Inclusion Criteria:

• Age ≥ 18 years old

• Patients must have histologic confirmation of follicular lymphoma (FL) (grade 1, 2, and 3A or classic follicular lymphoma)

• Meeting any one of the following criteria for therapy initiation:

  • Involvement of ≥ 3 nodal sites, each with diameter of ≥ 3 cm.
  • Any nodal or extranodal tumor mass with a diameter of ≥ 7 cm.
  • B symptoms (fever ≥ 38 degrees Celsius of unclear etiology, night sweats, weight loss > 10% within the prior 6 months) attributed to FL.
  • Risk of local compressive symptoms that may result in organ compromise.
  • Splenomegaly with the inferior margin below the umbilical line or splenic lesion without splenomegaly.
  • Significant cytopenia (absolute neutrophil count < 1500/mm3, platelets < 100,000/uL, hemoglobin < 10 g/dL)
  • Leukemia (> 5,0000/uL circulating lymphocytes)
  • Pleural effusion or ascites attributed to lymphoma

• Have measurable nodal disease, including at least 1 disease site measuring at least 1.5 cm in longest dimension on CT or fludeoxyglucose (FDG)-PET, or a FDG-avid extranodal measurable site measuring at least 1.0 cm in longest dimension. Measurable disease also includes spleen size more than 13 cm in vertical length

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• Absolute neutrophil count ≥ 1500/mm^3 (unless due to lymphoma involvement of the bone marrow or spleen)

• Platelets ≥ 75,000/mm^3 (unless due to bone marrow involvement by lymphoma)

• Hemoglobin ≥ 8 g/dL (unless due to bone marrow involvement by lymphoma)

• Total bilirubin ≤ 2.0 mg/dL, except for patients with documented lymphoma involvement of liver or with a known history of Gilbert's disease

• Alkaline phosphatase/aspartate aminotransferase (AST)/(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) ≤ 3 × institutional upper limit of normal, except for patients with documented liver involvement

• Creatinine clearance ≥ 30 ml/min

• Fertile male and women of child bearing potential (WOCBP) patients must be willing to use highly effective contraceptive methods from study recruitment to at least 6 months after the last dose of study treatment

• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

• FL grade 3B or transformed FL
• Patients receiving any other investigational agents
• Patients with known central nervous system involvement of lymphoma
• History of a second primary malignancy that could affect compliance with the protocol or interpretation of results except with permission of the principal investigator. Malignancies treated curatively or at low-risk of progressing at the judgment of the primary investigator (PI) may be included
• Known active and uncontrolled bacterial, viral, fungal, mycobacterial, or other infection at study enrollment
• Uncontrolled intercurrent illness such as: history of myocardial infarction (MI) in the last 6 months, congestive heart failure New York Heart Association (NYHA) Class III-IV, uncontrolled or symptomatic arrhythmia, stroke in last 6 months, liver cirrhosis, and autoimmune disorder requiring immunosuppression or long-term corticosteroids (> 10 mg daily prednisone equivalent)
• Prior use of any monoclonal antibody within 4 weeks before the first administration
• Breastfeeding or pregnant women
• Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody are eligible if the corresponding polymerase chain reaction (PCR) test is negative prior to enrollment. Hepatitis B core antibody (+) patients without evidence of HBsAg or Hep B PCR (+) are eligible with appropriate Hepatitis B reactivation prophylaxis as per institutional guidelines
• History of human immunodeficiency virus (HIV) infection uncles the viral load is undetectable and CD4 count is at least 400
• History or evidence of rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
• Major surgery (excluding lymph node biopsy) within 28 days prior to signing the informed consent form (ICF) unless the participant is recovered at the time of signing the ICF
• Any systemic anti-lymphoma and/or investigational therapy within 28 days prior to the start of cycle 1
• Administration of a live vaccine within 28 days prior to the start of study treatment (cycle 1 day 1)
• History of hypersensitivity to compounds of similar biological or chemical composition to tafasitamab, immunomodulatory drugs, rituximab, other monocolonal antibodies (mAbs), and/or the excipients contained in the study drug formulations