Study of the Drug Venetoclax in Children with Relapsed Acute Myeloid Leukemia (AML)

Acute leukemias are rapidly progressing, aggressive cancers that arise from immature white blood cells or bone marrow cells. These so-called blasts displace the healthy bone marrow, resulting in an insufficient production of functional blood cells. Typical symptoms include infections, a tendency to bleed, decreased energy, and shortness of breath. In acute myeloid leukemia (AML), the precursors of the so-called myeloid cell line of leukocytes are abnormal. Overall, AML is a rare disease—though it is the second most common type of blood cancer (leukemia) in children. The disease is classified into various genetic subgroups, which is crucial for targeted treatment planning. Treatment for AML typically involves intensive chemotherapy, which is divided into several phases: induction, consolidation, and, in certain cases, maintenance therapy. Despite intensive treatment, some patients experience a relapse or develop a form of the disease that does not respond to the initial therapy (refractory). In children with relapsed or refractory AML, further intensive chemotherapy is usually initiated. The goal is to (once again) bring the disease under control so that, if possible, a stem cell transplant can be performed. The medications used depend on the patient’s previous treatment and current condition. High-dose cytarabine is often combined with other active ingredients. If certain drugs, such as anthracyclines, can no longer be administered, a different chemotherapy regimen is used. Fludarabine, cytarabine, and gemtuzumab ozogamicin form a commonly used combination that is also being used in this study. Fludarabine and cytarabine are classic chemotherapy drugs. Gemtuzumab ozogamicin is an antibody-drug conjugate that delivers a cytotoxic agent directly into the leukemia cells. This so-called backbone chemotherapy forms the basis of treatment in this study and is also recommended as the standard therapy in this situation. Since relapses are often caused by resistant leukemia stem cells, it is important to also target the causes of this resistance. A known cause of resistance is the overexpression of the BCL-2 protein, which inhibits programmed cell death—known as apoptosis—and thus promotes the survival of cancer cells. The study drug venetoclax is a targeted inhibitor of BCL-2. It is already being used successfully to treat other forms of leukemia. In this specific situation, however, it has not yet been approved, and its use is therefore experimental. If a stem cell transplant is not possible after chemotherapy, maintenance therapy is used to keep the disease under control for as long as possible and prevent its progression. In this study, the drug azacitidine is used in such cases.

The goal of this Phase 3 study is to determine whether adding venetoclax to standard therapy can improve patient survival rates. To this end, patients are randomly assigned to two groups. Both groups initially receive two cycles of intensive chemotherapy consisting of fludarabine, cytarabine, and gemtuzumab ozogamicin; one group also receives venetoclax (study group), while the other does not (control group). One cycle lasts a total of 42 days. If a stem cell transplant is not possible afterward, maintenance therapy follows: in the control group with azacitidine alone, and in the study group with venetoclax and azacitidine. The study is open-label, meaning that both medical staff and patients know which treatment is being administered. The primary endpoint of the study is overall survival, defined as the length of time patients remain alive from the time of study enrollment, regardless of the course of the disease. Patients will be followed for up to 5 years after study enrollment.

Children, adolescents, and young adults with acute myeloid leukemia who are between 29 days and 21 years of age are eligible to participate in the study. Eligibility requires a first relapse in which further treatment with anthracyclines is not possible, or a second relapse. Patients who have already received a stem cell transplant may also be included. However, patients with an FLT3/ITD mutation or with Down syndrome are excluded.