Increased Prevalence of Prior Malignancies and Autoimmune Diseases in Patients Diagnosed with Chronic Myeloid Leukemia
Authors: Gunnarsson Niklas , Hoglund Martin , Stenke Leif , Wallberg Jonsson Solveig , Sandin Fredrik , Bjorkholm Magnus , Dreimane Arta , Lambe Mats , Markevarn Berit , Olsson-Stromberg Ulla , Wadenvik Hans , Richter Johan , Sjalander Anders 
Published: October 2019

Abstract

Background: In a recent, large population-based study we identified an increased risk of a second malignancy in patients following a diagnosis of Chronic Myeloid Leukemia (CML), as compared to an age- and gender-matched control cohort (Gunnarsson et al, Br J Haematol. 2015 Jun; 169(5): 683-8). If CML patients have an increased congenital or acquired susceptibility to develop any cancer, the prevalence of other prior malignancies would be expected to be increased already at the time of CML diagnosis.
There is a known association between autoimmune disease (AD) or chronic inflammatory disease (CID) and the development of some hematological malignancies. However, to date, studies on the prevalence of AD or CID detected prior to the CML diagnosis are few and inconclusive.
Our aim was to estimate the prevalence of other malignancies, AD or CID in CML patients at or before the time point of the CML diagnosis.
Materials and methods: We used the population-based Swedish CML Register to identify patients diagnosed with CML in Sweden between 2002-2013. This cohort was linked to the Swedish Cancer Register to retrieve information about malignancies reported before the diagnosis of CML and the Swedish National Patient Register to retrieve information about AD and CID.
For each of the 984 patients with CML, five age-, gender- and county of residence-matched controls were selected from the general population. All controls had to be free of CML and alive at the time of CML diagnosis for the corresponding case patient.
Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). We excluded diagnoses registered during the year prior to the CML diagnosis to avoid detection bias. In separate steps, analyses were also performed based on diagnoses of AD, CID or cancer three years before the date of CML diagnosis.
Results: A total of 984 CML patients were assessed with regard to a prior diagnosis of malignancy, AD or CID excluding the year immediately prior to their CML diagnosis, representing more than 45.000 person-years of follow-up. Compared to the matched population controls, the prevalence of prior malignancies and AD were elevated in CML patients: OR 1.47 (95%CI 1.20-1.82) and 1.55 (1.21-1.98), respectively. Breast-, gastrointestinal- and urinary tract cancers and melanomas were common cancer types and were all significantly more prevalent in the CML cohort, table I. After implementing a three-year exclusion period before the date of CML diagnosis, prior malignancies remained more prevalent in CML patients. Assessment of ADs was hampered by small numbers, sarcoidosis was the only AD with increased prevalence: OR 13.43; 95 % CI 3.56 - 50.73. No association was detected between CML and previous CID.
Conclusions: Based on a large population-based cohort, our findings indicate that CML patients have an increased prevalence of other malignancies and AD prior to the diagnosis of CML, suggesting that a hereditary or acquired predisposition to cancer and/or autoimmunity is involved in the pathogenesis of CML.
Table 1. Odds Ratios for malignancies prior to CML among 984 Swedish CML patients diagnosed between 2002 and 2013. Diagnoses of malignancy during the year immediately prior to CML diagnosis excluded to avoid detection bias. Participants Latency More Than 3 YearsBefore CML Diagnosis Variable CMLn=984 Controlsn = 4920 OR 95% CI CMLn=984 Controlsn = 4920 OR 95% CI Overall 128 453 1.47 1.20 - 1.82 113 381 1.55 1.24 - 1.93 Men 58 184 1.61 1.19 - 2.18 50 146 1.75 1.26 - 2.43 Women 70 269 1.32 1.01 - 1.74 63 235 1.36 1.02 - 1.82 Age <60 years 66 221 1.53 1.15 - 2.03 60 209 1.46 1.09 - 1.97 Age ≥ 60 years 62 232 1.36 1.02 - 1.81 53 172 1.57 1.15 - 2.16 Second cancer type Gastrointestinal 21 62 1.71 1.04 - 2.82 19 50 1.92 1.13 - 3.27 Breast 32 88 1.85 1.22 - 2.78 24 65 1.87 1.16 - 3.00 Gynecological 28 132 1.06 0.70 - 1.61 25 130 0.96 0.62 - 1.48 Ear-nose-throat 1 12 0.42 0.05 - 3.20 1 6 0.83 0.10 - 6.93 Endocrine Gland 9 13 3.48 1.49 - 8.17 7 11 3.20 1.24 - 8.27 Lung 1 7 0.71 0.09 - 5.81 1 4 1.25 0.14 - 11.20 Urinary tract 14 37 1.90 1.03 - 3.54 11 29 1.91 0.95 - 3.83 Malignant melanoma 13 32 2.05 1.07 - 3.91 12 21 2.88 1.41 - 5.87 Prostate 20 84 1.19 0.73 - 1.95 18 64 1.41 0.83 - 2.40 Non-Hodgkin Lymphoma 1 7 0.71 0.09 - 5.81 1 4 1.25 0.14 - 11.20 Chronic Lymphatic Leukemia 3 2 7.52 1.25 - 45.06 1 1 5.00 0.31 - 80.07 Polycythemia Vera 1 3 1.67 0.17 - 16.05 1 2 2.50 0.23 - 27.62 Central Nervous System 3 10 1.50 0.41 - 5.47 3 9 1.67 0.45 - 6.18 Testicle 2 3 3.34 0.56 - 20.00 2 2 5.01 0.70 - 35.60

Disclosures
Richter: Ariad: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Sjalander:Novartis: Honoraria.