435
Views
0
CrossRef citations to date
0
Altmetric
Reviews

Clonal evolution in aplastic anemia: failed tumor surveillance or maladaptive recovery?

ORCID Icon, & ORCID Icon
Pages 1389-1399 | Received 08 Apr 2023, Accepted 13 May 2023, Published online: 25 Jun 2023

References

  • Darwin C, Murray J, William C, et al. On the origin of species by means of natural selection, or, the preservation of favoured races in the struggle for life. London: John Murray, Albemarle Street; 1859.
  • Risitano AM, Kook H, Zeng W, et al. Oligoclonal and polyclonal CD4 and CD8 lymphocytes in aplastic anemia and paroxysmal nocturnal hemoglobinuria measured by V beta CDR3 spectratyping and flow cytometry. Blood. 2002;100(1):178–183. doi: 10.1182/blood-2002-01-0236.
  • Risitano AM, Maciejewski JP, Green S, et al. In-vivo dominant immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing. Lancet. 2004;364(9431):355–364. doi: 10.1016/S0140-6736(04)16724-X.
  • Zeng W, Maciejewski JP, Chen G, et al. Limited heterogeneity of T cell receptor BV usage in aplastic anemia. J Clin Invest. 2001;108(5):765–773. doi: 10.1172/JCI200112687.
  • Pagliuca S, Gurnari C, Awada H, et al. The similarity of class II HLA genotypes defines patterns of autoreactivity in idiopathic bone marrow failure disorders. Blood. 2021;138(26):2781–2798. doi: 10.1182/blood.2021012900.
  • Oguz FS, Yalman N, Diler AS, et al. HLA-DRB1*15 and pediatric aplastic anemia. Haematologica. 2002;87(7):772–774.
  • Yari F, Sobhani M, Vaziri MZ, et al. Association of aplastic anaemia and Fanconi’s disease with HLA-DRB1 alleles. Int J Immunogenet. 2008;35(6):453–456. doi: 10.1111/j.1744-313X.2008.00810.x.
  • Nakao S, Takamatsu H, Chuhjo T, et al. Identification of a specific HLA class II haplotype strongly associated with susceptibility to cyclosporine-dependent aplastic anemia. Blood. 1994;84(12):4257–4261. doi: 10.1182/blood.V84.12.4257.bloodjournal84124257.
  • Saunthararajah Y, Nakamura R, Nam JM, et al. HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood. 2002;100(5):1570–1574. doi: 10.1182/blood.V100.5.1570.h81702001570_1570_1574.
  • Maciejewski JP, Follmann D, Nakamura R, et al. Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome. Blood. 2001;98(13):3513–3519. doi: 10.1182/blood.v98.13.3513.
  • Savage SA, Viard M, O’HUigin C, et al. Genome-wide association study identifies HLA-DPB1 as a significant risk factor for severe aplastic anemia. Am J Hum Genet. 2020;106(2):264–271. doi: 10.1016/j.ajhg.2020.01.004.
  • Hirano N, Butler MO, Von Bergwelt-Baildon MS, et al. Autoantibodies frequently detected in patients with aplastic anemia. Blood. 2003;102(13):4567–4575. doi: 10.1182/blood-2002-11-3409.
  • Hirano N, Butler MO, Guinan EC, et al. Presence of anti-kinectin and anti-PMS1 antibodies in japanese aplastic anaemia patients. Br J Haematol. 2005;128(2):221–223. doi: 10.1111/j.1365-2141.2004.05317.x.
  • Feng X, Chuhjo T, Sugimori C, et al. Diazepam-binding inhibitor-related protein 1: a candidate autoantigen in acquired aplastic anemia patients harboring a minor population of paroxysmal nocturnal hemoglobinuria-type cells. Blood. 2004;104(8):2425–2431. doi: 10.1182/blood-2004-05-1839.
  • Jankovicova B, Skultety L, Dubrovcakova M, et al. Overlap of epitopes recognized by anti-carbonic anhydrase I IgG in patients with malignancy-related aplastic anemia-like syndrome and in patients with aplastic anemia. Immunol Lett. 2013;153(1-2):47–49. doi: 10.1016/j.imlet.2013.07.006.
