Abstract
Introduction
Tyrosine kinase inhibitors (TKI) have been demonstrated to prolong survival in patients with chronic myeloid leukemia (CML). However, TKIs may be associated with an increased risk of infections. This study compared healthcare resource utilization (HRU) and costs among patients with CML receiving dasatinib or nilotinib, with a focus on infection-related economic outcomes.
Methods
Two large administrative databases were used to identify adult patients newly diagnosed with CML who initiated dasatinib or nilotinib as first- (1L) or second-line (2L) therapy and were classified into the following 1L (dasatinib 1L/nilotinib 1L cohorts) or 2L (dasatinib 2L/nilotinib 2L) cohorts based on the initiated 1L/2L TKI therapy. Infection-related HRU and healthcare costs were compared between cohorts, separately for 1L and 2L.
Results
Cohorts included 1156 patients in the dasatinib 1L and 677 patients in the nilotinib 1L cohorts, 322 patients in the dasatinib 2L, and 207 in the nilotinib 2L cohorts. In 1L and 2L, infection-related HRU was higher for dasatinib than nilotinib cohorts. Infection-related inpatient (IP) days constituted a larger proportion of all-cause IP days in the 1L/2L dasatinib than 1L/2L nilotinib cohorts (dasatinib 1L/2L: 53%/58%; nilotinib 1L/2L: 50%/46%). Compared to the nilotinib cohort, the dasatinib cohort had higher all-cause total costs per patient per year by US$17,901 in 1L and $28,625 in 2L. Of the total cost difference, infection-related were $6048 (34%) in 1L and $28,192 (99%) in 2L, largely driven by IP cost differences (1L/2L: 96%/98%).
Conclusions
Dasatinib was associated with higher HRU and healthcare costs compared to nilotinib, particularly related to infections.
Funding
Novartis Pharmaceutical Corporation.
This is a preview of subscription content, access via your institution.



References
Bartram CR, de Klein A, Hagemeijer A, van Agthoven T, van Kessel AG, Bootsma D, et al. Translocation of c-abl oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1983;306:277.
Apperley JF. Chronic myeloid leukaemia. Lancet. 2015;385(9976):1447–59.
Hochhaus A, Ernst T, Eigendorff E, La Rosee P. Causes of resistance and treatment choices of second- and third-line treatment in chronic myelogenous leukemia patients. Ann Hematol. 2015;94(Suppl 2):S133–40.
Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119(5):1123–9.
Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354(24):2531–41.
Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;26(10):2197–203.
Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251–9.
Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260–70.
Pophali PA, Patnaik MM. The role of new tyrosine kinase inhibitors in chronic myeloid leukemia. Cancer J. 2016;22(1):40–50.
Novartis Pharmaceuticals Canada Inc. TASIGNA® product monograph 2006. https://www.novartis.ca/sites/www.novartis.ca/files/tasigna_scrip_e.pdf. Accessed 6 Jul 2018.
Bristol-Meyers Squibb. Sprycel (dasatinib) Highlights of Prescribing Information Revised November 2017. https://packageinserts.bms.com/pi/pi_sprycel.pdf. Accessed 6 Jul 2018.
Al-Ameri AM, Cortes JE, Kantarjian H, Burton E, Quintas-Cardama A, Jabbour E, et al. infectious events in patients with chronic myeloid leukemia treated with nilotinib as a front line therapy and after imatinib failure. Blood. 2010;116(21):1233.
Reinwald M, Boch T, Hofmann W-K, Buchheidt D. Risk of infectious complications in hemato-oncological patients treated with kinase inhibitors. Biomark Insights. 2015;10(Suppl 3):55–68.
Rodriguez GH, Ahmed SI, Al-akhrass F, Rallapalli V, Safdar A. Characteristics of, and risk factors for, infections in patients with cancer treated with dasatinib and a brief review of other complications. Leuk Lymphoma. 2012;53(8):1530–5.
