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Chronic Lymphocytic Leukemia

Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202

Leukemia volume 35, pages 2854–2861 (2021)Cite this article

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Abstract

Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AEsc) to compare AEs, calculated for each patient by summing over products of reporting period length and grade for each all-cause grade 1–4 AE and dividing by the length of time over which AEs are assessed. A total of 176 patients received BR and 361 ibrutinib alone or with six cycles of rituximab. At 38 months median follow-up, 64% remained on ibrutinib. Median AEsc was higher with BR versus ibrutinib in the first six cycles (7.2 versus 4.9, p < 0.0001). Within ibrutinib arms, median AEsc decreased significantly to 3.7 after six cycles (p < 0.0001). 10% and 14% of BR and ibrutinib patients discontinued treatment for AEs. In ibrutinib arms, cumulative incidence of grade 3 or higher atrial fibrillation, hypertension, and infection (AEs of clinical interest) at 12 months was 4.5%, 17.5%, and 12.8%, respectively, and increased more slowly thereafter to 7.7%, 25.4%, and 20.5% at 36 months. Analytical tools including the AEsc and cumulative incidence of AEs can help to better characterize AE burden over time. ClinicalTrials.gov identifier: NCT01886872.

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Fig. 1: Sample calculation of the AE score for a typical patient receiving bendamustine plus rituximab (BR).
Fig. 2: AE score by treatment group, across all assessments/cycles, the first 6 cycles of treatment, and after 6 cycles of treatment.
Fig. 3: Limited to grade \(3\mbox{/}4\) AEs, AE score by treatment group, across all assessments/cycles, the first 6 cycles, and after 6 cycles.
Fig. 4: Cumulative incidence of atrial fibrillation, hypertension, and infection, by treatment group.
Fig. 5: Progression-free survival from date of off-treatment for AE.

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Acknowledgements

Support: Research reported in this publication was supported in part by National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821, U10CA180882, and U24CA196171, (to the Alliance for Clinical Trials in Oncology), UG1CA232760, UG1CA233180, UG1CA233253, UG1CA233327, UG1CA233331, R35CA198183 (JCB), and R01CA192928 (JCB/JAW), U10CA180863 (CCTG). Also supported in part by Pharmacyclics which provided ibrutinib for the clinical trial. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Those providing support to Alliance for Clinical Trials in Oncology and Alliance Foundation Trials are found at https://acknowledgments.alliancefound.org.

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Author notes

  1. These authors contributed equally: Sumithra J. Mandrekar, Jennifer A. Woyach.

Authors and Affiliations

  1. Division of Hematology, The Ohio State University, Columbus, OH, USA

    Amy S. Ruppert, John C. Byrd & Jennifer A. Woyach

  2. Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA

    Amy S. Ruppert, Allison M. Booth & Sumithra J. Mandrekar

  3. Mayo Clinic, Rochester, MN, USA

    Wei Ding & Mark Litzow

  4. Washington University School of Medicine, St. Louis, MO, USA

    Nancy L. Bartlett

  5. Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA

    Danielle M. Brander & Harry Erba

  6. Stanford University School of Medicine, Stanford, CA, USA

    Steven Coutre

  7. Dana Farber/Partners CancerCare, Boston, MA, USA

    Jennifer R. Brown & Richard M. Stone

  8. Fort Wayne Medical Oncology & Hematology, Fort Wayne, IN, USA

    Sreenivasa Nattam

  9. University of Chicago Comprehensive Cancer Center, Chicago, IL, USA

    Richard A. Larson

  10. University of Calgary, Tom Baker Cancer Centre, Calgary, AB, Canada

    Carolyn Owen

  11. First Health of the Carolinas Cancer Center, Pinehurst, NC, USA

    Charles S. Kuzma

  12. Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Jeremy S. Abramson

  13. Division of Cancer Treatment and Diagnosis, NCI, Bethesda, MD, USA

    Richard F. Little

  14. Loyola University Chicago, Chicago, IL, USA

    Scott E. Smith

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Corresponding author

Correspondence to Amy S. Ruppert.