  • Lakota J, Lanz A, Dubrovcakova M, et al. Antibodies against carbonic anhydrase in patients with aplastic anemia. Acta Haematol. 2012;128(3):190–194. doi: 10.1159/000338826.
  • Qi Z, Takamatsu H, Espinoza JL, et al. Autoantibodies specific to hnRNP K: a new diagnostic marker for immune pathophysiology in aplastic anemia. Ann Hematol. 2010;89(12):1255–1263. doi: 10.1007/s00277-010-1020-3.
  • Goto M, Kuribayashi K, Takahashi Y, et al. Identification of autoantibodies expressed in acquired aplastic anaemia. Br J Haematol. 2013;160(3):359–362. doi: 10.1111/bjh.12116.
  • Takamatsu H, Feng X, Chuhjo T, et al. Specific antibodies to moesin, a membrane-cytoskeleton linker protein, are frequently detected in patients with acquired aplastic anemia. Blood. 2007;109(6):2514–2520. doi: 10.1182/blood-2006-07-036715.
  • Kelkka T, Tyster M, Lundgren S, et al. Anti-COX-2 autoantibody is a novel biomarker of immune aplastic anemia. Leukemia. 2022;36(9):2317–2327. doi: 10.1038/s41375-022-01654-6.
  • Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood. 2012;120(6):1185–1196. doi: 10.1182/blood-2011-12-274019.
  • Young ME, Potter V, Kulasekararaj AG, et al. Haematopoietic stem cell transplantation for acquired aplastic anaemia. Curr Opin Hematol. 2013;20(6):515–520. doi: 10.1097/MOH.0b013e328365af83.
  • Young NS, Bacigalupo A, Marsh JC. Aplastic anemia: pathophysiology and treatment. Biol Blood Marrow Transplant. 2010;16(1 Suppl):S119–S25. doi: 10.1016/j.bbmt.2009.09.013.
  • Dubey S, Shukla P, Nityanand S. Expression of interferon-gamma and tumor necrosis factor-alpha in bone marrow T cells and their levels in bone marrow plasma in patients with aplastic anemia. Ann Hematol. 2005;84(9):572–577. doi: 10.1007/s00277-005-1022-8.
  • Sloand E, Kim S, Maciejewski JP, et al. Intracellular interferon-gamma in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia. Blood. 2002;100(4):1185–1191. doi: 10.1182/blood-2002-01-0035.
  • Selleri C, Maciejewski JP, Sato T, et al. Interferon-gamma constitutively expressed in the stromal microenvironment of human marrow cultures mediates potent hematopoietic inhibition. Blood. 1996;87(10):4149–4157. doi: 10.1182/blood.V87.10.4149.bloodjournal87104149.
  • Alvarado LJ, Huntsman HD, Cheng H, et al. Eltrombopag maintains human hematopoietic stem and progenitor cells under inflammatory conditions mediated by IFN-γ. Blood. 2019;133(19):2043–2055. doi: 10.1182/blood-2018-11-884486.
  • Bestach Y, Sieza Y, Attie M, et al. Polymorphisms in TNF and IFNG are associated with clinical characteristics of aplastic anemia in Argentinean population. Leuk Lymphoma. 2015;56(6):1793–1798. doi: 10.3109/10428194.2014.966707.
  • El Mahgoub IR, Afify RA, Botros SK, et al. Immunoregulatory cytokines gene polymorphisms in Egyptian patients affected with acquired aplastic anemia. Ann Hematol. 2014;93(6):923–929. doi: 10.1007/s00277-013-1992-x.
  • Lee YG, Kim I, Kim JH, et al. Impact of cytokine gene polymorphisms on risk and treatment outcomes of aplastic anemia. Ann Hematol. 2011;90(5):515–521. doi: 10.1007/s00277-010-1102-2.
