PRIMARY OBJECTIVES:~I. To compare the bone marrow minimal residual disease (MRD)-negative complete response (CR) rate of acalabrutinib alone and acalabrutinib/obinutuzumab in early stage asymptomatic chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients who are high and very high risk by CLL-International Prognostic Index (IPI). (Arms A and B) II. To evaluate time to first therapy (TFT) in early stage asymptomatic CLL/SLL patients with low and intermediate-risk by CLL-IPI. (Arm C)~SECONDARY OBJECTIVES:~I. To compare the safety of acalabrutinib alone and acalabrutinib/obinutuzumab in early stage asymptomatic CLL/SLL patients who are high and very high risk by CLL-IPI.~II. To compare the overall response rate (ORR), progression-free survival (PFS), time to next therapy (TNT) and overall survival (OS) of acalabrutinib alone and acalabrutinib/obinutuzumab in early stage asymptomatic CLL/SLL patients who are at high and very high risk by CLL-IPI.~III. To determine the progression-free survival (PFS) and overall survival (OS) in early stage asymptomatic CLL/SLL patients with low and intermediate risk by CLL-IPI.~EXPLORATORY OBJECTIVE:~I. To evaluate the quality of life using Functional Assessment of Cancer Therapy-General (FACT-G) quality of life (QOL) survey.~CORRELATIVE RESEARCH:~I. To compare the peripheral blood immune profile using 8-color flow cytometry, to assess changes in T-cells, natural killer (NK)-cells, and NK-T cells at baseline and during active treatment among patients receiving either acalabrutinib alone or acalabrutinib and obinutuzumab.~II. To determine changes in the peripheral blood immune profile using 8-color flow cytometry to assess changes in T-cells, NK-cells, and NK-T cells at baseline and during event monitoring in patients with low and intermediate risk by CLL-IPI.~III. Signal pathway studies-BTK, ERK, PLC gamma and S6 protein levels and phosphorylation status will be assessed by Western blot methodology using specific antibodies to pull down specific proteins from cell lysates.~IV. To confirm if in vitro cell killing is via apoptosis we will also assess PARP and caspase 3 cleavage.~V. Apoptotic protein studies-MCL-1, XIAP levels will be determined by Western blot methodology using specific antibodies to pull down these specific proteins from cell lysates.~VI. Bone marrow aspirates will be studied for hematopoietic function in two ways:~VIa. Estimation of colony forming capacity by purified hematopoietic stem cells (HSCs).~VIb. Evaluation of the levels of HSCs and their differentiated progeny (i.e. MPP, CMP, CLP).~VII. Paired bone marrow and blood samples will be evaluated for the levels of innate effector cells.~VIII. Perform targeted sequencing of 59 genes mainly grouped in 8 biological pathways: NOTCH1, B-cell signaling, deoxyribonucleic acid (DNA) damage response, chromatin modifiers, ribonucleic acid (RNA) metabolism, NF-kappaB pathway, cell cycle and apoptosis.~IX. Screen 2 genes previously associated with resistance to BTK inhibitors (BTK and PLCG2).~OUTLINE: Patients with high or very high risk CLL-IPI are randomized to Arm A or Arm B. Patients with intermediate or low risk are assigned to Arm C.~ARM A: Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive acalabrutinib PO BID on days 1-84. Treatment repeats every 84 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment with acalabrutinib If MRD negative CR/CR with incomplete marrow recovery (CRi) is not achieved after 12 cycles.~ARM B: Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28 and obinutuzumab intravenously (IV) on days 1, 2, 8, and 15 of cycle 1 and days 1 of subsequent cycles. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive acalabrutinib PO BID on days 1-84. Treatment repeats every 84 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue treatment with acalabrutinib If MRD negative CR/CRi is not achieved after 12 cycles.~ARM C: Patients will be observed every 6 months for up to 2 years.~After completion of study treatment, patients are followed up every 6 months for up to 10 years.
This phase II trials studies how well acalabrutinib with or without obinutuzumab works in treating patients with early-stage chronic lymphocytic leukemia or small lymphocytic lymphoma. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving acalabrutinib with or without obinutuzumab will work better in treating patients with early-stage chronic lymphocytic leukemia or small lymphocytic lymphoma.