Abstract
Comorbid conditions are highly prevalent in chronic lymphocytic leukemia (CLL), nevertheless, detailed information on the association of specific comorbidities with CLL prognosis is missing. Using Danish, nation-wide registers, we followed consecutive patients from CLL-diagnosis in 1997–2018, until death or end of follow-up. Sub-grouping of comorbidities was defined using a modified Charlson comorbidity index. Patients were matched on sex, date of birth (±1 month), and region of residency with up to ten comparators from the general population. In total, 9170 patients with CLL were included in the study, with a median of 5.0 years of follow-up. All comorbid conditions studied were individually associated with increased mortality, and many also with increased cause-specific mortality, related or unrelated to CLL. Comorbidity correlated with increased mortality from infections and cardiovascular disease. CLL patients, particularly older, had a significant loss of lifetime compared with the general population. This study highlights a large subgroup of comorbid CLL patients with an unmet treatment-need and missing efficacy and safety data on treatment, who are under-prioritized in clinical trials. Also, studies assessing interventions that may provide better tolerability of treatment in older or comorbid patients, with cancer in general, and CLL in particular, are warranted.
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References
da Cunha-Bang C, Simonsen J, Rostgaard K, Geisler C, Hjalgrim H, Niemann CU. Improved survival for patients diagnosed with chronic lymphocytic leukemia in the era of chemo-immunotherapy: a Danish population-based study of 10455 patients. Blood. Cancer J. 2016;6:e499.
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;379:2517–28.
Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:43–56.
Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225–36.
Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, Borthakur G, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380:2095–103.
Shanafelt TD, Wang XV, Kay NE, Hanson CA, O’Brien S, Barrientos J, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432–43.
GBD 2017 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2018;392:1859–922.
Noone A, Howlader N, Krapcho M, Miller D, Brest A, Yu M, et al. SEER cancer statistics review, 1975–2015, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2015/, based on November 2017 SEER data submission, posted to the SEER web site, April 2018.
Strati P, Parikh SA, Chaffee KG, Kay NE, Call TG, Achenbach SJ, et al. Relationship between co-morbidities at diagnosis, survival and ultimate cause of death in patients with chronic lymphocytic leukaemia (CLL): a prospective cohort study. Br J Haematol. 2017;178:394–402.
Rigolin GM, Cavallari M, Quaglia FM, Formigaro L, Lista E, Urso A, et al. In CLL, comorbidities and the complex karyotype are associated with an inferior outcome independently of CLL-IPI. Blood. 2017;129:3495–8.
Thurmes P, Call T, Slager S, Zent C, Jenkins G, Schwager S, et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2008;49:49–56.
Conrad N, Judge A, Tran J, Mohseni H, Hedgecott D, Crespillo AP, et al. Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals. Lancet. 2018;391:572–80.
Zghebi SS, Steinke DT, Carr MJ, Rutter MK, Emsley RA, Ashcroft DM. Examining trends in type 2 diabetes incidence, prevalence and mortality in the UK between 2004 and 2014. Diabetes Obes Metab. 2017;19:1537–45.
Green A, Sortso C, Jensen PB, Emneus M. Incidence, morbidity, mortality, and prevalence of diabetes in Denmark, 2000–2011: results from the diabetes impact study 2013. Clin Epidemiol. 2015;7:421–30.
Mayer-Davis EJ, Lawrence JM, Dabelea D, Divers J, Isom S, Dolan L, et al. Incidence trends of type 1 and type 2 diabetes among youths, 2002–2012. N Engl J Med. 2017;376:1419–29.
Kingston A, Robinson L, Booth H, Knapp M, Jagger C. Projections of multi-morbidity in the older population in England to 2035: estimates from the population ageing and care simulation (PACSim) model. Age Ageing. 2018;47:374–80.
Baumann T, Delgado J, Santacruz R, Martinez-Trillos A, Royo C, Navarro A. et al. Chronic lymphocytic leukemia in the elderly: clinico-biological features, outcomes, and proposal of a prognostic model. Haematologica. 2014;99:1599–604.
Reyes C, Satram-Hoang S, Hoang K, Momin F, Guduru SR, Skettino S. What is the impact of comorbidity burden on treatment patterns and outcomes in elderly chronic lymphocytic leukemia patients?. Blood. 2012;120:758
Manda S, James S, Wang R, Krishnan R, Danilov AV. Impact of comorbidities on treatment outcomes in chronic lymphocytic leukemia: a retrospective analysis. Blood. 2014;124:1312.
Gordon MJ, Churnetski M, Alqahtani H, Rivera X, Kittai A, Amrock SM, et al. Comorbidities predict inferior outcomes in chronic lymphocytic leukemia treated with ibrutinib. Cancer. 2018;124:3192–200.