  • Dufour C, Capasso M, Svahn J, et al. Homozygosis for (12) CA repeats in the first intron of the human IFN-gamma gene is significantly associated with the risk of aplastic anaemia in Caucasian population. Br J Haematol. 2004;126(5):682–685. doi: 10.1111/j.1365-2141.2004.05102.x.
  • Kook H, Risitano AM, Zeng W, et al. Changes in T-cell receptor VB repertoire in aplastic anemia: effects of different immunosuppressive regimens. Blood. 2002;99(10):3668–3675. doi: 10.1182/blood.v99.10.3668.
  • Giudice V, Feng X, Lin Z, et al. Deep sequencing and flow cytometric characterization of expanded effector memory CD8(+)CD57(+) T cells frequently reveals T-cell receptor Vβ oligoclonality and CDR3 homology in acquired aplastic anemia. Haematologica. 2018;103(5):759–769. doi: 10.3324/haematol.2017.176701.
  • Patel BA, Giudice V, Young NS. Immunologic effects on the haematopoietic stem cell in marrow failure. Best Pract Res Clin Haematol. 2021;34(2):101276. doi: 10.1016/j.beha.2021.101276.
  • Giudice V, Risitano AM, Selleri C. Infectious agents and bone marrow failure: a causal or a casual connection? Front Med. 2021;8:757730. doi: 10.3389/fmed.2021.757730.
  • Olsson T. Epstein barr virus infection and immune defense related to HLA-DR15: consequences for multiple sclerosis. Eur J Immunol. 2021;51(1):56–59. doi: 10.1002/eji.202049030.
  • Angelini DF, Serafini B, Piras E, et al. Increased CD8+ T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis. PLoS Pathog. 2013;9(4):e1003220. doi: 10.1371/journal.ppat.1003220.
  • Hsieh YC, Chang ST, Huang WT, et al. A comparative study of flow cytometric T cell receptor Vβ repertoire and T cell receptor gene rearrangement in the diagnosis of large granular lymphocytic lymphoproliferation. Int J Lab Hematol. 2013;35(5):501–509. doi: 10.1111/ijlh.12041.
  • Zawit M, Bahaj W, Gurnari C, et al. Large granular lymphocytic leukemia: from immunopathogenesis to treatment of refractory disease. Cancers. 2021;13(17):4418. doi: 10.3390/cancers13174418.
  • Sugimori C, Yamazaki H, Feng X, et al. Roles of DRB1 *1501 and DRB1 *1502 in the pathogenesis of aplastic anemia. Exp Hematol. 2007;35(1):13–20. doi: 10.1016/j.exphem.2006.09.002.
  • Chowell D, Morris LGT, Grigg CM, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science. 2018;359(6375):582–587. doi: 10.1126/science.aao4572.
  • Hazane Leroyer E, Ziegler C, Moulin C, et al. Filling the gap: the immune therapeutic armamentarium for relapsed/refractory Hodgkin lymphoma. JCM. 2022;11(21):6574. doi: 10.3390/jcm11216574.
  • Gurnari C, Pagliuca S. Digging into the HLA pockets: a new association with acute leukaemias. Br J Haematol. 2023;200(2):123–125. doi: 10.1111/bjh.18529.
  • Boukouaci W, Rivera-Franco MM, Volt F, et al. Comparative analysis of the variability of the human leukocyte antigen peptide-binding pockets in patients with acute leukaemia. Br J Haematol. 2023;200(2):197–209. doi: 10.1111/bjh.18517.
  • Pagliuca S, Gurnari C, Hercus C, et al. Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation. Res Sq. 2023. PMID: 37066269
  • Ishigaki K, Lagattuta KA, Luo Y, et al. HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors. Nat Genet. 2022;54(4):393–402. doi: 10.1038/s41588-022-01032-z.
  • Moutsianas L, Jostins L, Beecham AH, et al. Class II HLA interactions modulate genetic risk for multiple sclerosis. Nat Genet. 2015;47(10):1107–1113.
  • Krause-Kyora B, Nutsua M, Boehme L, et al. Ancient DNA study reveals HLA susceptibility locus for leprosy in medieval europeans. Nat Commun. 2018;9(1):1569. doi: 10.1038/s41467-018-03857-x.
