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Second malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era
Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. (Sundsvall Research Unit, Umeå University)
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2015 (Engelska)Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 169, nr 5, s. 683-688Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Given that tyrosine kinase inhibitors (TKIs) have dramatically improved the survival of patients with chronic myeloid leukaemia (CML), we were interested in examining the possible risk of long-term adverse events, such as the emergence of other neoplasms. Therefore, we studied the development of second malignancies in 868 patients diagnosed with CML between 2002 and 2011 using the Swedish CML register, cross-linked to the Swedish Cancer register. With a median follow-up of 3·7 (range 0-9·9) years, 65 (7·5%) patients developed 75 second malignancies (non-haematological), 52 of which were of the invasive type. Compared to expected rates in the background population, the risk of second malignancies was higher in the CML cohort, with a standardized incidence ratio (SIR) of 1·52 (95% CI 1·13-1·99). The SIR before and after the second year following diagnosis of CML was 1·58 and 1·47, respectively. Among specific cancer types, gastrointestinal and nose and throat cancer were significantly increased. Founded on a population-based material, our results indicate that CML patients treated in the TKI era are at an increased risk of developing a second malignancy, with indications that this risk may more likely be linked to CML itself rather than to the TKI treatment.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2015. Vol. 169, nr 5, s. 683-688
Nyckelord [en]
chronic myeloid leukaemia, malignancy, treatment
Nationell ämneskategori
Hematologi
Identifikatorer
URN: urn:nbn:se:umu:diva-103945DOI: 10.1111/bjh.13346ISI: 000354489800009PubMedID: 25817799Scopus ID: 2-s2.0-84929234796OAI: oai:DiVA.org:umu-103945DiVA, id: diva2:816796
Tillgänglig från: 2015-06-04 Skapad: 2015-06-04 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
Ingår i avhandling
1. Chronic myeloid leukemia and cancer
Öppna denna publikation i ny flik eller fönster >>Chronic myeloid leukemia and cancer
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Background

Chronic myeloid leukemia (CML) is a relatively rare hematological malignancy with a constant incidence of approximately 90 new cases each year in Sweden (0.9 cases/100 000 inhabitants). The etiology is largely unknown but high doses of ionizing radiation are a known but rare risk factor. The treatment options were for a long time limited to chemotherapies i.e. hydroxyurea and busulfan, interferon’s and allogeneic hematopoietic stem cell transplantation and the median survival were only about four years.

Since the beginning of the 21st century a new way of treating CML has been introduced, the tyrosine kinase inhibitors (TKI), leading to a rapid decrease in leukemic cells and symptoms. Due to the TKIs, the overall 5-year survival is nowadays approximately 85 % and CML patients have time to develop other diseases, including other malignancies.

The aims of this thesis was to investigate the present and future prevalence of CML and the prevalence of other malignancies prior and subsequent to the diagnosis of CML, malignancies among first-degree relatives of persons with CML. In addition, the incidence of autoimmune and chronic inflammatory diseases among patients with CML was also investigated.

 

Methods

From the Swedish CML register, data over nearly all Swedish CML patients from 2002 and forward were obtained for paper II-IV.

For paper I, the Swedish cancer register was used to identify all Swedish CML patients since 1970 and the Swedish cause of death register was used to identify an eventual date of death for these patients. With a constant incidence and the relative survival rates for CML patients between 2006 and 2012 as a model, the present and future prevalence was calculated.

For paper II-IV, data from the Swedish cancer register was used to identify other malignancies than CML. For paper II, information about autoimmune and chronic inflammatory diseases was retrieved from the Swedish national patient register.

For paper II and IV, five controls matched for year of birth, gender and county of residence were randomly selected from the Swedish register of the total population. To calculate odds ratio (OR), conditional logistic regression was used.

To calculate the risk of a second malignancy for paper III, Standardized incidence ratio (SIR) was used.

In paper IV, first-degree relatives (parents, siblings and offsprings) for both cases and controls were retrieved from the Swedish multi-Generation Register, where persons born later than 1932 and registered in Sweden at some time since 1961 are registered.

 

Results

Prevalence and survival

As shown in paper I, the 5-year overall survival for CML patients increased remarkably from 0.18 to 0.82 between 1970 and 2012. The prevalence increased from 3.9 to 11.9 per 100 000 inhabitants in Sweden between 1985 and 2012. By assuming no further improvements in relative survival as compared to the survival rates between 2006 and 2012, the prevalence by 2060 is expected to increase to 22.0 per 100 000 inhabitants. This corresponds to 2 587 CML patients as compared to 1 137 CML patients in 2012.

 

Malignancies, autoimmune and chronic inflammatory diseases prior to CML

In study II, more than 45 000 person-years of follow-up were evaluated in 984 CML patients diagnosed between 2002 and 2012. With an OR of 1.47 (95 % CI 1.20–1.82) and 1.55 (95 % CI 1.21–1.98), respectively, the prevalence of prior malignancies and autoimmune diseases were significantly increased as compared to matched controls. On the other hand, no association between CML and chronic inflammatory diseases was shown.

 

Second malignancies

In 868 CML patients, diagnosed between 2002 and 2011, 52 malignancies were observed in the Swedish cancer register, as shown in paper III. When compared to expected rates in the background population, a significantly increased risk of second malignancies with a SIR of 1.52 (95 % CI 1.13–1.99) was shown. When looking at specific cancer types, gastrointestinal as well as nose and throat cancer were significantly increased.

 

Familial aggregation of malignancies

984 CML patients were identified in paper IV. However, 184 had a birth date prior to 1932, subsequently only 800 patients were analyzed. Among them, 4 287 first-degree relatives were identified, compared to 20 930 first-degree relatives of the matched controls. 611 malignancies were retrieved; no significant increase of malignancies in first-degree relatives of CML patients was shown (OR 1.06; 95 % CI: 0.96–1.16).

 

Conclusion

Since CML patients nowadays have a high survival rate, the calculations in this thesis shows that the prevalence of CML will almost double by 2060. CML patients have an increased risk of developing malignancies prior and subsequent to the diagnosis of CML, suggesting a hereditary or acquired predisposition to develop cancer. Since there is no familial aggregation of malignancies in CML patients, a hereditary predisposition to develop cancer is unlikely to be part of the pathogenesis of CML, leaving an acquired predisposition more likely.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2017. s. 70
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1925
Nyckelord
Chronic myeloid leukemia, Prevalence, Malignancies, Odds ratio, Standardized Incidence Ratio, Outcome, Autoimmune diseases, Survival
Nationell ämneskategori
Hematologi Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi
Forskningsämne
epidemiologi; medicin
Identifikatorer
urn:nbn:se:umu:diva-141144 (URN)978-91-7601-781-4 (ISBN)
Disputation
2017-11-24, Hörsal D, Unod T9, 9 tr, Norrlands Universitetssjukhus, Umeå, 13:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2017-11-02 Skapad: 2017-10-26 Senast uppdaterad: 2018-06-09Bibliografiskt granskad

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