Pharmacological Class
- PI3Kδ (phosphoinositide 3-kinase delta) inhibitor
Mechanism of Action
- Selectively inhibits the PI3Kδ isoform, predominantly expressed in leukocytes.
- Blocks signaling pathways critical for proliferation, survival, homing, and retention of malignant B cells in lymphoid tissues.
Indications (FDA-approved)
- Chronic Lymphocytic Leukemia (CLL):
In combination with rituximab in patients for whom rituximab alone is appropriate due to comorbidities. - Follicular Lymphoma (FL):
Relapsed after at least 2 prior systemic therapies. - Small Lymphocytic Lymphoma (SLL):
Relapsed after at least 2 prior systemic therapies.
(Note: Some regions have restricted use due to toxicity profile; NCCN still lists it as an option in select relapsed/refractory patients.)
Dosing
- 150 mg orally twice daily (with or without food).
- Continue until disease progression or unacceptable toxicity.
Key Toxicities
- Boxed Warnings:
- Severe hepatotoxicity (transaminase elevations, sometimes fatal)
- Severe, prolonged, and sometimes fatal diarrhea/colitis
- Pneumonitis (non-infectious, can be fatal)
- Intestinal perforation
- Other Common Adverse Effects:
- Neutropenia, infections (including opportunistic)
- Rash
- Fatigue, pyrexia
- Nausea, abdominal pain
Monitoring
- LFTs: Baseline, every 2 weeks for first 3 months, then every 4 weeks × 3 months, then every 1–3 months.
- CBC with differential: Regularly (risk of severe neutropenia).
- Pulmonary symptoms: Monitor for cough, dyspnea, hypoxia (risk of pneumonitis).
- GI toxicity: Prompt evaluation of diarrhea/colitis.
Drug Interactions
- CYP3A4 substrate → Avoid strong CYP3A inducers (rifampin, carbamazepine, St. John’s wort) and use caution with strong CYP3A inhibitors (ketoconazole, clarithromycin).
- May increase exposure to CYP3A substrates with narrow therapeutic index.
Clinical Pearls
- Prophylaxis for PJP (Pneumocystis jirovecii pneumonia) and monitoring for CMV reactivation is recommended during treatment.
- Often reserved for relapsed/refractory disease after failure of BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) and/or BCL-2 inhibitor (venetoclax).
- Due to toxicity concerns, its use has declined in favor of newer agents.