New combination therapy for children and adolescents with previously treated blood cancer (acute lymphoblastic leukemia and lymphoblastic leukemia) who have a RAS mutation

Acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) are forms of blood cancer that occur most frequently in children and adolescents and originate from immature white blood cells (lymphoblasts). While ALL primarily affects the blood and bone marrow, LBL often manifests as a tumor in lymph nodes or organs. With modern therapies, both diseases have good chances of cure—most children can be cured in the long term. In difficult cases, such as a relapse or when the disease does not respond to treatment (refractory), the prognosis is poorer. Therefore, new therapies are being sought to improve the chances of a cure. Genetic analyses have shown that mutations in the RAS-RAF-MAPK signaling pathway, particularly in the NRAS and KRAS genes, are associated with a poor prognosis. These mutations lead to uncontrolled cell division and the growth of cancer cells. Trametinib is a targeted drug that inhibits the MEK enzyme complex in the RAS-RAF-MAPK signaling pathway, thereby slowing or stopping the growth of cancer cells. The drug is approved for various types of cancer—including pediatric cancers—but has not yet been approved for ALL or LBL.

The goal of the HEM iSMART-D study is to test whether the drug trametinib, in combination with chemotherapy consisting of dexamethasone, cyclophosphamide, and cytarabine, is an effective and safe treatment option for patients with a confirmed RAS mutation. The HEM iSMART-D study has only one treatment arm, which means that all patients will receive the experimental combination therapy. The study is primarily designed to last 3 years (Phase I) or 6 years (Phase II). Follow-up will continue for a total of 7 years.

Children and adolescents aged 1 to 21 years who have acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) are eligible to participate in the study. Patients must not have responded to previous standard treatment (refractory) or must have suffered a relapse (recurrence). The exact number of prior treatments is not specified in the study. In addition, the patients’ cancer cells must have a RAS mutation.