Idelalisib (Zydelig) — Clinical FAQs

Question 1

What is Idelalisib FDA-approved to treat?

Accepted Answer

Idelalisib is FDA-approved for the following oncology indications: 1. Relapsed chronic lymphocytic leukemia (CLL) — in combination with rituximab, for patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities (FDA approved July 23, 2014) 2. Relapsed follicular B-cell non-Hodgkin lymphoma (FL) — patients who have received at least two prior systemic therapies (FDA approved July 23, 2014; accelerated approval based on ORR) 3. Relapsed small lymphocytic lymphoma (SLL) — patients who have received at least two prior systemic therapies (FDA approved July 23, 2014; accelerated approval based on ORR).

Question 2

How does Idelalisib work (mechanism of action)?

Accepted Answer

Idelalisib is a first-in-class, highly selective oral inhibitor of phosphatidylinositol 3-kinase delta (PI3K-delta), a lipid kinase isoform predominantly expressed in hematopoietic cells. PI3K-delta is constitutively activated in B-cell malignancies and plays a central role in B-cell receptor (BCR) signaling, cytokine receptor signaling (CXCR4/CXCL12, CXCR5/CXCL13), and integrin-mediated retention of malignant B-lymphocytes within protective lymph node and bone marrow microenvironments. Idelalisib inhibits PI3K-delta with sub-nanomolar potency (IC50 ~2.5 nM), resulting in downstream suppression of AKT phosphorylation, mTORC1 signaling, and MYC-driven proliferation. Critically, PI3K-delta inhibition disrupts chemokine-mediated homing of malignant lymphocytes to supportive niches, mobilizing them into the peripheral blood where they become susceptible to antibody-dependent cellular cytotoxicity (ADCC) from rituximab — the mechanistic basis for the idelalisib + rituximab synergy. Idelalisib exhibits >40-fold selectivity for PI3K-delta over the PI3K-alpha, -beta, and -gamma isoforms. Immune-mediated toxicities (colitis, pneumonitis, hepatotoxicity) arise from disruption of regulatory T-cell (Treg) function, which depends on PI3K-delta signaling for homeostasis.

Question 3

How is Idelalisib administered?

Accepted Answer

Idelalisib is administered Oral (PO). Administer idelalisib 150 mg orally twice daily (approximately every 12 hours), with or without food.

Question 4

What are the most common side effects of Idelalisib?

Accepted Answer

The most commonly reported side effects of Idelalisib (≥10% incidence) include: Diarrhea / colitis (47%; Grade 3/4 ~14%), Fatigue (30%), Nausea (29%), Pyrexia (28%), Cough (29%) and others (15 total). Consult your oncologist for complete prescribing information.

Question 5

Does Idelalisib have a black box warning?

Accepted Answer

Yes. Idelalisib carries FDA black box warning(s) regarding: 1. Fatal and serious hepatotoxicity: Severe hepatotoxicity, including fatal cases, has occurred. Monitor ALT/AST at least every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, then as clinically indicated. Withhold idelalisib for ALT/AST >5x ULN; permanently discontinue for recurrent hepatotoxicity. 2. Fatal and serious diarrhea or colitis: Severe (Grade 3/4) and life-threatening immune-mediated diarrhea and colitis have occurred. Interrupt for moderate (Grade 2) diarrhea; permanently discontinue for severe or life-threatening diarrhea/colitis. Systemic corticosteroids (budesonide or prednisone) are required for immune-mediated Grade 3+ colitis. 3. Fatal and serious pneumonitis: Noninfectious pneumonitis, including fatal cases, has occurred. Evaluate for pneumonitis in patients with new or worsening respiratory symptoms. Withhold idelalisib if pneumonitis is suspected; permanently discontinue if noninfectious pneumonitis is confirmed. 4. Fatal and serious intestinal perforation: Has occurred in idelalisib-treated patients. Permanently discontinue idelalisib upon confirmed intestinal perforation. 5. Serious and fatal skin reactions: Severe cutaneous reactions including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have occurred. Discontinue idelalisib for any life-threatening dermatologic reaction. 6. Anaphylaxis and serious allergic reactions: Serious anaphylaxis has occurred. Discontinue idelalisib permanently and institute appropriate emergency treatment. 7. Severe neutropenia: Grade 3/4 neutropenia has occurred. Monitor ANC at least every 2 weeks for the first 6 months of treatment.

Question 6

Is Idelalisib safe during pregnancy?

Accepted Answer

Idelalisib pregnancy safety: Can cause fetal harm based on mechanism of action (PI3K-delta signaling is essential for normal fetal immune development). Females of reproductive potential should use effective contraception during treatment and for at least 1 month after the last dose. Males with female partners of reproductive potential should use contraception during treatment and for at least 1 month after the last dose. May impair male fertility based on animal data. Not recommended during breastfeeding.. Oncologists should review the complete prescribing information and discuss reproductive risks with patients before initiating therapy.

Idelalisib — Drug Monograph

Mechanism of Action

FDA Indications

Common Side Effects

Clinical Pearl

Related Therapies & Mechanisms