Page 33 - Haematologica Vol. 107 - September 2022

REVIEW ARTICLE - ITP: diagnosis and second-line treatment J.B. Bussel and C.A. Garcia
Section IV: Third-line therapy for immune thrombocytopenia
and beyond
What happens if the thrombopoietin agent used in the two patients does not work or at least cannot be tapered? In the case of the young woman, the platelet count re- mained less than 20x109/L and the young woman had heavy menses, bruising and nosebleeds. The now 26-year-old woman opted for rituximab. She had a long-term response but unfortunately relapsed after 4 years. She considered re- peating the rituximab and undergoing splenectomy but opted to try a different thrombopoietin agent since she was not planning another pregnancy in the immediate future. Previously she used eltrombopag so she now tried avatrom- bopag. On a dose of 20 mg/day she was able to maintain an adequate platelet count and is very slowly tapering her dose. This choice was consistent with evidence that not re- sponding well to one TPO-RA does not preclude good re- sponse to another.
Our older, male patient, given his continued bruising and minor nosebleeds, was afraid of major bleeding; he also felt very tired even though he was not anemic. The now 64- year-old man opted to try rituximab since avatrombopag did not work well for him. He received the standard dose of ri- tuximab with dexamethasone. He responded which a pla- telet count of 60x109/L by 6 weeks after initiating treatment; however, his count started to fall monthly down to 30x109/L. He and his doctor decided to initiate mycophenolate mofetil and he began with a dose of 500 mg twice daily and then increased to 1000 mg twice a day. He tolerates this treat- ment well and his platelet counts remain around 40- 50x109/L.
Thus, both patients needed treatment. Some patients with low (not very low) platelet counts who have no bleeding or other issues e.g., need for anticoagulants or fatigue, may not require treatment. Avoiding treatment is always optimal if this does not jeopardize quality of life.
What if none of the obvious options (thrombopoietin agents, rituximab, splenectomy) helps and no single treatment, including fostamatinib and mycophenolate mofetil is effective?
It is difficult to predict what approach will be effective in these “refractory” patients. If a patient has been on too low a dose or for too short a period, it may not be clear that a given medication will not be helpful.
The approach to difficult-to-treat patients, such as these examples, is discussed at great length in our review of re- fractory ITP and in another recent review.1,83 The major prin- ciples are: (i) spend time reconfirming the diagnosis; reconsider all options if response to treatments of ITP is ab- sent or very limited: (ii) do a complete bone marrow exam-
ination, unless one was performed recently, with aspirate, biopsy, flow cytometry, and cytogenetics; (iii) if a treatment is ineffective, continue the treatment and add another treat- ment initiating combination therapy. In our opinion, this is preferable to discontinuing the ineffective treatment and starting another one; (iv) if indeed the case is refractory ITP, combination approaches are often better than single treat- ments. Including treatments with different mechanisms of effect is useful; however, there are situations in which two agents targeting the same mechanism are effective such as combining IVIG and IV anti-D;31 and (v) when using combina- tion treatments, it would be ideal to not give maximum doses and to select agents with differing toxicities. If an ad- verse event requiring a change in treatment occurs, it is then easier to choose the agent to stop and/or replace. In our re- view of published reports,1 a TPO agent was often a crucial component of combination treatments.
In difficult patients, the inability to define the pathogenesis in most cases makes the treatment selection blind. For- tunately, multiply refractory patients for whom no treatment seems to bring their platelet count up at all are very rare. More commonly at least one treatment will transiently in- crease the platelet count. This minimizes the chance of seri- ous bleeding and creates an approach for ongoing management, although continued steroid overuse must be avoided.
Section V. Agents currently under study
What are the experimental agents which are likely to be available in the future?
Various experimental agents for ITP are being studied and other drugs, currently used for other conditions, are now undergoing trials in ITP. It is uncertain whether, and if so in what context, any or all these agents will ultimately have a major role in the management of ITP. On the one hand, they could be more effective and less toxic than currently used agents and have specific areas of efficacy based on their unique mechanisms of effect. On the other hand, they might be redundant, have toxicities, and not provide substantial additional value.
FcRn inhibitors
The putative mechanism of effect of FcRn inhibitors is re- duction of antiplatelet IgG levels by inhibition of “normal” IgG recycling. IgG levels fall dramatically with FcRn in- hibition, and it is thought that the IgG anti-platelet antibody levels fall at least as much, resulting in less platelet de- struction and greater platelet production. Efgartigimod and rozanolixizumab have gone through phase II studies; the re- sults were published in 2020 and both studies demon-
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