Idelalisib, an inhibitor of phosphoinositide 3-kinase isoform delta (PI3Kδ), is an antineoplastic agent.1, 6, 7, 8, 9, 10
Idelalisib is used in combination with rituximab for the treatment of relapsed chronic lymphocytic leukemia (CLL) in patients in whom monotherapy with rituximab would be considered appropriate therapy due to other comorbidities;1, 2 idelalisib is designated an orphan drug by FDA for the treatment of this cancer.3
Idelalisib is not indicated and is not recommended for first-line treatment, including in patients with CLL, small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and other indolent non-Hodgkin's lymphomas.1 In addition, idelalisib is not indicated and is not recommended in combination with bendamustine and rituximab, or in combination with rituximab, for the treatment of patients with FL, SLL, and other indolent non-Hodgkin's lymphomas.1
The current indication for idelalisib in the treatment of relapsed CLL is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study in adults with relapsed CLL who were unable to tolerate standard chemotherapy because of coexisting medical conditions, impaired renal function (creatinine clearance less than 60 mL/minute), and/or severe myelosuppression (grade 3 or higher neutropenia or thrombocytopenia) resulting from prior therapy with cytotoxic agents.1, 2 In this study, 220 patients were randomized in a 1:1 ratio to receive either idelalisib (150 mg orally twice daily) in combination with rituximab (375 mg/m2 administered by IV infusion initially, followed by 500 mg/m2 by IV infusion every 2 weeks for 4 doses and then every 4 weeks for an additional 3 doses, for a total of 8 doses) or placebo in combination with rituximab.1, 2 Patients received idelalisib until disease progression or unacceptable toxicity occurred.1 The primary end point of this study was progression-free survival as assessed by an independent review committee; secondary end points included overall survival, overall response rate, and lymph node response.1, 2 The median age of patients was 71 years.1, 2 Patients enrolled in the study had received a median of 3 prior therapies; the majority (96%) of patients had received previous treatment with an anti-CD20 monoclonal antibody.1, 2 Approximately 45% of patients had previously received rituximab in combination with bendamustine, 34% received rituximab in combination with fludarabine and cyclophosphamide, 31% received single-agent rituximab, 17% received rituximab in combination with fludarabine, and 16% received chlorambucil.1
This study was terminated prematurely at the request of the Independent Data Monitoring Committee because of improved progression-free survival observed during the first pre-specified interim analysis in patients receiving idelalisib in combination with rituximab.1, 2 At the time of the second interim analysis, the progression-free survival benefit observed in patients receiving idelalisib in combination with rituximab remained statistically significant, although the median duration of progression-free survival had not yet been reached; the median progression-free survival in patients receiving placebo in combination with rituximab was 5.5 months.1, 2 The overall response rate was 81% for patients receiving idelalisib in combination with rituximab and 13% for those receiving placebo in combination with rituximab; there were no complete responses in either group.2 Median overall survival had not been reached at the time of the interim analysis.2
At the time of the final analysis, the median progression-free survival was 19.4 months for patients receiving idelalisib in combination with rituximab (median follow-up: 8.3 months) compared with 6.5 months for patients receiving placebo in combination with rituximab (median follow-up: 5.6 months).1 The overall response rate was 84% for patients receiving idelalisib in combination with rituximab and 16% for those receiving placebo in combination with rituximab; there were no complete responses in either group.1 The median duration of response was 6.2 months in patients receiving placebo in combination with rituximab and had not been reached in those receiving idelalisib in combination with rituximab.1
Idelalisib is administered orally without regard to meals.1 Idelalisib tablets should be swallowed whole.1
