Bone Marrow Fibrosis at Diagnosis and during the Course of Disease Is Associated with TP53 Mutations and Adverse Prognosis in Primary Myelodysplastic Syndrome

Abstract

The prognostic significance of bone marrow fibrosis (MF) grade in patients with myelodysplastic syndrome (MDS) is still debated and the molecular changes remain unclear. In our large cohort, a normal reticulum was found in 211 (25.9%) patients, whereas MF1, MF2 and MF3 were detected in 478 (58.7%), 90 (11.1%) and 35 (4.3%) patients at initial diagnosis, respectively. Patients with MF often correlated with some poor prognostic characteristics, including older age, anemia, unfavorable karyotype, higher BM blast and a higher IPSS-R category. For the entire cohort, the median OS was not reached, 30, 16 and 15 months for patients with MF 0, 1, 2 and 3, respectively. After adjusting for IPSS-R, the hazard ratio for mortality was 1.56 (95% CI, 1.18–2.06) for patients with MF1, 2.29 (95% CI, 1.61–3.27) for patients with MF2 and 2.75 (95% CI, 1.69–4.49) for patients with MF3 compared with those with MF0. The mutational landscape of 370 patients showed that TP53, U2AF1 and KMT2D mutations were more frequent in patients with MF2-3. In addition, of the 408 patients with MF0-1, 62 patients (15.1%) progressed to MF2-3 during the follow-up interval. The clinical features, mutation landscape and prognosis of patients with progressed fibrosis were similar to those of patients with MF2-3 at diagnosis. We concluded that BM fibrosis (MF1, 2 and 3) was an adverse prognosis feature in primary MDS and correlated with TP53 mutations both at the time of initial diagnosis and during the course of the disease. Therefore, BM fibrosis should be included in the revised prognostic scoring system and carefully considered in treatment selection.

Prognostic significance of bone marrow fibrosis in diffuse large B‐cell lymphoma

“…BMF in MDS is associated with deep cytopenias and increased need for red blood cell and platelet transfusion. 10,17,18 The depth of cytopenia and the need for transfusion remain as an important prognostic variable used in MDS patients, included in the International prognostic scoring system (IPSS) and the World Health Organization Prognostic Scoring System (WPSS). In a study of 301 patients with MDS, shorter overall survival and leukemia-free survival were found in patients with grade 2 and 3 BMF, and this effect was interpreted as an independent marker of increased blastic cell population in the bone marrow.…”

“…Another disease in which bone marrow fibrosis is most frequently detected is MDS. BMF in MDS is associated with deep cytopenias and increased need for red blood cell and platelet transfusion 10,17,18 . The depth of cytopenia and the need for transfusion remain as an important prognostic variable used in MDS patients, included in the International prognostic scoring system (IPSS) and the World Health Organization Prognostic Scoring System (WPSS).…”

Progression in Myeloid Neoplasms: Beyond the Myeloblast

“…Although more frequent in MPN, progressive MF occurs in MDS too, more often in occasions, which initially present with JAK2 V617F mutation. This is a very rare finding in MDS, associated with poor outcome that is independent of transformation to sAML [65]. In addition, MF progression is linked to the acquisition of JAK2 and SRSF2 mutations and increased gene expression of MMP2 , MMP14 , SMAD3 , SMAD4 , TGFB1 , THBS1 , TIMP1 , and miR-146b, as well as increased CD42b + pro-platelet deposition in the BM [66].…”

Updates in Classification of Myelodysplastic Syndrome

“…Hence, the nomenclature MDS-f applies only to fibrotic marrow (grade 2 or 3 on a 3-grade scoring system, based on reticulin and trichrome stains) with either 5% to 19% blasts in the bone marrow or 2% to 19% blasts in peripheral blood. Cumulative evidence has shown that MDS-f at the time of initial diagnosis is an independent factor associated with overall worse survival in patients treated with traditional hypomethylating agents 32,33 ; although fibrosis in MDS is associated with TP53 mutations, a multihit TP53 mutation is exclusionary of MDS-f. 8 Importantly, MDS-f does not apply to fibrotic MDS in the setting of low blast count. Given its adverse effect on prognosis that seems to extend to lower blast cases, reticulin staining and fibrosis grading should still be performed even on MDS cases with low blasts.…”