Polatuzumab

Usage

Polatuzumab vedotin-piiq is a CD79b-directed antibody-drug conjugate indicated in combination with bendamustine and a rituximab product for the treatment of adult patients with:

• Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, after at least two prior therapies.
• Previously untreated large B-cell lymphoma (LBCL), including DLBCL not otherwise specified (NOS), high-grade B-cell lymphoma, Epstein-Barr virus-positive (EBV+) DLBCL NOS, and T-cell/histiocyte-rich LBCL (in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone [R-CHP]).

Pharmacological Classification: Antineoplastic agent, antibody-drug conjugate.

Mechanism of Action: Polatuzumab vedotin targets the CD79b protein found on B-cells. After binding, it is internalized, releasing the cytotoxic agent monomethyl auristatin E (MMAE) inside the cell. MMAE inhibits cell division by disrupting microtubules, leading to cell death.

Alternate Names

• Polatuzumab vedotin-piiq
• Polivy™ (brand name)

How It Works

Pharmacodynamics: Polatuzumab vedotin exerts its anti-cancer effects by delivering MMAE specifically to B-cells, leading to their destruction. This targeted approach minimizes damage to healthy cells.

Pharmacokinetics:

• Absorption: Administered intravenously.
• Distribution: Distributes to target tissues expressing CD79b.
• Metabolism: Polatuzumab vedotin is catabolized to small peptides and amino acids, MMAE, and unconjugated MMAE-related catabolites. MMAE is metabolized by CYP3A4.
• Elimination: Elimination pathways are not fully characterized, but MMAE is primarily eliminated via hepatic metabolism and biliary excretion.

Mode of Action: The antibody component binds to CD79b, a protein essential for B-cell receptor signaling. Internalization of the antibody-drug conjugate delivers MMAE, which binds to tubulin, disrupting microtubule formation and inducing cell cycle arrest and apoptosis.

Receptor Binding: CD79b

Enzyme Inhibition: Tubulin polymerization

Elimination Pathways: Primarily hepatic metabolism and biliary excretion of MMAE

Dosage

Standard Dosage

Adults:

• Relapsed or Refractory DLBCL: 1.8 mg/kg administered as an intravenous infusion over 90 minutes every 21 days for 6 cycles in combination with bendamustine and rituximab. Subsequent infusions may be given over 30 minutes if tolerated. Maximum single dose per cycle 240mg.
• Previously Untreated LBCL: 1.8 mg/kg administered as an intravenous infusion on day 1 of each 21-day cycle, for a total of 6 cycles, given in combination with R-CHP.

Children:

Safety and efficacy have not been established in pediatric patients.

Special Cases:

• Elderly Patients: No dose adjustment is generally recommended, but closer monitoring is warranted due to higher incidence of adverse effects.
• Patients with Renal Impairment: No dose adjustment is needed for creatinine clearance ≥ 30 mL/min. No data are available for patients with severe renal impairment (CrCL < 30 mL/min).
• Patients with Hepatic Dysfunction: Contraindicated in moderate to severe hepatic impairment (bilirubin >1.5 times the upper limit of normal).
• Patients with Comorbid Conditions: Use with caution in patients with pre-existing peripheral neuropathy.

Clinical Use Cases

Polatuzumab vedotin is specifically indicated for the treatment of DLBCL and LBCL in the oncological setting, not for other clinical situations like intubation, surgical procedures, or emergency situations.

Dosage Adjustments

Dose modifications are based primarily on hematologic toxicity and peripheral neuropathy. See source material for specific guidance.

Side Effects

Common Side Effects

Neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia (fever), decreased appetite, pneumonia.

Rare but Serious Side Effects

Tumor lysis syndrome, infusion-related reactions, severe infections (including febrile neutropenia), progressive multifocal leukoencephalopathy.

Long-Term Effects

Potential long-term effects include peripheral neuropathy.

Adverse Drug Reactions (ADR)

Infusion-related reactions (fever, chills, flushing, dyspnea, hypotension, urticaria).

Contraindications

• Hypersensitivity to polatuzumab vedotin or any of its components.
• Moderate to severe hepatic impairment.
• Active severe infections.

Drug Interactions

• Strong CYP3A4 Inhibitors: May increase exposure to MMAE, leading to increased toxicity. Close monitoring is advised.
• Strong CYP3A4 Inducers: May decrease MMAE exposure, potentially reducing efficacy.
• See sources for a complete list of drug interactions (over 390 known interactions).

Pregnancy and Breastfeeding

• Pregnancy: Polatuzumab vedotin can cause fetal harm. Effective contraception is required during treatment and for at least 9 months after the last dose for women and 6 months after the last dose for men.
• Breastfeeding: Breastfeeding is contraindicated during treatment and for at least 3 months after the last dose.

Drug Profile Summary

• Mechanism of Action: Antibody-drug conjugate targeting CD79b on B-cells, delivering MMAE for cytotoxic effect.
• Side Effects: Common: Neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea. Serious: Tumor lysis syndrome, infusion reactions.
• Contraindications: Hypersensitivity, moderate to severe hepatic impairment, active severe infections.
• Drug Interactions: Numerous; strong CYP3A4 inhibitors and inducers are of particular concern.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: 1.8 mg/kg IV every 21 days for 6 cycles (in combination with other agents).
• Monitoring Parameters: Complete blood counts, liver function tests, neurological assessment.

Popular Combinations

• Bendamustine and rituximab (for relapsed/refractory DLBCL).
• R-CHP (for previously untreated LBCL).

Precautions

Pre-screening for hepatic impairment, pre-existing peripheral neuropathy, and active infections is essential. Monitor patients for myelosuppression and infusion-related reactions. Prophylactic measures for tumor lysis syndrome and infections should be considered.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Polatuzumab?

A: For relapsed/refractory DLBCL: 1.8 mg/kg IV every 21 days for 6 cycles in combination with bendamustine and rituximab. For previously untreated LBCL: 1.8 mg/kg IV every 21 days for 6 cycles in combination with R-CHP.

Q2: What are the most common side effects?

A: Neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, and diarrhea.

Q3: What are the contraindications to Polatuzumab?

A: Hypersensitivity to the drug, moderate to severe hepatic impairment, and active severe infections.

Q4: How does Polatuzumab work?

A: It’s an antibody-drug conjugate that targets CD79b on B-cells, delivering the cytotoxic agent MMAE inside the cells.

Q5: Can Polatuzumab be given to pregnant or breastfeeding women?

A: No, it’s contraindicated in both pregnancy and breastfeeding due to the potential for fetal harm and infant exposure.

Q6: What are the key drug interactions to be aware of?

A: Strong CYP3A4 inhibitors and inducers can significantly impact MMAE levels and thus Polatuzumab’s efficacy and toxicity profile. Many other drug interactions exist; consult a comprehensive resource before co-prescribing.

Q7: What monitoring is required during treatment?

A: Regular monitoring of complete blood counts, liver function tests, and neurological assessments are essential for managing potential side effects.

Q8: How are infusion-related reactions managed?

A: Premedication with an antihistamine and antipyretic is recommended. If a reaction occurs, interrupt the infusion and provide supportive care as needed (e.g., antihistamines, corticosteroids, fluids).

Q9. Are there any specific considerations for elderly patients?

A: Elderly patients tend to experience a higher incidence of grade 3 or higher adverse events, therefore, careful monitoring is recommended. No dose adjustment is required based on age alone.