Long term follow up of 93 families with myeloproliferative neoplasms: life expectancy and implications of JAK2V617F in the occurrence of complications

Abstract

The long-term evolution of familial myeloproliferative neoplasms was studied in 93 families with 227 subjects including 97 with polycythemia vera (PV), 105 essential thrombocythemia (ET), 14 primary myelofibrosis (PMF) and 11 chronic myeloid leukemia (CML). In PV patients, with 12 years of median follow-up, overall survival was 83% at 10 years and 37% at 20 years. A high JAK2^V617F allele burden was correlated with the transformation to myelofibrosis (p < 0.0001), but not with the transformation to acute leukemia. Among the 105 ET, with 8 years of median follow-up, overall survival was 83% at 10 years and 57% at 20 years. Progression to acute leukemia and progression to myelofibrosis were 10% and 13%. There was a trend toward a more frequent evolution to myelofibrosis when the JAK2^V617F mutated allele burden was > 50% (p = 0.09), but not to AML. Hematologic transformation of the MPN was responsible for 69% of the deaths, cerebral stroke for 7% and 4% died of myocardial infarction. Eleven JAK2^V617F mutated patients developed 13 deep splanchnic thromboses in PV and ET. Finally whereas patients with familial PV and ET have a comparable prognosis to non‐familial MPN, the JAK2^V617F mutation was associated with a more frequent occurrence of thrombosis in the entire population.

Introduction

Myeloproliferative neoplasms (MPN) are hematologic malignant diseases characterized by a clonal proliferation of one or several lineages [1]. They represent a phenotypically diverse group of chronic myeloid malignancies that are characterized by the presence of clonal hematopoiesis and an excessive production of terminally differentiated myeloid blood cells. Typically, they include four main clinical entities: polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukemia (CML) [2]. PV, ET and PMF are usually subcategorized as bcr-abl negative MPN.

The identification of the V617F somatic mutation of the JAK2 gene (JAK2^V617F) led to an important breakthrough in the understanding of MPN disease pathogenesis [3], [4], [5], [6]. The JAK2^V617F mutation is present in majority of PV patients (90–98%), whereas only about 50% of patients with ET and PMF are affected [7]. Since then, other acquired mutations have been found to be involved in the pathogenesis of MPN, such as mutations and deletions in exon 12 of the JAK2 gene [8], mutations in the thrombopoietin receptor gene MPL [9], or mutations of the ten-eleven translocation 2 gene (TET2) [10]. A susceptibility haplotype to JAK2 mutations has even been identified, referred to as 46/1 haplotype [11], [12], [13]. But it also appeared that the JAK2 mutation is not a MPN initiation event and a pre-JAK2 somatic mutation leading to the MPN clone is not yet known.

MPN have sporadic occurrences in most instances. However, familial clustering of MPN has been reported [14], [15], [16], [17], [18]. A large population-based study showed that first-degree relatives have a five to sevenfold higher risk of developing MPN compared with controls [19]. Previous extensive studies on PV cohorts found a prevalence of familial cases of 0.9 to 2.4% [20], [21], [22] but a more recent Italian study reported a prevalence of at least 7.6% of familial cases within a population of patients with MPN in a single center [23].

Whereas the common mutations such as JAK2, MPL and TET2 have been found in familial MPN cases, they appeared to be acquired as in sporadic cases [14], [16], [24], [25]. A germline predisposition to MPN has been hypothesized to explain familial clustering of MPN, but this matter is still under investigation.

Clinical features of sporadic MPN are well defined but available data show a great diversity in survival.

While sporadic PV and ET have long survival which may exceed 20 years [26], [27], PMF has a more aggressive course [28]. The part of the JAK2 mutation or other molecular events, often epigenetic events, on the evolution of these diseases is still being investigated [29]. The presence of a genetic predisposition factor as suggested in familial cases may also influence their evolution.

Whereas the presence of the mutation JAK2^V617F influences the clinical presentation, long term complication rates and outcomes of patients with familial MPN have not been addressed yet. To solve this issue, we have analyzed a large group of 93 families presenting with at least two cases of MPN that has been collected through a large collaborative network of hematologists in France and Belgium.