Introduction: Essential thrombocythemia (ET) and polycythemia vera (PV) are myeloproliferative

neoplasms (MPN) characterized by clonal thrombocytosis and erythrocytosis, had the risk of progression to myelofibrosis and acute myeloid leukemia. Recent studies had shown that a growing incidence in

adolescent and young adult (AYA) patients between the ages of 15 to 39 years old, who demonstrate distinct clinical trajectories and genomic heterogeneity compared to non-AYA patients.

Methods:This study retrospectively analyzed data from 33 Chinese medical centers, dividing patients into AYA and non-AYA groups. The cohort included 329 AYA and 1,400 non-AYA ET patients, as well as 110

AYA and 264 non-AYA PV patients. A comparison was made across: (1) clinical features (demographics, lab parameters), (2) prognostic outcomes (overall survival, myelofibrosis-free survival, leukemia-free

survival), and (3) genetic profiles based on next-generation sequencing (NGS). Differences between AYA and non-AYA patients, as well as between AYA ET and PV patients, were specifically examined.

Results:AYA ET patients had lower rates of male predominance (35.9% vs. 48.0%, P<0.001),

smoking(10.9% vs. 17.4%, P=0.004), hypertension(16.4% vs. 37.3%, P<0.001), diabetes(5.2% vs. 10.8%,

P=0.002), and prior thrombosis(4.9% vs. 15.1%, P<0.001) . Laboratory findings revealed lower WBC

(8.70×10^9/L vs. 9.00×10^9/L, P=0.035), MPV (9.1 fl vs.9.4 fl, P<0.001), RDW(13.3% vs. 14.0%, P<0.001),

and LDH (223U/L vs. 252U/L, P<0.001), but higher Hb (136g/L vs. 133g/L, P<0.001) and HCT (41.3% vs.

40.8%, P=0.040) . In PV cohorts, AYA patients had higher rates of male predominance (84.5% vs. 63.9%,

P<0.001) , but lower hypertension(28.2% vs. 52.1%, P<0.001), diabetes(4.5% vs. 13.0%, P=0.010), and prior thrombosis(2.7% vs. 16.3%, P=0.001) . Laboratory findings revealed lower WBC (8.03×10^9/L vs.

9.50×10^9/L, P=0.001), PLT (250×10^9/L vs. 317×10^9/L, P=0.005), RDW(13.6% vs. 15.8%, P<0.001), and LDH (244U/L vs. 286U/L, P=0.004). Compared to ET patients, PV AYA patients were diagnosed at an older age (32yr vs. 30yr, P<0.001), with a higher proportion of males (84.5% vs. 35.9%, P<0.001) and smoking (32.7% vs. 10.9%, P<0.001), and a greater of comorbidities such as hypertension (28.2% vs. 16.4%,

P=0.007) and splenomegaly(35.5% vs.19.1%, P<0.001). In addition to HB, HCT, and PLT indices, they also exhibited higher levels of MPV(15.8fl vs. 9.1fl, P<0.001), and LDH (244U/L vs. 223U/L, P=0.028).

In the ET cohort, AYA patients exhibited significantly superior overall survival (15-year OS: 98.2% vs.

90.1%, P=0.006), prolonged myelofibrosis-free survival (15-year OS: 81.6% vs. 60.9%, P=0.007), and

improved leukemia-free survival (15-year OS: 100% vs. 93.7%, P=0.007) to non-AYA patients. In contrast, no significant differences in prognosis were observed between AYA and non-AYA patients in the PV

cohort (P>0.05). Additionally, there were no significant differences in prognosis between AYA patients with ET and those with PV (P>0.05).

The AYA ET cohort had lower JAK2V617F (44.4% vs. 68.2%, P<0.001) but higher CALR (27.7% vs. 14.1%,

P<0.001) and triple-negative rates (27.7% vs. 16.4%, P<0.001). Non-driver mutations like KMT2C (18.3%) and KMTD (11.0%) were more common in AYA patients, while TET2 (29.9%) and DNMT3A (18.8%)

dominated in non-AYA patients. Similarly, the AYA PV cohort showed lower JAK2V617F (40.5% vs. 63.9%, P<0.001) but higher JAK2 exon 12 (4.5% vs. 1.4%, P=0.007) and JAK2-wild-type rates (20.7% vs.13.1%,

P=0.025). Non-driver mutations like ASXL1(18.8%) and KMT2A (12.5%) were enriched in AYA patients,

while TET2 (20.6%) and KMT2C (16.7%) were more common in non-AYA patients. No significant difference in JAK2V617F rates was observed between AYA PV and ET patients.

Conclusions:AYA patients showed better long-term outcomes in ET than non-AYA groups. In AYA patients,

KMT2C and KMT2D were the most common non-driver mutations in ET, while ASXL1 and KMT2A were more frequent in PV. Understanding these age-specific molecular patterns will help develop targeted therapies and better risk assessment, improving survival in this understudied group.

Acknowledgement:This research was funded by the Zhejiang Provincial Health High-level Innovative Talent Project (2022-2026).

*Correspondence to: Jian Huang, M.D., Ph.D., Department of Hematology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China. E-

mail:househuang@zju.edu.cn

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