Idiopathic thrombocytopenic purpura future or investigational therapies
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Future or Investigational Therapies
Experimental/Novel Agents
- AMG 531 (Romiplostum; Nplate) is an experimental treatment for stimulating platelet production. It is a thrombopoiesis stimulating Fc-peptide fusion protein (peptibody), a TPO peptide mimetic. Initial clinical trials show it to be effective in chronic ITP.[1]
- The novel agent eltrombopag (AKA Promacta) has been demonstrated to increase platelet counts and decrease bleeding in a dose-dependent manner.[2] It is indicated for the treatment of thrombocytopenia in patients with chronic ITP refractory to steroids, immunoglobulins or splenectomy. It is not indicated for the treatment of thrombocytopenia due to any cause other than ITP (eg NOT MDS). It is a thrombopoietin receptor agonist. It is of note that UGT type enzymes (eg UGT1A1 / UDP-glucoronosyltransferase) are inhibited by Promacta. UGT1A1 polymorphisms, under exposure from Promacta, have a decrease in glucoronidation which means to increased susceptibility to toxicity from some chemotherapy agents such as Irinotecan, for example. Promacta has a rapid onset of action and neither the presence of a spleen nor co-administration of steroids affects its efficacy. Greater than 70% of patients treated had an increase of the platelet count to greater than or equal to 50,000 after 6 weeks. Promacta should only be given to patients with decreased platelets that have an increased risk of bleeding. It should not be given to simply normalize the counts. The goal is to increase the platelet count to greater than 50,000. The usual dose of Promacta is 50 mg; given 25 mg for asian patients or those with hepatic impairment. It must be given on an empty stomach and not with multivitamins (containing cations). Decrease the dose to 25 mg if the platelet count exceeds 200,000; increase the dose to 75 mg if the platelet count decreases to less than 50,000. If the count exceeds 400,000 discontinue the medication; if the count then decreases to less than 150,000 restart the drug at 25 mg QD. Monitor the CBC weekly and the liver function studies q2 weeks.
- Toxicities.
- Hepatotoxicity manifests as an increase in the SGOT / SGPT to 3-4 x normal but no liver failure has been reported. Rarely does the bilirubin increase. It is recommended to discontinue the medication just the same.
- Promacta can cause the development and progression of reticulin fiber deposition in the bone marrow. Also excessive Promacta will cause thrombotic or thromboembolic problems.
- Cataracts
- Approximately 5% of patients on Promacta will have a "rebound thrombocytopenia" on discontinuation of the medication. This thrombocytpenia is usually worse than that which was treated initially and it occurs very quickly. This can lead to bleeding especially if the patient is on anticoagulants or antiplatelet agents. Patients must be monitored with qwk CBC / platelet checks for at least 4 weeks after the discontinuation of Promacta.
- Promacta may increase the risk of progression of underlying MDS or hematologic malignancies. There are thrombopoietin receptors on malignant cells of hematologic malignancies and they can potentially be stimulated by Promacta.
- Dapsone (also called Diphenylsulfone, DDS, or Avlosulfon) is an anti-infective sulfone drug. In recent years Dapsone has also proved helpful in treating lupus, rheumatoid arthritis and as a second-line treatment for ITP. The exact mechanism by which Dapsone assists in ITP is unclear. However, limited studies report successful increases in platelet counts of around 40–50% of patients taking the drug. [3][4]
- TPO is normally produced at a steady rate in the liver. TPO improves the platelet production rate in the bone marrow. Patients can form antibodies against recombinant TPO (rHuTPO) (ref Li et al Blood 2001;98:3241). Pegylated recombinant human megakaryocyte growth and development factor (PEG rHuMGDF) has activity but, like rHuTPO, antibody formation has prohibited its usefullness.
H. Pylori Eradication
- Researchers in Japan (including Ryugo Sato, Oita University) and Italy (including Massimo Franchini, University of Verona) have found a possible connection between H. Pylori (Helicobacter Pylori) infection and ITP. Some patients given antibiotic treatment to eradicate the bacterial infection have had their platelet count increase dramatically.
References
- ↑ Bussel JB, Kuter DJ, George JN; et al. (2006). "AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP". N. Engl. J. Med. 355 (16): 1672–81. doi:10.1056/NEJMoa054626. PMID 17050891.
- ↑ Bussel JB, Cheng G, Saleh MN; et al. (2007). "Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura". N. Engl. J. Med. 357: 2237–2247. PMID 18046028.
- ↑ Godeau B, Durand JM, Roudot-Thoraval F; et al. (1997). "Dapsone for chronic autoimmune thrombocytopenic purpura: a report of 66 cases". Br. J. Haematol. 97 (2): 336–9. PMID 9163598.
- ↑ http://www.itppeople.com/dapsone.htm