  • Menegatti J, Schub D, Schäfer M, et al. HLA-DRB1*15:01 is a co-receptor for Epstein-Barr virus, linking genetic and environmental risk factors for multiple sclerosis. Eur J Immunol. 2021;51(9):2348–2350. doi: 10.1002/eji.202149179.
  • Brown KE, Tisdale J, Barrett AJ, et al. Hepatitis-associated aplastic anemia. N Engl J Med. 1997;336(15):1059–1064. doi: 10.1056/NEJM199704103361504.
  • Kagan WA, Ascensão JA, Pahwa RN, et al. Aplastic anemia: presence in human bone marrow of cells that suppress myelopoiesis. Proc Natl Acad Sci U S A. 1976;73(8):2890–2894. doi: 10.1073/pnas.73.8.2890.
  • Locasciulli A, Bacigalupo A, Bruno B, et al. Hepatitis-associated aplastic anaemia: epidemiology and treatment results obtained in Europe. A report of the EBMT aplastic anaemia working party. Br J Haematol. 2010;149(6):890–895. doi: 10.1111/j.1365-2141.2010.08194.x.
  • Pol S, Driss F, Devergie A, et al. Is hepatitis C virus involved in hepatitis-associated aplastic anemia? Ann Intern Med. 1990;113(6):435–437. doi: 10.7326/0003-4819-113-6-435.
  • Crespo J, de las Heras B, Rivero M, et al. Hepatitis G virus infection as a possible causative agent of community-acquired hepatitis and associated aplastic anaemia. Postgrad Med J. 1999;75(881):159–160. doi: 10.1136/pgmj.75.881.159.
  • Dame C, Hasan C, Bode U, et al. Acute liver disease and aplastic anemia associated with the persistence of b19 DNA in liver and bone marrow. Pediatr Pathol Mol Med. 2002;21(1):25–29. doi: 10.1080/pdp.21.1.25.29.
  • Schenke C, Alejandre-Alcázar MA, Holter W, et al. Aplastic anemia following hepatitis associated with human herpesvirus 6. J Pediatr Gastroenterol Nutr. 2010;51(4):527–529. doi: 10.1097/MPG.0b013e3181e9636e.
  • Baranski B, Armstrong G, Truman JT, et al. Epstein-Barr virus in the bone marrow of patients with aplastic anemia. Ann Intern Med. 1988;109(9):695–704. doi: 10.7326/0003-4819-109-9-695.
  • Gargiulo L, Papaioannou M, Sica M, et al. Glycosylphosphatidylinositol-specific, CD1d-restricted T cells in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121(14):2753–2761. doi: 10.1182/blood-2012-11-469353.
  • Gargiulo L, Zaimoku Y, Scappini B, et al. Glycosylphosphatidylinositol-specific T cells, IFN-γ-producing T cells, and pathogenesis of idiopathic aplastic anemia. Blood. 2017;129(3):388–392. doi: 10.1182/blood-2016-09-740845.
  • Luzzatto L, Bessler M, Rotoli B. Somatic mutations in paroxysmal nocturnal hemoglobinuria: a blessing in disguise? Cell. 1997;88(1):1–4. doi: 10.1016/s0092-8674(00)81850-4.
  • Young NS, Maciejewski JP, Sloand E, et al. The relationship of aplastic anemia and PNH. Int J Hematol. 2002;76(Suppl 2):168–172. doi: 10.1007/BF03165111.
  • Van Kamp H, Van Imhoff GW, Wolf MD, et al. The effect of cyclosporine on haematological parameters in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol. 1995;89(1):79–82. doi: 10.1111/j.1365-2141.1995.tb08907.x.
  • Hill A, de Latour RP, Kulasekararaj AG, et al. Concomitant immunosuppressive therapy and eculizumab use in patients with paroxysmal nocturnal hemoglobinuria: an international PNH registry analysis. Acta Haematol. 2023;146(1):1–13. doi: 10.1159/000526979.
