Comparison of the combination therapy venetoclax + azacitidine with standard intensive chemotherapy in patients with acute myeloid leukemia (NPM1-mutated)

Acute myeloid leukemia (AML) is a malignant disease of the hematopoietic system characterized by the uncontrolled proliferation of myeloid blasts (immature white blood cells) in the bone marrow and blood. Young patients (under 75 years of age) without serious comorbidities and in good overall health should receive intensive chemotherapy as standard treatment. With this intensive treatment, complete remission can often be achieved, meaning that no cancer cells are detectable. However, this effective form of intensive therapy is often accompanied by many acute complications, such as infections, nausea, and organ damage, as well as prolonged hospital stays. In addition, there is an increased risk of long-term side effects, such as secondary tumors or cardiovascular diseases. For this reason, there is a need for future therapies that are effective and have fewer side effects. Due to the high mortality and complication rates—including severe side effects—this form of therapy is not suitable for older patients in particular.

For older patients with AML or patients who are not suitable for intensive chemotherapy, the effective combination therapy of venetoclax and azacitidine is already approved as an alternative. Azacitidine is a chemotherapy drug that directly attacks the leukemia cells. Venetoclax is a so-called BCL-2 inhibitor, which additionally induces natural cell death in cancer cells. The combination of the two drugs thus targets leukemia cells more specifically while sparing healthy cells in the tissue. Compared to intensive chemotherapy, it is better tolerated due to its targeted action and fewer acute side effects. Studies have shown that this treatment is particularly beneficial for patients with an NPM1 mutation. This is a genetic mutation found in approximately one-third of all AML patients. In studies, treatment with this well-tolerated combination therapy in patients with the NPM1 mutation showed very good response rates among patients for whom intensive therapy was not an option.

The goal of this Phase 2 study is to further investigate the efficacy and tolerability of the combination therapy venetoclax + azacitidine as an alternative to standard intensive chemotherapy in patients in good general health. Participants will be randomly assigned to 2 groups as part of the study. Group 1 will receive the combination therapy of venetoclax and azacitidine. A total of 12 cycles, each lasting 28 days, will be administered. Venetoclax is administered as a tablet on days 1–28, and azacitidine is administered as a subcutaneous injection on days 1–7 of each cycle. Group 2 will receive standard intensive chemotherapy plus gemtuzumab ozogamicin over a total of 5 cycles. The study is open-label, meaning that both the medical staff and the patient know which medications are being administered. Treatments and follow-up examinations as part of the study will continue for up to 4 years, during which the efficacy of the therapy and the occurrence of side effects from the various medications will be evaluated. The primary endpoint of the study is event-free survival (EFS), defined as the time after treatment without, for example, disease relapse, disease progression, or death due to the disease.

Women and men between the ages of 18 and 70 with untreated AML and good overall health are eligible to participate in this study. Additionally, the NPM1 mutation must be present, and the cancer cells must be CD33-positive.