Sillaber C, Herrmann H, Bennett K, Rix U, Baumgartner C, Bohm A, et al. Immunosuppression and atypical infections in CML patients treated with dasatinib at 140 mg daily. Eur J Clin Invest. 2009;39(12):1098–109.
Chang CS, Tsai CY, Yan SL. Hepatitis B reactivation in patients receiving targeted therapies. Hematology. 2017;22(10):592–8.
Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, Hobson S, et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol. 2007;25(9):1035–44.
Hantschel O, Rix U, Schmidt U, Burckstummer T, Kneidinger M, Schutze G, et al. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. Proc Natl Acad Sci USA. 2007;104(33):13283–8.
Rix U, Hantschel O, Durnberger G, Remsing Rix LL, Planyavsky M, Fernbach NV, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood. 2007;110(12):4055–63.
Manley PW, Drueckes P, Fendrich G, Furet P, Liebetanz J, Martiny-Baron G, et al. Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochim Biophys Acta. 2010;1804(3):445–53.
de Lavallade H, Khoder A, Hart M, Sarvaria A, Sekine T, Alsuliman A, et al. Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling. Blood. 2013;122(2):227–38.
Hayashi Y, Nakamae H, Katayama T, Nakane T, Koh H, Nakamae M, et al. Different immunoprofiles in patients with chronic myeloid leukemia treated with imatinib, nilotinib or dasatinib. Leuk Lymphoma. 2012;53(6):1084–9.
Rohon P, Porkka K, Mustjoki S. Immunoprofiling of patients with chronic myeloid leukemia at diagnosis and during tyrosine kinase inhibitor therapy. Eur J Haematol. 2010;85(5):387–98.
Breccia M, Girmenia C, Latagliata R, Loglisci G, Santopietro M, Federico V, et al. Low incidence rate of opportunistic and viral infections during imatinib treatment in chronic myeloid leukemia patients in early and late chronic phase. Mediterr J Hematol Infect Dis. 2011;3(1):e2011021.
Mattiuzzi GN, Cortes JE, Talpaz M, Reuben J, Rios MB, Shan J, et al. Development of Varicella-Zoster virus infection in patients with chronic myelogenous leukemia treated with imatinib mesylate. Clin Cancer Res. 2003;9(3):976–80.
Birnbaum HG, Morley M, Greenberg PE, Colice GL. Economic burden of respiratory infections in an employed population. CHEST. 2002;122(2):603–11.
Dixon RE. Economic costs of respiratory tract infections in the United States. Am J Med. 1985;78(6):45–51.
Fendrick A, Monto AS, Nightengale B, Sarnes M. The economic burden of non–influenza-related viral respiratory tract infection in the united states. Arch Intern Med. 2003;163(4):487–94.
Spiegel BM, Younossi ZM, Hays RD, Revicki D, Robbins S, Kanwal F. Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment. Hepatology. 2005;41(4):790–800.
Cella D, Jensen SE, Webster K, Hongyan D, Lai JS, Rosen S, et al. Measuring health-related quality of life in leukemia: the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaire. Value Health. 2012;15(8):1051–8.
Latremouille-Viau D, Guerin A, Nitulescu R, Gagnon PS, Joseph GJ, Chen L. Treatment patterns and healthcare costs among newly-diagnosed patients with chronic myeloid leukemia receiving dasatinib or nilotinib as first-line therapy in the United States. J Med Econ. 2017;20(1):63–71.
Smith BD, Liu J, Latremouille-Viau D, Guerin A, Fernandez D, Chen L. Treatment patterns, overall survival, healthcare resource use and costs in elderly Medicare beneficiaries with chronic myeloid leukemia using second-generation tyrosine kinase inhibitors as second-line therapy. Curr Med Res Opin. 2016;32(5):817–27.
Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med. 1999;131(3):207–19.
