Approved indication: chronic lymphocytic leukaemia, follicular lymphoma
Zydelig (Gilead)
100 mg and 150 mg tablets
Australian Medicines Handbook section 14.2.4

Like ibrutinib,1 idelalisib is an oral anticancer drug that targets B-cell cancers. It works by inhibiting phosphatidylinositol 3-kinase. This enzyme is overactive in B-cell cancers and is involved in driving proliferation, migration and survival of malignant cells.

Idelalisib is registered for two indications:

  • in combination with rituximab for chronic lymphocytic leukaemia and small lymphocytic lymphoma when chemotherapy is not suitable, in people who have relapsed after treatment or have the chromosome 17p deletion or TP53 mutation
  • monotherapy for refractory follicular lymphoma.

Chronic lymphocytic leukaemia

The approval of idelalisib for relapsed chronic lymphocytic leukaemia is based on a pivotal phase III trial of 220 patients.2 The median age of randomised patients was 71 years. Two-thirds of them had advanced disease and the median time since initial diagnosis was nine years. Patients were heavily pre-treated (regimens included rituximab, cyclophosphamide, fludarabine and bendamustine) and were considered too unwell for chemotherapy.

In total, 80% of the patients lacked somatic hypermutation of the gene encoding the immunoglobulin heavy-chain variable region, and 40% carried the 17p deletion or TP53 mutation. These genetic characteristics are generally associated with poorer outcomes.

Patients received intravenous rituximab with either oral idelalisib or placebo. After 24 weeks, the rate of progression-free survival was significantly higher with idelalisib than with placebo (p<0.001, see Table 1). The overall response rate, assessed using serial CT or MRI of the neck, chest, abdomen and pelvis, was significantly higher in the idelalisib group compared to the placebo group (81% vs 13%, p<0.001). These were all partial responses.2

Table 1 - Efficacy of idelalisib in relapsed chronic lymphocytic leukaemia 2

Outcome Idelalisib plus rituximab§
(110 patients)
Placebo plus rituximab§
(110 patients)
Progression-free survival after 24 weeks 93% 46%
Median duration of progression-free survival Not reached 5.5 months
Overall survival after one year 92% 80%
Overall response rate (all partial responses)# 81% (of a total of 88 patients that could be evaluated) 13% (of a total of 88 patients that could be evaluated)

Oral idelalisib 150 mg twice a day
§ Intravenous rituximab 375 mg/m2 body surface area, followed by 500 mg/m2 body surface area every 2 weeks for 4 doses and then every 4 weeks for 3 doses, for a total of 8 infusions
# Assessed using serial CT or MRI of the neck, chest, abdomen and pelvis 

Idelalisib was also better than placebo in subgroup analyses of patients with unmutated immunoglobulin heavy-chain variable region, or the 17p deletion or TP53 mutation. The trial was terminated at the interim analysis because of the superior efficacy of idelalisib combined with rituximab.

Single-arm trials of idelalisib combined with chemotherapy or immunotherapy generally found similar overall response rates (72% or above). However at the time of writing, these trials do not appear to have been published in full


Follicular lymphoma

The approval of idelalisib as a monotherapy for refractory follicular lymphoma was based on a pivotal phase II uncontrolled trial of 125 patients with relapsed indolent lymphoma.3 Of the participants, 72 had follicular lymphoma, 28 had small lymphocytic lymphoma, 15 had marginal-zone lymphoma and 10 had lymphoblastic lymphoma. Patients had received a median of four previous regimens and most of them were refractory to rituximab and an alkylating agent such as cyclophosphamide. Their median age was 64 years.

The median duration of treatment was 6.6 months. More than half of patients responded to treatment – these were mainly partial responses (see Table 2). Rates of response seemed to be comparable across the different disease subtypes.

Table 2 - Efficacy of idelalisib in relapsed indolent lymphoma3

Outcome Idelalisib monotherapy §
Overall response rate 57% (71/125 patients) – 7 complete responses, 63 partial responses, 1 minor response
Median duration of response 12.5 months
Median progression-free survival 11 months
Median overall survival 20.3 months

Tumour response and progression assessed by serial CT, laboratory testing and physical examination
§ Oral idelalisib 150 mg twice a day


Adverse effects and precautions

The most common adverse reactions (any grade) to idelalisib include neutropenia (50%), increased transaminases (50%), diarrhoea (38%), fever (32%), rash (24%) and pneumonitis (3%). These events can be serious (grade 3) in some cases and increased monitoring, dose interruption or treatment discontinuation may be needed.

In the indolent lymphoma trial there were 28 deaths. Most were related to disease progression (20 deaths). Other causes included pneumonia (3 patients), cardiac arrest, cardiac failure, splenic infarction, septic shock and pneumonitis (1 patient each).3

As elevated liver enzymes are so common, it is important to monitor alanine transaminase, aspartate transaminase and bilirubin fortnightly, at least for the first three months of treatment. Reactivation of hepatitis has occurred with idelalisib and all patients should be screened for hepatitis B and C before they start treatment. Close monitoring for toxicity is recommended if idelalisib is initiated in patients with severe hepatic impairment.

Severe diarrhoea or colitis occurred in 14% of patients across the trials. If diarrhoea occurs, make sure the patient is adequately hydrated, particularly those with pre-existing renal failure. Infections such as Clostridium difficile should be excluded. Intestinal perforation has been reported with idelalisib. This was fatal in some cases. Treatment should be stopped if perforation occurs.

Although live vaccines are not recommended during idelalisib treatment, they can be given to high-risk patients before treatment is started.



The recommended dose of idelalisib is 150 mg orally twice a day. Peak plasma concentrations are reached within 2–4 hours after oral administration. Idelalisib is mainly metabolised by aldehyde oxidase, but also by cytochrome P450 (CYP) 3A and UGT1A4. The elimination half-life is around eight hours and metabolites are excreted in the faeces (78%) and urine (15%).


Drug interactions

Concomitant strong CYP3A inducers (e.g. rifampicin, phenytoin, carbamazepine, St John’s wort) may reduce plasma concentrations of idelalisib and should be avoided. Strong inhibitors may elevate idelalisib concentrations so increased monitoring for toxicity is recommended.

Caution is urged if idelalisib is given to patients taking CYP3A substrates with a narrow therapeutic index (e.g. cisapride, fentanyl). Idelalisib is a strong inhibitor of CYP3A and may increase exposure to substrates such as warfarin, some antiarrhythmic drugs, calcium channel blockers and statins.



Idelalisib seems to benefit pre-treated, older patients with chronic lymphocytic leukaemia and follicular lymphoma. However, adverse effects are common and often limit treatment. In chronic lymphocytic leukaemia, the long-term safety and effectiveness of idelalisib remains to be determined.


🅃 manufacturer provided useful addition information

The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.

At the time the comment was prepared, information about this drug was available on the websites of the Food and Drug Administration in the USA and the European Medicines Agency.

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