Megakaryocyte Growth Factors

MEGAKARYOCYTE GROWTH FACTORS

Patients with thrombocytopenia have a high risk of hemorrhage. Although platelet transfusion is commonly used to treat throm-bocytopenia, this procedure can cause adverse reactions in the recipient; furthermore, a significant number of patients fail to exhibit the expected increase in platelet count. Thrombopoietin and IL-11 both appear to be key endogenous regulators of plate-let production. A recombinant form of IL-11 was the first agent to gain FDA approval for treatment of thrombocytopenia. Recombinant human thrombopoietin and a pegylated form of a shortened human thrombopoietin protein underwent extensive clinical investigation in the 1990s. However, further develop-ment was abandoned after autoantibodies to the native throm-bopoietin formed in healthy human subjects and caused thrombocytopenia. Efforts shifted to investigation of novel, non-immunogenic peptide agonists of the thrombopoietin receptor, which is known as Mpl. The first of these—romiplostim—was approved by the FDA for idiopathic thrombocytopenic purpura in 2008.

Chemistry & Pharmacokinetics

Interleukin-11 is a 65–85 kDa protein produced by fibroblastsand stromal cells in the bone marrow. Oprelvekin, the recombi-nant form of IL-11 approved for clinical use (Table 33–4), is produced by expression in Escherichia coli. The half-life of IL-11 is 7–8 hours when the drug is injected subcutaneously.

Romiplostim (AMG 531) is a member of new class of thera-peutics called “peptibodies,” which are peptides with key biologic activities covalently linked to antibody fragments that serve to extend the peptide’s half-life. Romiplostim contains two disulfide-bonded human F_c fragments, each covalently attached through a polyglycine sequence to a peptide chain containing two Mpl-binding peptides that are linked to one another by a second poly-glycine sequence. The Mpl-binding peptide was selected from a peptide library based on its ability in cell assays to activate the thrombopoietin receptor. The Mpl-binding peptide has no sequence homology with human thrombopoietin and there is no evidence in animal or human studies that the Mpl-binding pep-tide or romiplostim induces antibodies to thrombopoietin. After subcutaneous administration, romiplostim is eliminated by the reticuloendothelial system with an average half-life of 3–4 days. Its half-life is inversely related to the serum platelet count; it has a longer half-life in patients with thrombocytopenia and a shorter half-life in patients whose platelet counts have recovered to nor-mal levels.Eltrombopag, an orally active small molecule agonist at thethrombopoietin receptor, was licensed in 2008 for use in patients with severe idiopathic thrombocytopenia who have failed to respond adequately to first-line treatments. Because of concerns about hepatotoxicity and hemorrhage, eltrombopag is restricted to use by registered physicians and patients and its use requires close monitoring of liver enzymes.

Pharmacodynamics

Interleukin-11 acts through a specific cell surface cytokine recep-tor to stimulate the growth of multiple lymphoid and myeloid cells. It acts synergistically with other growth factors to stimulate the growth of primitive megakaryocytic progenitors and, most importantly, increases the number of peripheral platelets and neutrophils.

Romiplostim has high affinity for the human Mpl receptor. It causes a dose-dependent increase in platelet count that begins on day 5 after subcutaneous administration and peaks at days 12–15.

Clinical Pharmacology

Interleukin-11 is approved for the secondary prevention of throm-bocytopenia in patients receiving cytotoxic chemotherapy for treatment of nonmyeloid cancers. Clinical trials show that it reduces the number of platelet transfusions required by patients who experience severe thrombocytopenia after a previous cycle of chemotherapy. Although IL-11 has broad stimulatory effects on hematopoietic cell lineages in vitro, it does not appear to have significant effects on the leukopenia caused by myelosuppressive chemotherapy. Interleukin-11 is given by subcutaneous injection at a dose of 50 mcg/kg/d. It is started 6–24 hours after completionof chemotherapy and continued for 14–21 days or until the plate-let count passes the nadir and rises to more than 50,000 cells/μL.

In patients with chronic idiopathic thrombocytopenia (ITP) who failed to respond adequately to previous treatment with ste-roids, immunoglobulins, or splenectomy, romiplostim signifi-cantly increased platelet count in most patients. In a 6-week placebo-controlled study in which patients were treated weekly with 1 or 3 mcg/kg, 12 of 16 patients reached the targeted platelet range of 50,000–450,000 platelets/μL. Romiplostim does not appear to decrease the rate of platelet destruction in ITP as platelet counts returned to pretreatment levels after the drug’s discontinu-ation. An open label trial found that many patients maintained a platelet count of 100,000 platelets/μL or higher over a 48-week period and that over half of the patients were able to discontinue other therapies. Romiplostim is initiated as a weekly subcutaneous dose of 1 mcg/kg and then continued at the lowest dose required to maintain a platelet count of at least 50,000 platelets/μL.

Toxicity

The most common adverse effects of IL-11 are fatigue, headache, dizziness, and cardiovascular effects. The cardiovascular effects include anemia (due to hemodilution), dyspnea (due to fluid accu-mulation in the lungs), and transient atrial arrhythmias. Hypokalemia has also been seen in some patients. All of these adverse effects appear to be reversible.

Romiplostim appears to be well tolerated except for a mild head-ache on the day of administration. A potential long-term concern is that two patients treated with romiplostim had an increase in bone marrow reticulin, a possible marker of myelodysplastic or myelopro-liferative processes. However, neither patient had evidence of increased collagen fibrosis or of abnormal bone marrow cytogenetics.