Small Lymphocytic Leukemia

Background: Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) are diseases in which the body makes too many white blood cells that do not work properly. Because white cells play a role in immune function, people with CLL/SLL may be at greater risk of infections. CLL/SLL can be controlled with drugs, but many people develop resistance, and the treatments stop working. Objective: To test a new drug (nemtabrutinib) in people with CLL/SLL. Eligibility: People aged 18 years or older with CLL/SLL that persists despite treatment. Design: Participants will be screened. They will have imaging scans, blood and urine tests, and a test of their heart function. They will have a bone marrow biopsy: a sample of tissue and fluids will be drawn from inside their hip bone. They may also have a sample cut from a swollen lymph node, if one is safe to access. Nemtabrutinib is a tablet taken by mouth. Participants will take the drug once a day at home in 4-week cycles. They will have clinic visits at least every 4 weeks for the first 6 months and then every 3 months after that. Biopsies, imaging exams, and other tests may be repeated at these visits. Participants may also undergo lymphapheresis: Blood will be drawn from a tube inserted into a vein. The blood will pass through a machine that separates out cancer and immune cells. The remaining blood will be returned to the body through a different tube. Participants may stay in the study as long as the drug is helping them.

This phase III trial compares the effect of adding sonrotoclax to zanubrutinib versus zanubrutinib alone for the treatment of patients with untreated chronic lymphoblastic leukemia (CLL)/small lymphocytic lymphoma (SLL). Sonrotoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Zanubrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cell (a type of white blood cells) cancers such as mantel cell lymphoma at abnormal levels. This may help keep cancer cells from growing and spreading. Giving sonrotoclax and zanubrutinib may be more effective than zanubrutinib alone for the treatment of untreated CLL/SLL.