Читать книгу Pathy's Principles and Practice of Geriatric Medicine - Группа авторов - Страница 631

Platelet growth factors have been an area of active research and investigation. Thrombopoietin is the endogenous hormone responsible for maintaining normal platelet counts. A pegylated derivative, megakaryocyte growth and development factor (MGDF), has been tested as an adjunct to supportive care in patients with AML induction therapy.^90,91 Its use did not decrease bleeding complications or reduce platelet transfusions in AML. Furthermore, when tested in healthy volunteers, it resulted in antiplatelet antibodies and thrombocytopenia, halting further development of this compound. Low doses of recombinant human interleukin‐11, a thrombopoietic cytokine, have been tested in patients with MDS and bone marrow failure.⁹² Five of 11 evaluable patients with MDS had an increase of platelet counts with a median duration of 12–30 weeks. Side effects even at low doses included fluid retention, peripheral oedema, conjunctival injection, and myalgias. Romiplostin, a peptibody found to increase platelet production through the thrombopoietin (TPO) receptor c‐Mpl, has been tested in clinical studies involving healthy volunteers and patients with chronic immune thrombocytopenia and found to increase the platelet count.⁹³ In a phase 1 study using this agent as part of supportive care in patients with lower‐risk MDS, with baseline platelet counts of ≤50 × 10⁹ l⁻¹,⁹⁴ durable platelet responses were achieved in 19 of 44 patients (46%). Bleeding events and platelet transfusions were reduced in those patients who had sustained responses. One thrombotic event was noted, and reticulin grade in the marrow was increased in 7 patients, unchanged in 10 patients, and decreased in 7 patients. Non‐neutralizing antibodies to either romiplostim or endogenous TPO were found. Of concern was that two patients progressed to AML in the study, and four cases of transiently increased blast counts were noted. No changes in cytogenetics were noted for patients with baseline and end‐of‐study cytogenetics available. Romiplostim has been tested in patients with low‐ or intermediate‐risk MDS receiving azacitidine therapy as an adjunct to supportive care.⁹⁵ There was no statistically significant difference seen in the groups receiving romiplostim 500 or 750 μg or placebo in terms of clinically significant thrombocytopenic events or platelet transfusions. However, romiplostim 750 μg significantly raised the median platelet count during cycle 3 on day 1 and at the nadir compared with the placebo.

Eltrombopag is an oral small‐molecule non‐peptide agonist of the thrombopoietin receptor. In a phase 1 placebo‐controlled clinical trial of 73 healthy male subjects, eltrombopag given once daily in doses ranging from 5 to 75 mg resulted in a dose‐dependent increase in the platelet count. There were no adverse events in the subjects receiving drug or placebo.⁹⁶ Eltrombopag is currently being studied in patients with high‐risk MDS.