Comparative study of treatment outcomes of patients of aplastic anemia with combination therapy cyclosporine A + danazol + eltrombopag vs cyclosporine A + danazol + high dose Romiplostim

Background

Aplastic anemia (AA) was first described in a pregnant woman in 1888. The term now refers to a clinical syndrome defined as pancytopenia with hypocellular bone marrow without abnormal infiltration or increased reticulin. AA can be inherited or acquired. Acquired AA is usually the result of an autoimmune attack that appears to be directed at hematopoietic stem/progenitor cells.

Immunosuppressive therapies (IST) are effective, but reduced numbers of residual stem cells may limit their efficacy. In patients with AA, that was refractory to standard immunosuppressive therapy. Eltrombopag, a synthetic thrombopoietin-receptor agonist, has been tried alone or added to standard immunosuppressive therapy as routine care and has recently been approved by the FDA for treating aplastic anemia. High-dose Romiplostim is effective and well tolerated in treating patients with AA refractory to IST. Although ATG plus Cyclosporine A is the therapy for AA patients without a donor when neither HSCT nor IST is available, Danazol remains an acceptable therapeutic option. The tendency to achieve remission was similar among severity groups in a previous comparative study. We will compare the efficacy of standard immunosuppressive therapy combined with Eltrombopag and Danazol v/s high dose Romiplostim and Danazol in newly diagnosed cases of Aplastic anemia.

 Purpose of the study:

ATG has been used to treat patients ineligible for hematopoietic stem cell transplantation. However, the number of hematopoietic stem cells is a limiting factor for its response. Eltrombopag and Romiplostim are Thrombopoietic Receptor Agonists (TPO-RAs). Their role in managing Immune Thrombocytopenia (ITP) has been well established. It has been seen that TPO-RAs are also helpful in the management of Aplastic Anemia. However, there needs to be more literature on using these drugs, especially Romiplostim, in the first-line therapy of Aplastic anemia cases. Our study aims to compare the clinical outcomes of adding Eltrombopag and Danazol v/s High-dose Romiplostim and Danazol to standard immunosuppressive therapy.

References:

1.      DeZern AE, Brodsky RA. Clinicalmanagement of aplastic anemia. Expert Rev Hematol. 2011; 4(2):221-230.

2.      Tamary H, Nishri D, YacobovichJ, et al. Frequency and natural history of inherited bone marrow failuresyndromes: The Israeli inherited bone marrow failure registry. Haematologica.2010; 95(8):1300-1307.

3.      Maciejewski JP, Rivera C, KookH, Dunn D, Young NS. Relationship between bonemarrow failure syndromes and the presence of glycophosphatidylinositol-anchored protein-deficient clones. Br J Haematol. 2001;115(4):1015-1022.

4.      Brodsky RA, Jones RJ. Aplasticanaemia. Lancet. 2005; 365(9471):1647-1656.

5.      Desmond R, Townsley DM, DunbarC, Young NS. Eltrombopag in Aplastic Anemia. Semin Hematol. 2015; 52(1):31-37.

6.      Poorana PP, Subhashree AR. Roleof absolute reticulocyte count in evaluation of Pancytopenia-a hospital basedstudy. J Clin Diagnostic Res. 2014; 8(8).

7.      Mukhina GL, Buckley JT, et al.Multilineage glycosyl-phosphatidyl-inositol anchor- deficient hematopoiesis inuntreated aplastic anaemia. Br J Haematol. 2001; 115(2):476- 482.

8.      Matsui WH, Brodsky RA, et al.Quantitative analysis of bone marrow CD34 cells in aplastic anemia andhypoplastic Myelodysplastic syndromes. Leukemia. 2006; 20(3):458- 462.

9.      Orazi A, Albitar M, et al.Hypoplastic Myelodysplastic syndromes can be distinguished from acquiredaplastic anemia by CD34 and PCNA immunostaining of bone marrow biopsyspecimens. Am J Clin Pathol. 1997; 107(3):268274.

10.  Kim S-Y, Lee J-W, Lee S-E, et al. The characteristics andclinical outcome of adult patients with aplastic anemia and abnormal cytogeneticat diagnosis. Genes, Chromosom Cancer. 2010; 49(9):n/a-n/a.doi:10.1002/gcc.20793.

11.  Killick SB, Bown N, Cavenagh J,et al. Guidelines for the diagnosis and management of adult aplastic anaemia.Br J Haematol. 2016; 172(2):187-207.

12.  Clucas DB, Fox LC, Wood EM, etal. Revisiting acquired aplastic anaemia: current concepts in diagnosis andmanagement. Intern Med J. 2019; 49(2):152-159.

13.  Williams DM, Lynch RE,Cartwright GE. Prognostic factors in aplastic anaemia. Clin Haematol. 19

14.  Connolly GC, Khorana AA,Kuderer NM, Culakova E, Francis CW, Lyman GH. Leukocytosis, thrombosis andearly mortality in cancer patients initiating chemotherapy. Thromb Res. 2010;126(2):113-118.

15.  Yuan C, Boyd AM, Nelson J, etal. Eltrombopag for Treating Thrombocytopenia after Allogeneic Stem CellTransplantation. Biol Blood Marrow Transplant. 2019; 25(7):1320- 1324.

16.  M. B. Agarwal, Farah Jijina,Sandip Shah et al. Safety and efficacy of indigenous equine Antithymocyteglobulin along with cyclosporine in subjects with acquired aplastic anaemia  2015, 31(2): 174-179.

17.  JangJH, Tomiyama Y, Miyazaki K, Nagafuji K, Usuki K, et al. Efficacy and safety ofromiplostim in refractory aplastic anaemia: a Phase II/III, multicenter,open-label study. Br J Haematol. 2021 Jan; 192(1):190-199.

18.  Peffaultde Latour R, Kulasekararaj A,et al. Eltrombopag Added to Immunosuppression inSevere Aplastic Anemia. N Engl J Med. 2022 Jan 6; 386(1):11-23.

19.  Jaime-PérezJC, Colunga-Pedraza PR, Gómez-Ramirez CD, Gutiérrez-Aguirre CH, Cantú-RodríguezOG, Tarín-Arzaga LC, Gómez-Almaguer D. Danazol as first-line therapy foraplastic anemia. Ann Hematol. 2011 May;90(5):523-7.