PRIMARY OBJECTIVES:~I. To determine the overall response rate at the end of 4 cycles of therapy with rituximab, lenalidomide, acalabrutinib, tafasitamab in patients with high risk newly diagnosed non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL).~II. To determine the complete response rate at the end of 10 cycles of therapy with rituximab, lenalidomide, acalabrutinib, tafasitamab and chemotherapy (cyclophosphamide-hydroxydaunorubicin-oncovin-prednisone [CHOP]) in patients with high risk newly diagnosed non-GCB DLBCL.~SECONDARY OBJECTIVES:~I. To determine the overall response rate, survival outcomes (progression free and overall survival), and safety of rituximab, lenalidomide, acalabrutinib, tafasitamab and chemotherapy (CHOP) in patients with high risk newly diagnosed non-GCB DLBCL.~II. To evaluate the outcomes of patients who receive 10 cycles of rituximab, lenalidomide, acalabrutinib, tafasitamab with 6 concurrent cycles of CHOP in contrast to patients who receive a response adapted 2 concurrent cycles of CHOP in cohort 1.~III. To evaluate the outcomes of patients who receive 10 cycles of rituximab, lenalidomide, acalabrutinib, tafasitamab with 6 concurrent cycles of CHOP in contrast to patients who receive a response adapted 0 concurrent cycles of CHOP in cohort 2.~EXPLORATORY OBJECTIVE:~I. To evaluate the baseline and therapy induced changes in the profile of mutations, gene expression, minimal residual disease circulating tumor deoxyribonucleic acid (ctDNA) levels, immune cell subsets, in patients with newly diagnosed non-GCB DLBCL.~OUTLINE:~COHORT I (SMART STOP): Patients receive rituximab intravenously (IV) over 4-6 hours on day 1, acalabrutinib orally (PO) twice daily (BID) on days 1-21, lenalidomide once daily (QD) on days 1-10, and tafasitamab IV over 2 hours on days 1, 8, and 15. Treatments repeat every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.~COHORT II (uLTRA-CHOP): Patients who achieve a complete response to the Smart Stop in Cohort I, receive rituximab IV over 4-6 hours on day 1, acalabrutinib PO BID on days 1-21, lenalidomide QD on days 1-10, and tafasitamab IV over 2 hours on days 1, 8, and 15. Treatments repeat every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive cyclophosphamide IV over 1 hour, doxorubicin hydrochloride IV over 15 minutes, vincristine IV over 15 minutes on day 1, and prednisone PO QD on days 1-5. Treatments repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve less than a complete response, receive rituximab IV over 4-6 hours on day 1, acalabrutinib PO BID on days 1-21, lenalidomide QD on days 1-10, and tafasitamab IV over 2 hours on days 1, 8, and 15. Patients also receive cyclophosphamide IV over 1 hour, doxorubicin hydrochloride IV over 15 minutes, vincristine IV over 15 minutes on day 1, and prednisone PO QD on days 1-5. Treatments repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.~After completion of study treatment, patients are followed up every 3 months for 1 year, then every 4 months for 1 year.
This phase II trial studies the effect of rituximab, lenalidomide, acalabrutinib, tafasitamab alone and in combination with chemotherapy in treating patients with newly diagnosed non-germinal center diffuse large B-cell lymphoma. Rituximab and tafasitamab are monoclonal antibodies that may interfere with the ability of tumor cells to grow and spread. Acalabrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as lenalidomide, cyclophosphamide, doxorubicin, and vincristine, and work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Anti-inflammatory drugs, such as prednisone lower the body's immune response and are used with other drugs in the treatment of some types of cancer. Giving rituximab, lenalidomide, acalabrutinib, tafasitamab alone and with combination chemotherapy may help control non-germinal center diffuse large B-cell lymphoma.