The heart and science of medicine. UVMHealth.org/CancerCenter Enhancing the Khorana score: traditional VTE risk factors are important in predicting long term VTE risk in cancer outpatients initiating chemotherapy Daniel Douce MD Steven Ades MD, MSc Chris Holmes MD, PhD Mary Cushman MD, MSc Charles MacLean MD Neil Zakai MD, MSc American Society of Hematology Conference Atlanta, Georgia December 10th, 2017

Disclosures No disclosures to report

Background Individuals with cancer are at risk of Venous Thromboembolism (VTE) One fifth of all VTE occurs in patients with cancer¹ Second leading cause of death in patients with cancer² Khorana et al³ were instrumental in publishing a prediction model for VTE but has several limitations: 6 month VTE risk only Targeted enrollment of specific tumor types, chemotherapy Convenience sample Lee, A. Y. (2005). "Management of thrombosis in cancer: primary prevention and secondary prophylaxis." Br J Haematol 128(3): 291-302. Sorensen, H. T., et al. (2000). "Prognosis of cancers associated with venous thromboembolism." N Engl J Med 343(25): 1846-1850. Khorana, A. A., et al. (2008). "Development and validation of a predictive model for chemotherapy-associated thrombosis." Blood 111(10): 4902- 4907.

Khorana score Patient characteristic Points Very high risk cancer (stomach, pancreas) 2 High risk (lung, lymphoma, gynecologic, bladder, testicular 1 Pre-chemotherapy platelet count 350 x10⁹/L or more Hemoglobin level less than 10 g/dl, or use of red cell growth factors Pre-chemotherapy leukocyte count more than 11 x10⁹/L BMI 35 kg/m² or more Score ≥3=high risk, 2=intermediate risk, 0-1=low risk Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907

Aims Are age, sex, prior VTE and hospitalization risk factors for VTE in people with cancer? Do traditional factors enhance the Khorana Score?

Methods All individuals starting chemotherapy at University of Vermont Cancer Center from 2012-2014 Included internal jugular vein & portal vein thromboses, as well as superficial thrombophlebitis treated with full anticoagulation Prior history of VTE defined as occurring more than 90 days prior to starting chemotherapy Case ascertainment: VTE screened for using ICD-9 codes and confirmed by clinical chart review by a physician.

Analysis Traditional VTE risk factors (Age, Sex, VTE history) assessed in univariate analysis Logistic regression: 6 month interval since starting chemotherapy Cox proportional hazard ratios over the 3 year observation period Khorana score assessed using both Logistic regression and Cox models Traditional VTE risk factors adjusted for covariates derived from the Khorana score Hospitalizations assessed using time-varying covariates using Cox models

Results 1583 patients in the cohort 187 (11.8%) VTE events 64% of VTE events occurred within 6 months of starting chemotherapy 40% with lower extremity DVT 37% with PE 11% with both PE and DVT 6% with upper extremity DVT 5% with Portal Vein or IVC thrombus

Results Developed VTE No VTE Patient characteristic Mean age (SD) 61 (12) 60 (14) Sex (% male) 52.3 47.3 Mean Baseline BMI (SD) 32.6 (12.3)* 30.8 (11.4)* Hospitalizations (per person-year) 1.408** 0.829** Type of cancer (%): Lung 26 (13.9) 160 (11.5) Breast 12 (6.4)** 217 (15.5)** Gastrointestinal (colorectal, pancreas, biliary, stomach, esophagus, liver) 49 (26.2)** 221 (15.8)** Genitourinary (prostate, kidney, urothelial, bladder, testicular) 20 (10.7) 102 (7.3) Gynecologic (ovarian, uterine, cervical) 13 (7.0) 92 (6.6) Hematologic (leukemia, lymphoma, myeloma, myelodysplastic syndrome) 41 (22) 387 (27.8) Other (includes head & neck, brain, melanoma, sarcoma) 212 (15.2) * P < 0.05 ** P< 0.01

Traditional Risk Factors Odds Ratio (OR) and Hazard Ratios (HR) 95% Confidence interval (CI) Risk Factors for 6- Month Rate of VTE (129 VTE) OR (95% CI) Risk Factors for Incidence of VTE over 3 year period (187 VTE) HR (95% CI) Age (per 10 years older) 1.08 (0.95, 1.24) 1.04 (0.95, 1.15) Male Sex 1.36 (0.95, 1.96) 1.59 (1.21, 2.08) Prior history of VTE 1.46 (0.76, 2.82) 2.17 (1.44, 3.25)