For the treatment of relapsed chronic lymphocytic leukemia (CLL) in patients in whom monotherapy with rituximab would be considered appropriate therapy due to other comorbidities, the recommended dosage of idelalisib in adults is 150 mg twice daily in combination with rituximab.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1 The manufacturer states that safety and efficacy of idelalisib beyond several months of therapy have not been established; in the phase 3 study in patients with relapsed CLL, the median duration of exposure to idelalisib was 5 months.1
Dosage Modification for Toxicity
Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of idelalisib may be necessary in patients who develop severe hepatotoxicity, diarrhea, pneumonitis, infection, intestinal perforation, severe cutaneous reaction, serious hypersensitivity reaction, or myelosuppression.1
In patients experiencing other severe or life-threatening toxicities, withhold therapy with idelalisib until the toxicity has resolved.1 If clinically appropriate, idelalisib therapy may be resumed at a reduced dosage of 100 mg twice daily.1 If severe or life-threatening toxicities recur at a dosage of 100 mg twice daily, permanently discontinue treatment with idelalisib.1
In patients who exhibit increases in serum aminotransferase (ALT and/or AST) concentrations exceeding 3 up to 5 times the upper limit of normal (ULN) or bilirubin concentrations exceeding 1.5 up to 3 times the ULN, idelalisib therapy may be continued at the same dosage.1 Monitor liver function tests at least weekly until ALT, AST, and bilirubin concentrations return to within normal limits.1
In patients who exhibit increases in ALT and/or AST concentrations exceeding 5 up to 20 times the ULN or bilirubin concentrations exceeding 3 up to 10 times the ULN, withhold therapy with idelalisib and monitor liver function tests at least weekly.1 When ALT, AST, and bilirubin concentrations return to within normal limits, idelalisib therapy may be resumed at a reduced dosage of 100 mg twice daily.1
In patients who exhibit increases in ALT and/or AST concentrations exceeding 20 times the ULN or bilirubin concentrations exceeding 10 times the ULN, permanently discontinue therapy with idelalisib.1
In patients with moderate diarrhea (4-6 stools per day over baseline), idelalisib therapy may be continued at the same dosa monitor patients at least weekly until diarrhea resolves.1
In patients with severe diarrhea (7 or more stools per day over baseline) or diarrhea requiring hospitalization, withhold therapy with idelalisib and monitor patients at least weekly.1 When diarrhea resolves, idelalisib therapy may be resumed at a reduced dosage of 100 mg twice daily.1
In patients with life-threatening diarrhea, permanently discontinue therapy with idelalisib.1
In patients who develop any severity of symptomatic pneumonitis or organizing pneumonia, permanently discontinue idelalisib therapy.1
In patients who develop grade 3 or higher sepsis or pneumonia, withhold idelalisib therapy until infection has resolved.1
In patients with evidence of active CMV infection of any grade or viremia (positive PCR or antigen test), withhold idelalisib therapy until the viremia has resolved.1 If idelalisib therapy is resumed, monitor patients for CMV reactivation with PCR or antigen tests at least monthly.1
In patients with suspected PJP infection of any grade, withhold idelalisib therapy.1 If PJP infection of any severity is confirmed, permanently discontinue idelalisib therapy.1
In patients who develop intestinal perforation, permanently discontinue idelalisib therapy.1
In patients who develop serious hypersensitivity reactions, permanently discontinue idelalisib therapy.1
In patients with suspected Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS), withhold idelalisib therapy until the etiology of the reaction has been determined.1 In patients with confirmed SJS, TEN, or DRESS, or other severe or life-threatening (i.e., grade 3 or higher) cutaneous reactions, permanently discontinue idelalisib therapy.1
In patients with absolute neutrophil counts (ANC) of 1000/mm3 to less than 1500/mm3 or platelet counts of 50,000/mm3 to less than 75,000/mm3, idelalisib therapy may be continued at the same dosage.1
In patients with ANC of 500/mm3 to less than 1000/mm3 or platelet counts of 25,000/mm3 to less than 50,000/mm3, therapy with idelalisib may be continued at the same dosa ANC and platelet counts should be monitored at least weekly.1
In patients with ANC less than 500/mm3 or platelet counts less than 25,000/mm3, withhold idelalisib therapy and monitor ANC and platelet counts at least weekly.1 When ANC reaches or exceeds 500/mm3 or platelet counts reach or exceed 25,000/mm3, idelalisib may be resumed at a reduced dosage of 100 mg twice daily.1
