Comparing the Effectiveness of the Immunotherapy Agents Rituximab or Mosunetuzumab in Patients With Nodular Lymphocyte-Predominant Hodgkin Lymphoma

Inclusion Criteria:

• Histopathologically confirmed diagnosis of NLPHL as confirmed by local pathologist'sexpert review.

• Untreated NLPHL: stage IB to IV according to Cotswolds. The proportion ofpatients with stages I or II treated with consolidative radiotherapy will becapped at 40%.

• Previously treated NLPHL, any stage.

• According to the treating physician, the patient should not be observed andneeds therapy, notably because of B-symptoms (unexplained fever [temperature > 38 degrees Celsius (> 100.4 degrees Fahrenheit)], weight loss [unexplained lossof > 10 percent of body weight over the past six months], or drenching nightsweats), symptomatic nodal or extranodal disease, or patient preferences.

• Patients must have measurable disease according to the Lugano/Lymphoma Response toImmunomodulatory Therapy Criteria (LYRIC) classification.

• Age >= 18 years. Because no dosing or adverse event (AE) data are currentlyavailable on the use of mosunetuzumab in patients < 18 years of age, children areexcluded from this study.

• Eastern Cooperative Oncology Group performance status =< 2 (Karnofsky >= 60%).

• Absolute neutrophil count >= 1,000/mcL.

• Platelets >= 100,000/mcL.

• Total bilirubin =< 1.5 institutional upper limit of normal (ULN), except in patientswith Gilbert's syndrome as defined by > 80% unconjugated bilirubin.

• Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine transaminase (ALT)(serum glutamic-pyruvic transaminase [SGPT]) =< 3x institutional ULN.

• Glomerular filtration rate (GFR) >= 40mL /min= GFR (mL/Min/1.73 m^2) * body surfacearea (BSA)/1.73.

• Human immunodeficiency virus-infected patients on effective anti-retroviral therapywith undetectable viral load within 6 months are eligible for this trial.

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load.

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial.

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better.

• The effects of mosunetuzumab on the developing human fetus are unknown. For thisreason and because other therapeutic agents used in this trial are known to beteratogenic, women of childbearing potential and men must agree to use adequatecontraception (hormonal and/or barrier method of birth control; abstinence) (bothhormonal and barrier method of birth control are required for participants inCanada) prior to study entry and for the duration of study participation. Should awoman become pregnant or suspect she is pregnant while she or her partner isparticipating in this study, she should inform her treating physician immediately.Men and women treated or enrolled on this protocol must also agree to use adequatecontraception prior to the study, for the duration of study participation, and 3months after completion of mosunetuzumab administration and 12 months aftercompletion of rituximab administration.

• Ability to understand and the willingness to sign a written informed consentdocument. Legally authorized representatives may sign and give informed consent onbehalf of study participants.

Exclusion Criteria:

• Classical Hodgkin lymphoma (cHL) or composite lymphoma.

• Transformed NLPHL, concerns of the treating physician of an occult transformation orconcerns of the treating physician that the patient needs cytotoxic therapy.

• Previous therapy with rituximab.

• Patients who have not recovered from AEs due to prior anticancer therapy (i.e., haveresidual toxicities > grade 1) with the exception of alopecia.

• Patients who are receiving any other investigational agents.

• Patients with central nervous system (CNS) involvement as a result of lymphoma.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to mosunetuzumab or rituximab.

• Patients with uncontrolled intercurrent illness or any other significantcondition(s) that would make participation in this protocol unreasonably hazardous.

• Pregnant women are excluded from this study because there is an unknown butpotential risk for AEs in nursing infants secondary to treatment of the mother withmosunetuzumab; breastfeeding should be discontinued if the mother is treated withmosunetuzumab or rituximab. These potential risks may also apply to other agentsused in this study.

• Prior allogeneic stem cell or solid organ transplantation.

• Participants who have received a live, attenuated vaccine within 4 weeks beforefirst dose of study treatment or anticipation that such a live, attenuated vaccinewill be required during the study. Participants must not receive live, attenuatedvaccines (e.g., FluMist [registered trademark]) while receiving study treatment andafter the last dose until B-cell recovery to the normal ranges. Killed vaccines ortoxoids should be given at least 4 weeks prior to the first dose of study treatmentto allow development of sufficient immunity.

• Any other anti-cancer therapy, whether investigational or approved, including butnot limited to chemotherapy, within 4 weeks or 5 half-lives of the drug, whicheveris shorter, prior to initiation of study treatment.

• Evidence of any significant, concomitant disease that could affect compliance withthe protocol or interpretation of results as judged by the investigator, including,but not limited to:

• Significant cardiovascular disease (e.g., New York Heart Association class IIIor IV cardiac disease, myocardial infarction within the previous 6 months,unstable arrhythmia, or unstable angina).

• Significant pulmonary disease (such as obstructive pulmonary disease or historyof bronchospasm).

• Current or past history of CNS disease, such as stroke, epilepsy, CNSvasculitis, or neurodegenerative disease.

• Participants with a history of stroke who have not experienced a stroke ortransient ischemic attack in the past 1 year and have no residual neurologicdeficits as judged by the investigator are allowed.

• Participants with a history of epilepsy who have had no seizures in the past 2years with or without anti-epileptic medications can be eligible only for theexpansion cohort.

• History of confirmed progressive multifocal leukoencephalopathy (PML).

• Participants with infections requiring IV treatment with antibiotics orhospitalization (grade 3 or 4) within the last 4 weeks prior to enrollment or knownactive bacterial, viral (including SARS-CoV-2), fungal, mycobacterial, parasitic, orother infection (excluding fungal infections of nail beds) at study enrollment.

• Systemic immunosuppressive medications (including, but not limited to,cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosisfactor agents) within 2 weeks prior to first dose of study treatment.

• Known or suspected chronic active Epstein-Barr virus (EBV) or cytomegalovirus (CMV)infection.

• Known or suspected history of hemophagocytic lymphohistiocytosis (HLH).