Page 24 - Haematologica Vol. 107 - September 2022

REVIEW ARTICLE - ITP: diagnosis and second-line treatment J.B. Bussel and C.A. Garcia
higher in the combination arm.30 One surprise was that quality of life was significantly lower among patients treated with the combination despite them having a better platelet response. Another surprise was that more than 50% of patients on the steroid-alone arm were cured despite a low rate of dexamethasone usage and that 27% of the patients were over 65 years of age. The study nonetheless highlighted the potential advantage of earlier use of second-line treatment.
There are at least 20 studies of danazol, almost all of which demonstrated a positive effect on platelet counts; this drug induces facial hair and acne and may be toxic to the liver. Dapsone, beyond an immunosuppressive ef- fect, induces hemolysis which mimics IV anti-D; in pa- tients with glucose-6-phosphate dehydrogenase deficiency, the hemolysis can be severe. Azathioprine has a long-standing history of use in ITP and a contributing safety base in pregnancy in patients taking it following kidney transplantation; it may cause hepatic toxicity in 1%. We reported on its combination with danazol, with good results in 13 of 17 difficult-to-treat patients.31 Cyclo- sporine repolarizes cell membranes, which shuts down cell membrane pumps that extrude therapeutic agents from the cell. This may reinstate the effect of certain treatments e.g., steroids. Finally, cyclophosphamide can be given IV or orally. The best results appear to occur when using it IV in two or three infusions.32 Mechanistic information supporting the use of cyclophosphamide is that it has anti-plasma cell effects and that it spares megakaryocytes and platelets. Cyclophosphamde does, however, have well-known substantial side effects: hema- turia, bladder fibrosis, immunosuppression, and nausea and vomiting.
Thrombopoietin receptor agonists
Another option for second-line therapy would be a thrombopoietin receptor agonist (TPO-RA). The primary advantages of these drugs are the high response rate and low likelihood of induction of malignancy or other irrever- sible toxicity. The primary toxicity is development of ve- nous and arterial thrombosis. If our young female patient were on birth control, there may be an added risk of thrombosis.
There are three TPO-RA currently available in the USA and Western Europe: romiplostim,33 eltrombopag34 and avat- rombopag;35 their efficacy and toxicity have been outlined in a recent review, including discussion of class effects such as headache, myalgia, and thrombosis.36 The mech- anisms of effect of these agents differ by where they bind to the thrombopoietin receptor, in RNA upregulation of transcription factors by romiplostim and eltrombopag,37 and by the essential role of intracellular iron chelation by eltrombopag.38 The clinical importance of these mechan- istic differences is “confirmed” by “switch studies” in
which one of romiplostim or eltrombopag was effective when the other was not.39,40 Recent studies demonstrated that switching from one of these two TPO-RA to avatrom- bopag was also often effective.29,41 Toxicity and efficacy do not differentiate the three agents substantially, although one article suggests that romiplostim maintains efficacy at higher endogenous thrombopoietin levels than does el- trombopag29 and eltrombopag is thought to be associated with higher rates of transaminitis.34,36
Eltrombopag. Eltrombopag is an oral TPO-RA which requires a very empty stomach ideally 2 hours before and after taking it, which is intimately related to its require- ment to chelate intracellular iron as an integral part of its mechanism of effect.38 If eltrombopag has chelated cal- cium or iron during ingestion, it cannot chelate intracel- lular iron and will, therefore, be ineffective. Liver function tests must be monitored in patients taking eltrombopag, as hepatotoxicity is considered common (1-10%) and 3% of adults and children cannot tolerate eltrombopag for this reason.36
Romiplostim. Because romiplostim is injected subcu- taneously weekly, there are no issues of absorption or doubts about compliance. There may be more cycling of the platelet count as compared to that with the oral TPO- RA, likely because of romiplostim’s weekly instead of daily administration. As with all the TPO-RA, making small changes in dosing will limit the likelihood of cycling. De- velopment of antibodies, neutralizing and non-neutraliz- ing, to romiplostim is more common in children than in adults;44 however, these antibodies have surprisingly little effect on clinical efficacy for reasons that are not clear. Myalgia may be more common with romiplostim. As of writing, romiplostim can be self-injected by patients in Europe but not in the USA.
Avatrombopag. Avatrombopag, a second oral TPO-RA, has the least data describing its use. It is taken once daily using only tablets of 20 mg with dose ranges from 20 mg by mouth once a week to 40 mg (2 tablets) daily. There are very limited data on long-term usage. In one study, avatrombopag was associated with a 16.5% incidence of thrombosis but this was likely an artifact resulting from the small numbers of patient.42 Two recent studies testi- fied to the effect of avatrombopag in patients not re- sponding to romiplostim and/or eltrombopag.29,41 It is recommended that this TPO-RA is taken with food so that its absorption is more consistent.
There is much to recommend the use of a TPO-RA in our young woman.43,44 There is no reason to suspect that such an agent would have an adverse impact on the clinical course of COVID if an infection were to occur although there may be an additive risk of thrombosis.29 In the COVID pandemic, the oral agents would be preferred over romiplostim to lessen exposure to SARS-CoV-2 secondary to weekly attendance at an outpatient department. Local
Haematologica | 107 September 2022
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