Novel Thrombopoietic Agents

Abstract

Thrombocytopenia is a primary manifestation of immune thrombocytopenic purpura (ITP) and may occur as a result of hepatitis C, malignancy, and treatment with chemotherapy. There is a need for additional means to treat thrombocytopenia in these settings. Recombinant thrombopoietin-like agents became available after the cloning of thrombopoietin in 1994. In clinical trials, these agents showed some efficacy in chemotherapy-induced thrombocytopenia, but their use was ultimately discontinued due to the development of neutralizing antibodies that crossreacted with endogenous thrombopoietin and caused thrombocytopenia in healthy blood donors and other recipients. Subsequently, "second-generation" thrombopoietic agents without homology to thrombopoietin were developed. In the past 5 years, these second-generation thrombopoeitic growth factors have undergone substantial clinical development and have demonstrated safety, tolerability and efficacy in subjects with ITP and hepatitis C-related thrombocytopenia. These completed studies, many of which are available only in abstract form, and other ongoing studies suggest that thrombopoietic agents will enhance the hematologist's ability to manage these and other causes of thrombocytopenia.

Controversies in the diagnosis and management of childhood acute immune thrombocytopenic purpura

“…A survey of American Society of Pediatric Hematology Oncology members revealed that only one‐third would recommend splenectomy in a 5‐year‐old child who was refractory to treatment after 1 year 65. Trials of second‐generation thrombopoietic growth factors, such as the thrombopoietin peptide mimetic, AMG531 (Nplate or Romiplastin) and the non‐peptide, eltrombopag, have shown promise in increasing the platelet count in chronic ITP 66–68. All of these treatments should be reserved for patients with chronic, symptomatic disease.…”

Refractory immune thrombocytopenic purpura: current strategies for investigation and management

“…Clinical development of these agents was abruptly halted when both patients and healthy platelet donors receiving PEG‐rHu‐MGDF developed antibodies that cross‐reacted with endogenous TPO, resulting in severe, prolonged thrombocytopenia (Li et al , 2001). Nonetheless, these studies demonstrated ‘proof of principal’ that stimulation of TPO‐receptors with TPO growth factors could successfully and substantially increase platelet counts in healthy individuals, patients with ITP and in other thrombocytopenias (Andemariam et al , 2007).…”

Supportive Care in Pediatric Oncology

“…Prior to discontinuation, both agents had shown benefi ts in children and adults with solid tumors with a trend toward decreased platelet transfusion and level of thrombocytopenia; benefi t on survival was not reported and important side effects included risk for thromboembolism and dosedependent thrombocytosis (Basser et al 1997 ;Fanucchi et al 1997 ;Basser et al 2000 ;Vadhan-Raj et al 2000, 2003Angiolillo et al 2005 ;Muskowitz et al 2007 ). Second-generation TPO-receptor antagonists, notably TPO peptide mimetic romiplostim and non-peptide mimetic eltrombopag, have shown dose-dependent increases in platelet count without the development of neutralizing antibodies and both drugs have been FDA approved for the treatment of ITP in adult patients Andemariam et al 2007 ;Bussel et al 2007 ;Jenkins et al 2007 ;Kuter et al 2008 ;Bussel et al 2009 ). Two small, randomized, placebo-controlled studies in pediatric patients with ITP have similarly shown benefi t with no significant short-term side effects (Bussel et al 2011 ;Elafy et al 2011 ).…”

“…Two small, randomized, placebo-controlled studies in pediatric patients with ITP have similarly shown benefi t with no significant short-term side effects (Bussel et al 2011 ;Elafy et al 2011 ). No study has been published using second-generation TPO-receptor antagonists in chemotherapy-induced thrombocytopenia (Andemariam et al 2007 ). Although longer-term treatment in adult ITP patients has been shown safe, further study on the long-term effect of these agents in pediatric patients, especially in regard to the potential for thrombosis, tumor or leukemic cell growth, development of neutralizing antibodies and increased bone marrow reticulin or collagen deposition, is warranted Kuter et al 2013 ).…”