The proliferation index of specific bone marrow cell compartments from myelodysplastic syndromes is associated with the diagnostic and patient outcome

Abstract

Myelodysplastic syndromes (MDS) are clonal stem cell disorders which frequently show a hypercellular dysplastic bone marrow (BM) associated with inefficient hematopoiesis and peripheral cytopenias due to increased apoptosis and maturation blockades. Currently, little is known about the role of cell proliferation in compensating for the BM failure syndrome and in determining patient outcome. Here, we analyzed the proliferation index (PI) of different compartments of BM hematopoietic cells in 106 MDS patients compared to both normal/reactive BM (n = 94) and acute myeloid leukemia (AML; n = 30 cases) using multiparameter flow cytometry. Our results show abnormally increased overall BM proliferation profiles in MDS which significantly differ between early/low-risk and advanced/high-risk cases. Early/low-risk patients showed increased proliferation of non-lymphoid CD34(+) precursors, maturing neutrophils and nucleated red blood cells (NRBC), while the PI of these compartments of BM precursors progressively fell below normal values towards AML levels in advanced/high-risk MDS. Decreased proliferation of non-lymphoid CD34(+) and NRBC precursors was significantly associated with adverse disease features, shorter overall survival (OS) and transformation to AML, both in the whole series and when low- and high-risk MDS patients were separately considered, the PI of NRBC emerging as the most powerful independent predictor for OS and progression to AML. In conclusion, assessment of the PI of NRBC, and potentially also of other compartments of BM precursors (e.g.: myeloid CD34(+) HPC), could significantly contribute to a better management of MDS.

Figure 1. Impact of currently used prognostic classifications and other disease features on overall survival and risk of transformation to acute leukemia (AL) of patients with myelodysplastic syndromes (MDS; n = 106).

Overall survival (left column) and progression-free survival (transformation to AL; right column) curves are plotted for patients with MDS grouped according to the International Prognostic Scoring System (IPSS; row A), the World Health Organization-based Scoring System (WPSS; row B), the number of peripheral blood platelets at diagnosis (row C), the presence of multiple cytopenias (row D), transfusion dependency (row E), and serum LDH levels (row F).

Figure 2. Impact of the proliferation index (PI) of BM non-lymphoid (e.g.: myeloid plus immature) CD34⁺ precursors and nucleated red blood cells (NRBC) on the overall survival and progression (transformation to acute leukemia; AL) free survival of patients with myelodysplastic syndromes (MDS).

Overall survival and progression-free survival curves are plotted for groups of MDS patients classified according to the PI of non-lymphoid (e.g.: myeloid plus immature) CD34⁺ cells (panels A to D) and NRBC (panels E to H). In the left column all MDS patients (n = 106) are analyzed together, while in the right column only MDS patients in the low plus intermediate-1 IPSS risk categories (n = 56) are considered.