Platelet Growth Factors


Platelet growth factors or thrombopoietin (TPO) receptor agonsists, including romiplostim (Nplate®) and eltrombopag (Promacta®/Revolade®) stimulate the bone marrow to produce more platelets. Once thought to be only a disease of platelet destruction, recent research has shown that many people with ITP also have a platelet production problem.

TPO, a protein made in the liver, naturally stimulates platelet production in the bone marrow. TPO receptor agonists bind to the same receptor in the bone marrow as the TPO produced in the body. This prompts cells in the bone marrow to produce more platelets, sufficient enough to increase the platelet count in most people with ITP.

About 80 percent of people with ITP who receive treatment with platelet growth factors respond as long as the treatments are given.2 However, a small percent of people are able to discontinue these treatments and maintain a safe platelet count.It is important to understand the goal of these treatments is a platelet count of about 50,000/ml (per milliliter), not a normal platelet count.

The TPO receptor agonists romiplostim (Nplate) and eltrombopag (Promacta/Revolade) are approved by the Food and Drug Administration (FDA) for adults and by regulatory agencies in some other countries; eltrombopag was approved by the FDA for limited use in children in June 2015. Clinical trials are ongoing for other TPO receptor agonists.


Romiplostim (Nplate)

Romiplostim is a manufactured peptibody (part peptide and part antibody) liquid that is given through weekly subcutaneous (under the skin) injection. On September 4, 2008 the FDA approved romiplostim for adults with ITP (either splenectomized or not) who have failed at least one other treatment for the disease;3 other countries have since approved its use, sometimes adding other criteria.


Eltrombopag (Promacta/Revolade)

Eltrombopag is a small pill taken daily. The drug gained FDA approval in 2008 for use in adults with ITP with the same approval criteria as romiplostim. In addition, eltrombopag was FDA approved in 2015 for treatment of ITP in children under age 18.3 Other countries have also approved its use, sometimes adding other criteria.


Dosage

Romiplostim: The dose of romiplostim, from 1ug/kg (micrograms per kilogram) to 10 ug/kg, depends on the patient's weight and response to previous doses. The dose is reduced or discontinued if the platelet count rises too high or if the patient doesn't respond.2

Eltrombopag: The pill is given as a 25, 50 or 75 mg (milligram) daily dose. It must be taken on an empty stomach as other medications and food affect its absorption.2 People of Japanese heritage require a lower starting dose.7

When discontinuing these treatments, some doctors reduce the dose gradually to avoid a sharp drop in the platelet count.


Side Effects

Romiplostim: The most common adverse reactions are joint and muscle pain, dizziness, insomnia, indigestion, and a ‘pins and needles’ sensation. There is a slight potential for patients to develop reticulum (fibrous growths) in the bone marrow and also for the platelet count to drop below the pre-treatment count when the treatment is discontinued.6

Eltrombopag: The most common adverse reaction is a mild to moderate headache. Other side effects include nausea, diarrhea, upper respiratory tract infection, vomiting, rash, flu, sore throat, back pain, and tingling or numbness in the skin.8 A small percent of people develop elevated liver functions, which usually resolves when the treatment is discontinued.9


Assistance Programs

Because these treatments are expensive, the manufacturers of both romiplostim and eltrombopag have established several programs to assist those in the United States who are uninsured, underinsured or who cannot meet the insurance co-payments.

Romiplostim (NPlate) Financial Assistance (Amgen)

Eltrombopag (Promacta) Patient assistance program (Novartis)

In December 2011, the FDA approved modifications to the Risk Evaluation and Mitigation Strategies (REMS) for platelet-booster drugs romiplostim injection and eltrombopag tablets. The modifications include removal of certain elements of the REMS, including the requirements for restricted distribution and additional safety data collection. The FDA no longer requires patient participation in the NEXUS or CARES programs of the two drug companies.12


Predicting Success

Since these treatments stimulate TPO production, patients who produce a lot of TPO on their own may not benefit. In one study, patients with TPO levels greater than 95pg/mL (picogram per milliliter) did not respond well to the TPO agents.11 Quest Diagnostics has a test to measure TPO levels (test no. 16336)

In a separate study, the platelet lifespan of people who were able to sustain a remission were normal and able to be removed from the body in the same way as those without the disease.10


References

  1. Ghadaki B et al. "Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists." Transfusion. 2013 Mar 3.
    http://www.ncbi.nlm.nih.gov/pubmed/23451917"
  2. Provan, D, “International consensus report on the investigation and management of primary immune thrombocytopenia,” Blood. 2010 Jan 14; 115(2):168-86. http://bloodjournal.hematologylibrary.org/cgi/content/full/115/2/168
  3. https://www.cancer.gov/about-cancer/treatment/drugs/fda-eltrombopag
  4. Bussel JB et al. “A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia.” Blood. 2011 Jul 7;118(1):28-36. http://www.ncbi.nlm.nih.gov/pubmed/21502541
  5. Blanchette VS et al. "Health-Related Quality of Life in Children with Chronic Immune Thrombocytopenia Treated with Eltrombopag in the PETIT Study." 2012 American Society of Hematology meeting. Abstract 2197.
  6. Medline http://www.nlm.nih.gov/medlineplus/druginfo/meds/a609008.html#side-effects
  7. Tomiyama Y, et al. "A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia (ITP)." J Thromb Haemost. 2012 Mar 12. http://www.ncbi.nlm.nih.gov/pubmed/22409309
  8. FDA News Release https://www.cancer.gov/about-cancer/treatment/drugs/fda-eltrombopag
  9. Saleh MN et al. “Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study.” Blood. 2013 Jan 17;121(3):537-45. http://www.ncbi.nlm.nih.gov/pubmed/23169778
  10. Iuliano F. “Platelet Kinetic Study (PKS) May Early Identify a Subset of Patients with Immune Thrombocytopenia (ITP) Probably Cured by Romiplostim. Two Years Follow-up.” 2012 American Society of Hematology meeting. Abstract 2197.
  11. Makar RS et al. “Thrombopoietin (TPO) levels in patients with disorders of platelet production: Diagnostic potential and utility in predicting response to TPO Receptor agonists.” Am J Hematol. 2013 Aug 1. http://www.ncbi.nlm.nih.gov/pubmed/23913253
  12. FDA Drug Safety Communication: Modified Risk Evaluation and Mitigation Strategies (REMS) for Nplate (romiplostim) and Promacta (eltrombopag) Dec. 6, 2011. http://www.fda.gov/Drugs/DrugSafety/ucm280165.htm

 

 

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