Myelofibrosis in the genomic era : clinical and molecular heterogeneity, prognostic factors and targeted therapy

Abstract

With the advancements in the understanding of the pathophysiology and genomics of myeloproliferative neoplasms (MPN) and myelofibrosis (MF) over the past decade, the optimal treatment targets and therapeutic approach needs to be re-defined. The first study examined the natural history, survivals and prognostic indicators of a 270 patients with untreated myelofibrosis in Hong Kong. This study showed that the median overall survival (OS) of primary myelofibrosis (PMF) and secondary myelofibrosis (SMF) was 66 months and 44 months respectively. The 10-year cumulative risk of blastic transformation in PMF and SMF was 28.3% and 31.3% respectively. Thrombocytopenia and unfavourable karyotype predicted worse OS. The second study specifically examined the natural history of 352 patients with polycythaemia vera (PV) and essential thrombocythaemia (ET) and the predictors for disease progression to SMF and secondary acute myeloid leukaemia (AML). Age above 60 at presentation and the presence of splenomegaly were the key predictors of disease progression. The third study examined the molecular characteristics of 101 patients with PMF and SMF using next-generation sequencing (NGS) of a myeloid-gene panel. This study showed the unique adverse impact of TP53, transcription regulator genes (CUX1, ETV6), histone modification gene (ASXL1, EZH2), RNA splicing gene (SRSF2, U2AF1) and DNA methylation gene (IDH2, TET2) mutations on survivals. The fourth study was a 48-months prospective observational study in 125 patients with MPN treated with hydroxyurea, ruxolitinib and pegylated interferon α-2A (PEGIFNα- 2A). Efficacy [in terms of clinical, haematological and quality of life (QOL)], and toxicities were examined. 23, 56 and 46 patients with PV, ET and MF were recruited. Patients with ET had the best clinical-haematological responses when treated with PEG-IFNα-2A. All 3 agents had similar efficacy in patients with PV. Ruxolitinib achieved significantly better improvement in QOL and splenomegaly. 41% and 22% of patients treated with PEG-IFNα-2A and ruxolitinib showed bone marrow morphologic improvement shedding light to the possible disease-modifying effect. The final study examined the outcome of 27 molecularly annotated patients with myelofibrosis receiving allogeneic haematopoietic stem cell transplantation (HSCT). A favourable 5-year OS of 62.1% was achieved. Very high risk karyotype, and the higher molecular risk mutations (ASXL1, EZH2, IDH1/2, SRSF2 and U2AF1) did not impact on transplant outcome showing that allogeneic HSCT may overcome these adverse prognostic indicators. Persistence of marrow fibrosis at 12 months post-HSCT, and the presence ETV6, PHF6 and TP53 mutations predicted worse leukaemia-free survival following HSCT. In conclusion, this thesis showed the importance of functionally classifying MF using gene mutations to determine the best therapeutic strategy. Management of MPN and MF needs to be personalized strategy targeting symptom burden, preventing disease progression and improving survivals.