No dosage modifications are required in patients who develop lymphocytosis.1 Lymphocytosis associated with idelalisib is a pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical findings.1
The manufacturer makes no specific dosage recommendations for patients with preexisting hepatic impairment; however, such patients should be monitored for signs of toxicity, and dosage of idelalisib should be adjusted as appropriate.1
No dosage adjustment is necessary in patients with creatinine clearance ≥15 mL/minute.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Serious and/or fatal hepatotoxicity has been reported in 16% of patients receiving idelalisib in combination with rituximab or other drugs.1 A boxed warning about this risk has been included in the prescribing information for the drug.1 Elevations in aminotransferase (ALT or AST) concentrations exceeding 5 times the upper limit of normal (ULN) have occurred in patients receiving idelalisib.1 These elevations generally occurred during the initial 12 weeks of therapy.5 In the phase 3 study evaluating safety and efficacy of idelalisib in combination with rituximab in patients with relapsed chronic lymphocytic leukemia (CLL), elevations in ALT or AST concentrations occurred at a median of 93 or 92 days, respectively.5 Elevations in ALT or AST concentrations were reversible following temporary interruption of idelalisib therapy; however, following resumption of therapy at a reduced dosage, recurrence of ALT and AST elevations was reported in 26% of patients.1
Evaluate serum ALT and AST concentrations prior to initiation of therapy, every 2 weeks during the first 3 months of therapy, every 4 weeks during the next 3 months, and then every 1-3 months thereafter.1 If hepatotoxicity occurs, monitor liver function tests more frequently until levels return to within normal limits.1 Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of idelalisib may be necessary depending on the severity of hepatotoxicity.1 If ALT and/or AST concentrations increase to >20 times the ULN or bilirubin concentrations increase to >10 times the ULN, permanently discontinue idelalisib therapy.1 Idelalisib therapy also should be discontinued if hepatotoxicity recurs.1
Avoid concomitant use of idelalisib with drugs that may cause hepatotoxicity.1
Severe (grade 3 or greater) diarrhea or colitis has been reported in 20% of patients receiving idelalisib in combination with rituximab or other drugs.1 A boxed warning about this risk has been included in the prescribing information for the drug.1 Diarrhea can occur at any time and responds poorly to antimotility agents.1 Diarrhea resolves within a median of 1 week to 1 month following temporary interruption of idelalisib therapy and, in some instances, use of corticosteroids.1
Monitor patients receiving idelalisib for the development of severe diarrhea or colitis.1 If moderate or severe diarrhea occurs, monitor patients at least weekly until diarrhea resolves.1 Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of idelalisib may be necessary depending on the severity of diarrhea.1 If life-threatening diarrhea occurs, permanently discontinue therapy with idelalisib.1
Avoid concomitant use of idelalisib with drugs that may cause diarrhea.1
Serious or fatal pneumonitis has been reported in 4% of patients receiving idelalisib in combination regimens in clinical trials.1 A boxed warning about this risk has been included in the prescribing information for the drug.1 Clinical manifestations included interstitial infiltrates and organizing pneumonia; time to onset ranged from less than 1 month to 15 months.1
Patients receiving idelalisib who present with pulmonary manifestations (e.g., cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, a greater than 5% decrease in oxygen saturation) should be evaluated for pneumonitis.1 If pneumonitis is suspected, interrupt idelalisib therapy until the etiology of the pulmonary symptoms has been determined.1 If symptomatic pneumonitis or organizing pneumonia is confirmed, initiate appropriate treatment with corticosteroids and permanently discontinue idelalisib.1
Serious and/or fatal infection has been reported in 48% of patients receiving idelalisib in combination with rituximab or other drugs in clinical studies.1 A boxed warning about this risk has been included in the prescribing information for the drug.1 The most common infections observed were pneumonia, sepsis, and febrile neutropenia.1
Monitor patients receiving idelalisib for signs and symptoms of infection.1 If infection is suspected, interrupt idelalisib therapy.1 In patients who develop grade 3 or higher infection, interrupt idelalisib therapy until infection has resolved.1
