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.
Age >= 18 years willing to provide consent and follow-up
Biopsy-proven SLL according to WHO 2008 criteria, or
Peripheral blood B cell count of >= 5 x 10^9/L consisting of small to moderate size lymphocytes (If there are enough evidence to document the prior diagnosis of CLL, it is not required to meet the criteria of peripheral blood B cell count more than 5 x 10^9/L )
The predominant population of lymphocytes share both B-cell antigens (CD19, CD20 [typically dim expression], or CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.)
Symptomatic arrhythmias
Congestive heart failure
Myocardial infarction =< 3 months prior to registration
Any class 3 or 4 cardiac disease as defined by the New York Heart Association functional classification
Single group
Acalabrutinib
DrugGiven PO
Durvalumab
Biological/VaccineGiven IV
Venetoclax
DrugGiven PO
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow aspiration
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow biopsy
Positron Emission Tomography (PET)
Procedure/SurgeryUndergo PET/CT
Computed Tomography
Procedure/SurgeryUndergo PET/CT or CT
Progression free survival
Progression will be defined by Lugano positron emission tomography (PET)-computed tomography (CT) based criteria or chronic lymphocytic leukemia (CLL) criteria. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. If patients are censored prior to 6 months, a Kaplan Meier estimate for progression-free survival at 6 months along with the 95% confidence intervals will be reported.
Overall response rate
Overall response rate (for both Richter transformation \[RT\] and CLL, calculated separately) will be estimated by the total number of patients who achieve a complete metabolic response (CMR)/partial metabolic response (PMR) or complete response (CR)/complete response with incomplete marrow recovery (CRi)/nodular partial response (nPR)/partial remission (PR) divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true overall response rate will be calculated. The PR rate and CR rate will also be estimated.
Overall survival
The distribution of overall survival will be estimated using the method of Kaplan-Meier.
Progression-free survival (PFS)
The distribution of progression-free survival will be estimated using the method of Kaplan-Meier. PFS estimates will be calculated at 3, 6, 12, and 24 months.
Treatment-free survival
The distribution of treatment-free survival will be estimated using the method of Kaplan-Meier.
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