Observational Study on Eltrombopag in Hypocellular Myelodysplastic Neoplasms

Myelodyspastic neoplasms (MDS) are a heterogeneous group of clonal haematopoietic stem cell disorders characterised by ineffective haematopoiesis, morphological dysplasia and a variable risk of transformation into acute myeloid leukaemia (AML). These diseases generally occur in the elderly, with a median age of onset above 70 years.

Recently, major advances in molecular technology and the development of next-generation sequencing (NGS) have deepened our understanding of MDS pathobiology. Hence, the International Consensus Classification (ICC), and the World Health Organization (WHO) proposed in 2022 a revision to the current classification system.

Hypocellular MDS (h-MDS), defined as a bone marrow cellularity of less than 30% in individuals younger than 60 years of age or less than 20% in those older than 70 years, is a new entity included in the WHO-2022 classification but not present in the ICC, accounting for 10-27% of all MDS cases (2,5-7).

The different prevalences of h-MDS are reported because derive from heterogeneity across the studies in the criteria used to define bone marrow hypocellularity, or the inclusion of de novo or both de novo and secondary cases, or differences in genetic and environmental backgrounds among the populations studied and in the possible contamination with patients with aplastic anaemia (AA). Hypocellular MDS are characterized by bone marrow hypoplasia, a low rate of progression to acute myeloid leukemia (AML), and poor response to conventional MDS therapies. For at least some types of AA and MDS, the overwhelming body of evidence points to a shared pathogenesis and, more speculatively, a shared etiology.

The pathogenesis of h-MDS involves immune system activation against hemopoietic precursor, which may explain the favourable response to immunosuppressive therapy.

Recently, based on clinical features and immunologic and molecular studies, two phenotypes of h-MDS were identified and proposed: one with prevailing inflammation and immune activation defined AA-like, and the other characterized by genetic lesions, clonal selection and clonal evolution, named MDS-like.

Differential diagnosis between h-MDS and AA can be difficult as the two pathologies have partially overlapping diagnostic criteria (8,9). Although cellularity easily differentiates h-MDS from normo/hypercellular cases, the distinction from AA is harder when only clinical features are considered. The presence of >10% dysplasia of one lineage would distinguish h-MDS from AA in hypercellular cases and MDS from Idiopatic Cytopenia of Unknown Significance (ICUS). Compared to AA patients, h-MDS are usually older, show marrow dysplasia, and display more BM blasts and more frequent cytogenetic or molecular alterations. The occasional presence of PNH clones in the setting of h-MDS may point toward the diagnosis of AA. Cytogenetic abnormalities are found in about 50% of MDS and FISH analysis could help to better define category group including chromosome 3, 5, and 7 alterations.

Mutational pattern of h-MDS seems to overlap with the classic MDS pattern except for the relative absence of spliceosoma mutations or myeloproliferative features (SRSF2, ZRSR2, U2AF1) and lower frequency of RUNX1, ASXL1, DNMT3A, EZH2, and TP53 mutations.

Using the Internationally Prognostic Scoring System (IPSS) and its revised version (IPSS-R) , h-MDS are classified as low risk and associated with more favourable outcome versus non h-MDS The treatment options used were mainly directed at controlling cytopenias rather than eradication of disease. Lower Risk patients are commonly treated with lower intensity therapies such as hematopoietic growth factors or immunomodulatory agents, while hypomethylating agents, cytotoxic agents, or allo-HCT are typically reserved for higher risk patients.

In some series a hypocellular marrow predicted a higher likelihood of response, analogous to the response to immunosuppressive therapy (IST) in aplastic anemia.

Younger age, normal karyotype or trisomy 8, lack of transfusion dependence, and the presence of a PNH clone predicted response to immunosuppressive therapy, but none is a robust biomarker as responses have also been noted in lower risk MDS patients without these features.

Beyond IST therapy, thrombopoietin receptor agonists (TPO-RA have been studied in MDS with variable response rates.

Eltrombopag, a TPO-RA, was first used to treat thrombocytopenia in patients with idiopathic thrombocytopenic purpura, but has also been shown to improve hematologic response in patients with refractory severe AA and to increase overall and complete responses when combined with standard immunosuppression in treatment-naïve severe AA.

In a phase III study eltrombopag has shown activity in low risk MDS with thrombocytopenia. In a phase II study on 25 LR-MDS patients eltrombopag lead to a bilineage response in 44% of patients and hypocellularity was a predictor of response.

On the basis of this encouraging data eltrombopag has been used in Italy in h_MDS with clinically relevant cytopenias off-label. Data on eltrombopag use outside from clinical trials in a real-world setting, alone or in combination with other IST are missing.