Recent Updates in Venetoclax Combination Therapies in Pediatric Hematological Malignancies

Abstract

Venetoclax is a strongly effective B-cell lymphoma-2 inhibitor (BCL-2) with an ability to selectively restore the apoptotic potential of cancerous cells. It has been proven that in combination with immunotherapy, targeted therapies, and lower-intensity therapies such as hypomethylating agents (HMAs) or low-dose cytarabine (LDAC), the drug can improve overall outcomes for adult patients with acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), amongst other hematological malignancies, but its benefit in pediatric hematology remains unclear. With a number of preclinical and clinical trials emerging, the newest findings suggest that in many cases of younger patients, venetoclax combination treatment can be well-tolerated, with a safety profile similar to that in adults, despite often leading to severe infections. Studies aim to determine the activity of BCL-2 inhibitor in the treatment of both primary and refractory acute leukemias in combination with standard and high-dose chemotherapy. Although more research is required to identify the optimal venetoclax-based regimen for the pediatric population and its long-term effects on patients’ outcomes, it can become a potential therapeutic agent for pediatric oncology.

Venetoclax Combination Treatment of Acute Myeloid Leukemia in Adolescents and Young Adult Patients

“…Some of these (16) are established in AML treatment, while others (selinexor, revumenib, and sorafenib) are currently under investigation in ongoing clinical trials. According to real-world evidence, venetoclax regimens can be used both as an emergency therapy in the case of treatment-resistant leukemias and as a bridge therapy if it is necessary to perform a HSCT [115]. All studies in the AML AYA population included both relapsed and primary refractory cases.…”

Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review

“…B cell lymphoma-2 (BCL-2) family is a key apoptotic factor in the endogenous apoptotic signaling pathway, which inhibits apoptosis and plays an important role in tumorigenesis and development. 1 Many hematological tumors show the overexpression of the anti-apoptotic protein BCL-2, [2][3][4] such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), so BCL-2 inhibitors have a broad application prospect in hematological malignancies. Venetoclax (VEN) is the world's first approved oral BCL-2 inhibitor targeting the apoptotic pathway in tumors.…”