Gazyva - Drug Monograph

Introduction

Gazyva (obinutuzumab) is a glycoengineered, humanized type II anti-CD20 monoclonal antibody developed by Genentech. It represents a next-generation anti-CD20 therapy designed to enhance antibody-dependent cellular cytotoxicity (ADCC) and direct cell death compared to earlier anti-CD20 antibodies. Approved by the FDA in 2013, Gazyva is primarily used in the treatment of various B-cell malignancies and has demonstrated improved efficacy over existing therapies in multiple clinical trials.

Mechanism of Action

Gazyva binds specifically to the CD20 antigen expressed on pre-B and mature B lymphocytes. Its mechanism of action involves three primary pathways:

1. Antibody-dependent cellular cytotoxicity (ADCC): Enhanced through glycoengineering that reduces fucose content, improving binding to FcγRIII receptors on immune effector cells 2. Direct cell death induction: As a type II antibody, it induces non-apoptotic cell death through homotypic adhesion and lysosomal permeabilization 3. Complement-dependent cytotoxicity (CDC): Though less pronounced than with type I antibodies, it still contributes to B-cell depletion

These mechanisms result in rapid and sustained depletion of circulating and tissue-based B cells.

Indications

FDA-approved indications include:

• Previously untreated chronic lymphocytic leukemia (CLL) in combination with chlorambucil
• Previously untreated follicular lymphoma (FL) in combination with chemotherapy followed by Gazyva maintenance
• Relapsed or refractory follicular lymphoma (after prior rituximab-containing regimen) in combination with chemotherapy

Dosage and Administration

• Cycle 1: 100 mg IV on day 1, 900 mg IV on day 2, 1000 mg IV on days 8 and 15
• Cycles 2-6: 1000 mg IV on day 1

• Cycle 1: 1000 mg IV on days 1, 8, and 15
• Cycles 2-6 (or 2-8): 1000 mg IV on day 1
• Maintenance: 1000 mg IV every 2 months for up to 2 years

• Premedicate with glucocorticoid, acetaminophen, and antihistamine
• Initiate infusion at 50 mg/hr; may increase by 50 mg/hr every 30 minutes to max 400 mg/hr
• Monitor closely during first infusion for infusion-related reactions
• Dose reductions not recommended; delay for toxicity

• Renal impairment: No dosage adjustment necessary
• Hepatic impairment: No specific recommendations (use with caution)
• Elderly: No dosage adjustment required
• Pediatrics: Safety and effectiveness not established

Pharmacokinetics

Contraindications

• Known hypersensitivity to obinutuzumab or any component of the formulation
• Active hepatitis B infection (must be screened and managed prior to initiation)
• Severe, active infections (until resolved)

Warnings and Precautions

• Hepatitis B virus (HBV) reactivation: Can cause fulminant hepatitis, hepatic failure, and death
• Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death

• Infusion-related reactions: Can be severe including hypotension, tachycardia, dyspnea, and bronchospasm
• Tumor lysis syndrome: Particularly in patients with high tumor burden
• Infections: Increased risk of bacterial, viral, and fungal infections
• Cytopenias: Neutropenia, thrombocytopenia, and anemia
• Immunization: Live vaccines not recommended during treatment
• Pregnancy: May cause fetal harm (Category C)

Drug Interactions

• Live vaccines: Contraindicated due to immunosuppression
• Other immunosuppressive agents: Increased risk of infections
• CYP450 substrates: Potential for altered exposure due to cytokine-mediated effects on CYP enzymes
• Antihypertensive medications: May enhance hypotensive effects during infusion

Adverse Effects

• Infusion-related reactions (69%)
• Neutropenia (40%)
• Thrombocytopenia (29%)
• Anemia (19%)
• Fatigue (21%)
• Cough (20%)
• Diarrhea (20%)

• Grade 3-4 neutropenia (33%)
• Grade 3-4 thrombocytopenia (11%)
• Serious infections (10%)
• Hepatitis B reactivation
• Progressive multifocal leukoencephalopathy

Monitoring Parameters

• HBV screening (HBsAg, anti-HBc, anti-HBs)
• Complete blood count with differential
• Renal and hepatic function tests
• Pregnancy test (if applicable)

• CBC with differential before each cycle and as clinically indicated
• Monitor for infusion reactions during and for several hours after infusion
• Signs/symptoms of infection
• Tumor lysis syndrome monitoring (especially first cycle)
• Hepatic function monitoring for HBV reactivation

• Monitor for delayed cytopenias
• HBV reactivation monitoring for several months after completion
• Immune reconstitution monitoring

Patient Education

• Report any signs of infection (fever, chills, cough) immediately
• Understand the risk of infusion reactions and report any symptoms during infusion
• Avoid live vaccines during and after treatment
• Use effective contraception during and for 12 months after treatment
• Report unusual bleeding, bruising, or fatigue
• Understand the need for regular blood tests
• Be aware of potential risk of HBV reactivation even if previously resolved
• Report neurological symptoms (vision changes, confusion, coordination problems)

References

1. FDA Prescribing Information: Gazyva (obinutuzumab). 2023 2. Goede V, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-1110 3. Marcus R, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017;377(14):1331-1344 4. NCCN Guidelines: B-Cell Lymphomas. Version 3.2023 5. Salles G, et al. Obinutuzumab plus CHOP for previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2021;39(19):2088-2100 6. Product Monograph: Gazyva. Genentech Inc. 2023 7. ClinicalTrials.gov: Various obinutuzumab trials