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V. Jachiet et al.
leading to an insufficient marrow compensatory response, a progressive/variable degree of bone marrow dysplasia, and ultimately overt bone marrow failure.19 Even if none of these features is pathognomonic of ITP, the probable peripheral origin of thrombocytopenia in MDS/CMML was based, in our study, on the following: (i) a clear-cut response, either partial or complete, to glucocorticoids; (ii) a discrepancy between an increased megakaryocyte count and profound thrombocytopenia; (iii) prominent dysim- mune features in most cases, including positive antiplatelet antibodies, polyclonal hypergammaglobulinemia and other dysimmune diseases and/or autoantibodies; (iv) the lack of efficacy of platelet transfusions; and (v) mainly low- risk underlying MDS. Isotopic measurement of platelet lifespan and assessment of the site of platelet destruction might help to predict the efficacy of splenectomy in ITP patients24-26 but such investigations are not usually per- formed routinely in France. Mahevas et al. recently showed that platelet kinetic studies could be used to predict the efficacy of splenectomy even in ITP patients treated with TPO-RA.27 Furthermore, Bourgeois et al. showed that 15% of low-risk MDS patients had peripheral platelet destruc- tion, as demonstrated by isotopic autologous platelet kinetic studies.16 However, the small proportion of patients who have benefited from platelet scintigraphy does not allow the results to be generalized in this population of patients with MDS/CMML-associated ITP.
Finally, the most striking conclusion from our study is that ITP in the setting of MDS/CMML could be raised as a hypothesis to explain the thrombocytopenia in some cases and the benefit of immunomodulation could be test- ed in patients who do not need a specific treatment for their MDS.
The most challenging issue is the management of pre-
sumed immune peripheral cytopenias in the setting of MDS/CMML (Figure 4). Few studies have assessed the outcome and management of MDS/CMML-associated ITP. The previous French case series of eight patients showed better response rates to IVIg among patients with primary ITP than among patients with MDS/CMML- associated ITP.15 In this population of elderly patients, TPO-RA seem to be an interesting therapy because of their efficacy in our series and an acceptable safety profile. In a meta-analysis, Dodillet et al. found that treatment with TPO-RA resulted in a lower number of MDS patients suffering from bleeding events. Although some studies have highlighted the potential risk of TPO-RA in acceler- ating leukemic progression or an increase of blasts in MDS patients,28-30 more recent data from randomized controlled trials31-33 and meta-analyses34,35 did not seem to confirm this. Moreover, preclinical studies found that eltrombopag could inhibit leukemic cell growth in tissue culture and in animal models of leukemia.23,36-39 While waiting for further clinical studies, close monitoring of peripheral blood counts and bone marrow and cytogenetic evaluations should be performed in patients who are on TPO-RA. Beyond their effect of stimulating megakaryopoiesis, additional mechanisms of action of TPO-RA include immunomodulating activity, such as the modulation of T- regulatory cells21 and restoration of the Fc-γ receptor bal- ance in phagocytes.40 Finally, the efficacy of TPO-RA in patients with MDS/CMML-associated ITP is probably due to the fact that these drugs are efficient in both ITP and MDS. The efficacy of azacytidine for immune ITP must be interpreted with caution because of the small number of patients treated. An ongoing phase II French trial is currently assessing the efficacy and safety of azacy- tidine in various steroid-dependent/refractory
Figure 4. Proposed therapeutic strategy for suspected immune thrombocytopenia associated with myelodysplastic syndrome or chronic myelomonocytic leukemia.
MDS: myelodysplastic syndrome; CMML: chronic myelomonocytic leukemia; TPO-RA: thrombopoietin receptor agonist.
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haematologica | 2021; 106(5)