in 2008 as a public-private partnership by the DKFZ and the Dietmar Hopp Foundation.
With more than 3,000 employees, the German Cancer Research Center (DKFZ) is the largest biomedical research facility in Germany. More than 1,300 scientists at the DKFZ research how cancer develops, record cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods with which tumors can be diagnosed more precisely and cancer patients can be treated more successfully. At the Cancer Information Service (KID) of the DKFZ, those affected, interested citizens and specialist groups receive individual answers to all questions on the subject of cancer. Together with partners from the university clinics, the DKFZ operates the National Center for Tumor Diseases (NCT) at the Heidelberg and Dresden sites, and the Hopp Children’s Cancer Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translation centers at seven university partner locations. The combination of excellent university medicine with the top-class research of a Helmholtz center at the NCT and DKTK locations is an important contribution to transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients. The DKFZ is funded 90 percent by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg and is a member of the Helmholtz Association of German Research Centers.