SYK inhibitor fostamatinib disodium hexahydrate (TAVALISSE™) is approved by the Food and Drug Administration (FDA) for adults as a second line treatment for ITP, similarly to the TPO agents.
Fostamatinib Disodium Hexahydrate (TAVALISSE™)
Fostamatinib disodium hexahydrate (TAVALISSE™) is the first spleen tyrosine kinase (SYK) inhibitor approved by the FDA for the treatment of chronic ITP in adults when a prior treatment has not worked well enough. Fostamatinib comes in tablet form and is taken twice daily with or without food.
Spleen tyrosine kinase (SYK) is part of a network of proteins (found in certain cells of the immune system) that triggers platelet destruction. When the back end of the antibodies attached to platelets contact their receptors on immune cells, an important way that they trigger platelet destruction is to signal the immune cells into action. This signal goes through SYK so blocking SYK blocks transmission of the signal. The immune cells then no longer react to the antibodies on the platelets and no longer destroy the platelets. Fostamatinib works differently than other treatments by specifically targeting SYK. The drug limits platelet destruction by the immune system by blocking the action of the scavenger cells (macrophages) which in turn raises platelet counts in the body and thus helps reduce the risk of severe bleeding.
Fostamatinib is started as one tablet of 100 mg taken twice a day for the first month, and the dose can be increased to one 150 mg tablet twice a day if tolerated to increase platelet counts (if needed). Almost all of the responders in the initial treatment study increased their treatment to the higher dose. The dose can also be adjusted to help manage side effects (see below). Fostamatinib can be taken with or without food.
Fostamatinib is a new medication so many physicians are not very familiar with its use. In the beginning, one should start with 100mg twice a day. Blood counts and liver tests should be checked every 2 weeks in the beginning. Blood counts should be checked every 2 weeks until the count is stable. Liver tests and other labs should be checked every 4 weeks. Blood pressure should be checked at every visit.
- If the count does not go up, then the dose could be increased to 150 mg twice a day if side effects allow. If the platelet counts do not go up in another 4 weeks, it is very unlikely that fostamatinib will work.
- If side effects occur, then depending upon which they are, they may be able to be treated. Increased blood pressure can be managed with anti-hypertension medication. Diarrhea can be managed with medication to slow bowel movements. However, abnormal liver tests would require stopping fostamatinib (at least temporarily) depending on how abnormal the tests are.
- Side effects that either did not occur or were tolerable at 100mg twice a day may be worse or intolerable at 150mg twice a day. Of the 43 responders to fostamatinib in the initial trials, only one had to discontinue treatment because of side effects but another 1-2 had to reduce their dose.
If there are any issues, check with your physician.
Fostamatinib can cause serious side effects, including high blood pressure, liver problems, diarrhea, and a decrease in white blood cell counts. On average, fostamatinib increased blood pressure slightly in everyone treated. Patients who already had high blood pressure and were on medication for it might have a greater increase in blood pressure, thus necessitating an increased dose of anti-hypertensive medication. Some patients on treatment saw an increase in liver function tests; treatment discontinuation may be needed which could be temporary. GI complaints like diarrhea occurred in 10% or more of patients. This was either loose stools or urgency in need to have a bowel movement right away or both. Decrease in white blood cells can occur but did not tend to lead to infections. The majority of side effects were mild or moderate but one quarter or so were more serious. The most common less serious side effects seen in the clinical trial were nausea, rash, dizziness, tiredness, respiratory infection, chest pain, and stomach (abdomen) pain.
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In a study of 150 adults with chronic ITP, fostamatinib was compared to placebo (an inactive tablet that looked like the real medication) to see how effective it was in raising platelet counts with subjects taking it for up to 6 months of treatment1. At the beginning of the study, the median platelet counts for people enrolled were equal to or less than 16,000 per microliter; it had to be < 30,000/uL to enter the study. On average, the people in the trial had had long-standing chronic ITP for 8.5 years. All individuals in the study had had at least one prior treatment, such as steroids, immunoglobulins, rituximab, a thrombopoietin receptor agonist (platelet growth factor), and/or splenectomy. The patients who benefited from fostamatinib did so regardless of whether or not they had had a specific prior treatment and whether or not they had responded temporarily to that treatment.
Patients who had a stable response (about 1 in 5 patients) to fostamatinib achieved a median platelet count of approximately 95,000 per microliter at the end of the 6-month study. A stable response was defined as a platelet count greater than or equal to 50,000 per microliter for 4 (or more) doctor visits during the last 3 months (6 visits) of the 6-month study. Most of the patients who had an increased platelet count (a little more than 2 out of 5 patients) with fostamatinib already saw an increase in their platelet count at their first on treatment visit (approximately 2 weeks). In a clinical trial of continuing long-term treatment that is still ongoing, the last visit at 28 months found that many of the people who responded to fostamatinib were still responding which was why they were continuing treatment.
1. Bussel, James et al. “Fostamatinib for the Treatment of Adult Persistent and Chronic Immune Thrombocytopenia: Results of Two Phase 3, Randomized, Placebo‐controlled Trials.” American Journal of Hematology 93.7 (2018): 921–930. PMC. Web. 22 Aug. 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055608/