Development and External Validation of Thrombosis Lymphoma /Throly/ Score–Interim Analysis

Lymphoma patients are at increased risk of thromboembolic events (TE) but thromboprophylaxis in these patients is largely underused. Actual guidelines recommend Padua and Khorana score For thromboembolic risk estimation in cancer patients. Suggested models are of limited use in lymphoma patients as their development is not based on characteristics specific for this patient population. In this study, we sought to develop and validate a simple model, based on individual clinical and laboratory patient characteristics that would designate lymphoma patients at risk for thromboembolic event. The study population included consecutive patients with a confirmed diagnosis of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL). Data were collected for patients treated in two lymphoma centers in Serbia (derivation and internal validation cohorts) from 2006 to 2014, and for patients treated in four lymphoma centers from USA, France, Spain and Macedonia during 2015 to 2016 (external validation cohort). Data for newly diagnosed and relapsed patients who had completed a minimum of one chemotherapy cycle were collected for all venous and arterial TE events from time of diagnosis to 3 months after the last cycle of therapy. Specific demographic, clinical, and laboratory variables known to be associated with predictive scores were also extracted. Moreover, potential disease-related risk factors were gathered. The model was developed using data from a derivation cohort, which included 1236 patients. Once a final model was defined, patients were divided into low risk and at risk groups. The final model was then assessed in the internal (584 patients) and external validation cohort (n=822 patients). Sixty-five patients (5.3%) in the derivation cohort and 34 (5.8%) patients in the validation cohort developed thromboembolic events. The two cohorts were well balanced with respect to all assessed patient characteristics. The mean patient's age was 53.1 years (range, 15-87 years). Most patients (83%) were newly diagnosed and had advanced stage disease: Ann Arbor stage III, 14.7% and stage IV, 44%. A total of 778 patients (42.7%) had high-grade lymphoma; 351 (19.3%) had low-grade lymphoma; 266 (14.6%) had HL; 156 (8.6%) had other forms; and 269 (14.8%) had CLL/SLL. Of all the patients included in the study, 99 (5.4%) developed at least one TE during the follow-up period. There were 73 patients with venous TE (73.7%), and 25 with arterial TE (25.3%), while 1 patient had both. Patients with aggressive NHL had significantly higher odds of developing TE compared to patients with any other lymphoma type (RR=1.5; 95% CI for RR 1.1-2.4; p=0.027). The incidence of thromboembolism was 81 (5.3%) in the newly diagnosed patients and 18 (6.2%) in relapsed patients. Overall, 35.4% (35/99) of the patients with thromboembolism experienced the event before the start of chemotherapy. The majority of patients (64.6%) had TE events during chemotherapy or within 3 months after chemotherapy. The variables independently associated with risk for thromboembolism in derivation cohort were: previous venous and/or arterial events, mediastinal involvement, BMI>30 kg/m2, reduced mobility, extranodal localization, development of neutropenia and hemoglobin level < 100g/L. For patients classified at risk in derivation cohort, the model produced negative predictive value of 98.5%, positive predictive value of 25.1%, sensitivity of 75.4%, and specificity of 87.5%. The diagnostic performance measures retained similar values in the internal validation cohort. External validation cohort consisted of 248 (30.2%) indolent NHL, 291 (35.4%) agressive NHL, 149 (18%) CLL/SL and 125 (15.2%) HL patients, out of which 60 (7%) patients developed thromboembolic events. For patients classified at risk in external validation cohort, the model produced negative predictive value of 97%, positive predictive value of 15%, sensitivity of 71%, and specificity of 67%. Having in mind previosly mentioned data from interim analysis based we can conclude that developed prognostic Thrombosis Lymphoma - ThroLy score is more specific for lymphoma patients than any other available score targeting thrombosis in cancer patients. Model calibration will be needed based on data from large prospective cohort studies.