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;114:3382–91.
Goede V, Cramer P, Busch R, Bergmann M, Stauch M, Hopfinger G, et al. Interactions between comorbidity and treatment of chronic lymphocytic leukemia: results of German chronic lymphocytic leukemia study group trials. Haematologica. 2014;99:1095–100.
Michallet AS, Cazin B, Bouvet E, Oberic L, Schlaifer D, Mosser L, et al. First immunochemotherapy outcomes in elderly patients with CLL: a retrospective analysis. J Geriatr Oncol. 2013;4:141–7.
Strugov V, Stadnik E, Virts Y, Andreeva T, Zaritskey A. Impact of age and comorbidities on the efficacy of FC and FCR regimens in chronic lymphocytic leukemia. Ann Hematol. 2018;97:2153–61.
Vojdeman FJ, Van’t Veer MB, Tjonnfjord GE, Itala-Remes M, Kimby E, Polliack A, et al. The HOVON68 CLL trial revisited: performance status and comorbidity affect survival in elderly patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2017;58:594–600.
Schmidt M, Schmidt SAJ, Adelborg K, Sundboll J, Laugesen K, Ehrenstein V, et al. The Danish health care system and epidemiological research: from health care contacts to database records. Clin Epidemiol. 2019;11:563–91.
Pedersen CB. The Danish civil registration system. Scand J Public Health. 2011;39(7 Suppl):22–5.
Gjerstorff ML. The Danish cancer registry. Scand J Public Health. 2011;39(7 Suppl):42–5.
da Cunha-Bang C, Geisler CH, Enggaard L, Poulsen CB, de Nully Brown P, Frederiksen H, et al. The Danish national chronic lymphocytic leukemia registry. Clin Epidemiol. 2016;8:561–5.
Schmidt M, Pedersen L, Sorensen HT. The Danish civil registration system as a tool in epidemiology. Eur J Epidemiol. 2014;29:541–9.
Lynge E, Sandegaard JL, Rebolj M. The Danish national patient register. Scand J Public Health. 2011;39(7 Suppl):30–3.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83.
Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011;173:676–82.
Hansen DL, Moller S, Andersen K, Gaist D, Frederiksen H. Evans syndrome in adults—incidence, prevalence, and survival in a nationwide cohort. Am J Hematol. 2019;94:1081–90.
Ewertz M, Land LH, Dalton SO, Cronin-Fenton D, Jensen MB. Influence of specific comorbidities on survival after early-stage breast cancer. Acta Oncol. 2018;57:129–34.
Wasterlid T, Mohammadi M, Smedby KE, Glimelius I, Jerkeman M, Bottai M, et al. Impact of comorbidity on disease characteristics, treatment intent and outcome in diffuse large B-cell lymphoma: a Swedish lymphoma register study. J Intern Med. 2018;285:455–68.
Plana-Ripoll O, Pedersen CB, Holtz Y, Benros ME, Dalsgaard S, de Jonge P, et al. Exploring comorbidity within mental disorders among a danish national population. JAMA Psychiatry. 2019;76:259–70.
Valderas JM, Starfield B, Sibbald B, Salisbury C, Roland M. Defining comorbidity: implications for understanding health and health services. Ann Fam Med. 2009;7:357–63.
Helweg-Larsen K. The Danish register of causes of death. Scand J Public Health. 2011;39(7 Suppl):26–9.
Miller MD, Towers A. A manual of guidelines for scoring the cumulative illness rating scale for geriatrics (CIRS-G).
Salvi F, Miller MD, Grilli A, Giorgi R, Towers AL, Morichi V, et al. A manual of guidelines to score the modified cumulative illness rating scale and its validation in acute hospitalized elderly patients. J Am Geriatr Soc. 2008;56:1926–31.
Jorgensen TL, Hallas J, Friis S, Herrstedt J. Comorbidity in elderly cancer patients in relation to overall and cancer-specific mortality. Br J Cancer. 2012;106:1353–60.
Raji MA, Kuo YF, Freeman JL, Goodwin JS. Effect of a dementia diagnosis on survival of older patients after a diagnosis of breast, colon, or prostate cancer: implications for cancer care. Arch Intern Med. 2008;168:2033–40.
Gupta SK, Lamont EB. Patterns of presentation, diagnosis, and treatment in older patients with colon cancer and comorbid dementia. J Am Geriatr Soc. 2004;52:1681–7.
Khan AE, Gallo V, Linseisen J, Kaaks R, Rohrmann S, Raaschou-Nielsen O, et al. Diabetes and the risk of non-Hodgkin’s lymphoma and multiple myeloma in the European prospective investigation into cancer and nutrition. Haematologica. 2008;93:842–50.
Wideroff L, Gridley G, Mellemkjaer L, Chow WH, Linet M, Keehn S, et al. Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst. 1997;89:1360–5.
Sogaard M, Thomsen RW, Bossen KS, Sorensen HT, Norgaard M. The impact of comorbidity on cancer survival: a review. Clin Epidemiol. 2013;5(Suppl 1):3–29.
Delgado J, Pratt G, Phillips N, Briones J, Fegan C, Nomdedeu J, et al. Beta2-microglobulin is a better predictor of treatment-free survival in patients with chronic lymphocytic leukaemia if adjusted according to glomerular filtration rate. Br J Haematol. 2009;145:801–5.
Al-Sawaf O, Bahlo J, Robrecht S, Fischer K, Herling CD, Hoechstetter M, et al. Outcome of patients aged 80 years or older treated for chronic lymphocytic leukaemia. Br J Haematol. 2018;183:727–35.
Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, 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;17:928–42.
Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011;29:3457–65.
Furstenau M, Hallek M, Eichhorst B. Sequential and combination treatments with novel agents in chronic lymphocytic leukemia. Haematologica. 2019;104:2144–54.
Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LF, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015;29:1602–4.
Fischer K, Ritgen M, Al-Sawaf O, Robrecht S, Tandon M, Fink AM, et al. Quantitative analysis of minimal residual disease (MRD) shows high rates of undetectable MRD after fixed-duration chemotherapy-free treatment and serves as surrogate marker for progression-free survival: a prospective analysis of the randomized CLL14 trial. Blood. 2019;134(Supplement_1):36.
Rotbain EC, Frederiksen H, Hjalgrim H, Rostgaard K, Egholm GJ, Zahedi B, et al. IGHV mutational status and outcome for patients with chronic lymphocytic leukemia upon treatment: a Danish nationwide population-based study. Haematologica. 2020;105:1621–9.
Andersen MA, Moser CE, Lundgren J, Niemann CU. Epidemiology of bloodstream infections in patients with chronic lymphocytic leukemia: a longitudinal nation-wide cohort study. Leukemia 2019;33:662–70.
Nabhan C, Mato A, Flowers CR, Grinblatt DL, Lamanna N, Weiss MA, et al. Characterizing and prognosticating chronic lymphocytic leukemia in the elderly: prospective evaluation on 455 patients treated in the United States. BMC Cancer. 2017;17:198.
Morrison VA. Infectious complications in patients with chronic lymphocytic leukemia: pathogenesis, spectrum of infection, and approaches to prophylaxis. Clin Lymphoma Myeloma. 2009;9:365–70.
Da Cunha-Bang C, Agius R, Kater AP, Levin MD, Österborg A, Mattsson M, et al. PreVent-ACaLL Short-term combined acalabrutinib and venetoclax treatment of newly diagnosed patients with CLL at high risk of infection and/or early treatment, who do not fulfil IWCLL treatment criteria for treatment. A randomized study with extensive immune phenotyping. Blood. 2019;134 (Supplement_1):4304.
Johansson LA, Bjorkenstam C, Westerling R. Unexplained differences between hospital and mortality data indicated mistakes in death certification: an investigation of 1094 deaths in Sweden during 1995. J Clin Epidemiol. 2009;62:1202–9.
Acknowledgements
This study was supported in part by grants from Novo Nordisk Foundation grant NNF16OC0019302 and AstraZeneca to CUN and Neye Fonden to HHJ. AstraZeneca was provided with the opportunity to prospectively review the manuscript. The funding sources had no role in the study design, collection, analysis, or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication.
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ECR and KR conducted the data management and analyzed the data. ECR and HF wrote the first draft of the paper. All authors contributed to the study concept and design, writing of the manuscript, and approved the final paper.
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ECR received consultancy fees or travel grants from Abbvie, Janssen, and AstraZeneca. HF received support outside this work from Alexion, Gilead, Abbvie, Janssen Pharmaceuticals, and Novartis. CC-B received consultancy fees and/or travel grants from Abbvie, and Gilead. CUN received support from Novo Nordisk Foundation NNF16OC0019302 and AstraZeneca within this work. CUN received support, consultancy fees, or travel grants from Abbvie, Gilead, Janssen, Roche, CSL Behring, Acerta, Genmab, Sunesis, and Astra Zeneca outside this work. HHJ received support from Neye Fonden outside this work. KR reports no conflicts of interest.
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Rotbain, E.C., Niemann, C.U., Rostgaard, K. et al. Mapping comorbidity in chronic lymphocytic leukemia: impact of individual comorbidities on treatment, mortality, and causes of death. Leukemia 35, 2570–2580 (2021). https://doi.org/10.1038/s41375-021-01156-x
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DOI: https://doi.org/10.1038/s41375-021-01156-x
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