A practical tool for predicting outcomes in essential thrombocythemia: Triple (or quadruple) a risk model

Abstract Introduction: Essential thrombocythemia (ET) is generally an indolent disease, but it can be complicated by thrombosis, bleeding, progression to myelofibrosis (MF) and leukemia. As treatment is guided by risk stratification, there is a need for prognostic models with strong predictive value. Triple A(AAA risk model, which incorporates Age at diagnosis, Absolute neutrophil and Absolute lymphocyte counts), is a newly proposed scoring system. In this study, we aimed to evaluate the utility of the Triple A model in ET patients in an independent patient cohort, assess its predictive ability for complications, and explore potential improvements as incorporating absolute monocyte count and neutrophil-to-lymphocyte ratio (NLR) to the model. Methods We retrospectively collected demographic, clinical, and laboratory data of adult patients with ET from five centers. Treatment details, complications including thrombosis, bleeding, MF- and leukemic transformations and survival data were analyzed. Besides the Triple A risk score, prognostic scores including International Prognostic Score for ET (IPSET) for overall survival (OS) and the IPSET-Thrombosis (IPSET-T), and Revised IPSET-T for thrombosis risk were calculated. Monocytosis (accepted as >800 x 106/L) and NLR were evaluated for inclusion into the model. Kaplan Meier method was used to estimated survival probabilities. Model comprasion was performed using Akaike Information Criterion (AIC) , models with lower AIC values were considered to have a better predictive performance. Results A total of 565 patients were included. Median age was 53 years (interquartile range (IQR), 38 – 65 years) and 63.5% of the patients were female. At the time of diagnosis, 330 patients (58.4%) had at least one comorbidity. One hundred thirty-five patients (23.8%) had a history of either arterial or venous thrombosis, while 60 patients (10%) were presented with a history of bleeding. With a median follow-up of 5.99 years (IQR, 2.66 – 10.19 years), 62 patients (10.9%) died and 10.3% (n=58) developed thrombosis, 4.4% (n=25) experienced bleeding, and 5.1% (n=29) progressed to MF and 1% (n=6) to leukemia. Patients with secondary malignancy (n=43) had 1.8 times higher risk of thrombosis compared to those without; however, this difference was not statistically significant (HR:1.8, %95 CI:0.85-3.82, p=0.123). According to Triple A score, 44.2% (n=250), 40.4% (n=228), 6.6% (n=37), and 8.8% (n=50) of the cases were low-, intermediate-1, intermediate-2, and high-risk, respectively. There were significant differences in OS (p<0.001) and thrombosis-free survival (p=0.0003) across risk groups; however, MF-free and bleeding-free survivals remained comparable (p=0.21 and p=0.52, respectively). Among the evaluated risk models, the Triple A score demonstrated the lowest AIC values for both survival (AIC values; Triple A: 583.369, IPSET: 609.328) and thrombosis (AIC values; Triple A: 652.978, Revised IPSET-T: 665.256, IPSET-T: 663.396) prediction. Monocytosis at diagnosis was linked to increased mortality (HR: 1.79, %95 CI: 1.05–3.05, p=0.033) and the strong association between the Triple A risk score and mortality risk was also preserved in this model. Furthermore, according to the logistic regression analysis, its prevalence increased progressively with higher Triple A scores (p<0.001). Patients with monocytosis had significantly increased risk of thrombosis (HR: 1.99, 95% CI: 1.08–3.66, p=0.03), but only intermediate-2 group showed a statically significant increase in thrombotic risk compared to low-risk patients (p=0.01) which indicates the predictive power of this score for thrombosis varied across different risk categories. A higher NLR was associated with a higher risk of mortality (p<0.001), but lost its significance when included in the Triple A score. Conclusion The Triple A score is an effective and user-friendly tool for predicting both survival and thrombosis in ET patients. Its predictive performance for survival surpasses that of the IPSET, and its ability to predict thrombosis is superior to both the Revised IPSET-T and IPSET-T. Incorporation of monocytosis seems to enhance to performance of this score, possibly making it so called “AAA+A or Quadruple A” risk model. NLR may still serve as an independent risk marker for outcomes in patients with ET.