PRIMARY OBJECTIVE:~I. Determine the progression free survival (PFS) at 6 months of the combination therapy of acalabrutinib, venetoclax, and durvalumab in patients with Richter transformation from chronic lymphocytic leukemia (CLL).~SECONDARY OBJECTIVES:~I. Determine the safety of the combination therapy of acalabrutinib, venetoclax and durvalumab in patients with Richter transformation from CLL.~II. Evaluate the overall response rate (ORR), complete response (CR) rate, and partial response (PR) rate of the above combination therapy.~III. Overall survival, PFS, and treatment free survival of this above combination therapy.~CORRELATIVE RESEARCH OBJECTIVES:~I. Determine the biomarkers that predict clinical response of this above combination therapy.~II. Determine the immune profiles of patients while receiving this combination of therapy.~OUTLINE:~Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28, durvalumab intravenously (IV) over 1 hour on day 1, and venetoclax PO once daily (QD) on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.~MAINTENANCE: Patients receive acalabrutinib PO BID and venetoclax PO QD on days 1-90. Treatment repeats every 90 days for 4 cycles in the absence of disease progression or unacceptable toxicity.~After completion of study treatment, patients are followed up at 30 days and then every 90 days until 5 years from study enrollment.
This phase II trial tests whether acalabrutinib, venetoclax, and durvalumab work in treating patients with Richter transformation from chronic lymphocytic leukemia or small lymphocytic lymphoma. Richter transformation is a rare condition in which chronic lymphocytic leukemia or small lymphocytic lymphoma changes into a fast-growing type of lymphoma. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Venetoclax 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. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving acalabrutinib, venetoclax, and durvalumab may help improve survival in patients with Richter transformation.