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

Simple Summary To understand the role of bone marrow fibrosis and its molecular changes in myelodysplastic syndrome, we retrospectively analyzed data from 814 patients. Older age, lower hemoglobin, unfavorable karyotype and higher BM blast were more often observed in patients with moderate/severe fibrosis. Cases with bone marrow fibrosis had reduced overall survival. TP53, U2AF1 and KMT2D mutations were more frequent in patients with moderate/severe fibrosis. In addition, 15.1% of patients progressed to moderate/severe fibrosis during the follow-up interval. The clinical features, mutation landscape and prognosis of patients with progressed fibrosis were similar to those patients with moderate/severe fibrosis at diagnosis. We concluded that bone marrow fibrosis was associated with reduced overall survival in primary MDS and correlated with TP53 mutations both at the time of initial diagnosis and during the course of the disease. 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.

Automated summary

The presence of bone marrow fibrosis in patients with myelodysplastic syndrome is associated with adverse prognostic characteristics, reduced overall survival, and higher frequency of TP53, U2AF1, and KMT2D mutations. Progression to moderate/severe fibrosis is observed in a subset of patients during follow-up, with similar clinical features, mutation landscape, and prognosis to those with fibrosis at diagnosis. These findings highlight the importance of considering bone marrow fibrosis in the prognosis and treatment selection for MDS patients.