  • Pagliuca S, Risitano AM, De Fontbrune FS, et al. Combined intensive immunosuppression and eculizumab for aplastic anemia in the context of hemolytic paroxysmal nocturnal hemoglobinuria: a retrospective analysis. Bone Marrow Transplant. 2018;53(1):105–107. doi: 10.1038/bmt.2017.220.
  • Gurnari C, Pagliuca S, Patel BJ, et al. Implication of PIGA genotype on erythrocytes phenotype in paroxysmal nocturnal hemoglobinuria. Leukemia. 2021;35(8):2431–2434. doi: 10.1038/s41375-020-01113-0.
  • Takahashi M, Takeda J, Hirose S, et al. Deficient biosynthesis of N-acetylglucosaminyl-phosphatidylinositol, the first intermediate of glycosyl phosphatidylinositol anchor biosynthesis, in cell lines established from patients with paroxysmal nocturnal hemoglobinuria. J Exp Med. 1993;77(2):517–521. doi: 10.1084/jem.177.2.517.
  • Araten DJ, Luzzatto L. The mutation rate in PIG-A is normal in patients with paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2006;108(2):734–736. doi: 10.1182/blood-2006-01-0256.
  • Clemente MJ, Przychodzen B, Hirsch CM, et al. Clonal PIGA mosaicism and dynamics in paroxysmal nocturnal hemoglobinuria. Leukemia. 2018;32(11):2507–2511. doi: 10.1038/s41375-018-0138-5.
  • Gurnari C, Graham AC, Efanov A, et al. Frequency and perturbations of various peripheral blood cell populations before and after eculizumab treatment in paroxysmal nocturnal hemoglobinuria. Blood Cells Mol Dis. 2021;87:102528. doi: 10.1016/j.bcmd.2020.102528.
  • Risitano AM, Marotta S, Ricci P, et al. Anti-complement treatment for paroxysmal nocturnal hemoglobinuria: time for proximal complement inhibition? A position paper from the SAAWP of the EBMT. Front Immunol. 2019;10:1157. doi: 10.3389/fimmu.2019.01157.
  • Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355(12):1233–1243. doi: 10.1056/NEJMoa061648.
  • Kulasekararaj AG, Hill A, Rottinghaus ST, et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019;133(6):540–549. doi: 10.1182/blood-2018-09-876805.
  • Giudice V, Selleri C. Aplastic anemia: pathophysiology. Semin Hematol. 2022;59(1):13–20. doi: 10.1053/j.seminhematol.2021.12.002.
  • Cooper JN, Young NS. Clonality in context: hematopoietic clones in their marrow environment. Blood. 2017;130(22):2363–2372. doi: 10.1182/blood-2017-07-794362.
  • Zhu C, Lian Y, Wang C, et al. Single-cell transcriptomics dissects hematopoietic cell destruction and T-cell engagement in aplastic anemia. Blood. 2021;138(1):23–33. doi: 10.1182/blood.2020008966.
  • Pagliuca S, Gurnari C, Hercus C, et al. Molecular landscape of immune pressure and escape in aplastic anemia. Leukemia. 2023;37(1):202–211. doi: 10.1038/s41375-022-01723-w.
  • Przychodzen B, Makishima H, Sekeres MA, et al. Fanconi anemia germline variants as susceptibility factors in aplastic anemia, MDS and AML. Oncotarget. 2018;9(2):2050–2057. doi: 10.18632/oncotarget.23328.
  • Pagliuca S, Gurnari C, Rubio MT, et al. Individual HLA heterogeneity and its implications for cellular immune evasion in cancer and beyond. Front Immunol. 2022;13:944872. doi: 10.3389/fimmu.2022.944872.
  • O’Donnell JS, Teng MWL, Smyth MJ. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat Rev Clin Oncol. 2019;16(3):151–167. doi: 10.1038/s41571-018-0142-8.
  • Young NS, Maciejewski JP. Genetic and environmental effects in paroxysmal nocturnal hemoglobinuria: this little PIG-A goes “why? Why? Why? J Clin Invest. 2000;106(5):637–641. doi: 10.1172/JCI11002.
