Rituximab, Lenalidomide, Acalabrutinib, Tafasitamab Alone and With Combination Chemotherapy for the Treatment of Newly Diagnosed Non-germinal Center Diffuse Large B-Cell Lymphoma, Smart Stop Study

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.

Inclusion Criteria: 1. Histopathologically confirmed diagnosis of DLBCL. 2. No prior treatment except a prior limited-field radiotherapy, a short course of glucocorticoids ≤50mg daily of prednisone equivalent which must be no more than 4 days in duration and cease prior to day 1 of cycle 1, and/or 1 dose of cyclophosphamide 750mg/m2 for an urgent lymphoma related problem at diagnosis (e.g. epidural cord compression, superior vena cava syndrome). 3. Age ≥ 18 years and able to provide informed consent. 4. Participants must have bi-dimensional measurable disease, as defined as radiographically apparent disease with the longest dimension of ≥1.5cm. 5. Participants with performance status of ≤3 (3 only allowed if decline in status is deemed related to lymphoma and felt potentially reversible by the treating physician). 6. Serum bilirubin \