Prognostic Impact of Bone Marrow Fibrosis in Polycythemia Vera: Validation of the IWG-MRT Study and Additional Observations

Abstract

BackgroundIncreased 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.MethodsStudy 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.ResultsPatient 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 fibrosisA 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).ConclusionWe 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. DisclosuresNo relevant conflicts of interest to declare.