Idelalisib was not found to increase the risk for bleeding events in patients with chronic lymphocytic leukemia (CLL) or indolent forms of non-Hodgkin lymphoma (NHL) who received the agent in combination with anticoagulation or antiplatelet therapy, according to findings of a post-hoc analysis of data from the idelalisib registration trials reported in Leukemia and Lymphoma.1
Real-world studies of ibrutinib, an oral, B-cell-directed kinase inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of patients with CLL and indolent forms of B-cell NHL,2 have shown ibrutinib to be associated with a high risk of major bleeding in patients receiving concomitant anticoagulation or antiplatelet therapy. Furthermore, cardiovascular comorbidities associated with the use of anticoagulation/antiplatelet therapy are common in patients with CLL or indolent NHL with a median age at diagnosis of 65 years or older.
“Serious hemorrhage may become a concern in these patients given the following risk factors: baseline thrombocytopenia from bone marrow infiltration, poor marrow reserve from the use of a prior myelosuppressive regimen, and the possibility of coexisting autoimmune cytopenias,” the study authors said.
Idelalisib is another B-cell-directed therapy that has received FDA approval in the CLL and indolent NHL settings.3 Specifically, idelalisib is a first-in-class phosphatidylinositol 3-kinase delta inhibitor indicated for use with rituximab for patients with relapsed CLL. It is also approved as a monotherapy for patients with relapsed follicular B-cell NHL or relapsed small lymphocytic lymphoma (SLL) who previously received 2 lines of systemic therapy.
The use of anticoagulant and/or antiplatelet agents or an increased risk of disease-related bleeding were not contraindications to enrollment in the 2 registration trials of idelalisib. The registration trials of focus comprised a randomized phase 3 study that compared rituximab plus idelalisib with rituximab alone in relapsed/refractory CLL (ClinicalTrials.gov Identifier: NCT01539512), and a phase 2 trial of idelalisib monotherapy (ClinicalTrials.gov Identifier: NCT01282424) in patients with rituximab-refractory indolent NHL, including follicular lymphoma and SLL.
A main goal of the post-hoc analysis was to evaluate bleeding risks for idelalisib-receiving patients with comorbidities necessitating concomitant treatment with anticoagulants/antiplatelet drugs, as well as those with thrombocytopenia.
Of the 345 patients included in the analysis, 220 and 125 were diagnosed with CLL and indolent NHL, respectively. The median duration of treatment was 8.1 months for patients receiving idelalisib plus rituximab, 4.6 months for those treated with single-agent rituximab, and 6.6 months for patients treated with idelalisib monotherapy.
Use of concomitant anticoagulation/antiplatelet therapy at any time throughout the study period was high, at 63%, 36%, and 47%, in the idelalisib plus rituximab, rituximab, and idelalisib monotherapy groups, respectively. In addition, rates of grade 3 or higher thrombocytopenia were 16.4%, 27.8%, and 2.4% in these respective groups at baseline.
Overall, no relationship was detected between treatment-emergent bleeding events and the presence of comorbidities in these patients. Further, the bleeding event rate was similar in the 3 treatment groups.
For the overall patient cohort, the rates of grade 1, grade 2, and grade 3 or higher bleeding events were 0.9%, 0.9%, and 3.2% for those treated with idelalisib plus rituximab, rituximab, and single-agent idelalisib, respectively. Of the 59 bleeding events reported, 68%, 22%, and 10% were classified as grade 1, grade 2, or grade 3 or higher, respectively. No central nervous system-related bleeding occurred in any of these patients.
The median time to onset of first bleeding event of any grade was 37 days for patients receiving idelalisib plus rituximab, 29 days for those treated with rituximab, and 189 days for patients receiving idelalisib monotherapy.
In their concluding remarks, the study authors commented, “although idelalisib is well known to cause other serious or even fatal toxicities (colitis, pneumonitis, transaminitis, and infections), our data show no increase in bleeding events in patients with relapsed/refractory CLL or [indolent NHL] treated with idelalisib.”
Disclosures: Some of the study authors disclosed financial relationships with the pharmaceutical industry and/or the medical device industry. For a full list of disclosures, please refer to the original study.
- Barrientos JC, Hillmen P, Salles G, et al. No increased bleeding events in patients with relapsed chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma treated with idelalisib. Leuk Lymphoma. Published online December 10, 2020. doi:10.1080/10428194.2020.184533.
- Ibrutinib (Imbruvica) [package insert]. Sunnyvale, CA: Pharmacyclics LLC; 2020.
- Idelalisib (Zydelig) [package insert]. Foster City, CA: Gilead Sciences, Inc. 2020.