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      An observational study on risk of secondary cancers in chronic myeloid leukemia patients in the TKI era in the United States

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          Abstract

          Introduction

          The treatment with tyrosine kinase inhibitors (TKIs) has drastically improved the outcome of chronic myeloid leukemia (CML) patients. This study was conducted to examine the risk of secondary cancers (SCs) in the CML patients who were diagnosed and treated in the TKI era in the United States.

          Methods

          The surveillance epidemiology and end results (SEER) database was used to identify CML patients who were diagnosed and received treatment during January 2002–December 2014. Standardized incidence ratios (SIRs) and absolute excess risks (AER) were calculated.

          Results

          Overall, 511 SCs (excluding acute leukemia) developed in 9,200 CML patients followed for 38,433 person-years. The risk of developing SCs in the CML patients was 30% higher than the age, sex and race matched standard population (SIR 1.30, 95% CI: 1.2–1.40; p < 0.001). The SIRs for CLL (SIR 3.4, 95% CI: 2–5.5; p < 0.001), thyroid (SIR 2.2, 95% CI: 1.2–3.5; p < 0.001), small intestine (SIR 3.1, 95% CI: 1.1–7; p = 0.004), gingiva (SIR 3.7, 95% CI: 1.2–8.7; p = 0.002), stomach (SIR 2.1, 95% CI: 1.1–3.5; p = 0.005), lung (SIR 1.4, 95% CI: 1.1–1.7; p = 0.006) and prostate (SIR 1.3, 95% CI: 1.02–1.6; p = 0.026) cancer among CML patients were significantly higher than the general population. The risk of SCs was higher irrespective of age and it was highest in the period 2–12 months after the diagnosis of CML. The risk of SCs in women was similar to that of the general population.

          Conclusion

          CML patients diagnosed and treated in the TKI era in the United States are at an increased risk of developing a second malignancy. The increased risk of SCs in the early period after CML diagnosis suggests that the risk of SCs may be increased due to the factors other than TKIs treatment.

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          Most cited references31

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          Comparison of SEER Treatment Data With Medicare Claims

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            Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib.

            Imatinib slows development of chronic myeloid leukemia (CML). However, available information on morbidity and mortality is largely based on sponsored trials, whereas independent long-term field studies are lacking. Consecutive CML patients who started imatinib treatment before 2005 and who were in complete cytogenetic remission (CCyR) after 2 years (± 3 months) were eligible for enrollment in the independent multicenter Imatinib Long-Term (Side) Effects (ILTE) study. Incidence of the first serious and nonserious adverse events and loss of CCyR were estimated according to the Kaplan-Meier method and compared with the standard log-rank test. Attainment of negative Philadelphia chromosome hematopoiesis was assessed with cytogenetics and quantitative polymerase chain reaction. Cumulative incidence of death related or unrelated to CML progression was estimated, accounting for competing risks, according to the Kalbleisch-Prentice method. Standardized incidence ratios were calculated based on population rates specific for sex and age classes. Confidence intervals were calculated by the exact method based on the χ(2) distribution. All statistical tests were two-sided. A total of 832 patients who were treated for a median of 5.8 years were enrolled. There were 139 recorded serious adverse events, of which 19.4% were imatinib-related. A total of 830 nonserious adverse events were observed in 53% of patients; 560 (68%) were imatinib-related. The most frequent were muscle cramps, asthenia, edema, skin fragility, diarrhea, tendon, or ligament lesions. Nineteen patients (2.3%) discontinued imatinib because of drug-related toxic effects. Forty-five patients lost CCyR, at a rate of 1.4 per 100 person-years. Durable (>1 year) negative Philadelphia chromosome hematopoiesis was attained by 179 patients. Twenty deaths were observed, with a 4.8% mortality incidence rate (standardized incidence ratio = 0.7; 95% confidence interval = 0.40 to 1.10, P = .08), with only six (30%) associated with CML progression. In this study, CML-related deaths were uncommon in CML patients who were in CCyR 2 years after starting imatinib, and survival was not statistically significantly different from that of the general population.
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              Tyrosine kinase inhibitor usage, treatment outcome, and prognostic scores in CML: report from the population-based Swedish CML registry.

              Clinical management guidelines on malignant disorders are generally based on data from clinical trials with selected patient cohorts. In Sweden, more than 95% of all patients diagnosed with chronic myeloid leukemia (CML) are reported to the national CML registry, providing unique possibilities to compile population-based information. This report is based on registry data from 2002 to 2010, when a total of 779 patients (425 men, 354 women; median age, 60 years) were diagnosed with CML (93% chronic, 5% accelerated, and 2% blastic phase) corresponding to an annual incidence of 0.9/100,000. In 2002, approximately half of the patients received a tyrosine kinase inhibitor as initial therapy, a proportion that increased to 94% for younger ( 80 years) patients during 2007-2009. With a median follow-up of 61 months, the relative survival at 5 years was close to 1.0 for patients younger than 60 years and 0.9 for those aged 60 to 80 years, but only 0.6 for those older than 80 years. At 12 months, 3% had progressed to accelerated or blastic phase. Sokal, but not European Treatment and Outcome Study, high-risk scores were significantly linked to inferior overall and relative survival. Patients living in university vs nonuniversity catchment areas more often received tyrosine kinase inhibitors up front but showed comparable survival.
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                Author and article information

                Contributors
                Journal
                PeerJ
                PeerJ
                PeerJ
                PeerJ
                PeerJ
                PeerJ Inc. (San Francisco, USA )
                2167-8359
                12 February 2018
                2018
                : 6
                : e4342
                Affiliations
                [1 ]Department of General Internal Medicine, Brigham and Women’s Hospital , Boston, MA, USA
                [2 ]Department of Anesthesia, Maimonides Medical Center , New York, NY, USA
                [3 ]Department of Pediatrics, Maimonides Medical Center , New York, NY, USA
                [4 ]Department of Hematology and Oncology, Yuma Regional Medical Center Cancer Center , Yuma, AZ, USA
                Author information
                http://orcid.org/0000-0003-4379-5651
                http://orcid.org/0000-0002-6262-886X
                Article
                4342
                10.7717/peerj.4342
                5813591
                29456888
                f2082ab7-d3f3-469c-ba71-e5294ef6bcfb
                © 2018 Kumar et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                : 23 October 2017
                : 18 January 2018
                Funding
                Funded by: Foundation of Yuma Regional Medical Center on behalf of the Richard Michael McDaniel Endowment Fund for Cancer Care
                This project was partly funded by the Foundation of Yuma Regional Medical Center on behalf of the Richard Michael McDaniel Endowment Fund for Cancer Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Epidemiology
                Internal Medicine
                Oncology

                cml,tyrosine kinase inhibitors,tki,seer,sir,relative risk,secondary cancers,population based,observational,excess risk

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