Page 24 - Haematologica March 2020

Editorials
receptor agonist romiplostim in patients with myelodys- plasia and thrombocytopenia was halted early despite leading to an increase in the platelet count and improve- ment in bleeding symptoms because of concern regarding progression to acute myeloid leukemia (AML). In the final analysis, however, the AML progression risk was not sig- nificant, with a hazard ratio of 1.20 and a 95% confidence interval of 0.38-3.84.9 No such concern was observed in a subsequent trial of eltrombopag monotherapy in similar settings.10
As mentioned before, there are at least 40 different genes associated with inherited thrombocytopenia.11 At this stage, it is not known whether patients with other gene mutations will respond to eltrombopag in the same way, or whether any of these disorders will respond to the other TPO receptor agonists such as romiplostim; while the answer to both of these questions is likely to be yes, this is still speculation and needs to be confirmed in clinical trials or case series.
Considering the rarity and variety of the inherited thrombocytopenias, as well as the brief period for which most of these individuals require treatment to improve their platelet count, it is unlikely that a pharmaceutical manufacturer will perform the required trials to get approval of their drug for this indication.
The study by Zanetti et al. is important because it establishes eltrombopag as a therapeutic entity in the treatment of inherited thrombocytopenia. At this stage, we do not know if patients with mutations in other genes, or even different mutations in the same gene, will respond the same way, if at all. In view of this, it would be sensible to offer patients soon after diagnosis a 3-week therapeutic trial of 50mg of eltrombopag daily with the option of another three weeks at 75mg daily in the non- or poor-responders. In this way, at moments of possible future need, it will already be known whether they are eltrombopag responders or not, in which case they are likely to require platelet transfusions. I believe that, for elective procedures, the use of eltrombopag as a first-line agent is a very reasonable proposition, even when the drug is not licensed for this indication.
Although in many countries there are national reg- istries of patients with inherited bleeding disorders, these tend to be for individuals with clotting factor defi- ciencies and do not include persons with inherited thrombocytopenia. I believe that all patients with inher- ited thrombocytopenia should be entered in registries so that the natural history, as well as the response to TPO receptor agonist treatment for all the different genetic defects, can be established. It is unlikely that this will be achieved for most of the disorders without international collaboration.
References
1. Balduini CL, Pecci A, Noris P. Diagnosis and management of inherit- ed thrombocytopenias. Semin Thromb Hemost. 2013;39(2):161-171. 2. Fernandez-Prado R, Carriazo-Julio SM, Torra R, Ortiz A, Perez- Gomez MV. MYH9-related disease: it does exist, may be more fre- quent than you think and requires specific therapy. Clin Kidney J.
2019;12(4):488-493.
3. Kelley MJ, Jawien W, Ortel TL, Korczak JF. Mutation of MYH9,
encoding for non-muscle myosin heavy chain A, in May-Hegglin
anomaly. Nat Genet. 2000;26(1):106-108.
4. Noris P, Pecci A. Hereditary thrombocytopenias: a growing list of
disorders. Hematology Am Soc Hematol Educ Program.
2017;2017(1):385-399.
5. Galera P, Dulau-Florea A, Calvo KR. Inherited thrombocytopenia
and platelet disorders with germline predisposition to myeloid neo-
plasia. Int J Lab Hematol. 2019;41 Suppl 1:131-141.
6. Pecci A, Gresele P, Klersy C, et al. Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations.
Blood. 2010;116(26):5832-5837.
7. PecciA.Pathogenesisandmanagementofinheritedthrombocytope-
nias: rationale for the use of thrombopoietin-receptor agonists. Int J
Hematol. 2013;98(1):34-47.
8. ZaninettiC,GreseleP,BertomoroA,etal.Eltrombopagforthetreat-
ment of inherited thrombocytopenias: a phase 2 clinical trial.
Haematologica. 2020;105(3):820-828.
9. Giagounidis A, Mufti GJ, Fenaux P, et al. Results of a randomized
double-blind study of romiplostim versus placebo in patients with low/intermediate-1-risk myelodysplastic syndrome and thrombocy- topenia. Cancer. 2014;120(12):1838-1846.
10. Mittelman M, Platzbecker U, Afanasyev B, et al. Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebo-con- trolled, phase 2 trial. Lancet Haematol. 2018;5(1):e34-e43.
11. Almazni I, Stapley R, Morgan NV. Inherited Thrombocytopenia: Update on genes and genetic variants which may be associated with bleeding. Front Cardiovasc Med. 2019;6:80.
538
haematologica | 2020; 105(3)