Serious or fatal Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia (PJP) or cytomegalovirus (CMV) has been reported in <1% of patients receiving idelalisib.1 Provide appropriate prophylaxis for PJP during therapy with idelalisib.1 Interrupt idelalisib therapy in patients with suspected PJP infection of any grade; if PJP infection of any grade is confirmed, permanently discontinue idelalisib.1
Regular clinical and laboratory monitoring for CMV infection is recommended in patients with a history of CMV infection or positive CMV serology at the start of treatment with idelalisib.1 In case of a positive CMV PCR or antigen test, interrupt idelalisib therapy until the viremia has resolved.1 If idelalisib is resumed in patients who developed clinical CMV infection or viremia during therapy, monitor for CMV reactivation by polymerase chain reaction (PCR) or antigen test at least monthly.1
Severe or fatal intestinal perforation has been reported in patients receiving idelalisib.1 A boxed warning about this risk has been included in the prescribing information for the drug.1 At the time of perforation, some patients had moderate to severe diarrhea.1 Idelalisib should be permanently discontinued if intestinal perforation occurs.1
Serious hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving idelalisib.1 Idelalisib is contraindicated in patients with a history of serious hypersensitivity reactions to idelalisib.1 Idelalisib should be permanently discontinued, and supportive treatment instituted, in patients who experience a severe hypersensitivity reaction.1
Other Warnings and Precautions
Fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving idelalisib.1 Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) also have occurred.1
Idelalisib is contraindicated in patients with a history of TEN.1 If SJS, TEN, or DRESS is suspected, interrupt idelalisib therapy until the etiology of the reaction has been determined.1 If SJS, TEN, or DRESS is confirmed, permanently discontinue idelalisib.1
Other severe (grade 3 or greater) or life-threatening dermatologic reactions, including exfoliative dermatitis, rash (i.e., erythematous, generalized, macular, maculopapular, papular, pruritic, and exfoliative rash), and toxic skin reactions have been reported in patients receiving idelalisib.1
Patients receiving idelalisib should be monitored for development of severe dermatologic reactions.1 If severe or life-threatening dermatologic reactions occur, idelalisib should be permanently discontinued.1
Severe (grade 3 or 4) neutropenia has been reported in 58% of patients receiving idelalisib in combination with rituximab or other drugs in clinical studies.1 Monitor complete blood cell (CBC) counts at least every 2 weeks during the first 6 months of therapy.1 If absolute neutrophil count (ANC) decreases to less than 1000/mm3, monitor CBCs more frequently.1 Temporary interruption of idelalisib therapy followed by dosage reduction may be necessary depending on the severity of neutropenia.1
Fetal/Neonatal Morbidity and Mortality
Idelalisib may cause fetal harm if administered to pregnant women;1 teratogenicity and embryofetal toxicity have been demonstrated in animals receiving idelalisib at dosages equivalent to 12-30 times the human exposure at the recommended dosage.1 Females of reproductive potential should be advised to use an effective method of contraception while receiving the drug and for 1 month after the last dose.1 Males with female partners of reproductive potential should be advised to use effective contraception during treatment with idelalisib and for 3 months after the last dose.1 If idelalisib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
Idelalisib may cause fetal harm if administered to pregnant women.1 Effective contraceptive measures are required.1 If idelalisib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
It is not known whether idelalisib is distributed into milk in humans.1 The effects of idelalisib on milk production or the breast-fed infant also are not known.1 Because of the potential for serious adverse reactions to idelalisib in nursing infants, women should be advised not to breast-feed during idelalisib therapy and for 1 month after the last dose.1
Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential prior to starting idelalisib therapy.1 Advise such females to use effective contraception during therapy and for 1 month after the last dose.1
