The purpose of this research is to see if Loncastuximab Tesirine in combination with Rituximab will result in higher complete response rate when given to treat follicular lymphoma.

Inclusion Criteria:

1. Men and women ≥ 18 years of age.

2. Patients must have histologic confirmation of Follicular Lymphoma (FL) (grade 1, 2 and 3A). Note: Participants who have received previous CD19-directed therapy must have a biopsy which shows CD19 expression after completion of the CD19-directed therapy.

3. Patients with relapsed or refractory FL previously treated with ≥1 line of systemic therapy having ≥ 1 Groupe d'Etude des Lymphomes (GELF) criteria for therapy, or Progression of Diseases within 24 months (POD24), or second relapse.

4. Baseline FDG-PET/CT scans must demonstrate positive lesions compatible with CT defined anatomical tumor sites. Patients should have at least one measurable site of disease per Lugano classification.

5. Patient should have ≥ 1 Groupe d'Etude des Lymphomes (GELF) criteria for treatment 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).
   • Risk of local compressive symptoms that may result in organ compromise
   • Splenomegaly or splenic lesion without splenomegaly
   • Leukopenia (leukocytes < 1000/mm3)
   • Leukemia (> 5.000 lymphoma cells/mm3)
   • Bone lesions detected on FDG-PET/CT; or

6. Progression or relapse within 24 months of frontline treatment in patients previously treated with ≥1 line of systemic therapy; or

7. Second FL relapse/progression after ≥1 line of systemic therapy. These patients will be eligible independently of GELF criteria and POD24.

8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

9. Life expectancy of greater than 6 weeks.

10. Patients must have normal organ and marrow function as defined below,

    • Absolute neutrophil count ≥1000/mm3 (unless due to lymphoma involvement of the bone marrow or spleen).
    • Platelets ≥100,000/mm3 or ≥ 60,000/mm3 in case of bone marrow involvement by lymphoma.
    • Hemoglobin ≥ 10 g/dL or ≥8 g/dL in case of bone marrow involvement by lymphoma.
    • Total bilirubin < 1.5 x within normal institutional limits (unless due to lymphoma involvement of liver or a known history of Gilbert's disease).
    • Gamma-Glutamyl Transpeptidase (GGT)/Aspartate Aminotransferase (AST)/(SGOT)/Alanine Aminotransferase (ALT)(SGPT) ≤ 2.5 × institutional upper limit of normal.
    • Creatinine within normal institutional limits, or creatinine clearance ≥30 ml/min/1.7m^2 for patients with creatinine levels above institutional normal (unless due to lymphoma).

Exclusion Criteria:

1. FL grade 3B or transformed FL.
2. [Removed]
3. ≥ 6 lines of systemic immunochemotherapy for treatment of FL.
4. Patients with clinically significant pleural effusions and/or ascites requiring drainage or associated with shortness of breath.
5. Patients receiving any other investigational agents.
6. Patients with known central nervous system involvement of lymphoma.
7. 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).
8. Breastfeeding or pregnant women.
9. 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 will need a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.) Hepatitis C antibody positive patients are eligible if PCR is negative. Hepatitis B core antibody (+) patients without evidence of HBsAg or Hep B PCR (+) are eligible with appropriate Hepatitis B reactivation prophylaxis.
10. History of Human immunodeficiency virus (HIV) infection. Note: HIV screening test is optional
11. Patients with impaired decision-making capacity.