Eltrombopag use in higher risk myeloid cancers: fitting a square “pag” into a round hole?
Mené sur 148 patients atteints d'une leucémie myéloïde aiguë, cet essai de phase II évalue la toxicité de l'eltrombopag (un agoniste du récepteur de la thrombopoïétine) dispensé pendant une chimiothérapie d'induction à base d'anthracyclines
There is a need and belief for eltrombopag to be a potent adjuvant anticancer and supportive care drug for patients with higher risk myelodysplastic syndromes and acute myeloid leukaemia. Thrombocytopenia and bleeding are prevalent, necessitating the administration of short-lived platelet transfusions associated with infections and alloimmunisation. Eltrombopag binds to a transmembrane domain of the thrombopoietin receptor, an effect that is additive to that of thrombopoietin. Preclinical evidence suggests that eltrombopag might have potent antileukaemic effects independent of the thrombopoietin receptor by modulating the intracellular iron content and inducing myeloid differentiation, without stimulating leukaemia cell-line proliferation. Preclinical evidence also suggests that eltrombopag combined with lenalidomide is antiproliferative toward leukaemia cell growth while retaining the stimulatory effect toward megakaryocyte growth. Most importantly, previous randomised controlled trials showed safety and efficacy with eltrombopag monotherapy in higher risk myelodysplastic syndromes and acute myeloid leukaemia. In the initial smaller randomised phase 1–2 trial, eltrombopag was safe in a high-risk myelodysplastic syndrome and acute myeloid leukaemia population and resulted in numerically lower incidences of grade 3–4 bleeding and higher incidences of platelet transfusion independence, without a deleterious effect on leukaemia-free survival in patients with acute myeloid leukaemia or high-risk myelodysplastic syndromes. In the ensuing ASPIRE study, a lower incidence of clinically relevant thrombocytopenia events was seen in the eltrombopag group than the placebo group (54% vs 69%; p=0·03), although this result was a composite endpoint that included a platelet count of less than 10 × 10 9/L (the dominant factor that was improved). No differences were found in progression-free survival or leukaemia-free survival, quality of life, incidences of haematological improvement, the number of units of platelets transfused, and grades 3–4 bleeding (6% vs 13%), although the proportion of patients with no bleeding overall was higher with eltrombopag than placebo.
The Lancet Haematology , commentaire, 2018