Polatuzumab Vedotin

Approved Indication:

• Diffuse Large B-Cell Lymphoma (DLBCL):
  Polatuzumab Vedotin, in combination with bendamustine and rituximab (BR), is indicated for the treatment of adult patients with relapsed or refractory DLBCL, not otherwise specified, after at least two prior therapies.

Clinically Accepted Off-label Uses:

• Refractory Aggressive B-cell Non-Hodgkin Lymphoma (NHL):
  Investigational use in primary refractory or early relapsing B-cell NHL after stem cell transplant or other chemotherapy.
• Bridge to CAR-T Therapy:
  Used in select cases for tumor debulking prior to chimeric antigen receptor T-cell therapy (CAR-T), especially in aggressive or high tumor-burden lymphomas.

Adults:

• Recommended Dose:
  1.8 mg/kg intravenously every 21 days for 6 cycles, in combination with bendamustine and rituximab.
• Route & Duration:
  Administer as an intravenous infusion over 90 minutes for the first dose. If well tolerated, subsequent doses may be given over 30 minutes.
• Premedication:
  Administer an antihistamine and antipyretic before infusion to reduce the risk of infusion-related reactions.

Special Populations:

• Renal Impairment:
  No dose adjustment is necessary in mild to moderate renal impairment. Use cautiously in severe impairment (CrCl <30 mL/min); limited clinical data are available.
• Hepatic Impairment:
  No dose adjustment for mild hepatic impairment. Avoid use in moderate to severe hepatic impairment, as exposure to MMAE may be increased.
• Geriatric Patients:
  No specific dosage adjustments. Monitor closely for adverse effects, particularly neutropenia and infections.

Pediatric Use:

• Safety and efficacy in patients under 18 years of age have not been established.

Polatuzumab Vedotin is a CD79b-directed antibody-drug conjugate (ADC). It consists of a humanized monoclonal antibody targeting the B-cell receptor component CD79b, conjugated to monomethyl auristatin E (MMAE), a potent anti-microtubule agent. Upon binding to CD79b on B-cells, the ADC is internalized into the cell. Inside the lysosome, MMAE is released and binds to tubulin, disrupting the microtubule network, which leads to cell cycle arrest at the G2/M phase and apoptosis. This mechanism enables selective cytotoxicity toward malignant B-cells, minimizing off-target effects.

• Absorption:
  Given intravenously; complete bioavailability.
• Distribution:
  Volume of distribution is approximately 3.15 L, indicating limited distribution beyond plasma and interstitial space.
• Metabolism:
• MMAE is metabolized primarily by CYP3A4.
• The monoclonal antibody component undergoes proteolytic degradation like endogenous IgG.
• Elimination:
• Terminal half-life of the ADC: ~12 days
• MMAE half-life: ~4 days
• MMAE is eliminated predominantly via feces (72%) and to a lesser extent via urine (17%).
• Steady-State:
  Reached after approximately 3 doses.

• Pregnancy:
  There is no assigned FDA pregnancy category. Based on its mechanism and animal data, Polatuzumab Vedotin may cause embryo-fetal toxicity and malformations. Use during pregnancy is contraindicated unless the potential benefit justifies the risk. Women of childbearing potential should use effective contraception during treatment and for at least 9 months after the last dose.
• Lactation:
  It is not known whether polatuzumab vedotin or MMAE is excreted into human milk. Due to the potential for serious adverse reactions in breastfed infants, breastfeeding is not recommended during therapy and for 3 months after the final dose.

• Class: Antineoplastic Agent
• Subclass: CD79b-directed Antibody-Drug Conjugate (ADC)
• Cytotoxic Component: Microtubule Inhibitor (MMAE – Monomethyl Auristatin E)

• Known hypersensitivity to polatuzumab vedotin or any component of the formulation
• Moderate to severe hepatic impairment (due to increased MMAE exposure)
• Pregnancy due to embryo-fetal toxicity
• Concomitant use with live vaccines

• Peripheral Neuropathy:
  Monitor for signs and symptoms of neuropathy; may require dose delay or discontinuation.
• Severe Myelosuppression:
  Neutropenia, anemia, and thrombocytopenia are common. Monitor complete blood counts before and during treatment. Use growth factors if necessary.
• Serious Infections:
  Risk of opportunistic infections (e.g., pneumonia, sepsis). Monitor and initiate prompt treatment.
• Infusion-Related Reactions:
  Premedicate to minimize risk. Discontinue infusion if severe reactions occur.
• Hepatotoxicity:
  Monitor liver function tests. Elevations in AST, ALT, or bilirubin may occur.
• Tumor Lysis Syndrome (TLS):
  May occur in patients with high tumor burden. Monitor electrolytes and renal function.
• Embryo-Fetal Toxicity:
  Avoid use during pregnancy. Counsel patients on contraception and fetal risk.

Common (≥20%):

• Hematologic: Neutropenia, anemia, thrombocytopenia
• Gastrointestinal: Diarrhea, nausea, constipation
• General: Fatigue, fever, decreased appetite
• Infections: Respiratory tract infections, pneumonia
• Nervous System: Peripheral neuropathy

Serious/Rare:

• Febrile neutropenia
• Sepsis
• Progressive multifocal leukoencephalopathy (PML) – extremely rare
• Infusion-related anaphylactic reactions
• Severe hepatic injury

• CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole):
  May increase MMAE levels → increased toxicity risk.
• CYP3A4 Inducers (e.g., rifampin, phenytoin):
  May reduce exposure to MMAE → reduced efficacy.
• Live Vaccines:
  Avoid during and after treatment due to immunosuppression.
• QT-Prolonging Drugs:
  MMAE may prolong QT interval; monitor ECGs when co-administered with other QT-prolonging agents.

• FDA Update (2023):
  Reinforced the importance of monitoring for serious infections and cytopenias; recommended consideration of G-CSF support in high-risk patients.
• NCCN Guidelines (2024 – DLBCL):
  Polatuzumab Vedotin + BR is listed as a preferred regimen for third-line treatment of relapsed/refractory DLBCL.
• Ongoing Clinical Trials (2025):
  Evaluation of Polatuzumab Vedotin as front-line therapy in DLBCL in combination with rituximab, cyclophosphamide, and prednisone (R-CHP) versus standard R-CHOP (POLARIX study expansion).

• Unopened Vial:
  Store at 2°C to 8°C (refrigerated). Do not freeze. Keep in the original carton to protect from light.
• Reconstituted Solution:
  Stable for 24 hours at room temperature or 72 hours refrigerated (2°C to 8°C). Protect from light. Do not freeze.
• Diluted Solution (Ready for Infusion):
  Should be used within 24 hours, including infusion time, whether stored at room temperature or refrigerated.