Excess mortality in younger patients with myeloproliferative neoplasms

Abu-Zeinah, Khalid; Saadeh, Khalil; Silver, Richard T.; Scandura, Joseph M.; Abu‐Zeinah, Ghaith

doi:10.1080/10428194.2022.2070914

Cited by 11 publications

(13 citation statements)

References 8 publications

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“…Based on these investigations, young patients are often classified as low-risk and thus do not need to undergo active therapy. However, a recent study showed a considerable increase in excess mortality among younger patients with MPNs [ 32 ]. In this study, excess mortality was defined as the ratio of the observed mortality in patients with MPNs to the mortality predicted for patients of the same age.…”

Section: Unmet Needs In Current Pv/et Treatmentmentioning

confidence: 99%

Novel therapeutic strategies for essential thrombocythemia/polycythemia vera

Yoon

Won

2023

Blood Res

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Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells; these include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPNs are inflammatory cancers, wherein the malignant clone generates cytokines that sustain the inflammatory drive in a self-perpetuating vicious cycle. The course of MPNs follows a biological continuum, that is, from early cancer stages (ET/PV) to advanced myelofibrosis as well as impending leukemic transformation. MPN-related symptoms, e.g., fatigue, general weakness, and itching, are caused by inflammatory cytokines. Thrombosis and bleeding are also exacerbated by inflammatory cytokines in patients with MPN. Until recently, the primary objective of ET and PV therapy was to increase survival rates by preventing thrombosis. However, several medications have recently demonstrated the ability to modify the course of the disease; symptom relief is expected for most patients. In addition, there is increasing interest in the active treatment of patients at low risk with PV and ET. This review focuses on the ET/PV treatment strategies as well as novel treatment options for clinical development.

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Section: Unmet Needs In Current Pv/et Treatmentmentioning

confidence: 99%

Novel therapeutic strategies for essential thrombocythemia/polycythemia vera

Yoon

Won

2023

Blood Res

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“…Although young patients with MPNs have prolonged survival compared with older patients, they clearly experience symptoms, vascular complications, and disease progression leading to shortened life spans. 10 Given the rarity of pediatric MPNs, there are no studies defining optimal cytoreductive therapy for younger patients. A primary goal for clinicians caring for younger MPN patients is to limit disease-associated complications while minimizing toxicity from therapy.…”

Section: Therapeutic Goals For Young Mpn Patientsmentioning

confidence: 99%

“…One group reported mean time to AML transformation to be about 3 decades, indicating that AML develops in adulthood after years of living with an MPN in those diagnosed as children or young adults 7 . Despite improved survival in older adult cohorts, patients <60 years with MPNs have increased mortality compared to age matched controls (with the leading causes of death in the young PV and ET populations being cardiovascular events and cancers, respectively) 10 …”

Section: Do Young Patients Get Mpns?mentioning

confidence: 99%

Position paper: The time for cooperative group study of ropeginterferon alfa‐2b in young patients with myeloproliferative neoplasms is now

Kucine

Jessup²,

Cooper

et al. 2023

Pediatric Blood & Cancer

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“…Venous thromboembolism and arterial thromboses such as myocardial infarction and strokes remain the leading causes of death in PV 1–3 . The risk of these cardiovascular events (hereafter, collectively referred to as thrombosis) in patients with PV is at least 2-3 fold higher than individuals without PV 4 , and the age-adjusted cardiovascular mortality is almost twice that of the general population 5 . Control of excessive erythropoiesis and use of antiplatelet therapy can reduce thrombosis risk, and these interventions have been the backbone of PV therapy for many decades 1,6,7 .…”

Section: Introductionmentioning

confidence: 99%

“…Control of excessive erythropoiesis and use of antiplatelet therapy can reduce thrombosis risk, and these interventions have been the backbone of PV therapy for many decades 1,6,7 . Nonetheless, thrombosis risk for patients with PV remains well above that observed in healthy controls, indicating that further progress must be made 3,5,8 . Yet, because the near-term thrombosis risk for most patients with PV adherent to the standard-of-care hematocrit < 45% is only ∼1-3% per year 6 , clinical trials designed to reduce thrombosis risk in PV are infeasible.…”

Section: Introductionmentioning

confidence: 99%

Facilitating clinical trials in Polycythemia vera (PV) by identifying patient cohorts at high near-term risk of thrombosis using rich data and machine learning

Abu-Zeinah,

Krichevsky,

Erdos

et al. 2024

Preprint

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Thrombosis remains the leading cause of morbidity and mortality for patients (pts) with polycythemia vera (PV), yet PV clinical trials are not powered to identify interventions that improve thrombosis-free survival (TFS). Such trials are infeasible in a contemporary PV cohort, even when selecting high-risk pts based on Age >60 and thrombosis history, because thousands of patients would be required for a short-term study to meet TFS endpoint. To address this problem, we used artificial intelligence and machine learning (ML) to dynamically predict near-term (1-year) thrombosis risk in PV pts with high sensitivity and positive predictive value (PPV) to enhance pts selection. Our automation-driven data extraction methods yielded more than 16 million data elements across 1,448 unique variables (parameters) from 11,123 clinical visits for 470 pts. Using the AutoGluon framework, the Random Forest ML classification algorithm was selected as the top performer. The full (309-parameter) model performed very well (F1=0.91, AUC=0.84) when compared with the current ELN gold-standard for thrombosis risk stratification in PV (F1=0.1, AUC=0.39). Parameter engineering, guided by Gini feature importance identified the 21 parameters (top-21) most important for accurate prediction. The top-21 parameters included known, suspected and previously unappreciated thrombosis risk factors. To identify the minimum number of parameters required for the accurate ML prediction, we tested the performance of every possible combination of 3-9 parameters from top-21 (>1.6M combinations). High-performing models (F1> 0.8) most frequently included age (continuous), time since dx, time since thrombosis, complete blood count parameters, blood type, body mass index, and JAK2 mutant allele frequency. Having trained at tested over 1.6M practical ML models with a feasible number of parameters (3-9 parameters in top-21 most predictive), it is clear that study cohorts of patients with PV at high near-term thrombosis risk can be identified with high enough sensitivity and PPV to power a clinical trial for TFS. Further validation with external, multicenter cohorts is ongoing to establish a universal ML model for PV thrombosis that would facilitate clinical trials aimed at improving TFS.

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Excess mortality in younger patients with myeloproliferative neoplasms

Cited by 11 publications

References 8 publications

Novel therapeutic strategies for essential thrombocythemia/polycythemia vera

Novel therapeutic strategies for essential thrombocythemia/polycythemia vera

Position paper: The time for cooperative group study of ropeginterferon alfa‐2b in young patients with myeloproliferative neoplasms is now

Facilitating clinical trials in Polycythemia vera (PV) by identifying patient cohorts at high near-term risk of thrombosis using rich data and machine learning

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