The association of rituximab and a thrombopoietin receptor agonist in high-risk refractory immune thrombocytopenic purpura

Dear Sir,

We describe here the case of a young patient with severe immune thrombocytopenic purpura (ITP) unresponsive to intravenous immunoglobulin (IVIg) and steroids in whom the association of rituximab with a thrombopoietin receptor (TPO-R) agonist rapidly led to a sustained increase in platelet count.

A 31-year old man was admitted to his local hospital on December 26^th, 2011 because of a sudden onset of diffuse petechiae and purpura, together with mild gingival and nose bleeding. The haemogram showed severe thrombocytopenia (2×10⁹/L). The other blood cell counts and differential were normal. Examination of a peripheral blood smear confirmed thrombocytopenia without other abnormalities. At bone marrow smear examination megakaryocytic hyperplasia in the absence of additional abnormal findings was observed. On the basis of these findings, and despite the search for antiplatelet antibodies were negative, the diagnosis of ITP was made. Although prompt and appropriate treatment with steroids (prednisolone 1 mg/kg/day), IVIg (400 mg/kg/day for 5 days) and daily platelet infusions, the platelet count remained far below 10×10⁹/L and haematuria also occurred during the following days. On January 4^th, 2012 the patient was admitted to our section of Haematology, when his platelet count was 3×10⁹/L associated with severe haemorrhagic manifestations. One more cycle of IVIg (1 g/kg for 1 day) and high-dose dexamethasone (40 mg/d for 5 days) were administered without any improvement of the platelet count or the haemorrhagic syndrome. Splenectomy did not appear feasible because of the risk of the procedure in a patient such a very low platelet count.

Since the patient appeared to be at a high risk of fatal bleeding, contemporary treatment with rituximab and a TPO-R agonist was taken into consideration. Our aim was to obtain a rapid increase of platelet count promoted by the TPO-R agonist¹, which could act as a bridge therapy until the later response eventually obtained by rituximab. The planned therapy was applied from January 11^th (rituximab 375 mg/m² once a week for 4 weeks and romiplostim 1 mg/kg once a week for 6 weeks). As assumed, over the next 7 days the platelet count increased up to 110×10⁹/L, and there was a progressive resolution of haemorrhagic manifestations. One month later the platelet count was within the normal range (284×10⁹/L) and remained stable over time after the discontinuation of the TPO-R agonist. At the last control (October 19^th, 2014) the platelet count was 252×10⁹/L (Figure 1).

Figure 1.

Treatment and platelet count over time.

TPOR-a: thrombopoietin rceceptor agonist; PDN 100: prednisolone 100 mg/day for 7 days; IVI g: intravenous immunoglobulin 400 mg//kg/day for 5 days; DMS: dexamethasone 40 mg/day for 5 days; IVI g 1 gr: intravenous immunoglobulin 1 g/kg for 1 day.

Thrombocytopenia in ITP can be associated with increased platelet destruction and/or insufficient platelet production². The association of an immunomodulatory agent with a TPO-R agonist may, therefore, have enhanced efficacy. Rituximab reduces platelet destruction through an immunomodulatory effect, depleting B cells, increasing T CD4+ regulatory cells and down-regulating the immunoreactivity of dendritic cells. A persistent response is present in about 40% of cases after 2 years. However, the increase in platelet count may require some weeks to be achieved³. In contrast, it is supposed that TPO-R agonists mainly stimulate platelet production, promoting a rapid increase in platelet count which does not persist after discontinuation of the drugs. As a consequence, the temporary use of a TPO-R agonist might be considered at the beginning in severe and symptomatic ITP, when IVIg and steroids have been ineffective. The rapid increase of platelet count might safely cover the wait for response to other therapy, such as rituximab, or enable splenectomy to be performed safely, if feasible. However, Mahevas et al. reported prolonged remissions in 8/28 (29%) adults with chronic ITP after temporary use of TPO-R agonists alone⁴. The patients, initially unresponsive to steroids, received a TPO-R mimetic at least 6 months after an eventual splenectomy or treatment with rituximab. The authors concluded that the effects of TPO-R mimetics are not limited to causing proliferation of megakaryocytes in ITP. In fact, it has been reported that during treatment with TPO-R agonists treatment there was a significant reduction in the serum titre of antiplatelet antibodies and rescue of T CD4+ regulatory cells in an ITP mouse model, and the restoration of T CD4+ regulatory balance and activation of the JAK/STAT signalling pathway in ITP patients. As a consequence, it is possible that TPO-R may also have immunomodulatory effects. In our opinion, clinical studies evaluating the results of temporary treatment with TPO-R, in association with conventional therapy, in adults with severe ITP at diagnosis would be of great interest.