Abstract Topic: 16. Myeloproliferative neoplasms - Clinical
Background: Myelofibrosis (MF) is a heterogeneous disease regarding its mutational landscape as well as its clinical presentation and outcome. A genomic classification with prognostic implications of myeloproliferative neoplasms has been proposed by Grinfeld et al (NEJM, 2018); however, this classification has hardly been implemented in MF.
Aims: To evaluate the genomic classification of MF in a large series of MF patients from a single institution, taking into account whether cases are primary or secondary (post-polycythemia vera or post-essential thrombocythemia.
Methods: A total of 175 patients, diagnosed with primary MF (PMF n=81) or secondary MF (sMF n=94) were selected. Using the information provided by Next-Generation Sequencing (NGS), patients were hierarchically allocated into 8 molecular groups as follows: TP53 disruption or aneuploidy (TP53 mutation, Chr17pLOH or Chr5-/Chr5q-); ≥1 genetic aberrations in chromatin or spliceosome genes (EZH2, IDH1, IDH2, ASXL1, PHF6, CUX1, ZRSR2, SRSF2, U2AF1, KRAS, NRAS, GNAS, CBL, Chr7/7qLOH, Chr4q/LOH, RUNX1, STAG2 and BCOR); CALR mutation; MPL mutation; homozygous JAK2 mutation; heterozygous JAK2 mutation; other mutation; no known mutation. NGS analysis was carried out using a commercial panel targeting myeloid genes. Variants with an allele frequency ≥1% and classified as pathogenic or probably pathogenic were considered for analysis. Only mutations and copy number variation information derived from NGS were taken into account for genomic classification, as cytogenetics was not available is most of the cases.
Results: MF with TP53 disruption (n=12, 7%) was more frequent (9% vs 5%) and showed higher allele burden (57% versus 15%, p=0.01) in sMF than in PMF. Median survival of MF with TP53 disruption was 5.3 years, and 4 out of 12 patients progressed to acute myeloid leukemia (AML) (5-year probability of 52%).
MF with mutation in chromatin/spliceosome genes (n=73, 42%) represented the most frequent genomic group in PMF; median survival was 6.2 years and 11 out of 73 showed progression to AML (5-year probability of 14%). Of note, 60% of them became transfusion-dependent during disease evolution.
MF with homozygous JAK2 mutation (n=40, 23%) was enriched with old patients with sMF after long-standing polycythemia vera. Median survival was 7.3 years and 5-year probability of AML was calculated to be 18%. MF with heterozygous JAK2 mutation (n=22, 13%) was similarly distributed among PMF and sMF. Median survival was not reached and no cases of progression to AML were detected during follow-up.
MF with CALR mutation (n=19, 11%) was equally represented by type 1 and type 2 CALR mutations, with a mean allele frequency of 46%. There was a predominance of post-essential thrombocythemia sMF. Median survival was 10.7 years and no cases of progression to AML were detected.
The remainder 9 patients were classified as MF with MPL mutation (n=4), MF with other mutation (n=2) and MF with no known driver mutation (n=3). Main characteristics of genomic subgroups are shown in table 1.
Summary/Conclusion: Genomic profiling and classification reveals distinctive molecular landscapes between primary and secondary myelofibrosis. In addition, genomic classification provides relevant information for prognosis evaluation, including prediction of progression to AML.
Keywords: Myelofibrosis, Myeloproliferative disorder, Mutation analysis