Advise males with female partners of reproductive potential to use effective contraception during treatment with idelalisib and for 3 months after the last dose.1
Safety and efficacy of idelalisib have not been established in pediatric patients.1
In clinical studies evaluating idelalisib in patients with relapsed CLL, 55% of patients were ≥65 years of age.1 Patients ≥65 years of age with CLL had higher incidences of serious adverse reactions, death, or discontinuance of idelalisib due to adverse reactions compared with younger adults.1
Systemic exposure of idelalisib is increased up to 1.7-fold in individuals with ALT, AST, or bilirubin concentrations above the ULN compared with individuals with normal hepatic function.1 Patients with preexisting hepatic impairment should be monitored for signs of toxicity during idelalisib therapy.1
There is limited information on idelalisib exposure in patients with baseline ALT or AST concentrations exceeding 2.5 times the ULN or bilirubin concentrations exceeding 1.5 times the ULN.1
Systemic exposure of idelalisib is not affected in patients with renal impairment (creatinine clearance ≥15 mL/minute).1
Adverse effects reported in ≥30% of patients with relapsed chronic lymphocytic leukemia (CLL) receiving idelalisib in combination with rituximab or other drugs include diarrhea, pneumonia, pyrexia, fatigue, rash, cough, and nausea.1 Laboratory abnormalities reported in ≥28% of patients with relapsed CLL receiving idelalisib in combination with rituximab or other drugs include neutropenia and elevated aminotransferase (ALT or AST) concentrations.1
Idelalisib is metabolized by aldehyde oxidase, cytochrome P-450 (CYP) isoenzyme 3A, and, to a lesser extent, uridine diphosphate-glucuronosyl transferase (UGT) 1A4.1
In vitro, idelalisib is a substrate of CYP3A, aldehyde oxidase, and UGT1A4.1 Idelalisib inhibits CYP isoenzymes 2C8, 2C19, and 3A.1 Idelalisib also inhibits UGT1A1.1 In vitro studies show that idelalisib induces CYP isoenzyme 2B6.1
In vitro, idelalisib is a substrate of efflux transporter P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); the drug is not a substrate of organic anion transport protein (OATP) 1B1, OATP1B3, renal organic anion transporter (OAT) 1, OAT3, or organic cation transporter (OCT) 2.1
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP3A Isoenzymes
Concomitant use of idelalisib with potent inhibitors of CYP3A may result in increased systemic exposure to idelalisib, resulting in increased risk of adverse effects.1 When the potent CYP3A and P-gp inhibitor ketoconazole was administered concomitantly with idelalisib in healthy individuals, area under the plasma concentration-time curve (AUC) of idelalisib increased by 1.8-fold; however, peak plasma concentrations of idelalisib were not affected.1 If possible, use alternative agents that are not potent inhibitors of CYP3A.1 If use of alternative agents is not possible, patients receiving idelalisib concomitantly with CYP3A inhibitors should be monitored frequently for signs of idelalisib toxicity.1 If severe adverse effects occur, temporary interruption of idelalisib therapy followed by dosage reduction may be necessary.1
Concomitant use of idelalisib with potent inducers of CYP3A may result in decreased systemic exposure to idelalisib, possibly resulting in decreased efficacy.1 When the potent CYP3A and P-gp inducer rifampin was administered concomitantly with idelalisib in healthy individuals, AUC and peak plasma concentrations of idelalisib decreased by 75 and 58%, respectively.1 Concomitant use of idelalisib with potent CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]) should be avoided.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP3A Isoenzymes
Idelalisib is a potent inhibitor of CYP3A and may increase systemic exposure of other drugs metabolized by CYP3A.1 When the CYP3A substrate midazolam was administered concomitantly with idelalisib in healthy individuals, peak plasma concentration and AUC of midazolam were increased 2.4- and 5.4-fold, respectively.1, 14 Concomitant use of idelalisib with sensitive CYP3A substrates should be avoided.1
Drugs Affecting the P-glycoprotein Transport System
When the potent CYP3A and P-gp inhibitor ketoconazole was administered concomitantly with idelalisib, systemic exposure to idelalisib was increased.1
Concomitant use of idelalisib with an inducer of P-gp may result in decreased systemic exposure to idelalisib.1 When the potent CYP3A and P-gp inducer rifampin was administered concomitantly with idelalisib, systemic exposure to idelalisib was decreased.1
Substrates of P-glycoprotein or OATP Transport Systems
