Oprelvekin

Abstract: Thrombocytopenia occurs at various grades of severity in patients with nonmyeloid malignancies undergoing chemotherapy with myelosuppressive agents. Frequently, it is the major dose-limiting hematologic toxicity, especially in the treatment of potentially curable malignancies such as leukemia, lymphomas, and pediatric cancers. This is becoming increasingly important given the recent trend toward the use of dose-intensive combination chemotherapy regimens facilitated by supportive hematopoietic colony-stimulating factors to prevent chemotherapy-induced febrile neutropenia. The standard preventive measure against chemotherapy-induced depression of platelets in subsequent treatment cycles has been dose reduction and/or dose delay. However, follow-up data from studies in various populations of patients with cancer suggest a correlation between delivery of lower than intended doses and poor outcomes, including reduced disease-free periods and overall survival. Other consequences of thrombocytopenia include the need for platelet transfusions and subsequent exposure to the risk of numerous complications, including bacterial and viral infections; febrile, nonhemolytic transfusion reactions; and transfusion-induced immunosuppression. Furthermore, a large proportion of multitransfused patients become refractory to subsequent infusions. Refractoriness to platelet transfusions is quickly becoming more prominent. The availability of a platelet growth factor--recombinant human interleukin-11(rhIL-11, also known as oprelvekin [Neumega])--provides an effective means of preventing chemotherapy-induced thrombocytopenia and accelerating platelet recovery, thereby facilitating the administration of full doses of chemotherapy during subsequent cycles and avoiding the need for rescue with platelet transfusions.

Abstract: Thrombocytopenia in patients with chronic hepatitis C virus (HCV) infection is a major problem. The pathophysiology is multifactorial, with auto-immunogenicity, direct bone marrow suppression, hypersplenism, decreased production of thrombopoietin and therapeutic adverse effect all contributing to thrombocytopenia in different measures. The greatest challenge in the care of chronic HCV patients with thrombocytopenia is the difficulty in initiating or maintaining IFN containing anti-viral therapy. Although at present, it is possible to avoid this challenge with the use of the sole Direct Antiviral Agents ( DAAs) as the primary treatment modality, thrombocytopenia remains of particular interest, especially in cases of advanced liver disease. The increased risk of bleeding with thrombocytopenia may also impede the initiation and maintenance of different invasive diagnostic and therapeutic procedures. While eradication of HCV infection itself is the most practical strategy for the remission of thrombocytopenia, various pharmacological and non-pharmacological therapeutic options, which vary in their effectiveness and adverse effect profiles, are available. Sustained increase in platelet count is seen with splenectomy and splenic artery embolization, in contrast to only transient rise with platelet transfusion. However, their routine use is limited by complications. Different thrombopoietin analogues have been tried. The use of synthetic thrombopoietins, such as recombinant human TPO and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMDGF), has been hampered by the development of neutralizing antibodies. Thrombopoietin-mimetic agents, in particular, eltrombopag and romiplostim, have been shown to be safe and effective for HCV-related thrombocytopenia in various studies, and they increase platelet count without eliciting any immunogenicity Other treatment modalities including newer TPO analogues- AMG-51, PEG-TPOmp and AKR-501, recombinant human IL- 11 (rhIL-11, Oprelvekin), recombinant human erythropoietin (rhEPO), danazol and L-carnitine have shown promising early result with improving thrombocytopenia. Thrombocytopenia in chronic HCV infection remain a major problem, however the recent change in DAAs without IFN, as the frontline therapy for HCV, permit to avoid the dilemmas associated with initiating or maintaining IFN based anti-viral therapy.

Abstract: Safety data from two randomized phase II and one abbreviated phase III placebo-controlled, double-blind clinical studies in adult patients with nonmyeloid malignancies indicate that recombinant human interleukin-11 (rhIL-11, also known as oprelvekin [Neumega]) has an acceptable toxicity profile as therapy for the mitigation of chemotherapy-induced thrombocytopenia. Preliminary data also indicate that rhIL-11 is well tolerated by pediatric patients with similar types of cancers. Adverse events associated with rhIL-11 are generally mild or moderate, reversible with drug discontinuation, and easily managed. Many of the common adverse events of rhIL-11--including edema, dyspnea, pleural effusions, conjunctival injection, and in some patients, atrial arrhythmia--occur in association with fluid retention. However, these adverse events can be medically managed and need not limit the use of rhIL-11, particularly if ameliorative measures, such as salt restriction and occasional prophylaxis with a potassium-sparing diuretic to minimize peripheral edema, have been instituted along with close monitoring of fluid and electrolyte status. Such measures are suggested for any patient treated with a diuretic, especially patients with cancer who are receiving multiple medications that complicate overall care. Administration of sequential cycles of rhIL-11 treatment does not appear to result in an increased incidence of adverse events or bone marrow exhaustion. rhIL-11 does not appear to interact adversely with concomitantly administered chemotherapeutic agents or agents commonly used for supportive care, including granulocyte colony-stimulating factor (G-CSF, filgrastim [Neu-pogen]).

Abstract: UNLABELLED Oprelvekin is a recombinant human interleukin-11. Its predominant haemopoietic activity is stimulation of megakaryocytopoiesis. Oprelvekin is indicated for the prevention of severe thrombocytopenia and the reduction of platelet transfusion requirements following myelosuppressive chemotherapy in patients with nonmyeloid malignancies at high risk of severe thrombocytopenia. It is the first available pharmacological alternative to platelet transfusions for these patients. Oprelvekin stimulates platelet progenitor cells (megakaryoblasts and colony-forming unit megakaryocytes). The drug also increases megakaryocyte size and ploidy. The recommended adult dosage of subcutaneous oprelvekin is 50 microg/kg once daily, administered until the platelet count is >or=50 000/microl after the expected nadir, but for not more than 21 days per chemotherapy cycle. Three placebo-controlled trials involving patients with cancer (mostly breast cancer) undergoing dose-intensive cancer chemotherapy, with or without autologous bone marrow transplantation (n = 75 to 82), have been conducted. Compared with placebo, oprelvekin 50 microg/kg/day was associated with significantly fewer patients requiring platelet transfusions and a trend towards a lower median number of platelet transfusions. There was also at least a trend towards reduced time to platelet recovery in oprelvekin recipients. The efficacy of oprelvekin is unaffected by previous platelet transfusion requirements and/or chemotherapy. To date the drug has not been shown to ameliorate chemotherapy-induced leucopenia or neutropenia or to have effects on time to neutrophil engraftment or red blood cell transfusion requirements in clinical trials. The most common adverse events with this agent (oedema and dyspnoea) are considered attributable to drug-induced fluid retention and increased plasma volume; these events are usually mild to moderate, reversible on drug discontinuation and dose related. Cardiovascular events including atrial arrhythmias are also considered attributable to increased plasma volume. CONCLUSIONS Evidence suggests that oprelvekin reduces severe thrombocytopenia, accelerates platelet recovery and reduces the need for platelet transfusions in patients with nonmyeloid malignancies receiving chemotherapy regimens associated with severe thrombocytopenia. If further studies confirm these findings, oprelvekin is likely to be a valuable means of allowing patients to receive their full planned chemotherapy course.