The grade of stromal changes impacts on prognosis in patients with primary myelofibrosis

Background: Recently, a detailed grading system for the assessment of bone marrow stromal changes has been proposed in primary myelofibrosis, proved to be reproducible and adopted by the updated WHO 2016 classification. Aims: In this study, we aim to evaluate any possible prognostic implications of this grading system in a series of patients with primary myelofibrosis. Methods: The study involved 122 consecutive patients with primary myelofibrosis diagnosed between 1998 and 2015 at the Oncohematology Division of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan, for which an adequate bone marrow trephine biopsy (more than 1 cm in length) performed at the time of first observation was available, together with complete clinical, laboratory and follow-up data. Results: Reticulin myelofibrosis (MF), collagen deposition (Co) and osteosclerosis (Ost) were evaluated and graded from 0 to 3 in the bone marrow trephine biopsies for each patient at diagnosis. In detail, the stromal changes were graded as follows: bone marrow fibrosis: MF-0 in 9 cases, MF-1 in 60, MF-2 in 31 and MF-3 in 22; collagen deposition: Co-0 in 64 cases, Co-1 in 23, Co-2 in 21 and Co-3 in 14; osteosclerosis: Ost-0 in 72 cases, Ost-1 in 24, Ost-2 in 19 and Ost-3 in 7. Patients’ population was composed of 56 males and 66 females (M/F=1/1,2) with a median age at diagnosis of 68 years (range 30–85). Clinically, at presentation, anemia with hemoglobin values less than 10 g/dL was present in 20 (16%) patients, leukocytosis more than 25 x109/L was identifiable in 4 (3%) patients, and platelets count less than 100 x109/L in 7 (6%) cases. JAK2V617F mutation was detected in 81 cases (66%). Among the remaining 41 JAK2-negative patients, 4 and 27 carried MPL and CALR mutations, respectively; 10 out of 122 resulted “triple-negative”. According to the International Prognostic Scoring System, 38 cases were stratified as low risk, 51 as intermediate-1 risk, 21 as intermediate-2 risk, and the remaining 12 as high risk. By the time of the analysis, 21 (17%) patients had died: leukemic evolution occurred in 14 (11.5%) patients, whereas thrombotic or hemorrhagic events occurred in 25 (20.5%). Subsequently, a comprehensive grade of bone marrow stromal changes ranging from 0 to 9 allows us to distinguish 88 (72%) cases with low-grade stromal changes (total score: 0-4) and 34 (28%) with high-grade stromal changes (total score: 5-9). Clinically, patients with high-grade stromal changes presented more frequently with anemia, thrombocytopenia, leukocytosis, peripheral blood blasts and increased lactate dehydrogenase levels. The grade of bone marrow stromal changes resulted strictly associated with the International Prognostic Scoring System and the overall mortality (low-grade: 10 dead out of 88 vs high-grade: 11 dead patients out of 34; p=0.013). Finally, the grade of bone marrow stromal changes was effective in discriminating the overall survival of the patients with low-grade and high-grade stromal changes (Log-Rank test: p=0.0002). Summary/Conclusions: A detail evaluation of the bone marrow stromal changes has important prognostic implications and can be used at diagnosis in the clinical stratification of the patients affected by primary myelofibrosis. Further studies are needed to test if the prognostic significance of this grading system remains during the follow-up.