Efficacy of bleximenib as an adjunct to standard therapy (venetoclax + azacitidine) in patients with newly diagnosed acute myeloid leukemia who cannot tolerate intensive chemotherapy

Acute leukemias are rapidly progressing, aggressive cancers that arise from immature white blood cells or bone marrow cells and usually spread very quickly. The malignant leukemia cells develop in the bone marrow and displace the healthy bone marrow, preventing the production of sufficient numbers of functional blood cells. Typical symptoms include frequent infections, bleeding, fatigue, and shortness of breath. In younger patients, intensive chemotherapy is often used, which can achieve complete remission in many cases. For older patients with AML or for patients who are not suitable candidates for intensive chemotherapy, the effective combination therapy of venetoclax and azacitidine has already been approved as an alternative. Azacitidine is a chemotherapy drug that directly attacks leukemia cells. Venetoclax is a so-called BCL-2 inhibitor that additionally triggers the natural death of cancer cells. The combination of the two drugs targets leukemia cells more precisely while sparing healthy cells. Compared to intensive chemotherapy, it is better tolerated due to its targeted action and fewer acute side effects.

This form of therapy has proven particularly effective in cases of AML with the NPM1 mutation, which occurs in about one-third of patients. Another particularly aggressive genetic alteration is the KMT2A rearrangement—a gene fusion that promotes the uncontrolled growth of white blood cells. This is precisely where bleximenib comes in: It specifically blocks key enzymes in a pathologically activated signaling pathway that plays a central role in these genetic alterations. Although bleximenib has not yet been approved, initial studies show promising results.

The goal of the Phase III study is to investigate whether adding bleximenib to the established combination of venetoclax and azacitidine improves efficacy and, consequently, survival.

The study is randomized and double-blind. This means that patients are randomly assigned to a treatment group, and neither they nor the medical staff know who is receiving the study drug or a placebo. A treatment cycle lasts 28 days. During this time, all study participants receive venetoclax daily. On days 1 through 7 of each cycle, azacitidine is also administered—either as an infusion or subcutaneously. Starting on day 4, patients begin taking bleximenib or a placebo—twice daily in tablet form. Treatment continues until the disease progresses or the therapy can no longer be tolerated. Eligible participants are adult women and men with newly diagnosed acute myeloid leukemia and a confirmed KMT2A rearrangement or NPM1 mutation who are not suitable for intensive chemotherapy. There must be more than 10% leukemia cells (blasts) in the bone marrow.