Factors in Khorana Score Risk Factors for 6- Month Rate of VTE OR (95% CI) Risk Factors for Incidence of VTE over 3 year period HR (95% CI) High risk cancer type 1.61 (1.22, 2.11) 1.43 (1.16, 1.76) Platelets ≥ 350 x 109/L 1.09 (0.67, 1.78) 0.88 (0.59, 1.31) Hgb <10 g/dL 1.44 (0.91, 2.27) 1.78 (1.28, 2.47) WBC ≥ 11 x 109/L 1.16 (0.76, 1.78) 1.17 (0.85, 1.63) BMI ≥ 35 kg/m2 1.73 (1.16, 2.59) 1.21 (0.89, 1.65)

Unadjusted Hazard Ratio Hospitalizations Unadjusted Hazard Ratio HR (95% CI) Adjusted for Khorana Risk Factors HR (95% Cl) Hospitalization only 1.75 (0.72, 4.28) 1.30 (0.47, 3.51) Hospitalization +30 days 3.09 (2.12, 4.51) 2.87 (1.97, 4.20) Hospitalization + 90 days 2.87 (2.06, 4.00) 2.69 (1.92, 3.75)

Addition of Traditional Risk Factors to Khorana Score Risk Factors for 6- Month VTE Risk, Adjusting for Khorana Score OR (95% CI) Risk Factors for Incidence of VTE over 3 year period, Adjusting for Khorana Score HR (95% CI) Age (per 10 years older) 1.08 (0.94, 1.24) 1.05 (0.95, 1.16) Male Sex 1.36 (0.94, 1.96) 1.57 (1.21, 2.07) Prior history of VTE 1.41 (0.73, 2.75) 2.12 (1.41, 3.18)

Does adding male sex and prior VTE ‘enhance’ the Khorana score? C-Statistic for Khorana score in first 6 months: 0.61 (95% CI 0.56, 0.65) C-index for Khorana score over 3 years: 0.59 C-index for Khorana score + male sex and VTE history: 0.61

Conclusions Addition of traditional VTE risk factors to the Khorana score does not improve predictive accuracy in the first 6 months of therapy Traditional risk factors of male sex and prior VTE history significantly impact VTE incidence after the first 6 months Recent hospitalizations were a stronger predictor of VTE risk than any other variable evaluated Risk of cancer-related VTE varies over time, risk needs to be re-evaluated over the course of a patient’s treatment

Limitations Retrospective Data: Administrative database using ICD-9 codes: chance of misclassification Limited to patients starting chemotherapy, not all cancer patients Could not adjust for performance status VTE events at outside hospitals may have been missed Single institution study

Acknowledgements Jeffords Institute for Quality, The UVM Medical Center Supported in part by an educational grant from the Lake Champlain Cancer Research Organization Inc.

Risk Factors for 6-Month Incidence of VTE Risk Factors for Incidence of VTE over 3 year observation period Unadjusted Odds Ratio Odds Ratio adjusted for Khorana Risk Factors Hazard Ratio Hazard ratio Adjusted for Khorana Risk Factors 129 VTE events within 6 months 187 VTE events over 3 years Khorana Score Components High risk cancer type 1.61 (1.22, 2.11) 1.43 (1.16, 1.76) Platelets ≥ 350 x 109/L 1.09 (0.67, 1.78) 0.88 (0.59, 1.31) Hgb <10 g/dL 1.44 (0.91, 2.27) 1.78 (1.28, 2.47) WBC ≥ 11 x 109/L 1.16 (0.76, 1.78) 1.17 (0.85, 1.63) BMI ≥ 35 kg/m2 1.73 (1.16, 2.59) 1.21 (0.89, 1.65) Traditional Risk Factors Age (per 10 years older) 1.08 (0.95, 1.24) 1.08 (0.94, 1.24) 1.04 (0.95, 1.15) 1.05 (0.95, 1.16) Male Sex 1.36 (0.95, 1.96) 1.36 (0.94, 1.96) 1.59 (1.21, 2.08) 1.57 (1.21, 2.07) Prior history of VTE 1.46 (0.76, 2.82) 1.41 (0.73, 2.75) 2.17 (1.44, 3.25) 2.12 (1.41, 3.18) Hospitalization Hospitalization + 90 days 2.87 (2.06, 4.00) 2.69 (1.92, 3.75) Hospitalization +30 days 3.09 (2.12, 4.51) 2.87 (1.97, 4.20) Hospitalization only 1.75 (0.72, 4.28) 1.30 (0.47, 3.51)