Clinical Drug Experience Knowledgebase

The incidence of delayed thrombocytopenia in patients who undergo allogeneic hemopoietic stem cell transplant (SCT) is nearly 20-40% (1-2). Chronic graft versus host disease (cGVHD) seems to be the most frequent pathologic condition associated with post SCT delayed thrombocytopenia. Previous studies indicated the occurrence of delayed thrombocytopenia as a poor prognostic factor for the outcome of patients undergoing SCT, particularly for those patients with cGVHD. In our experience, 27 out of 71 patients (38%) developed post SCT delayed thrombocytopenia, with a median platelet count of 29 x 109/L (range 7-86 x 109/L); cGVHD was associated with delayed thrombocytopenia in 54% of cases. The platelet count was >50 <100 x 109/L in 8 patients (30%) patients and 50 x 109/L in 19 (70%) among whom 9 had 20 x 109/L. The median post SCT survival was 12 months in patients who developed delayed thrombocytopenia vs. > 36 months in patients without delayed thrombocytopenia. The rate of patients alive 12, 24 and 33 months after SCT was 41%, 41% and 7% among patients with delayed thrombocytopenia vs. 93%, 87% and 87% (p< 0.0001). In patients with cGVHD the incidence of mortality was significantly higher in those who developed post SCT thrombocytopenia, i.e. 8 out of 13 (61.5%) vs. 2 out of 19 (10.5%) (p=0.005). Our data confirms the results of previous studies. Therefore, the occurrence of delayed thrombocytopenia in patients undergoing SCT is a very poor prognostic factor and the improvement of this condition may favourably affect patients' outcome. The pathophysiology of cGVHD relayed post SCT delayed thrombocytopenia is complex and only partial understood. Biological and clinical evidences support an autoimmune-like thrombocytopenia with increased platelet destruction; this mechanism is also suggested by the response to some therapeutic strategies generally adopted to treat classical immune thrombocytopenia as steroids, high dose intravenous immunoglobulin, splenectomy, rituximab. However a mechanism consistent with impaired platelet production has also been suggested. Adopting an index for plasma glycocalicin, plasma thrombopoietin (TPO), and circulating B cells producing anti-GPIIb-IIIa antibodies, Yamazaki et al. studied 23 SCT recipients who had prolonged and isolated thrombocytopenia with no apparent causes such as engraftment failure, recurrence of the underlying malignancy, microangiopathy or drugs and compared data with those observed in a similar cohort of SCT recipients with no thrombocytopenia, in patients with primary immune thrombocytopenia (ITP) and aplastic anemia. Despite the frequent occurrence of an antiplatelet antibody response, patients with post SCT thrombocytopenia showed a glycocalicin index and TPO status similar to that seen in aplastic anemia. TPO levels were normal in nearly 30% of patients. Recently, Bao et al. showed an improved regulatory T-cell (T-regs) activity in patients with chronic primary immune thrombocytopenia (ITP) treated with thrombolytic agents, suggesting a possible role of platelet count in improving T-reg function and restore immune tolerance.

On this grounds and similarly to ITP, the stimulation of thrombopoiesis with the thrombolytic agents could be beneficial in some patients with persistent post SCT thrombocytopenia both on platelet count and on cGVHD manifestations. Eltrombopag (Revolade) is a thrombopoietin receptor agonist indicated for the treatment of adult patients with ITP relapsed/refractory to splenectomy; eltrombopag may be considered as second line treatment for adult non-splenectomised patients where surgery is contraindicated. Eltrombopag is also under development for the treatment of thrombocytopenia due to hepatitis C virus HCV, for chemotherapy-induced thrombocytopenia and in MDS/AML.