Prefibrotic Primary Myelofibrosis As an Entity Distinct from Other Philadelphia-Chromosome Negative Myeloproliferative Neoplasms - Data from the Austrian Reclassification Project
Authors: Jeryczynski Georg , Gisslinger Bettina , Schalling Martin , Krauth Maria Theresa , Muellauer Leonhard , Schiefer Ana-Iris , Kornauth Christoph , Simonitsch-Klupp Ingrid , Thiele Jürgen , Gisslinger Heinz 
Published: October 2019

Abstract
Introduction:
The distinction between essentialthrombocythemia(ET) and early, prefibrotic primary myelofibrosis (prePMF) by strictly applying the criteria of the WHO classification results in a newly defined subgroup of myeloproliferative neoplasm (MPN) in which the frequency and severity of clinical features are currently poorly characterized.
Since prePMF was usually summarized under the subgroup of ET in previous classifications, little is known about the frequency of prePMFamong MPN. The importance of accurate diagnosis, however, is underlined by various publications that could demonstrate a significant impact on management and outcome of these patients.
Aims:
The aim of this study was to describe the clinical characteristics and symptoms at diagnosis of prePMF as a distinct entity and to evaluate the course of the disease in regard to survival, transformation into overt myelofibrosis and acute leukemia.
Methods:
All patients with representative bone marrow biopsies at presentation and complete clinical data at time of diagnosis and follow up were included in this study. All patients included were recruited from the MPN cohort of the Medical University of Vienna.
Results:
In total, 807 MPN patients diagnosed according to the WHO 2008 criteria were analyzed. The relative frequency of prePMF in our cohort was 17.6% (n=142) as opposed to 27.4% (221) in ET (Fig. 1). The median age for prePMF patients was 63.4 years (range 26.9-88.1) and 55.1% were female. The majority showed an elevated platelet count (median 770 G/l, range 78-2869), hemoglobin levels were on the lower end of the normal range in both genders (median 13.9, range 8.1-18.4 and 13.2, range 7.9-16.2 in men and women respectively). Leukocyte counts in the upper range of normal were common (median 9.87, range 4.0-46.0). The lactate dehydrogenase levels (LDH) were markedly elevated (median 303, range 153-729 with an institutional cut-off of 250 U/L). Therewasalso a considerate proportion of patients with splenomegaly (39.8%). Further, 22.6% of patients reported constitutional symptoms such as night sweats and weight loss. Fiber grade of 1 of a three-graded score in the bone marrow biopsy was reported in 26.2% of cases. 27.0% of patients presented withleftshiftingwith a few peripheral blasts. JAK2 positivity was found in 57.1%, CALR in 32.7 and MPL in 3.3% of cases. Only 5.9% were triple negative. 5-, 10- and 20-year survival rates were 87.6%, 67.0% and 28.8% respectively (38.2% of patients followed to death). Cumulative rate of progression into overt fibrosis was 34.2% after 10 and 58.8% after 20 years (Fig. 2).
Discussion:
Our data highlight important features of prePMF. Firstly, compared to ET, it has a later onset. More importantly, thrombocytosis is not a feature limited to ET, but is also frequently seen in prePMF and is therefore not suitable to accurately characterize MPN at time of diagnosis. However, leukocytosis and elevated LDH levels are features uncommon for ET as is fiber grade > 0 that is almost never seen in the WHO-defined ET, but relatively common in prePMF. Splenomegaly and presence of a few blasts are generally signs of beginningextramedullaryhematopoiesis are therefore more commonly associated with early stages primary myelofibrosis. Lastly, overall survival and fibrosis-free survival is substantially impaired in prePMF in comparison to data previously published for ET and similar to polycythemiavera.
In conclusion, prePMF is a distinct entity, that while sharing some features of ET, most notably thrombocytosis, shows several striking features that should be regarded when investigating newly diagnosed MPN patients.
Figure Figure. Figure Figure.

Disclosures
Gisslinger: Baxalta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria.