Cytogenetic Abnormalities in Polycythemia Vera: Phenotypic Correlates and Prognostic Relevance in 669 Informative Cases
Authors: Iftikhar Moazah , Rana Masooma S , Jadoon Yamna , Abdelmagid Maymona , Reichard Kaaren K. , Zepeda Mendoza Cinthya , Pardanani Animesh D. , Tefferi Ayalew , Gangat Naseema 
Published: December 2024

Background
Abnormal karyotype is not infrequent in polycythemia vera (PV) and has been associated with shortened survival (BJH 2018;182:437). In the current study, we utilized a large institutional database, in order to describe the spectrum and prevalence of specific cytogenetic abnormalities in PV, during different stages of the disease, and examine their clinical, molecular, and prognostic correlates, in the context of previously established risk factors.
Methods
After institutional review board approval, we identified 669 cytogenetically-annotated patients with PV, evaluated at the Mayo Clinic between 1973 and 2023, and met the International Consensus Classification diagnostic criteria (Arber et al. Blood 2022;140;1200). Cytogenetic reporting was in accordance with the International System for Human Cytogenomic Nomenclature.
Results
i) Prevalence of cytogenetic abnormalities at diagnosis and at different stages of the disease
436 of 669 (65%) patients with PV underwent cytogenetic evaluation within one year of diagnosis, 116 (17%) within 1-10 years, 47 (7%) after 10 years, and 70 (10%) at time of fibrotic or leukemic transformation. In patients with cytogenetic information obtained within 1 year of diagnosis, karyotype was normal in 369 (85%), showed loss of Y chromosome (-Y) in 15 (3%), and other abnormalities in 52 (12%). Most common abnormalities included trisomy 9 (n=11; 3%), del(20q) (n=10; 2%), trisomy 8 (n=4; 1%), other sole abnormalities (n=16; 4%), and ≥ 2 abnormalities (n=11; 3%) including complex karyotype (n=4; 0.9%). Frequency of abnormal karyotype was higher with longer disease duration; 15% within a year of diagnosis, 28% in 1-10 years, 49% over 10 years after diagnosis, and 50% at time of fibrotic or leukemic transformation (p&lt;0.01). Sole del (20q), single abnormalities excluding 20q-, +8, +9, or -Y, and ≥ 2 abnormalities including complex karyotype were progressively acquired; respective frequencies within a year of diagnosis, over 10 years after diagnosis, and at time of fibrotic or leukemic transformation were 2%/21%/10% (del (20q), 4%/17%/14% (single abnormality excluding 20q-, +8, +9, or -Y), 3%/11%/19% (≥ 2 abnormalities), 1%/ 2%,/10% (complex karyotype) (all p-values &lt;0.01). In addition, sole +8 displayed highest frequency at fibrotic transformation compared to within a year of diagnosis (5% vs 0.9%; p=0.04).
ii) Phenotypic and Molecular Correlates
436 patients with PV (51% males; median age; 64 years) who underwent cytogenetic testing within one year of diagnosis were examined for clinical and molecular correlations. Abnormal karyotype compared to normal karyotype, correlated with older age (median: 70 vs 63 years, p&lt;0.01), male gender (64% vs 48%, p=0.02) and lower platelet count (370 vs 465 × 109/L, p&lt;0.01). Sole del (20q) compared to normal karyotype was associated with older age (median: 76 vs 63 years, p&lt;0.01); sole +8 exclusively occurred in patients ≥ 60 years (p=0.03); sole +9 was associated with venous thrombosis history (45% vs 17%, p=0.03). TET2 and SRSF2 mutations were found to cluster with normal karyotype (18% vs 4%; p=0.04 and 5% vs 0%; p=0.14 in normal vs abnormal karyotype, respectively).
iii) Prognostic Impact of Cytogenetic Abnormalities
At a median follow-up of 7.4 years (range; 0.04-42.4 years), a total of 163 (37%) patients have died, 50 (11%) and 14 (3%) underwent fibrotic and leukemic transformation, respectively. In univariate analysis for overall survival (OS), abnormal karyotype compared to normal karyotype, was associated with inferior survival (median OS; 10.5 vs 16.3 years, p&lt;0.01). In multivariate analysis, the adverse impact of abnormal karyotype remained significant (p=0.02; HR 2.0, 95% CI 1.2-3.3), along with age ≥60 years, leukocyte count ≥15 × 109/L, and SRSF2 mutations. Abnormal karyotype was also an independent predictor of myelofibrosis-free survival (p&lt;0.01; HR 3.7, 95% CI 1.8-7.8), along with SRSF2 mutations. Analysis of leukemia-free survival revealed abnormal karyotype to be a significant risk factor in univariate (p&lt;0.01), but not multivariate analysis that included SRSF2 mutation (p&gt;0.1).
Conclusions
The current study provides the distribution of cytogenetic abnormalities at different stages of PV and affirms the prognostic significance of abnormal karyotype at the time of diagnosis, highlighting the importance of incorporating cytogenetic studies in the diagnostic evaluation of PV.