Myeloid Blast Phase of PV Can be Differentiated from De Novo AML with JAK2 Mutation By Its Adverse Cytogenetics and Distinct Molecular Profile
Authors: Hidalgo Lopez Juliana , Kanagal-Shamanna Rashmi , Rojas Sáurez Rafael , Bueso-Ramos Carlos E. 
Published: October 2019

Abstract
Introduction:
Blast phase (BP) of polycythemia Vera (PV) develops in 10-15% of cases at 10 years. Myeloid BP frequently presents with myelodysplasia (88%) and is associated with poor prognosis, median OS of 4 months. De novo JAK2 mutated (mut) AML usually presents with multilineage dysplasia and median OS of 14 months. We hypothesize that cytogenetics (CG) and molecular profile can aid in the distinction of these different entities with similar clinical phenotype. We compared the molecular profile by targeted next-generation sequencing (NGS) of de novo JAK2mut AML and JAK2mut BP of PV.
Methods:
We identified all cases with diagnosis of (1) de novo JAK2mut AML (2) JAK2mut BP of PV in the MDACC files in the last 14 years (2004 - 2018) using WHO 2016 criteria. We collected demographic, clinical, morphological, cytogenetic (CG), and NGS data.
Results:
A total of 23 patients were included. 11 pts were de novo AML with JAK2mut and 12 pts were JAK2mut BP-PV. Median age at diagnosis was 73 and 67 yrs, respectively. At AML presentation, median bone marrow (BM) blast percentage was 40% and 28%, respectively. BM dysplasia was present in all patients in at least one lineage. ELN risk stratification for CG risk in de novo AML JAK2mut showed: 5 pts (45%) as adverse, 4 pts (36%) intermediate and 2 (18%) favorable as risk category; in JAK2mut BP-PV, 9 pts (75%) were adverse and 3 pts (25%) intermediate risk. Median allelic frequency for JAK2mut AML was 32% vs. 64% in BP-PV.
In de novo AML with JAK2mut, none of pts 0/11 (0%) harbored mutations in the activating signaling genes other than JAK2; in JAK2mut BP-PV 3/12 patients (25%) had mutations other than JAK2 [NRAS (2 pts) and PTPN11]. In de novo AML with JAK2mut, epigenetic modifier genes were more frequently mutated 4/11 (36%) [ASXL1 (3 pts) and EZH2] than in JAK2mut BP-PV 1/12 (8%) (ASXL1 and EZH2). DNA methylation genes showed no difference in the frequency of mutations in de novo AML JAK2mut, 6/11 (54%) [DNMT3A, TET2 (2 pts), IDH1 (2 pts), IDH2 (2 pts)] vs. JAK2mut BP-PV, 8/12 (66%) [DNMT3A (3 pts), TET2 (4 pts), IDH1 (2 pts), IDH2 (3 pts)]. Mutations in myeloid transcription genes were similar between JAK2mut AML 2/8 (25%) [RUNX1 (2pts)] and JAK2mut BP-PV 4/12 (33%) [RUNX1 (4 pts)]. The presence of mutated TP53 in de novo AML with JAK2mut was 1/11 (9%) vs. 7/12 (58%) in JAK2mut BP-PV, (p = 0.02), respectively. Spliceosome mutations were more frequent in de novo AML with JAK2mut 4/8 (50%) [SRSF2 (4 pts)], than JAK2mut BP-PV 2/8 (25%) (SRSF2, SF3B1), respectively.
Conclusion:
Myeloid BP of PV presents with distinct molecular profile that includes increased frequency of TP53 mutations and adverse genetics by ELN risk stratification while de novo AML with JAK2 mutations shows increased frequency spliceosome mutations. These molecular features aid in the differentiation of BP of PV from JAK2mut AML that have similar phenotype but different prognosis and require aggressive intervention.

Disclosures
No relevant conflicts of interest to declare.