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Competing interests

The authors would like to disclose conflicts of interest. ASR has acted as a consultant or advisor to Telios Pharma. WD has received clinical research support from Merck. NLB has acted as a consultant or advisor to Seattle Genetics, and has received clinical research support from ADC Therapeutics, Autolus, Bristol-Myers Squibb, Celgene, Forty Seven, Genentech, Immune Design, Janssen, Kite Pharma, Merck, Millennium, Pharmacyclics, and Seattle Genetics. DMB has received honoraria from Genentech, Abbvie, Teva, TG Therapeutics, has acted as a consultant or advisor to Genentech, Abbvie, Novartis Pharma SAS, Pharmacyclics, Teva, TG Therapeutics, has had travel and accommodation expenses paid for by Abbvie, Teva, and TG Therapeutics, and has declared other relationships with Novartis Pharma SAS. SC has stock and other ownership interests in Abbvie/Pharmacyclics, has received honoraria from Janssen Oncology and Pharmacyclics, has acted as a consultant or advisor to Abbie, Adpative Biotechnologies, Astellas Pharma, AstraZeneca, BeiGene, Celgene, Genentech/Roche, Gilead Sciences, Janssen Oncology, Novartis, and Pharmacyclics, has received clinical research support from Abbvie, Acerta Pharma/AstraZeneca, Celgene, Janssen Oncology, Pharmacyclics, and Takeda, provided expert testimony for Genentech, and has had travel and accommodation expenses paid for by Abbvie, BeiGene, Celgene, Genentech, Janssen Oncology, and Pharmacyclics. JRB has received honoraria from Abbvie and Janssen, has acted as a consultant or advisor to Astellas Pharma, AstraZeneca, Celgene, Gilead Sciences, Infinity Pharmaceuticals, Abbvie, Janssen, Pharmacyclics, Redx Pharma, Roche/Genentech, and Sun Pharma and has received clinical research support from Gilead Sciences. RAL has acted as a consultant or advisor to Novartis, Amgen, Ariad/Takeda, Astellas, Celgene/BMS, CVS/Caremark, Epizyme, and MorphoSys, and has received clinical research support from Novartis, Astellas, Celgene, Cellectis, Daiichi Sankyo, Forty Seven, Rafael Pharmaceuticals, and royalties from UpToDate. HE has acted as a consultant or advisor to Agios, Amgen, Astellas Pharma, Celgene, Daiichi Sankyo, Glycomimetics, Immunogen, Incyte, Jazz Pharmaceuticals, Macrogenics, Novartis, Pfizer, and Seattle Genetics, was on a Speakers’ Bureau for Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis, has received clinical research support from Abbvie, has declared other relationships with Celgene and Glycomimetics, and has declared uncompensated relationships with Daiichi Sankyo. ML has acted as a consultant or advisor to Newlink Genetics and Sanofi, and has received clinical research support from Abbvie, Abbvie/Genentech, Actinium Pharmaceuticals, Amgen, Astellas Pharma, Pluristem Therapeutics, and Tolero Pharmaceuticals. JSA has acted as a consultant or advisor to Abbvie, Allogene, Bayer, Bristol-Myers Squibb, Celgene, EMD Serono, Genentech, Gilead Sciences, Janssen, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma, Merck, MorphoSys, Novartis, and Verastem, and has received clinical research support from AI Therapeutics, Celgene, and Seattle Genetics. RMS has received honoraria from DAVA Pharmaceuticals, Medscape, Prime Oncology, and Research to Practice, has acted as a consultant or advisor to Abbvie, Actinium Pharmaceuticals, Ageios, Amgen, argenx, Arog, Astellas Pharma, AstraZeneca, Biolinerx, Celgene, Celgene/Jazz, Cornerstone Pharmaceuticals, Daiichi Sankyo, Gemoab, Macrogenics, Novartis, Otsuka, Pfizer, Roche/Genentech, Stemline Therapeutics, Syntrix, Takeda, Trovagene, and has received clinical research support from Abbvie/Genentech, Agios, and Novartis. JCB has acted as a consultant or advisor to Acerta Pharma, Genentech, Jazz Pharmaceuticals, and Pharmacyclics, and has received clinical research support from Acerta Pharma, Genentech, Janssen, and Pharmacyclics. SJM has acted as a consultant or advisor to Pfizer and Pique and has declared other relationships with BioGene. JAW has acted as a consultant or advisor to ArQule, AstraZeneca, Janssen, and Pharmacyclics, and has received clinical research support from Abbvie, Janssen, Karyopharm Therapeutics, Loxo, MorphoSys, and Verastem. All other authors declare no competing interests.

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Ruppert, A.S., Booth, A.M., Ding, W. et al. Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202. Leukemia 35, 2854–2861 (2021). https://doi.org/10.1038/s41375-021-01342-x

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