Bone Marrow Fibrosis in Patients with Inherited Bone Marrow Failure Syndromes.

Bone marrow fibrosis has been reported in many benign and malignant disorders, and it may be associated with a poor prognosis in patients with chronic idiopathic myelofibrosis and adult myelodysplastic syndrome (MDS). There are no data on the incidence or significance of bone marrow fibrosis in patients with the inherited bone marrow failure syndromes (IBMFS), genetic disorders characterized by cytopenias, distinctive clinical features, varied molecular pathways and high risks of MDS and acute myeloid leukemia. We have now studied marrow fibrosis in the four most common IBMFS: Fanconi anemia (FA), Diamond-Blackfan anemia (DBA), dyskeratosis congenita (DC), and Shwachman-Diamond syndrome (SDS).

Blinded bone marrow biopsies were analyzed from 42 patients: 12 FA, 13 DBA, 13 DC, and 4 SDS. Reticulin fibrosis was graded on a scale of 1-4 according to the quantity and pattern of distribution of reticulin. The frequencies of abnormalities in marrow fibrosis, cellularity, MDS, cytogenetic clones, blood counts, erythropoietin levels and treatment were compared between the disorders. Fisher exact test was used to compare frequencies and two-sided Wilcoxon rank sum test was used to compare continuous variables. P value of less than 0.05 was considered statistically significant for all tests.

See Table. Patients with FA, DBA and DC were older than those with SDS; there was an excess of females with FA and males with DC and DBA. Patients with FA, DC and SDS had multilineage cytopenias, while most patients with DBA had only anemia. All patients with FA and DC had bone marrow hypocellularity; it was less frequent in those with DBA or SDS (P<0.001). A significantly higher proportion of patients with FA or DC (75%) had increased reticulin fibrosis (grade 2 or 3) compared with DBA or SDS (P=0.002). Most patients had grade 2 fibrosis; only 2 patients with FA had grade 3 fibrosis, and none had grade 4 fibrosis. In a multivariate analysis, bone marrow fibrosis correlated significantly with the presence of thrombocytopenia (P=0.01) and neutropenia (P=0.01), but not with anemia (P=0.8). The presence of fibrosis correlated significantly with the presence of high erythropoietin levels (P=0.006) and the presence of hypocellularity (P=0.003); contrary to expectations, even very hypocellular marrow biopsies had increased reticulin. Fibrosis did not correlate with the need for treatment, morphologic MDS (P=0.7) or cytogenetic abnormalities (P=0.2).

This is the first report of bone marrow fibrosis in patients with an IBMFS. The frequency of grade 2 or 3 bone marrow fibrosis was as high as 75% in FA and DC. There was a direct correlation between the presence of marrow hypoplasia and fibrosis in patients with FA and DC. Longitudinal studies are required to determine the prognostic significance of increased marrow fibrosis in patients with an IBMFS.

No relevant conflicts of interest to declare.