Page 25 - Haematologica Vol. 107 - September 2022

REVIEW ARTICLE - ITP: diagnosis and second-line treatment J.B. Bussel and C.A. Garcia
laboratory counts and virtual visits lessen this risk for pa- tients; home nursing visits for injections would do the same.
Fostamatinib
Fostamatinib is a first-in-class, orally active spleen tyro- sine kinase (Syk) inhibitor indicated for the treatment of ITP. The primary studies underestimated its efficacy, pro- bably because the median duration of ITP in the trial population was more than 8 years and in 47% of patients a TPO-RA had failed.45,46 While the starting dose is 100 mg twice daily, 89% of responders increased to 150 mg twice daily. Long-term use and in vitro experiments have sug- gested that fostamatinib is anti-thrombotic but not pro- hemorrhagic because blocking Syk reduces signaling via the C-type lectin-like type II transmembrane receptor (CLEC2) and glycoprotein VI (GPVI) pathways. These two pathways have less redundancy in thrombosis than in control of bleeding. Fostamatinib is also thought to be anti-inflammatory and potentially useful in COVID, inde- pendently of any platelet effects.47 On the other hand, of all approved second-line agents for ITP, it may be the least tolerable. It increases blood pressure in most recipients and there are relatively frequent gastrointestinal effects, including nausea with very occasional vomiting and the development of diarrhea; 5% of patients may develop transaminitis. There has not been evidence of increased frequency or severity of infections in association with fos- tamatinib use even though Syk is present in macrophages as well as in B cells and in other cells.
Splenectomy
The American Society of Hematology guidelines and inter- national consensus report recommend that splenectomy be delayed to at least 1 year after the diagnosis of ITP, since the rate of resolution of ITP within the first 1-3 years of disease appears substantial even in adults.4,5 Lapar- oscopic splenectomy is infrequently complicated by peri- operative problems; response rates are initially 80% which relapse reduces to 60%. Late relapse beyond 2 years after splenectomy is very uncommon. Whether delaying sple- nectomy reduces its efficacy is a concern; a recent study from France48 suggests that efficacy is maintained, and some patients responded better to TPO-RA after splenec- tomy.
There are long-term risks of adverse effects of splenec- tomy which are clinically significant, including not only overwhelming sepsis but also thrombosis, especially stroke. The risk of sepsis is based on less efficient blood stream phagocytosis and is exacerbated by low antibac- terial antibody levels. Pneumococci are a more frequent cause of post-splenectomy sepsis than all other infections
combined.49 Following splenectomy, individuals also have an elevated risk of infections by encapsulated Gram- negative pathogens, e.g., Capnocytophaga canimorsus and Bordetella holmesii, as well as intraerythrocytic parasites, such as malaria and Babesia, as noted in a recent review of post-splenectomy infections.50
Providing patients appropriate and timely immunization for pneumococci, Hemophilus influenzae B, and meningo- coccus, antibiotic prophylaxis, education, and prompt treatment of infection mitigates this risk;51 when to repeat pneumococcal and other vaccinations remains unclear. While vaccination appears more effective if given at least 2 weeks prior to splenectomy, vaccination can be admin- istered after splenectomy if there is not time before the splenectomy or if vaccination would likely be ineffective because the patient is receiving high-dose immunosup- pression or has recently received rituximab.
The risk of post-splenectomy thrombosis was not initially appreciated. Population studies using a Danish registry identified this risk, particularly with regard to stroke, with confirmation in other populations, e.g., the Nurses’ Health Study.52 Splenectomy for hemolytic anemias has been complicated by pulmonary hypertension, with mitigation by partial splenectomy and reduction in the use of sple- nectomy. Partial splenectomy may “hit the sweet spot” by reducing red blood cell phagocytosis but maintaining enough phagocytosis to prevent pulmonary hypertension and sepsis. The apparent absence of pulmonary hyperten- sion after splenectomy for ITP suggests that partial sple- nectomy, like splenic embolization and radiation, is very rarely if ever used.
How we treated the young woman with immune thrombocytopenia
As this woman could not taper her prednisone success- fully, still had bleeding, and had a platelet count <20x109/L, she met the criteria to receive a second-line treatment. After the considerations provided above and with her primary ITP, she opted for a TPO-RA which was based on her fear of COVID and need for vaccination and being in the first year of her disease. She chose to reserve rituximab, fostamatinib and immunosuppressives. She took a TPO-RA for a year and then was gradually able to discontinue it. She maintained a platelet count of 60- 90x109/L on no treatment for several years without mani- festations of bleeding. She was not troubled by fatigue or heavy menstrual bleeding.
Section II. Immune thrombocytopenia in pregnancy
Years later, our patient becomes pregnant.
Haematologica | 107 September 2022
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