  • Afable MG, II, Wlodarski M, Makishima H, et al. SNP array–based karyotyping: differences and similarities between aplastic anemia and hypocellular myelodysplastic syndromes. Blood. 2011;117(25):6876–6884. doi: 10.1182/blood-2010-11-314393.
  • Mizumaki H, Hosomichi K, Hosokawa K, et al. A frequent nonsense mutation in exon 1 across certain HLA-A and -B alleles in leukocytes of patients with acquired aplastic anemia. Haematologica. 2021;106(6):1581–1590.
  • Zaimoku Y, Patel BA, Adams SD, et al. HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia. Blood. 2021;138(26):2799–2809. doi: 10.1182/blood.2021012895.
  • Zaimoku Y, Takamatsu H, Hosomichi K, et al. Identification of an HLA class I allele closely involved in the autoantigen presentation in acquired aplastic anemia. Blood. 2017;129(21):2908–2916. doi: 10.1182/blood-2016-11-752378.
  • Babushok DV, Duke JL, Xie HM, et al. Somatic HLA mutations expose the role of class I-mediated autoimmunity in aplastic anemia and its clonal complications. Blood Adv. 2017;1(22):1900–1910. doi: 10.1182/bloodadvances.2017010918.
  • Olson TS, Frost BF, Duke JL, et al. Pathogenicity and impact of HLA class I alleles in aplastic anemia patients of different ethnicities. JCI Insight. 2022;7(22):e163040. doi: 10.1172/jci.insight.163040.
  • Gurnari C, Pagliuca S, Prata PH, et al. Clinical and molecular determinants of clonal evolution in aplastic anemia and paroxysmal nocturnal hemoglobinuria. J Clin Oncol. 2023;41(1):132–142. doi: 10.1200/JCO.22.00710.
  • Groarke EM, Patel BA, Shalhoub R, et al. Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia. Leukemia. 2022;36(9):2328–2337. doi: 10.1038/s41375-022-01636-8.
  • Gurnari C, Pagliuca S, Kewan T, et al. Is nature truly healing itself? Spontaneous remissions in paroxysmal nocturnal hemoglobinuria. Blood Cancer J. 2021;11(11):187. doi: 10.1038/s41408-021-00582-5.
  • Gurnari C, Visconte V. From bone marrow failure syndromes to VEXAS: disentangling clonal hematopoiesis, immune system, and molecular drivers. Leuk Res. 2023;127:107038. doi: 10.1016/j.leukres.2023.107038.
  • Gurnari C, Fabiani E, Falconi G, et al. From clonal hematopoiesis to therapy-related myeloid neoplasms: the silent way of cancer progression. Biology. 2021;10(2):128. doi: 10.3390/biology10020128.
  • Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015;373(1):35–47. doi: 10.1056/NEJMoa1414799.
  • Yoshizato T, Nannya Y, Atsuta Y, et al. Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation. Blood. 2017;129(17):2347–2358. doi: 10.1182/blood-2016-12-754796.
  • Kulasekararaj AG, Jiang J, Smith AE, et al. Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome. Blood. 2014;124(17):2698–2704. doi: 10.1182/blood-2014-05-574889.
  • Lane AA, Odejide O, Kopp N, et al. Low frequency clonal mutations recoverable by deep sequencing in patients with aplastic anemia. Leukemia. 2013;27(4):968–971. doi: 10.1038/leu.2013.30.
  • Babushok DV, Perdigones N, Perin JC, et al. Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia. Cancer Genet. 2015;208(4):115–128. doi: 10.1016/j.cancergen.2015.01.007.
  • Heuser M, Schlarmann C, Dobbernack V, et al. Genetic characterization of acquired aplastic anemia by targeted sequencing. Haematologica. 2014;99(9):e165-7–e167. doi: 10.3324/haematol.2013.101642.
  • Maciejewski JP, Risitano A, Sloand EM, et al. Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood. 2002;99(9):3129–3135. doi: 10.1182/blood.v99.9.3129.
