Evidence that prefibrotic myelofibrosis is aligned along a clinical and biological continuum featuring primary myelofibrosis.

Giovanni Barosi,Margherita Massa,Antonina M Isgrò,Umberto Magrini,Elisa Bonetti,Gianluca Viarengo,Adriana Carolei,Rita Campanelli,Paolo Catarsi,Vittorio Rosti,Laura Villani,Valentina Poletto,Letizia Lupo,William Tse

doi:10.1371/journal.pone.0035631

Abstract

PurposeIn the WHO diagnostic classification, prefibrotic myelofibrosis (pre-MF) is included in the category of primary myelofibrosis (PMF). However, strong evidence for this position is lacking.Patients and MethodsWe investigated whether pre-MF may be aligned along a clinical and biological continuum in 683 consecutive patients who received a WHO diagnosis of PMF.ResultsAs compared with PMF-fibrotic type, pre-MF (132 cases) showed female dominance, younger age, higher hemoglobin, higher platelet count, lower white blood cell count, smaller spleen index and higher incidence of splanchnic vein thrombosis. Female to male ratio and hemoglobin steadily decreased, while age increased from pre-MF to PMF- fibrotic type with early and to advanced bone marrow (BM) fibrosis. Likely, circulating CD34+ cells, LDH levels, and frequency of chromosomal abnormalities increased, while CXCR4 expression on CD34+ cells and serum cholesterol decreased along the continuum of BM fibrosis. Median survival of the entire cohort of PMF cases was 21 years. Ninety-eight, eighty-one and fifty-six percent of patients with pre-MF, PMF-fibrotic type with early and with advanced BM fibrosis, respectively, were alive at 10 years from diagnosis.ConclusionPre-MF is a presentation mode of PMF with a very indolent phenotype. The major consequences of this contention is a new clinical vision of PMF, and the need to improve prognosis prediction of the disease.

Highlights

Primary myelofibrosis (PMF) is recognized as a distinct clinical entity among classical Philadelphia-negative myeloproliferative neoplasms (MPNs) which include essential thrombocythemia (ET) and polycythemia vera (PV) [1]
In the 90s’, Thiele and co-workers disrupted the dogma of bone marrow (BM) fibrosis being an intrinsic and necessary stigma of PMF, and they first proposed a new category of patients characterized by absence of relevant reticulin fibrosis in BM with dual megakaryocytic and granulocytic myeloproliferation associated with characteristic megakaryocyte dysplasia [7,8,9]
Since the phenotype of prefibrotic myelofibrosis (pre-MF) resembles that of ET, in the last years the research on the disease has established the stronger tendency of patients with pre-MF to have bleeding [21], to evolve into overt PMF and leukemia [22,23], and to have shorter survival with respect to ET [22,23]

Summary

Introduction

Primary myelofibrosis (PMF) is recognized as a distinct clinical entity among classical Philadelphia-negative myeloproliferative neoplasms (MPNs) which include essential thrombocythemia (ET) and polycythemia vera (PV) [1]. In the 90s’, Thiele and co-workers disrupted the dogma of BM fibrosis being an intrinsic and necessary stigma of PMF, and they first proposed a new category of patients characterized by absence of relevant reticulin fibrosis in BM with dual megakaryocytic and granulocytic myeloproliferation associated with characteristic megakaryocyte dysplasia [7,8,9]. This variant, called prefibrotic myelofibrosis (pre-MF), has been included as a prodromic phase of PMF into the WHO classification of MPNs since 2001 [10], and the criteria for the diagnosis were further outlined in 2008 [11]. Pre-MF has joined the ranks of the diagnostic categories used in the practice of most of the hematopathologists worldwide, even though there is still a number of unresolved issues concerning its diagnostic reproducibility [12,13,14,15,16], and molecular and biological identity [17,18,19,20].

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