Inclusion Criteria:  Histopathologically confirmed diagnosis of DLBCL of the non-GCB DLBCL subtype via the Hans algorithm No prior treatment except a prior limited-field radiotherapy, a short course of glucocorticoids =< 25 mg daily of prednisone equivalent which must cease prior to day 1 of cycle 1, and/or 1 dose of cyclophosphamide 750 mg/m2 for an urgent lymphoma related problem at diagnosis (e.g. epidural cord compression, superior vena cava syndrome) Patient or durable power of attorney (DPA) for healthcare must be able to understand and voluntarily sign an Institutional Review Board (IRB)-approved informed consent form Age >= 18 years at the time of signing the informed consent Patients must have bi-dimensional measurable disease, as defined as radiographically apparent disease with the longest dimension of >= 1.5 cm Patients 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) Serum bilirubin < 1.5 x upper limit of normal (ULN) except in patients with Gilbert's syndrome as defined by > 80% unconjugated bilirubin who must have a serum bilirubin of < 4 x ULN Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN or < 5 x ULN if hepatic metastases are present Absolute neutrophil count (ANC) > 1000/mm^3 unless deemed related to lymphoma involvement in the bone marrow and felt potentially reversible by the treating physician Platelets > 100,000/mm^3 unless deemed related to lymphoma involvement in the bone marrow and felt potentially reversible by the treating physician Calculated creatinine clearance >= 30 ml/min by Cockcroft-Gault formula Patients must be willing to receive transfusions of blood products All study participants must be registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the REMS program Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) at screening and must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program Women of childbearing potential and men who are sexually active with a woman of childbearing potential must be practicing a highly effective method of during and after the study (12 months after study drug for women and 3 months after study drug for men), consistent with local regulations regarding the use of birth control methods for subjects participating in this clinical study. Men must agree to not donate sperm during and for up to 3 months after their conclusion of therapy on study Able to take aspirin (81 mg) daily or alternative therapy as prophylactic anticoagulation  Exclusion Criteria:  Any serious medical condition including but not limited to uncontrolled hypertension, uncontrolled congestive heart failure within past 6 months prior to screening (class 3 [moderate] or class 4 [severe] cardiac disease as defined by the New York Heart Association Functional classification), uncontrolled or symptomatic arrhythmias with corrected QT interval (QTc) > 480 msec at screening, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), left ventricular ejection fraction (LVEF) less than 40%, renal failure, uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura active infection, history of invasive fungal infection, moderate to severe hepatic disease (Child Pugh class B or C), active hemorrhage, laboratory abnormality, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form. Patients with history of cardiac arrhythmias should have cardiac evaluation and clearance Pregnant or lactating females Known hypersensitivity to lenalidomide or thalidomide, acalabrutinib, tafasitamab, rituximab, vincristine, doxorubicin, cyclophosphamide, or prednisone Known human immunodeficiency virus (HIV) infection. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative DNA polymerase chain reaction (PCR) and must be willing to undergo DNA PCR testing during the study to be eligible. Those who are HBsAg positive or hepatitis B DNA PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative DNA PCR result to be eligible. Those who are hepatitis C DNA PCR positive will be excluded All patients with known central nervous system involvement with lymphoma Diagnosis of prior malignancy within the past 2 years with the exception of successfully treated basal cell carcinoma, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast. History of other malignancies are allowed if in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated, with a life expectancy > 3 years Significant neuropathy (grades 2 or grade 1 with pain) within 14 days prior to enrollment Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis not due to lymphoma Patients with active pulmonary embolism or deep vein thrombosis (diagnosed within 30 days of study enrollment) Patients with severe bradycardia (heart rate < 40 bpm, hypotension, lightheadedness, syncope) Major surgery within 4 weeks of study entry, or wound that is not healed from prior surgery or trauma History of stroke or intracranial hemorrhage within 6 months prior to study entry Requires anticoagulation with warfarin or equivalent vitamin K antagonists Requires chronic treatment with strong CYP3A inhibitors Vaccinated with live, attenuated vaccines within 4 weeks of study entry Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease) Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura) Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening Prothrombin time (PT)/international normalized ratio (INR) or activated partial thromboplastin time (aPTT) (in the absence of lupus anticoagulant) > 2 x ULN Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study Concurrent participation in another therapeutic clinical trial