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Chronic lymphocytic leukemia

Risk factors for grade 3/4 transaminase elevation in patients with chronic lymphocytic leukemia treated with idelalisib

Leukemia volume 34, pages 3404–3407 (2020)Cite this article

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Idelalisib, a specific inhibitor of the delta isoform of phosphatidylinositol 3 kinase (PI3Kδ), is approved with rituximab for the therapy of relapsed refractory patients with CLL in the United States and Europe [1, 2]. Idelalisib has been associated with a characteristic pattern of toxicities that include transaminase elevation, diarrhea/colitis, pneumonitis, and rash [3, 4]. Transaminase elevation (TAE) has been observed in all CLL clinical trials involving idelalisib, with company-sponsored studies showing rates of grade 3+ elevations ranging from ~10% [5,6,7] to 41% [8]. Cross-study comparison has suggested that these toxicities tend to be more frequent among previously untreated patients [9]. This trend was particularly notable in an investigator-sponsored study at Dana-Farber Cancer Institute, in which grade 3–4 transaminitis occurred early in more than 50% of untreated patients with CLL receiving single agent idelalisib prior to planned addition of ofatumumab 2 months later [4]. Risk factors for transaminitis in that small study included younger age <65 and mutated IGHV, which together explained almost all of the risk for this event [4]. We undertook the present study in order to understand risk factors for grade 3 or higher TAE across all fully enrolled, Gilead sponsored phase 2 and 3 studies, involving 853 total patients.

Data were included from all patients who received at least 1 dose of idelalisib in any of 6 phase 2 or 3 studies (Supplementary Table 1), three for treatment naive (TN) and three for relapsed/refractory (R/R) CLL. Patients with underlying liver disease or elevated liver function tests were excluded from these trials. The following variables were analyzed in univariable and multivariable analysis: age, prior therapy (Y vs N), combination with bendamustine plus rituximab (BR; Y vs N), del(17p) (Y vs N), and IGHV status (mutated vs unmutated). In addition, association of transaminase elevation with specific other drug exposures (allopurinol, acetaminophen, trimethoprim-sulfamethoxazole, and acyclovir) was assessed by assuming a potential association if the first occurrence of any grade TAE that was continuous with the grade 3 event occurred within 7 days of exposure to the concomitant medication.

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Fig. 1: Kaplan–Meier curve of first onset of grade 3 or higher transaminase elevation among 853 patients treated with idelalisib, by significant risk factor.

References

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Acknowledgements

JRB acknowledges funding from NCI 1R01CA213442-01A1, as well as Gilead, the National Comprehensive Cancer Network, and the Melton and Rosenbach Funds.

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Authors and Affiliations

  1. Dana-Farber Cancer Institute/Harvard Cancer Center, Boston, MA, USA

    Jennifer R. Brown

  2. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Andrew Zelenetz

  3. Weill Cornell Medical College, New York, NY, USA

    Richard Furman

  4. Herbert Irving Comprehensive Cancer Center (New York-Presbyterian Columbia University Medical Center), New York, NY, USA

    Nicole Lamanna

  5. Center for Chronic Lymphocytic Leukemia, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Anthony Mato

  6. Hematology Department, Niguarda Cancer Center, Milan, Italy

    Marco Montillo

  7. Chao Family Comprehensive Cancer Center at UC Irvine Medical Center, Orange, CA, USA

    Susan O’Brien

  8. Gilead Sciences, Inc, Foster City, CA, USA

    Ronald Dubowy, Lin Gu & Veerendra Munugalavadla

  9. Medical University of Lodz, Lodz, Poland

    Tadeusz Robak

  10. Experimental Haematology, University of Leeds, Leeds, UK

    Peter Hillmen

Authors
  1. Jennifer R. Brown
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Contributions

Conception and design: JR Brown and R Dubowy. Acquisition of data (acquired and managed patients, provided facilities and tools, etc.): JR Brown, A Zelenetz, R Furman, N Lamanna, A Mato, M Montillo, S O’Brien, T Robak, and P Hillmen. Analysis and interpretation of data: JR Brown, R Dubowy, L Gu, and V Munugalavadia. Writing, review, and/or revision of the manuscript: JR Brown wrote the first draft; all authors reviewed and approved the final draft.

