Page 22 - Haematologica March 2020

Editorials
References
1. Liesveld J. Management of AML: who do we really cure? Leuk Res. 2012;36(12):1475-1480.
2. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447.
3. ThomasD,MajetiR.Biologyandrelevanceofhumanacutemyeloid leukemia stem cells. Blood. 2017;129(12):1577-1585.
4. Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367(6464):645-648.
5. Shlush LI, Zandi S, Mitchell A, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;506(7488):328-333.
6. Pollyea DA, Gutman JA, Gore L, Smith CA, Jordan CT. Targeting acute myeloid leukemia stem cells: a review and principles for the development of clinical trials. Haematologica. 2014;99(8):1277-1284.
7. Ng SW, Mitchell A, Kennedy JA, et al. A 17-gene stemness score for
rapid determination of risk in acute leukaemia. Nature.
2016;540(7633):433-437.
8. Bill M, Nicolet D, Kohlschmidt J, et al. Mutations associated with a
17-gene leukemia stem cell score and the score’s prognostic rele- vance in the context of the European LeukemiaNet classification for acute myeloid leukemia. Haematologica.2020;105(3):721-729.
9. Duployez N, Marceau-Renaut A, Villenet C, et al. The stem cell- associated gene expression signature allows risk stratification in pediatric acute myeloid leukemia. Leukemia. 2019;33(2):348-357.
10. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17.
11. PollyeaDA,StevensBM,JonesCL,etal.Venetoclaxwithazacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med. 2018;24(12):1859- 1866.
12. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728-1740.
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Thrombopoietin receptor agonists for the treatment of inherited thrombocytopenia
Michael Makris1,2
1Department of Infection, Immunity and Cardiovascular disease, University of Sheffield, and 2Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, UK
E-mail: m.makris@sheffield.ac.uk doi:10.3324/haematol.2019.241786
The inherited thrombocytopenias are a heteroge- neous group of increasingly recognized disorders, which can be associated with bleeding of variable severity. Their prevalence has been estimated to be around 1 in 100,000 of the population,1 but it is likely that this is an underestimate due to many individuals being undiagnosed, wrongly diagnosed or not recorded on reg- istries after a correct diagnosis. More recently, it has been reported that the prevalence of MYH9-related disorders can be as frequent as 1 in 20,000 of the population.2
The inherited nature of the thrombocytopenias has been recognized for decades, with the main disorders being the May-Hegglin anomaly, and the Sebastien, Fechtner and Epstein syndromes. These disorders were associated with a variable degree of renal impairment, deafness and cataracts. Although initially believed to be different disorders, when the genes responsible were iden- tified, it became clear that all of these syndromes were variants of defects in the same MYH9 gene encoding for non-muscle myosin heavy chain A.3 The nomenclature was subsequently changed to reflect this, and they are now known as the MYH9-related disorders (MYH9-RD).
The recent introduction of high throughput sequencing (HTS), together with the formation of consortia with large numbers of clinicians caring for inherited thrombo- cytopenia patients, has led to a dramatic increase in the number of genes responsible for the disorder. Inherited thrombocytopenias can be syndromic, predisposing to renal failure, hearing loss and cataracts, as in MYH9-RD, while others, such as the RUNX1, ANKRD26 and ETV6, can be associated with predisposition to hematologic malignancy.4,5
In contrast to the major advances in the genetic basis of inherited thrombocytopenia, the management of these
disorders has hardly changed, with the main therapeutic decision being whether to transfuse platelets or not. Part of the difficulty is the variability in the number of platelets, as well as the bleeding tendency which is often not directly proportional to the platelet count. A possible explanation for this is the variable and often large size of the platelets in some of these disorders; since hemostatic reactions take place on the cell surface, disorders associ- ated with larger platelets would be expected to be associ- ated with less bleeding. Treatment is usually required when patients are actively bleeding, or to prevent bleed- ing prior to surgery or invasive procedures.
Platelet transfusions, however, can be problematic because of the potential for adverse events. They carry the risk of transfusion-transmitted infection, alloimmu- nization with production of platelet specific or HLA anti- bodies, allergic reactions and transfusion-related acute lung injury (TRALI). As a result, the use of platelet trans- fusions tends to be avoided if possible, and clinicians use tranexamic acid, sometimes with desmopressin, as non- specific hemostatic agents to treat these patients.
Thrombopoietin receptor agonists have been available for the treatment of immune thrombocytopenia in adults and children for some time. The two products with the longest availability are eltrombopag, which is given oral- ly, and romiplostim, which is administered subcuta- neously. In the UK, eltrombopag is available for use in patients with thrombocytopenia of at least six months duration whilst romiplostim is approved for ITP of 12 months duration or more.
In an important initial publication from 2010, Pecci et al. showed that eltrombopag could increase the platelet count of patients with MYH9-related thrombocytopenia.6 Twelve patients with a platelet count of <50x109/L were
haematologica | 2020; 105(3)