New combination therapy for children and young adults with relapsed or treatment-resistant acute lymphoblastic leukemia or lymphoblastic lymphoma with specific genetic alterations

Acute lymphocytic, or lymphoblastic, leukemia (ALL) is a malignant disease of the white blood cells characterized by the uncontrolled production of white blood cell precursors (blasts) in the bone marrow and blood. The overproduction of blasts disrupts normal blood formation and the immune system. In ALL, other organs or the central nervous system may also be affected. Consequently, fatigue, anemia, an increased tendency to bleed, fever, and an increased susceptibility to infections may occur. Lymphoblastic lymphoma (LBL) is a rare form of non-Hodgkin lymphoma that affects lymphocytes, a subtype of white blood cells. It is very similar to acute lymphoblastic leukemia (ALL), but unlike ALL, it typically affects the lymph nodes and organs rather than the bone marrow. The malignant cells can also spread to the central nervous system (CNS, brain, and spinal cord). Although the chances of a cure are often good in children, there are cases in which the cancer returns (recurrence) or does not respond to treatment (refractory). In these situations, new therapeutic approaches are needed. Genetic alterations in the tumor can, among other things, promote cell growth by influencing cellular signaling pathways. At the same time, these alterations in signaling pathways represent new targets for targeted treatment approaches. The ABL1 gene (e.g., NUP214-ABL1 fusion gene) is one such rare genetic alteration that can occur in acute leukemias. The fusion of two genes results in a persistently active enzyme (tyrosine kinase) that promotes cancer growth but also serves as a target for targeted therapy. Dasatinib is a tyrosine kinase inhibitor that specifically blocks this persistently active signaling pathway in cancer cells. In addition to dasatinib, the study treatment combines four other active ingredients. Venetoclax is a drug that specifically targets the BCL-2 protein, thereby inducing programmed cell death in cancer cells. Dexamethasone is a corticosteroid with anti-inflammatory effects. Cyclophosphamide and cytarabine are chemotherapeutic agents that inhibit the proliferation of cancer cells.

The goal of this Phase 1/2 study is to investigate the efficacy and safety of dasatinib and venetoclax in combination with chemotherapy. The study consists of two phases: In Phase 1 of the study, patients in small groups receive treatment with different drug doses to determine the maximum tolerated dose. Subsequently, in Phase 2 (dose-expansion), the safety, tolerability, and efficacy of the optimal dose identified in Phase 1 will be evaluated in a larger group. Treatment consists of two cycles, each lasting 28 days. Dasatinib and venetoclax are taken daily, while chemotherapy is administered on specific days. The study is open-label, meaning that medical staff and patients know which medications are being taken. The primary endpoint of Phase 2 is the overall response rate to treatment at up to 6 years.

Children and young adults (ages 1 to 21) with relapsed or refractory ALL or LBL who have been found to have a corresponding genetic alteration in the MAPK/SRC signaling pathway (e.g., ABL1 fusions) are eligible to participate. The initial diagnosis must have been made between the ages of 1 and 18. Important eligibility criteria include adequate organ function (heart, liver, kidneys) and good overall health. Patients with certain mutations that could cause resistance to venetoclax are excluded from participation.