Comorbidity in risk and outcome of hematological malignancies

Abstract: Hematological malignancies are a group of neoplasms that originate from the bone marrow or lymphatic tissues representing close to 10% of the overall cancer burden in the world. Clinical course, prognosis and survival varies greatly from very aggressive disease requiring intensive systemic chemotherapy-based treatment to indolent forms without need of therapy at diagnosis. Patients are typically diagnosed at old age and may have other comorbid diseases that have to be taken into account for optimal treatment and care. Comorbid diseases may constitute risk factors for the development of subtypes of hematological malignancies, and/or determinants of complications and death. The aim of this thesis was to evaluate the association and impact of comorbid diseases on mortality in leukemia, myeloma and lymphoma, risk of suicidal behavior and death following diagnoses of hematological malignancies, especially considering mental comorbidity, and finally evaluating appendectomy as a potential risk factor for hematological malignancy of lymphoid origin. The study cohorts of the four papers in this thesis were created by linkage between Swedish national health care registers (studies I-III) and the national Swedish quality register for lymphoma (study IV). In study I, we evaluated risk of attempted and completed suicide in a cohort of 46,309 patients diagnosed with lymphoma, myeloma or leukemia in Sweden 1992-2009 compared with a set of cancer-free individuals using Poisson regression. The relative risk of completed suicide was 3.5-fold increased among patients with myeloma and 1.9-fold increased among patients with lymphoma but not significantly increased among patients with leukemia. Risk of attempted suicide was also increased among patients with myeloma and lymphoma. History of mental disorders conferred highly increased risks. Next (study II), we evaluated the association and impact of comorbidity in general and specific comorbid diseases (defined according to the Charlson index) on all-cause and cancer-specific mortality in patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML) or myeloma, accounting for competing risks in analyses of cancer-specific death. Comorbidity was associated with increased all-cause as well as cancer-specific mortality. Disorders associated with higher cancer-specific mortality were renal disease (in AML, CML, myeloma), cerebrovascular conditions, dementia, psychiatric disease (AML, myeloma), liver and rheumatic disease (AML), cardiovascular and pulmonary disease (myeloma). In study III, we evaluated the association between comorbid disease history and lymphoma characteristics, treatment selection and lymphoma-specific mortality among patients with diffuse large B-cell lymphoma (DLBCL), an aggressive lymphoma subtype. Comorbid patients had a significantly higher relative probability of presenting with low performance status compared with patients without comorbidity, and a lower relative probability of receiving curative treatment, leading to increased risks of all-cause as well as lymphoma-specific death. Among patients selected for curative treatment, comorbid disease was associated with all-cause but not lymphoma-specific death. Finally, in study IV, in light of mixed results in previous studies, we examined risk of lymphoid neoplasms in a cohort of 337,437 appendectomized patients <60 years of age in Sweden 1975-2009. We did not observe any clear associations between appendectomy and risk of non-Hodgkin lymphoma overall or major subtypes, myeloma or acute lymphoblastic leukemia. An increased risk of Hodgkin lymphoma was noted among patients diagnosed with appendicitis and for the nodular sclerosis subtype of HL, which could reflect a true association, or shared susceptibility to infection/inflammation among individuals prone to develop HL.