Increased Risk of Second Hematological and Non-Hematological Malignancies in CLL Patients Treated with Chemotherapy As Compared to Untreated Patients and Matched Controls - Results from a Danish Population Based Study
Authors: Da Cunha-Bang Caspar , Rostgaard Klaus , Simonsen Jacob , Geisler Christian H , Hjalgrim Henrik , Frederiksen Henrik , Grønbæk Kirsten , Niemann Carsten Utoft 
Published: October 2019

Abstract
Background
The management of chronic lymphocytic leukemia (CLL) is in rapid transition and tailored individual therapy is a likely future scenario for those needing treatment. Previous studies of CLL have revealed an increased risk of second cancers. The underlying mechanisms are unclear, but may involve shared risk factors, weakened immune surveillance, and chemotherapy exposure. However, little is known about the impact of CLL treatment on second cancer risk. We followed Danish population-based cohorts of treated and untreated CLL patients and compared their risk of second cancers with that of matched controls.
Methods
All patients registered with a diagnosis of CLL in the Danish Cancer Registry 2002-2013 were included in the analyses. For each CLL patient, we randomly selected 50 CLL-free control persons matched on age and gender from the general population. Patients and controls were followed for new cancers registered in the Danish Cancer Registry 2002-2013 using ICD10 codes. Information about CLL treatment was available from The Danish National Patient Registry allowing us to stratify patients accordingly. Follow up of the patients and controls were done separately for each cancer type without competing risk. Adjusted hazard ratios (HR) and 95% confidence intervals (95%CI) for new cancers by time since CLL diagnosis /matching date for controls were calculated using Cox regression analyses.
Results
Overall, 4,919 CLL patients with a median person-years of follow-up (PYFU) of 3.9 and 245,877 controls with a median PYFU of 4.6 were included. During follow-up, a total of 694 new malignancies, 54 hematological (excluding CLL) and 640 non-hematological, were registered among the CLL patients (eight patients developed both hematological and non-hematological malignancies). This corresponded to increased relative risks for combined groups of hematological (HR, 1.3; 95% CI, 1.0 to 1.7) and of non-hematological (HR, 1.4; 95% CI, 1.3 to 1.5) cancers, respectively, compared to the controls. Chemotherapy treatment was registered for 1,664 (34%) of the CLL patients during follow-up, and this was accompanied by increased relative risks of both hematological cancers excluding CLL (HR, 2.7; 95% CI, 1.9 to 4.1) and non-hematological cancers (HR, 1.8; 95% CI, 1.6 to 2.1). In contrast, risks of hematological cancer were not increased (HR, 0.9; 95% CI, 0.6 to 1.3) and risk of non-hematological cancers only slightly increased (HR, 1.3; 95% CI, 1.1 to 1.4), among untreated CLL patients. In site-specific analyses the increased risk among treated CLL patients pertained to Hodgkin and non-Hodgkin lymphomas, myelodysplastic syndrome, lung, skin, and thyroid cancer with HR's ranging from 1.8 to 13.3.
Conclusions
CLL patients treated with chemotherapy are at increased risk of other hematological and non-hematological malignancies. Increased awareness and possibly cancer screening programs are warranted for CLL patients receiving chemotherapy. Detailed analyses of the role of different types of CLL specific treatments on risk of second cancers based on the Danish Cancer Registry, the Danish National Patient Registry and the Danish National CLL Registry are ongoing.

Disclosures
Geisler: Roche: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy. Niemann:Abbvie: Research Funding; Roche: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; Janssen: Consultancy.