  • Saumell S, Florensa L, Luño E, et al. Prognostic value of trisomy 8 as a single anomaly and the influence of additional cytogenetic aberrations in primary myelodysplastic syndromes. Br J Haematol. 2012;159(3):311–321. doi: 10.1111/bjh.12035.
  • Gurnari C, Prata PH, Catto LFB, et al. IPSS-M in myelodysplastic neoplasms arising from aplastic anemia and paroxysmal nocturnal hemoglobinuria. Blood. 2023. doi: 10.1182/blood.2023020108.
  • Reilly CR, Shimamura A. Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: biological insights and clinical advances. Blood. 2023;141(13):1513–1523. doi: 10.1182/blood.2022017739.
  • Kennedy AL, Myers KC, Bowman J, et al. Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome. Nat Commun. 2021;12(1):1334. doi: 10.1038/s41467-021-21588-4.
  • Ogawa S. Clonal hematopoiesis in acquired aplastic anemia. Blood. 2016;128(3):337–347. doi: 10.1182/blood-2016-01-636381.
  • Sun L, Babushok DV. Secondary myelodysplastic syndrome and leukemia in acquired aplastic anemia and paroxysmal nocturnal hemoglobinuria. Blood. 2020;136(1):36–49. doi: 10.1182/blood.2019000940.
  • Gurnari C, Maciejewski JP. Aplastic anemia: quo vadis? Semin Hematol. 2022;59(1):54–55. doi: 10.1053/j.seminhematol.2021.12.001.
  • Peffault de Latour R, Kulasekararaj A, Iacobelli S, et al. Eltrombopag added to immunosuppression in severe aplastic anemia. N Engl J Med. 2022;386(1):11–23. doi: 10.1056/NEJMoa2109965.
  • Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. 2017;376(16):1540–1550. doi: 10.1056/NEJMoa1613878.
  • Drexler B, Passweg J. Current evidence and the emerging role of eltrombopag in severe aplastic anemia. Ther Adv Hematol. 2021;12:2040620721998126. doi: 10.1177/2040620721998126.
  • Patel BA, Groarke EM, Lotter J, et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study. Blood. 2022;139(1):34–43. doi: 10.1182/blood.2021012130.
  • Negoro E, Nagata Y, Clemente MJ, et al. Origins of myelodysplastic syndromes after aplastic anemia. Blood. 2017;130(17):1953–1957. doi: 10.1182/blood-2017-02-767731.
  • Socié G, Henry-Amar M, Bacigalupo A, et al. Malignant tumors occurring after treatment of aplastic anemia. European bone marrow transplantation-severe aplastic anaemia working party. N Engl J Med. 1993;329(16):1152–1157. doi: 10.1056/NEJM199310143291603.
  • Arber DA, Orazi A, Hasserjian RP, et al. International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200–1228. doi: 10.1182/blood.2022015850.
  • Khoury JD, Solary E, Abla O, et al. The 5th edition of the world health organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703–1719. doi: 10.1038/s41375-022-01613-1.
  • Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 ELN recommendations from an international expert panel. Blood. 2022;140(12):1345–1377. doi: 10.1182/blood.2022016867.
  • Bernard E, Tuechler H, Greenberg PL, et al. Molecular international prognostic scoring system for myelodysplastic syndromes. NEJM Evid. 2022;1(7):EVIDoa2200008.
  • Kewan T, Bahaj W, Durmaz A, et al. Validation of the molecular international prognostic scoring system in patients with myelodysplastic syndromes. Blood. 2023;141(14):1768–1772. doi: 10.1182/blood.2022018896.
  • Gurnari C, Gagelmann N, Badbaran A, et al. Outcome prediction in myelodysplastic neoplasm undergoing hematopoietic cell transplant in the molecular era of IPSS-M. Leukemia. 2023;37(3):717–719. doi: 10.1038/s41375-023-01820-4.
  • Gurnari C, Prata PH, Bazzo Catto LF, et al. Molecular international prognostic scoring system (IPSS-M) in myelodysplastic syndromes arising from aplastic anemia and paroxysmal nocturnal hemoglobinuria. Blood. 2022;140(Supplement 1):5788–5789. doi: 10.1182/blood-2022-160458.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.