When the OATP1B1 and OATP1B3 substrate rosuvastatin was administered concomitantly with idelalisib in healthy individuals, systemic exposure to rosuvastatin was not affected.1, 14
When the P-gp substrate digoxin was administered concomitantly with idelalisib in healthy individuals, systemic exposure to digoxin was not affected.1, 14
Idelalisib, a selective inhibitor of phosphoinositide 3-kinase isoform delta (PI3Kδ), is an antineoplastic agent.1, 6, 7, 8, 9, 10 Phosphoinositide 3-kinases (PI3Ks) are lipid kinases consisting of a catalytic subunit that exists in 4 different isoforms (α, β, γ, δ).2, 6, 8, 9, 11, 13 The delta isoform of PI3K (PI3Kδ) is highly expressed in hematopoietic cells and mediates B-cell receptor (BCR) signaling critical for B-cell homeostasis and function.2, 8, 9, 12 Oversignaling of PI3K, particularly the delta isoform, has been implicated in the development of lymphoid malignancies.2, 8, 13 Idelalisib blocks constitutive PI3K/Akt signaling which results in apoptosis.8, 11, 12 The drug also has demonstrated inhibition of several cell signaling pathways, including BCR, CXCR4, and CXCR5, which are involved in the migration of B-cells to lymph nodes and bone marrow.1 Idelalisib induced apoptosis and inhibited proliferation in cell lines derived from malignant B-cells and in primary tumor cells.1 Treatment of lymphoma cells with idelalisib resulted in inhibition of chemotaxis and adhesion, and reduced cell viability.1
Systemic exposure to idelalisib increases in a less than dose-proportional manner over a dosage range of 50-350 mg twice daily.1 Systemic exposure of idelalisib was increased by 1.4-fold following administration of a single dose of the drug with a high-fat meal compared with administration in the fasted state.1 Idelalisib is ≥84% bound to plasma proteins.1 Idelalisib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A and aldehyde oxidase; the drug is metabolized only to a minor extent by uridine diphosphate-glucuronosyl transferase (UGT) 1A4.1 The mean terminal half-life of idelalisib is 8.2 hours.1 Following oral administration of a single 150-mg dose of radiolabeled idelalisib, 78% of the dose was recovered in feces and 14% was recovered in urine.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 100 mg | ||
150 mg | Zydelig® | Gilead Sciences |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions January 30, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Gilead Sciences, Inc. Zydelig® (idelalisib) tablets prescribing information. Foster City, CA; 2022 Feb. [Web]
2. Furman RR, Sharman JP, Coutre SE et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med . 2014; 370:997-1007. [PubMedCentral][PubMed 24450857]
3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2014 Oct 21. [Web]
4. Gopal AK, Kahl BS, de Vos S et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med . 2014; 370:1008-18. [PubMedCentral] [PubMed 24450858]
5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206545Orig1s000: Medical review(s). From FDA website. [Web]
6. Hoellenriegel J, Meadows SA, Sivina M et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood . 2011; 118:3603-12. [PubMedCentral][PubMed 21803855]
7. Fiorcari S, Brown WS, McIntyre BW et al. The PI3-kinase delta inhibitor idelalisib (GS-1101) targets integrin-mediated adhesion of chronic lymphocytic leukemia (CLL) cell to endothelial and marrow stromal cells. PLoS One . 2013; 8:e83830. [PubMedCentral][PubMed 24376763]
8. Flinn IW, Kahl BS, Leonard JP et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood . 2014; 123:3406-13. [PubMedCentral][PubMed 24615776]
9. Meadows SA, Vega F, Kashishian A et al. PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood . 2012; 119:1897-900. [PubMed 22210877]
10. Herman SE, Gordon AL, Wagner AJ et al. Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood . 2010; 116:2078-88. [PubMedCentral] [PubMed 20522708]
11. Han TT, Fan L, Li JY et al. Role of chemokines and their receptors in chronic lymphocytic leukemia: function in microenvironment and targeted therapy. Cancer Biol Ther . 2014; 15:3-9. [PubMed 24149438]
12. Lannutti BJ, Meadows SA, Herman SE et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood . 2011; 117:591-4. [PubMedCentral][PubMed 20959606]
13. Castillo JJ, Furman M, Winer ES. CAL-101: a phosphatidylinositol-3-kinase p110-delta inhibitor for the treatment of lymphoid malignancies. Expert Opin Investig Drugs . 2012; 21:15-22. [PubMed 22112004]
14. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206545Orig1s000: Clinical Pharmacology and biopharmaceutics review(s). From FDA website. [Web]