Impact of Bone Marrow Fibrosis Grade in Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis. a Study of the Mysec Group
Authors: Mora Barbara , Rumi Elisa , Guglielmelli Paola , Maffioli Margherita , Barraco Daniela , Rambaldi Alessandro , Caramella Marianna , Komrokji Rami S. , Gotlib Jason , Kiladjian Jean-Jacques , Cervantes Francisco , Devos Timothy , Palandri Francesca , De Stefano Valerio , Ruggeri Marco , Silver Richard T. , Benevolo Giulia , Albano Francesco , Cavalloni Chiara , Uccella Silvia , Siracusa Claudia , Barbui Tiziano , Iurlo Alessandra , Bertù Lorenza , Merli Michele , Cazzola Mario , Vannucchi Alessandro M. , Passamonti Francesco 
Published: November 2019

Background: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms that can progress to post-PV (PPV) myelofibrosis (MF) and post-ET (PET) MF, also known as secondary myelofibrosis (SMF). The 2009 International Working Group for Myelofibrosis Research and Treatment group (IWG-MRT) diagnostic criteria for SMF require the presence of grade 2 or 3 bone marrow fibrosis (BMF) according to the European classification.
The prognostic value of BMF in primary MF has been recently explored. Aim of this study is to describe the relevance of BMF grading in terms of presentation and outcome in SMF.
Methods: The MYSEC (Myelofibrosis Secondary to PV and ET Collaboration) project is an international retrospective collaboration that collected 805 SMF cases. BMF grade at time of SMF evolution was defined as grade 2 (BMF2) in case of a diffuse increase in reticulin with extensive intersections, occasional bundles of collagen and/or osteosclerosis, or as grade 3 (BMF3) if presenting with coarse bundles of collagen, often associated with osteosclerosis.
Chi-square or Fisher exact test for categorical variables, Wilcoxon rank-sum test for continuous ones and multiple logistic regression analysis were applied in order to explore pattern of association between BMF grading and patients' characteristics.
A Poisson regression model was applied to estimate incidence rate of events, together with 95% Confidence Interval (CI). Survival was estimated using the Kaplan-Meier method. Differences between BMF groups were compared by a Log-rank test.
The MYSEC study was approved by the Review Board of each Institution and conducted in accordance with the Declaration of Helsinki.
Results: Detailed information about BMF grade was available in 675 patients: BMF2 was reported in 443 (65.6%) and BMF3 in 232 (34.4%). We did not find any correlation between BMF grade and advanced age, marrow blasts percentage, spleen and liver size, presence of constitutional symptoms, abnormal karyotype at the time of SMF diagnosis. No imbalance was evident for gender and for time to progression from PV/ET to SMF. Looking at genotype, BMF grading was not differently distributed among the 3 phenotypic driver mutations as well as the "triple negative" cases.
On the contrary, in univariate analysis we found a significant association between BMF3 and previous diagnosis of ET vs. PV, decreased hemoglobin levels, reduced platelet and leukocyte counts, higher percentage of circulating blast cells and higher LDH value (Table 1).
In a multivariate analysis that took into consideration SMF subtypes, complete blood count and circulating blast cells in 437 SMF patients, PET-MF, lower hemoglobin levels and reduced platelet count maintained their association with BMF3 (Table 2).
The cumulative incidence of thrombosis after SMF was 3.2% (CI 95%: 2.4-4.2) person-year of follow up (PYFU) in BMF2, equivalent to BMF3 (2.7% PYFU, CI 95%: 1.2-5.7) (P = 0.44). Besides, BMF grade did not impact on the cumulative incidence of post-SMF blast phase, which resulted 2.4% (CI 95%: 1.8-3.3) PYFU in case of BMF2 and 3% (CI 95%: 1.3-6.9) PYFU in the BMF3 cohort (P = 0.68).
Overall, MYSEC-PM (MYSEC-Prognostic Model) risk categories were differently distributed between BMF grades: patients with BMF2 were more frequently included in lower risk groups, while those with BMF3 were enriched in the higher categories (Table 1).
Finally, we found a significantly higher mortality in patients with BMF3 vs. BMF2, mainly due to SMF progression (Table 1). Figure 1 shows the Kaplan-Meier estimate of survival in the 2 populations, resulting significantly different. Nevertheless, when considering the MYSEC-PM score in a multivariate analysis, BMF grade lost its prognostic impact on survival.
Conclusions: This study provides evidence that BMF grade does correlate with specific clinical phenotype in SMF. BMF3 was associated with a more "cytopenic" phenotype (lower hemoglobin levels and reduced platelet count) and clustered with higher MYSEC-PM scores. Survival is significantly reduced in patients with BMF3. In conclusion, irrespectively of the PV/ET duration, progressive anemia and thrombocytopenia imply more frequently BMF3, finally resulting in a worse survival. This highlights the need of performing bone marrow biopsy earlier in disease evolution.

Disclosures
Rumi: novartis: Honoraria, Research Funding. Rambaldi:Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau. Komrokji:Incyte: Consultancy; pfizer: Consultancy; JAZZ: Speakers Bureau; celgene: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; Agios: Consultancy; DSI: Consultancy. Gotlib:Deceiphera: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Promedior: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy. Cervantes:Novartis: Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Palandri:Novartis: Consultancy, Honoraria. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Benevolo:Novartis Pharmaceuticals: Consultancy. Albano:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Iurlo:Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria. Vannucchi:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Passamonti:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau.