Page 34 - Haematologica Vol. 107 - September 2022

REVIEW ARTICLE - ITP: diagnosis and second-line treatment J.B. Bussel and C.A. Garcia
strated more than 50% acute platelet responses.84,85 Both agents are in ongoing phase III trials which, like many studies, were slowed by the COVID pandemic. Since FcRn inhibition does not lower IgA and IgM levels nor does it af- fect T-cell or macrophage function, trials have not been complicated by the development of infections despite very low IgG levels being reached. Nonetheless, there is concern that IgG levels below 200 mg/dL (lower limit of normal: 639 mg/dL) may be dangerous. With one FcRn inhibitor, albumin levels were lowered, and cholesterol increased; FcRn also recycles albumin.
Active studies of FcRn inhibitors include treatment of myas- thenia gravis, pemphigus vulgaris, hemolytic disease of the fetus and newborn, and antibody-mediated neurological diseases. In the phase III studies, the FcRn inhibitors are being administered weekly by subcutaneous administration with the goal of eventual home administration.
Bruton tyrosine kinase inhibitors
The most widely used Bruton tyrosine kinase (BTK) inhibitor is ibrutinib for chronic lymphocytic leukemia and non-Hodg- kin lymphoma with excellent results in treating these en- tities; anecdotally, several thrombocytopenic patients with chronic lymphocytic leukemia had substantial platelet im- provements. Thus, it was natural to think of BTK inhibition for B-cell diseases like ITP. However, ibrutinib was found to lead to serious bleeding in about 1% of cases, an effect that was subsequently suggested to be caused by inhibition of collagen-platelet interactions. Newer BTK inhibitors, e.g., ril- zabrutinib, designed to allow normal platelet function for patients with ITP, have been effective in ITP in phase II trials, with a 50% response rate seen at the top dose, 400 mg twice a day.86 As was seen in trials with fostamatinib and FcRn inhibitors, the patients enrolled have been heavily pre- treated with long-term histories. It is highly likely that BTK inhibitors will inhibit response to SARS-CoV-2 vaccination.
Complement inhibitors
Studies of complement pathway inhibitors in ITP would have begun years ago if the cost of the Alexion anti-C5 mono- clonal antibody (eculizumab) had not been so enormous. Early results of C1S inhibition are impressive but still pre- liminary. This strategy has yielded good results in cold ag- glutinin disease, demonstrating its biological effect on the complement system which is translated into clinical hema- tologic efficacy.
Conclusions
What would we have liked to have been able to offer our two patients with immune thrombocytopenia?
First, it would have been nice to have been able to predict
their course including many factors: risk of bleeding, likeli- hood of chronicity, which treatments would be most effec- tive, and which most toxic.
Second, it would have been nice to have a curative but non- toxic treatment to offer. We discussed the use of rituximab in a younger woman as there is good likelihood of cure in a patient of this age and gender. But in other patients, there is very little likelihood of cure and in her case, vaccination for SARS-CoV-2 was a problem. This leaves splenectomy which is remarkably effective; recent work suggests that it remains effective even in patients who have been treated with thrombopoietin agents.48 Why are patients so unwilling to undergo splenectomy? Perhaps the primary reasons are the inability to know whether a patient will get better on their own, whether the splenectomy will be successful, and the irreversibility of it. Furthermore, post-splenectomy risks of sepsis and thrombosis continue lifelong. In the future, use of combinations of agents (dexamethasone and rituxi- mab, steroids and mycophenolate mofetil, dexamethasone and eltrombopag, or others) within 1 week of diagnosis may provide a higher level of cure and justify the extra expense and higher risks of these interventions.
Finally, treatment selection could be more rational if data were provided by randomized, controlled trials comparing agents and regimens. To date, all the randomized controlled double-blind trials of second-line agents have involved comparison of a treatment to placebo. We are not aware of any trials comparing one second-line agent to another, al- though Chinese hematologists have recently compared a given agent to the same agent plus a second agent. Examples include rituximab with and without thrombopoie- tin, and dexamethasone with and without eltrombopag. More of these studies are urgently needed.
In summary, it is not possible to have a “one size fits all” approach to ITP. Rather we have tried to emphasize that in- dividualizing treatment is important and should include shared decision-making. The optimal choices vary with gender and age and the COVID pandemic has an impact as well. As additional information is accrued, management in certain situations may be clarified but there is a long way to go to achieve for ITP what we all take for granted in the evidence-based management of leukemia.87
Disclosures
JBB is a consultant or on an advisory board for Amgen, No- vartis, Sobi, Rigel, UCB, Argenx, Sanofi, Astra-Zeneca, Pfizer, and CSL-Behring; and is a member of a Data and Safety Monitoring Board for UCB, CSL-Behring. CAG has no conflicts of interest to disclose.
Contributions
JBB and CAG wrote and edited the manuscript and both agreed to its submission for publication.
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