The MPN registry was the largest collection specifically for patients with various sub-types of MPN in Malaysia. The mean mortality age of patients with MPN was 67.5 years, clearly shorter than the expected Malaysia life expectancy, ranged from 72–78 years. Patients who were diagnosed at an older age was associated with an unsatisfactory outcome. A similar result was also demonstrated in many studies. [11–13, 18]. The possible postulation for these findings is that elderly patients had likely more aggressive disease and with the presence of other co-morbidities, which resulted in a higher rate of hospitalization and treatment-related complications . According to several myelodysplastic/myeloproliferative neoplasms studies in the United States, ageing is linked to the rising incidence of cancer as a result of immune senescence, autoimmunity, chronic inflammation and accumulating DNA damage [14–16].
We found similar gender distribution in our population with the rest of the world [14, 17]. The male MPN patients tend to do worse compared to female MPN patients. Female MPN patients tend to do better compared to their counterpart [11, 13]. The observed gender disparity possibly due to hormonal effect, occupational exposures, lifestyle factors [14, 19, 20].
The only peculiar thing that we discovered in our registry was Chinese ethnicity had a higher incidence of ET despite being a much smaller ethnic group compared to Malay. There is a similar finding to the previous paper of epidemiology of this MPN cohort in which Chinese seems to have a relatively higher incidence of death in MPN compared to Malay considering the racial distribution of 21.2% for Chinese and 61.8% for Malay in Malaysia. Despite the statistical insignificance, geography and ethnicity are found to influence the survival in other countries . Maynadie et al. revealed that the survival rates of 74% in Northern Europe in comparison to only 27% survival rates in Eastern Europe . Another study from China also reported the Chinese MPN patients were significantly younger, had less splenomegaly or constitutional symptoms with significantly better survival when compared with the Caucasian MPN patients .
JAK2 V617F mutation was shown to have some influence on the survival outcome in our patient cohort. This is in contrast to the International Prognostic Scoring System (IPSS) of PMF in which the presence of JAK2 V617F did not influence the prognosis of PMF . Nevertheless, several studies had demonstrated that there is an association between JAK2 V617F allelic burden with clinical phenotype and disease outcomes in PV patients [24, 25]. The suggestion of a possible link between the homozygous allele burden and older age, male gender, pruritus, splenomegaly, thrombosis and MF transformation . Alvarez-Larrán et al. revealed that there was an increased risk of myelofibrotic transformation in association with high (\(\ge\)50%) or unstable JAK2 V617F burden during follow-up and a trend for a higher incidence of thrombosis than patients with allele burden < 50% . Unfortunately, this information was not captured in our study.
Our study demonstrated that PMF had the worst OS in comparison to PV and ET. This is consistent with the findings from many studies [11, 13, 27, 28]. Low JAK2 V617F allele burden at diagnosis in patients with PMF is associated with shortened survival in PMF [28–30]. The inferior OS of PMF in our study can be possibly a result of leukaemic transformation and systemic infections which are documented in the Mayo Clinic study  and in the Italian study respectively .
The MPN-U was noted to have second-worst overall survival after the PMF. The MPN-U was associated with inferior survival of 12.4 months, compared to 16 months with MDS and 41.5 months with PMF (p < 0.001) in a study by DiNardo et al. . This is further supported by Chaudhury et al. study stating that MDS/MPN-U is associated with poor outcomes in view of a variable disease course .
The bone marrow fibrosis grade 2 to grade 4 was associated with worse overall survival in our study. The accurate evaluation of bone marrow fibrosis has been highlighted to be a key point to predict prognosis in PMF . Guglielmelli et al. showed that there was a correlation between the higher grades of fibrosis and survival despite the IPSS variables and mutational status . The median survival was significantly reduced in patients with grade 2 and 3 fibrosis in comparison to grade 1 in a multivariate analysis [34, 35]. The bone marrow fibrosis of grade 2 and above is linked to a more advanced clinical presentation encompassing constitutional symptoms, cytopenias, larger splenomegaly, a higher IPSS risk category and more frequent adverse mutations (ASXL and EZH2) .
The patients presented with vasomotor symptoms such as headache, dizziness, tinnitus, syncope, tingling, visual changes, acrocyanosis or erythromelalgia were not significantly associated with adverse survival outcome in our study. Twenty-five per cent (25%) to 35% of patients were asymptomatic, and the thrombocytosis were incidental findings . The presence of vasomotor symptoms resulted in patients seeking medical attention and treatment early, hence better OS. Whereas, bleeding episodes as an initial clinical presentation was seemingly linked to worse OS in our study. This was evidenced by the causes of mortality in which the bleeding events were the most frequent reason for death due to underlying disease.
Older age and the presence of diabetes mellitus were the risk factors found to have statistical significance for mortality in this study. According to Gangat et al. age, haemoglobin level, leukocyte count, smoking, diabetes mellitus, thrombosis, male sex and the absence of microvascular symptoms are independent predictors of inferior survival . Advanced age, leukocytosis and thrombosis are the risk factors for survival in ET and PV. [38–40]
The ET patients seemingly had a similar OS in comparison to PV patients within the first ten years in which conventionally ET is believed to be doing much better compared to other subtypes. The reason maybe there was a possibility of “prefibrotic” MF mimicking ET in its presentation. This was probably missed as many patients did not undergo bone marrow biopsy. The revised 2016 WHO classification system categorized “prefibrotic” MF from “overtly fibrotic” PMF and it is prognostically relevant to differentiate between the two. The presence of JAK2 V617F mutation was statistically significant for OS in ET and PMF in this study could possibly related to the “prefibrotic” MF.
The PMF had the worst overall survival in this study. The molecular landscape of the MF has evolved in recent years beyond the identification of driver mutations in JAK2, CALR and MPL resulting in the development of genetically based prognostic scoring systems (MIPPS70, MIPSS70 + version 2.0 and GIPPS. GIPPS (Genetically inspired prognostic scoring system) is tabulated from mutations and karyotype which offers a more simplified prognostic tool while MIPSS70 + version 2.0 (Mutation and karyotype-enhanced international prognostic scoring system) is formed based on genetic and clinical risk factors.
Based on the model assumption in proportionality and linearity, effective sample size and clinical significance, age, JAK2 V617F mutation, Ethnic groups, MPN sub-types, Jak 2 V617F, splenomegaly, BM fibrosis, bleeding episodes, hypertension, diabetes mellitus, smoking and obesity were included into the multivariable Cox PH model for assessment of variable predictability in patient’s survival outcome (Table 3). The multivariable model showed that patient’s age at diagnosis, Male, MPN subtypes, especially PMF and MPN-U, might independently predict the survival outcome of MPN patients.
There is a number of limitations in this study which includes loss of data, lack of treatment data and inability to determine the cause and effect. The MPN registry included prevalent cases instead of incident cases hence the long survivors would be overrepresented in the registry whereas those who passed away prior to year 2009 would not be included. However, this is the only registry for MPN patients in Malaysia that can provide us with many informative findings which can be utilized to improve the management of MPN patients in the future.