The Impact of Diabetes on Clinical Outcomes in Chronic Lymphocytic Leukemia

Introduction: Diabetes negatively influences cancer-related outcomes in several malignancies. Previous studies have demonstrated key drivers in the pathogenesis of chronic lymphocytic leukemia (CLL) involving the insulin and insulin-like receptor pathways. We aimed to investigate whether hyperinsulinemic states such as diabetes impact clinical outcomes in CLL patients.

Methods: This is a retrospective cohort study of 291 patients enrolled into a CLL translational clinical trial from 2004-2011 at a single university. Clinical outcomes were evaluated through exhaustive medical record review. Diabetes was classified as Type 1, Type 2, or steroid-induced diabetes requiring therapy. Covariates included Rai stage and intensity of CLL treatment, determined on whether patients had low- or high-intensity regimens. The primary end points were disease-specific and overall survival. Overall survival and disease-specific survival was measured from date of diagnosis to date of death, or date of censoring, which was February 2015. Disease-specific death was defined as death due to infection, CLL progression and/or complication from CLL therapy. Causes of death were verified by 2 independent physician reviewers with expertise in CLL, and dates of death were confirmed by the national death index database. Disease-specific and overall survival was calculated using Kaplan-Meier analysis. Proportional hazards (Cox) regression models were fit to the data using overall or disease-specific survival as endpoints. We also performed a separate parallel survival analysis including only patients who were untreated prior to enrollment. Multivariate analyses were performed incorporating known high-risk CLL features including Rai stage, IgVH mutation status, del11q, del17p, and TP53 mutation status. Cox proportional hazards were used in the multivariate analysis.

Results: Over ten years, 291 CLL patients were enrolled into our study. Of these, 19% had diabetes (Type 2 DM, n = 46, Type 1 DM, n = 2, steroid-induced DM, n = 8). Only 5 patients were treated with low-intensity regimens. Disease-specific survival was significantly shorter in diabetics compared to non-diabetics. The median disease-specific survival in diabetic patients was 128.4 months, compared to non-diabetics, which was not reached (p=0.0068). Overall survival was also significantly shorter in the diabetic patients. The median overall survival in diabetic patients was 124.5 months, compared to 260.0 months in non-diabetic patients (p=0.0002). The majority of deaths in the diabetic cohort (71%) and the non-diabetic cohort (77%) were due to CLL-specific deaths. There was a substantial amount of infection-related deaths in the diabetic cohort (46%) and the non-diabetic cohort (32%). The presence of diabetes retained its significance as a prognostic variable of survival when analyzed against high-risk CLL features.

Table 1:  Multivariate analysis of 236 CLL patients with available data points

Patient variable	Hazard Ratio	p-value	95% CI
Diabetes	2.19	0.001	1.36-3.53
Rai stage	1.29	0.309	0.79-2.08
IgVH unmutated	2.81	0.000	1.74-4.54
Deletion 17p/mTP53	2.30	0.001	1.41-3.76
Deletion 11q	1.29	0.429	0.68-2.45

When analyzing only CLL patients untreated prior to enrollment, diabetes maintained a significantly poorer disease-specific and overall survival- as well as independent prognostic variable status against high-risk CLL features.

Conclusion: Diabetes is associated with significantly worse disease-specific and overall survival among patients with CLL. The 11 year difference in median overall survival is impressive, as the life expectancy of an average diabetic patient at the median age of our cohort is estimated to be 19 to 22 years based on recent national studies. CLL-related deaths comprised the majority of both diabetic and non-diabetic deaths. Diabetes is an independent poor prognostic variable when analyzed against known high-risk features of CLL. Future investigations into other clinical variables, including glycemic control and benefits of therapies with less hematologic toxicity and/or infectious risk, are of interest.