Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202
Amy S Ruppert, Allison M Booth, Wei Ding, Nancy L Bartlett, Danielle M Brander, Steven Coutre, Jennifer R Brown, Sreenivasa Nattam, Richard A Larson, Harry Erba, Mark Litzow, Carolyn Owen, Charles S Kuzma, Jeremy S Abramson, Richard F Little, Scott E Smith, Richard M Stone, John C Byrd, Sumithra J Mandrekar, Jennifer A Woyach, Amy S Ruppert, Allison M Booth, Wei Ding, Nancy L Bartlett, Danielle M Brander, Steven Coutre, Jennifer R Brown, Sreenivasa Nattam, Richard A Larson, Harry Erba, Mark Litzow, Carolyn Owen, Charles S Kuzma, Jeremy S Abramson, Richard F Little, Scott E Smith, Richard M Stone, John C Byrd, Sumithra J Mandrekar, Jennifer A Woyach
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.
Conflict of interest statement
Competing Interests
All other authors declare no competing interests.
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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References
- Eichhorst B, Dreyling M, Robak T, Montserrat E, Hallek M. Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2011; 22(Supplement 6): vi50–vi54.
- Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009; 114(16): 3382–3391.
- Eichhorst B, Fink AM, Bahlo J, Busch R, Math D, Kovacs G et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016. July; 17(7):928–942.
- Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P et al. RESONATE-2 Investigators. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015. December 17; 373(25):2425–2437.
- Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W et al. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. N Engl J Med. 2018. December 27; 379(26):2517–2528.
- Hilal T, Gea-Banacloche JC, Leis JF. Chronic lymphocytic leukemia and infection risk in the era of targeted therapies: Linking mechanisms with infections. Blood Rev. 2018. September; 32(5):387–399.
- Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL et al. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018. September; 103(9):1502–1510.
- National Cancer Institute: CTEP. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Bethesda, MD: National Institutes of Health; 2009.
- Fine JP and Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Amer Statist Assoc. 1999; 94(446):496–509.
- Thanarajasingam G, Hubbard JM, Sloan JA, Grothey A. The Imperative for a new approach to toxicity analysis in oncology clinical trials. J Natl Cancer Inst. 2015. October; 107(10).
- Carbini M, Suárez-Fariñas M, Maki RG. A method to summarize toxicity in cancer randomized cinical trials. Clin Cancer Res. 2018. October 15; 24(20):4968–4975.
- Trotti A, Pajak TF, Gwede CK, Paulus R, Cooper J, Forastiere A et al. TAME: development of a new method for summarising adverse events of cancer treatment by the Radiation Therapy Oncology Group. Lancet Oncol. 2007. May 31; 8(7):613–624.
- Lee SM, Hershman DL, Martin P, Leonard JP, Cheung YK. Toxicity burden score: a novel approach to summarize multiple toxic effects. Ann Oncol. 2012. February; 23(2):537–541.
- Le-Rademacher JG, Hillman S, Storrick E, Mahoney MR, Thall PF, Jatoi A et al. Adverse event burden score – a versatile summary measure for cancer clinical trials. Cancers. 2020. November 4; 12(11): 3251.
- Schuurhuizen CS, Verheul HM, Braamse AM, Buffart LM, Bloemendal HJ, Dekker J et al. The predictive value of cumulative toxicity for quality of life in patients with metastatic colorectal cancer during first-line palliative chemotherapy. Cancer Manag Res. 2018. August 29; 10:3015–3021.
- Sivendran S, Latif A, McBride RB, Stensland KD, Wisnivesky J, Haines L et al. Adverse event reporting in cancer clinical trial publications. J Clin Oncol. 2014. January 10; 32(2):83–89.
- Hillman SL, Mandrekar SJ, Bot B, DeMatteo RP, Perez EA, Ballman KV et al. Evaluation of the value of attribution in the interpretation of adverse event data: a North Central cancer treatment group and american college of surgeons oncology group investigation. J Clin Oncol. 2010. June 20; 28(18):3002–3007.
- George GC, Barata PC, Campbell A, Chen A, Cortes JA, Hyman DM et al. Improving attribution of adverse events in oncology clinical trials. Cancer Treat Rev. 2019; 76:33–40.
- Bercusson A, Colley T, Shah A, Warris A, Armstrong-James D. Ibrutinib blocks Btk-dependent NF-ĸB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis. Blood. 2018. November 1; 132(18):1985–1988.
- Rogers KA, Mousa L, Zhao Q, Bhat SA, Byrd JC, El Boghdadly Z et al. Incidence of opportunistic infections during ibrutinib treatment for B-cell malignancies. Leukemia. 2019. October; 33(10):2527–2530.
- Shanafelt TD, Wang V, Kay NE, Hanson CA, O’Brien SM, Barrientos JC et al. Ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia (CLL): extended follow-up from the E1912 trial. Blood. 2019. November 13; 134(Supplement_1):33 (abstract 642).
Source: PubMed