The prognostic impact of bone marrow fibrosis in primary myelofibrosis
Authors: Paola Guglielmelli, Alessandro M. Vannucchi
Journal: American Journal of Hematology (2016)

To the Editor: We thank Dr Elliott and Dr Tefferi for raising such important points in their Letter to the Editor 1 regarding our study on the prognostic impact of bone marrow fibrosis in patients with primary myelofibrosis (PMF) 2. They argue that, since the 2016 revised WHO classification includes fibrosis grade 0 and 1 in the category of preMF 3, the analysis of the impact of fibrosis grade should consider the whole spectrum of disease, thereby including both patients with preMF (fibrosis grade 0-1) and overt MF (fibrosis grade 2–3). Considering the updated WHO criteria, and prior evidences in support of a biological and clinical continuum in MF development and progression 4, we agree that a revised evaluation of the whole series of 540, fully molecular annotated, PMF patients from which the study originated 2 would be informative, and possibly clinically relevant. Therefore, the current analysis deals with 230 patients (42.6%) with fibrosis grade 0–1 (preMF according to the 2016 criteria) and 310 (57.4%) with overt MF (fibrosis grade 2 and 3). Patients with over MF were older, had lower hemoglobin level and were more frequently anemic, had lower platelet count and more frequently circulating blasts ≥1%, presented more frequently constitutional symptoms and splenomegaly and were mostly included in intermediate-2 and high IPSS categories (49% vs 24.7%, P<0.0001) in comparison to patients with preMF (Supporting Information Table I). The current re-analysis confirms a similar distribution of phenotypic driver mutations (JAK2, MPL and CALR), as well as of triple negativity, in preMF and overt MF. Conversely, patients with high molecular risk mutations (HMR) 5, and the proportion of those with ≥2 HMR mutations, were enriched in the overt MF group compared with preMF (37.7% vs. 23.5%, P<.0001; and, 10.3% vs. 3.5%, P<.0001, respectively) (Supporting Information Table I); this was mainly due to a higher proportion of overt MF patients having ASXL1 and EZH2 mutations (28.1% vs. 14.3% and 10% vs. 3.5%; P<.0001 and P = 0.002, respectively), while frequency of SRSF2 and IDH1/2 mutated patients was comparable. Kaplan Meier analysis of overall survival (OS) was conducted separately for each grade of fibrosis (0–3; Fig. 1, panel A) and for 2016 WHO revised diagnosis (preMF vs overt MF; Fig. 1 panel B). The data strengthen the impact of fibrosis grade on overall survival (OS): OS was not reached in grade 0, 14.7 years in grade 1, 6.7 years and 7.2 years in grade 2–3, with statistically significant differences between grade 0 (used as reference) and grade 1 (HR 3.9, 95%CI 1.4-10.9) and grade 2 (HR 7.3, 95%CI 2.7-20.0) and 3 (HR 8.7, 95%CI 3.1-24.2). When preMF (fibrosis grade 0 and 1) and overt MF (grade 2 and 3) were compared each other, OS was significantly shorter in the latter category of patients (HR 2.4, 95%CI 1.7-3.3). Impact of fibrosis grade in bone marrow biopsies at diagnosis on the overall survival (/OS) of patients with PMF. In panel A, patients were divided according to the grade of fibrosis, 0–3; the 0 category was assumed as reference to calculate hazard ratio (HR) and the 95% confidence interval (CI) of the other groups. In panel B, patients were divided in preMF (corresponding to fibrosis grade 0–1) and overt MF (fibrosis grade 2–3) and the OS was calculated; reference group were patients with preMF. In summary, the re-analysis of our series after including patients with grade 0 fibrosis and adopting the 2016 WHO criteria to distinguish preMF and overt MF, as suggested by Drs Elliott and Tefferi, confirm the negative prognostic impact of higher grades of fibrosis and highlight clinical and molecular uniqueness of preMF in comparison to overt MF, indirectly reinforcing the rationale at the basis of the revised WHO diagnostic criteria. Paola Guglielmelli,1,2 Alessandro M. Vannucchi1,2* on behalf of AGIMM Investigators 1CRIMM-Centro Ricerca E Innovazione Delle Malattie Mieloproliferative, Azienda Ospedaliera-Universitaria Careggi, and 2Department of Experimental and Clinical Medicine, University of Florence, DenoThe Excellence Center, Florence, Italy Additional Supporting Information may be found in the online version of this article. Supporting Information Table 1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.