Prefibrotic Versus Overtly Fibrotic Primary Myelofibrosis: Clinical, Cytogenetic, Molecular and Prognostic Comparisons

Background

The 2016 revised World Health Organization (WHO) classification system distinguishes prefibrotic (pre-PMF) from overtly fibrotic (overt PMF) primary myelofibrosis, based on the respective absence or presence of grade ≥2 bone marrow (BM) reticulin fibrosis (Blood. 2016;127:2391). The main objective of the current study was to determine the prognostic relevance of this distinction and compare clinical and genetic features between the two entities.

Methods

Study patients fulfilled the 2016 WHO criteria for the diagnosis of pre-PMF or overt PMF (Blood. 2016;127:2391). 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). Targeted next generation sequencing was used to screen for prognostically-relevant mutations (Blood 2015 126:354). Statistical analyses considered clinical and laboratory parameters obtained at time of BM examination that was graded for reticulin fibrosis.

Results

Patient characteristics:

Analysis was conducted on 467 patients (median age 64 years; 62% males), including 63 with pre-PMF and 404 with overt PMF. 302 (65%) patients harbored JAK2 mutations, 90 (19%) CALR, 24 (5%) MPL and 51 (11%) were "triple-negative"; among the 90 CALR-mutated cases, 74 (82%) were classified as "type 1/type 1-like". Dynamic international prognostic scoring system (DIPSS)-plus risk distribution (JCO 2011;29:392) was 30% high, 38% intermediate-2, 16% intermediate-1 and 15% low; 29% displayed red cell transfusion-dependency, 29% constitutional symptoms, 70% palpable splenomegaly and 37% abnormal karyotype, including 13% with unfavorable karyotype. 308 patients were screened for ASXL1 mutations with 39% mutated, 305 for SRSF2 mutations with 16% mutated, 291 for U2AF1 with 18% mutated, 264 for SF3B1 with 6% mutated, 240 for EZH2 with 5% mutated and 118 for IDH1/2 with 7% mutated. BM reticulin fibrosis was reported as grade '0' in 5 (1%) patients, grade '1' in 58 (12%), grade '2' in 169 (36%) and grade '3' in 235 (50%). After a median follow up of 3 years, 273 (59%) deaths and 42 (9%) leukemic transformations were documented.

Clinical, cytogenetic and molecular comparisons between pre-PMF vs overt PMF:

Significant differences included higher hemoglobin level (p<0.0001), higher platelet count (p<0.0001), higher incidence of thrombocytosis (p<0.0001), lower circulating blast percentage (p=0.0002), lower incidence of constitutional symptoms (p=0.003), lower incidence of palpable splenomegaly and lower DIPSS-plus risk distribution (p=0.0004), in pre-PMF, compared to overt PMF. There were significantly more triple-negative patients with pre-PMF (22% vs 9% for overt PMF; p=0.02) but otherwise no significant difference in the distribution of ASXL1, SRSF2, U2AF1, SF3B1, EZH2 or IDH1/2 mutations or incidence of unfavorable karyotype.

Survival analysis:

In univariate analysis, all 8 variables included in DIPSS-plus were significantly associated with shortened survival (p<0.001 in all instances). Significant risk factors in univariate analysis also included overt PMF vs pre-PMF (p=0.002; HR 2.0, 95% CI 1.3-3.1), absence of CALR type 1/type 1-like (p<0.0001) and presence of ASXL1 (p<0.0001) or SRSF2 (p<0.0001) mutations. The significant difference in survival between pre-PMF and overt PMF was independent of DIPSS-plus (p=0.03), driver mutational status (p=0.001), ASXL1 (p=0.008) and SRSF2 (p=0.02) mutations; no significant difference in leukemia-free survival was noted (p=0.25). The survival difference between pre-PMF and overt PMF was most evident in high/intermediate-2 DIPSS-plus risk groups (Figure). Of note, we found no difference in survival when patients with grade '0' were compared to those with grade '1' reticulin fibrosis (p=0.96) and when those with grade '2' were compared with grade '3' (p=0.08).

Conclusion

The current study demonstrates the risk-adjusted prognostic relevance of the WHO distinction between pre-PMF and overt PMF. The two clinic-pathologic entities were otherwise similar in their spectrum of prognostically-relevant mutations or cytogenetic abnormalities, although pre-PMF clustered with thrombocythemic and triple-negative phenotype and overt PMF with adverse clinical features.

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