Idelalisib is an oral kinase inhibitor that is approved for use in combination with rituximab in relapsed or refractory chronic lymphocytic leukemia (CLL) and as monotherapy for relapsed follicular B cell, small lymphocytic lymphoma and indolent non-Hodgkin lymphoma. Idelalisib is associated with a high rate of serum enzyme elevations during therapy and has been reported to cause clinically apparent acute liver injury that can be severe and even fatal.


Idelalisib (eye del" a lis' ib) is an orally available, small molecule inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ), which is an essential component in the B cell signaling pathways that drive migration of B cells to lymph nodes and bone marrow. Inhibition of this pathway inhibits B cell chemotaxis and adherence and reduces cell viability. This pathway is upregulated in many B cell malignancies and has been shown to be critical for proliferation and survival of leukemia and lymphomatous malignant B lymphocytes. Idelalisib was approved for use in the United States as therapy for relapsed CLL in combination with rituximab and as monotherapy for indolent forms of non-Hodgkin’s lymphoma in 2014. It is not recommended as a first-line therapy of leukemias or lymphomas. Idelalisib is available as tablets of 100 and 150 mg under the brand name Zydelig. The recommended dose is 150 mg twice daily until disease progression or unacceptable toxicity. Side effects are common but usually mild-to-moderate in severity, and include nausea, diarrhea, headache, stomatitis, fever, pain, rash, infections, arthralgia and fatigue. Common laboratory abnormalities can include cytopenias, liver enzyme elevations, hyper- or hypo-glycemia, and hyponatremia. Severe adverse events (for which it has a black box warning) can include liver failure, severe diarrhea, pneumonitis, intestinal perforation, severe skin rash, anaphylaxis, neutropenia and embryo-fetal toxicity.


In clinical trials of idelalisib combined with rituximab in patients with CLL and lymphoma, the rates of serum enzyme elevations during therapy ranged from 25% to 35% and were above 5 times the ULN in 5% to 8% (compared to 1% with placebo and rituximab). Severe instances of severe acute hepatocellular injury and acute liver failure were reported in patients receiving idelalisib alone and with rituximab, but the clinical features of the cases were not be described in detail. Serum enzyme elevations typically arose within 4 to 12 weeks of starting therapy and usually resolved rapidly with temporary discontinuation. In some instances, however, serum aminotransferases remained high despite stopping therapy, and in this situation corticosteroids appeared to have a beneficial effect. Most patients who developed significant serum enzyme elevations with idelalisib had a rapid recurrence upon rechallenge. In patients receiving corticosteroids, however, recurrence was less common and generally mild, allowing for restarting of therapy in many patients. Thus, idelalisib is a frequent cause of acute hepatocellular injury which may have an autoimmune component. Because of its many serious adverse events and limited efficacy in comparison to other agents, idelalisib has not been widely used and it potential for causing acute clinically apparent liver injury with jaundice has not been well defined.

Because, idelalisib affects B cell function, it may also be capable of inducing reactivation of hepatitis B, although in published trials of the agent, reactivation was not reported.

Likelihood score: D (possible cause of clinically apparent liver injury).

Mechanism of Injury

The reason why idelalisib causes serum enzyme elevations is not known, but may be a direct toxicity to hepatocytes caused by inhibition of PI3K activity or the result of change in B cell activity and caused by induction of autoimmunity. Idelalisib is metabolized primarily by aldehyde oxidase which is present in many tissues, but highest concentrations are in the liver. The cytochrome P450 system plays a minor role in the metabolism (CYP 3A4) of idelalisib, but concentrations may be affected by drugs that induce or inhibit CYP 3A activity.

Outcome and Management

Serum enzyme elevations are not uncommon during cancer chemotherapy with idelalisib and may be dose limiting. Idelalisib should not be used with other agents with hepatotoxic potential. Furthermore, regular monitoring of liver tests every 2 to 4 weeks is recommended during the first six months of idelalisib therapy and every 1 to 3 months thereafter, with more frequent monitoring if serum aminotransferase values rise. Idelalisib should be held if ALT or AST values rise above 5 times the ULN, and treatment resumed only if and when values fall into the normal range and then with a reduced dose and careful monitoring. Elevations of aminotransferase values of more than 20 times the ULN, or appearance of jaundice or symptoms of liver injury should trigger permanent discontinuation. Corticosteroids are often used if the liver injury does not resolve rapidly with stopping idelalisib, and continuing the corticosteroids may help prevent recurrence of injury with restarting therapy. There is no known cross sensitivity to hepatic injury among the different protein kinase inhibitors.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors



Idelalisib – Zydelig®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 12 July 2022

Abbreviations: CLL, chronic lymphocytic leukemia; PI3K, phosphatidylinositol 3-kinase; SLL, small cell lymphocytic lymphoma.

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    (Among 310 patients with relapsed or refractory CLL treated with acalabrutinib vs idelalisib and rituximab with or without bendamustine, the 12 month predicted progression-free survival was 88% vs 68% and serious adverse event rates were 29% vs 56% and ALT elevations above 5 times ULN arose in 1% vs 6%).
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    (An early phase trial of idelalisib in patients with metastatic pancreatic cancer was terminated after enrollment of only 16 patients because of concerns over safety, ALT elevations above 5 times ULN arising in 25%, frequently accompanied by rash).
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    (Among 110 patients with CLL treated with idelalisib and rituximab analyzed in a retrospective study from the UK, the overall response rate was 88% but adverse events were common, led to discontinuation in 49%, and include pneumonia [10%], colitis [6%], neutropenic sepsis [4.5%], rash [3%] and ALT elevations [1%]).
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    (Long term follow up [6 years] of a phase 2 study of idelalisib for relapsed indolent lymphoma demonstrated that the adverse event profile changed, most ALT elevations arising during the initial 6 months of treatment, while diarrhea, nausea, fever and infections continued to occur: “idelalisib monotherapy may be a reasonable treatment option when standard therapies have been exhausted”).
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    (Among 147 patients with CLL or follicular lymphoma treated with idelalisib in Germany between 2015 and 2020, the overall response rate among patients with CLL was 70% and with lymphoma was 36% while frequent adverse events were diarrhea, nausea, pneumonia, rash, and fatigue with ALT elevations above 5 times ULN in 3%).
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