Prognostic Impact of Bone Marrow Fibrosis in Polycythemia Vera: Validation of the IWG-MRT Study and Additional Observations
Authors: Barraco Daniela , Cerquozzi Sonia , Hanson Curtis A. , Ketterling Rhett P. , Pardanani Animesh , Gangat Naseema , Tefferi Ayalew 
Published: October 2019

Abstract
Background
Increased bone marrow (BM) reticulin fibrosis in polycythemia vera (PV) has been reported in 20% (Ann Hematol. 1999;78:495) to 51% (Eur J Haematol. 2011;86:148) of patients at diagnosis. In a previous report by the international working group for myeloproliferative neoplasms (MPN) research and treatment (IWG-MRT), the presence of BM fibrosis (≥ grade 1) at diagnosis was associated with a lower incidence of thrombosis during the clinical course and a higher risk of fibrotic progression while it did not affect overall (OS) or leukemia-free (LFS) survival (Blood. 2012;119:2239). The objectives for the current single center study of 262 PV patients were to validate the observations from the IWG-MRT and also identify other risk factors for myelofibrosis-free survival (MFFS) in PV.
Methods
Study patients were selected from our institutional database of MPN and fulfilled the 2016 World Health Organization (WHO) criteria for the diagnosis of PV (Blood. 2016;127:2391). Cytogenetic analysis and reporting was done according to the International System for Human Cytogenetic Nomenclature (Cytogenetic and Genome Research 2013;141:1-6). The degree of BM reticulin fibrosis was based on "real life" BM reports from Mayo Clinic hematopathologists and often in accordance with the European consensus scoring system (Haematologica 2005;90:1128). Statistical analyses considered clinical and laboratory parameters obtained at time of diagnosis.
Results
Patient characteristics:
Analysis was conducted on 262 patients (median age 62 years; 50% males) who met 2016 WHO criteria for diagnosis of PV. Median (range) values were: hemoglobin 18 g/dl (14.8-24), leukocyte count 11.7 x109/L (4.3-59.3) and platelet count 454 x109/L (44-2747). Among informative cases, palpable splenomegaly was present in 27%, pruritus in 33% and erythromelalgia in 6%. Thrombosis history at diagnosis was documented in 28% of the patients and 23% experienced thrombotic events after diagnosis. Information on cytogenetics was available in 142 patients and karyotype was abnormal in 19%. BM reticulin fibrosis was reported to be absent in 135 patients (MF-0, 52%), grade 1 (MF-1) in 101 (39%), grade 2 (MF-2) in 22 (8%) and grade 3 (MF-3) in 4 (2%) patients. After a median follow up of 85 months, 107(41%) deaths, 30 (11%) fibrotic progression and 5 (2%) leukemic transformations were documented.
Comparison of patients with and without bone marrow fibrosis
A number of clinical and laboratory parameters were evaluated for possible association with the presence of ≥ grade 1 BM reticulin fibrosis and none, including age, sex, complete blood count, palpable splenomegaly, pruritus or erythromelalgia displayed a significant association.
In univariate analysis, the presence of BM fibrosis (MF-0 versus MF-1 or greater) did not affect OS (p=0.5), LFS (p=0.2) or thrombosis-free survival (p=0.97) whereas a significant association was noted for MFFS (p=0.009; HR 2.9, 95% CI 1.3-6.7). Others risk factors for MFFS, in a univariate analysis, were leukocytosis ≥15 x 109/L (p=0.02; HR 2.7, 95% CI 1.17-6.48), presence of splenomegaly (p=0.02; HR 2.6, 95% CI 1.16-6) and abnormal karyotype (p=0.0005; HR 4.6, 95% CI 1.9-11). During multivariable analysis, not including karyotype, leukocytosis ≥15 x 109/L (p=0.04), presence of splenomegaly (p=0.04) and presence of BM reticulin fibrosis (p=0.01) remained significant; however, this significance for leukocytosis ≥15 x 109/L, presence of splenomegaly and BM reticulin fibrosis was lost when abnormal karyotype was added as covariate to each risk factor individually (p=0.4, p=0.1 and p=0.9, respectively).
Conclusion
We report a not infrequent (48% incidence) occurrence of ≥ grade 1 BM reticulin fibrosis at time of initial diagnosis of PV. In the current study, we did not find a prognostic impact for the presence of BM reticulin fibrosis, in terms of OS, LFS or thrombosis-free survival; however, a significant association was confirmed for MFFS that was independent of other non-genetic risk factors. The preliminary observation on the adverse prognostic impact of abnormal karyotype on MFFS requires additional studies.

Disclosures
No relevant conflicts of interest to declare.