Kantarjian HM, Deisseroth A, Kurzrock R, Estrov Z, Talpaz M. Chronic myelogenous leukemia: a concise update. Blood. 1993;82(3):691–703.
Kantarjian HM, Keating MJ, Smith TL, Talpaz M, McCredie KB. Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia. Am J Med. 1990;88(1):1–8.
Hantschel O, Rix U, Superti-Furga G. Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib. Leuk Lymphoma. 2008;49(4):615–9.
Kneidinger M, Schmidt U, Rix U, Gleixner KV, Vales A, Baumgartner C, et al. The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils. Blood. 2008;111(6):3097–107.
Schade AE, Schieven GL, Townsend R, Jankowska AM, Susulic V, Zhang R, et al. Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Blood. 2008;111(3):1366–77.
Food and Drug Administration. Highlights of prescribing information SPRYCEL® (dasatinib) 2010. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021986s7s8lbl.pdf. Accessed 24 Jul 2018.
Food and Drug Administration. Highlights of Prescribing Information TASIGNA® (nilotinib) 2010. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022068s004s005lbl.pdf. Accessed 24 Jul 2018.
Gala S, Shah A, Mwamburi M. Economic burden associated with chronic myeloid leukemia (CML) treatments in the United States: a systematic literature review. Value Health 2016;19(7):727.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia, Version 1.2016. https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed 15 Mar 2016.
Chang H, Hung YS, Chou WC. Pneumocystis jiroveci pneumonia in patients receiving dasatinib treatment. Int J Infect Dis. 2014;25:165–7.
Acknowledgements
Funding
Sponsorship for this study and article processing charges were funded by Novartis Pharmaceutical Corporation. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
Medical Writing, Editorial, and Other Assistance
The authors thank Islam Sadek, an employee of Novartis, for review of the data and scientific input. Medical writing assistance was provided by Sara Kaffashian, an employee of Analysis Group Inc. Analysis Group received consulting fees from Novartis for the conduct of this study.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures
Karen Seiter has received consulting fees from Novartis as a consultant. Dominick Latremouille-Viau is an employee of Analysis Group, Inc., which has received consultancy fees from Novartis. Annie Guerin is an employee of Analysis Group, Inc., which has received consultancy fees from Novartis. Irina Pivneva is an employee of Analysis Group, Inc., which has received consultancy fees from Novartis. Patrick Gagnon-Sanschagrin is an employee of Analysis Group, Inc., which has received consultancy fees from Novartis. Briana Ndife is an employee of Novartis. Karen Habucky is an employee of Novartis and owns stocks in Novartis and J&J. Derek H. Tang is an employee of Novartis and owns stocks in Novartis. George J. Joseph is an employee of Novartis and owns stocks in Amgen, Pfizer, and Express Scripts.
Compliance with Ethics Guidelines
Data were de-identified to comply with the confidentiality requirements of the Health Insurance Portability and Accountability Act and the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Therefore, no institutional review was required.
Data Availability
The claims databases used in this study are proprietary. The authors do not have permission to disseminate the data without the vendor’s approval. The study sponsor has purchased access to the databases and the authors have been granted access to the data on a contract per project use. Access to these datasets are available to any other interested parties for a fee set by the vendor.
Author information
Authors and Affiliations
Corresponding author
Additional information
Enhanced digital content
To view enhanced digital content for this article go to https://doi.org/10.6084/m9.figshare.6945575.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Seiter, K., Latremouille-Viau, D., Guerin, A. et al. Burden of Infections Among Chronic Myeloid Leukemia Patients Receiving Dasatinib or Nilotinib: A Real-World Retrospective Healthcare Claims Study in the United States. Adv Ther 35, 1671–1685 (2018). https://doi.org/10.1007/s12325-018-0772-3
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12325-018-0772-3
Keywords
- Chronic myeloid leukemia
- Costs
- Dasatinib
- Infections
- Healthcare resource utilization
- Nilotinib
- Oncology