Corresponding author

Correspondence to Jennifer R. Brown.

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Conflict of interest

JRB has served as a consultant for Abbvie, Acerta, Astra-Zeneca, BeiGene, Catapult, Dynamo Therapeutics, Genentech/Roche, Gilead, Juno/Celgene, Kite, Loxo, MEI Pharma, Nextcea, Novartis, Octapharma, Pfizer, Pharmacyclics, Sunesis, TG Therapeutics, Verastem; received honoraria from Janssen and Teva; received research funding from Gilead, Loxo, Sun and Verastem; and served on data safety monitoring committees for Morphosys and Invectys. AZ has served as a consultant for JUNO/Celgene, Genentech/Roche, Gilead, BeiGene, Amgen, Pharmacyclics, Janssen, Astra-Zeneca, Novartis/SANDOZ, MEI Pharma; received research support from Genentech/Roche, Gilead, BeiGene, MEI Pharma; and served on scientific advisory boards for the Lymphoma Research Foundation and Adaptive Biotechnologies. RF has served as a consultant for Abbvie, Acerta, Astra-Zeneca, Beigene, Genentech, Janssen, Loxo Oncology, Oncotracker, Pharmacyclics, Sunesis, TG Therapeutics, Verastem Oncology; received speaking fees from Janssen; received research funding from TG Therapeutics and AstraZeneca; and served on the data safety and monitoring board for Incyte. NL has served as a consultant for Abbvie, Astra-Zeneca, Bei-Gene, Celgene, Gilead, Genentech, Juno, Janssen/Pharmacyclics, Octapharma; received research funding from Abbvie, Astra-Zeneca, BeiGene, Genentech, Juno, Infinity/Verastem, Octapharma, Oncternal, Ming Therapeutics, TG Therapeutics; and served on advisory boards for Abbvie, Astra Zeneca, BeiGene, Celgene, Gilead, Genentech, Juno, Janssen/Pharmacyclics, and Octapharma. ARM holds a consultancy role for TG Therapeutics, Abbvie, Pharmacyclics, Johnson & Johnson, Regeneron, Astra-Zeneca, Genentech, Loxo, Celgene, Sunesis, Adaptive; received research funding from TG Therapeutics, Abbvie, Pharmacyclics, Johnson & Johnson, Regeneron, Genentech, Loxo, Portola, DTRM, Adaptive, Acerta; and served on the data safety monitoring board for TG Therapeutics and Celgene. MM has received honoraria from Abbvie, Gilead, Janssen, Roche; and served on the advisory board for Abbvie, Acerta/Astra-Zeneca, Gilead, Janssen, Roche, and Verastem. SO has served as a consultant for Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, Abbvie, Alexion, Verastem, Eisai, Juno Therapeutics, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunsesis; and received research support from Kite, Regeneron, Acerta, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, and Sunesis. RD has served as a consultant for Acerta Pharma; was formerly employed by Gilead; is currently employed by Juno Therapeutics (BMS); and owns stock in Gilead Sciences, Bristol-Myers-Squibb, and Forty Seven. LG has served as an independent contractor for Gilead; and is employed by Gilead. VM worked as an employee of Gilead while the work was conducted; is currently employed with Acerta Pharma; and owns stock in Astra-Zeneca and Gilead Sciences. TR has served in an advisory role for Gilead; received honoraria from Gilead; and received research funding from Gilead. PH has received honoraria from Janssen and Abbvie; received research funding from Janssen, Abbvie, Pharmacyclics, Gilead, Roche, Apellis; and has served on an advisory board for Janssen, Abbvie, and Alexion.

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Brown, J.R., Zelenetz, A., Furman, R. et al. Risk factors for grade 3/4 transaminase elevation in patients with chronic lymphocytic leukemia treated with idelalisib. Leukemia 34, 3404–3407 (2020). https://doi.org/10.1038/s41375-020-0974-y

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