Clinical Features and Outcomes in Adolescents and Young Adults with Philadelphia-Negative Myeloproliferative Neoplasms: Implications for Age-Specific Risk Stratification

Background/Objectives: Adolescents and young adults (AYAs) with Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-negative MPNs) constitute a distinct yet understudied population. We aimed to characterize the clinical features, treatment patterns and outcomes of AYAs with Ph-negative MPNs and to examine whether age group remains associated with thrombosis and survival after adjustment for relevant covariates. Methods: We retrospectively studied 1023 patients with Ph-negative MPNs diagnosed between 1995 and 2022 at two centers, classified as AYA (15–39 years, n = 203) or non-AYA (≥40 years, n = 820). Thrombosis and overall survival were analyzed with multivariable logistic and Cox regression adjusted for sex, MPN subtype, cardiovascular risk factors and JAK2V617F status, and transformation as cumulative incidence with death as a competing event. Results: AYA patients were more often female, more often had essential thrombocythemia, and presented with lower leukocyte counts, higher platelet counts, fewer cardiovascular risk factors (45.3% vs. 77.3%) and a lower frequency of the JAK2V617F mutation (64.0% vs. 72.7%). Arterial thrombosis was less frequent in AYAs (11.3% vs. 30.2%), whereas venous thrombosis (22.2% vs. 10.2%) and splanchnic vein thrombosis (SVT; 14.3% vs. 5.1%) were more frequent, consistently across MPN subtypes. After adjustment, AYA status remained associated with venous thrombosis (odds ratio [OR] 2.88, 95% confidence interval [CI] 1.86–4.47) and SVT (OR 3.81, 95% CI 2.17–6.70) and with lower odds of arterial thrombosis (OR 0.39, 95% CI 0.24–0.63). Cytoreductive therapy was used less often in AYAs, with a preference for interferon over hydroxyurea and ruxolitinib. The 15-year cumulative incidences of leukemic (2.0% vs. 4.9%) and myelofibrotic transformation (1.2% vs. 2.4%) did not differ significantly, although events were few. Mortality was lower (3.0% vs. 22.6%) and overall survival longer in AYAs (adjusted hazard ratio 0.11, 95% CI 0.05–0.24). Conclusions: Within the limits of a retrospective design, AYAs with Ph-negative MPNs display a venous-predominant thrombotic phenotype and favorable survival; these hypothesis-generating findings support the prospective evaluation of age-adapted risk assessment in this population.