Abstract
To assess the incidence rates and risk factors for clonal evolutions in aplastic anemia (AA) patients, we studied 802 hospitalization cases from January 1991 through December 2007 by using the cumulative incidence curves and the Cox proportional hazards mode. We found that the case of 19 patients had evolved to myelodysplastic syndrome or acute myeloid leukemia (MDS/AML), while 21 patients (two of them with concurrent MDS) developed paroxysmal nocturnal hemoglobinuria (PNH). The cumulative incidence of clonal evolutions was assessed as 3.7%, whereas the incidences of MDS/AML and PNH were 1.7% and 2.1%, respectively, at 5 years. By multivariate analysis, age, severity of the disease, and the number of days of rhuG-CSF therapy were the risk factors for AA evolution to MDS/AML. The relative risk (RR) for very severe AA was approximately seven times higher than that for severe AA (SAA) and non-SAA (NSAA) (P = 0.001), but the latter two did not differ significantly (P = 0.743). PNH clone was monitored sequentially in 237 patients; positive clones were detected in 41% of the patients, but more than half of them were transient or instable. White blood cell count at initial diagnosis was identified as the only significant risk factor for AA evolution to PNH (P = 0.007). Our results suggest that the transformation to PNH for subpopulations of AA patients may be natural evolution as the clinical manifestation and pathogenesis between AA and PNH were closely related. Furthermore, normalizing hematopoiesis of AA may represent a viable approach to prevent clone evolutions, especially to MDS/AML.
Similar content being viewed by others
References
Young N, Griffith P, Brittain E, Elfenbein G, Gardner F, Huang A, Harmon D, Hewlett J, Fay J, Mangan K (1988) A multicenter trial of antithymocyte globulin in aplastic anemia and related diseases. Blood 72:1861–1869
Bacigalupo A, Bruno B, Saracco P, Di Bona E, Locasciulli A, Locatelli F, Gabbas A, Dufour C, Arcese W, Testi G, Broccia G, Carotenuto M, Coser P, Barbui T, Leoni P, Ferster A (2000) Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia and the Gruppo Italiano Trapianti di Midolio Osseo (GITMO). Blood 95:1931–1934
Locasciulli A, Oneto R, Bacigalupo A, Socié G, Korthof E, Bekassy A, Schrezenmeier H, Passweg J, Führer M (2007) Outcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade: a report from the European Group for Blood and Marrow Transplantation (EBMT). Haematologica 92:11–18. doi:10.3324/haematol.10075
Passweg JR, Tichelli A (2009) Immunosuppressive treatment for aplastic anemia: are we hitting the ceiling? Haematologica 94:310–312. doi:10.3324/haematol.2008.002329
Tichelli A, Gratwohl A, Würsch A, Nissen C, Speck B (1988) Late haematological complications in severe aplastic anaemia. Br J Haematol 69:413–418. doi:10.1111/j.1365-2141.1988.tb02382.x
de Planque MM, Bacigalupo A, Würsch A, Hows JM, Devergie A, Frickhofen N, Brand A, Nissen C (1989) Long-term follow-up of severe aplastic anaemia patients treated with antithymocyte globulin. Severe Aplastic Anaemia Working Party of the European Cooperative Group for Bone Marrow Transplantation (EBMT). Br J Haematol 73:121–126. doi:10.1111/j.1365-2141.1988.tb02382.x
Tichelli A, Gratwohl A, Nissen C, Signer E, Stebler Gysi C, Speck B (1992) Morphology in patients with severe aplastic anemia treated with antilymphocyte globulin. Blood 80:337–345
Socié G, Henry-Amar M, Bacigalupo A, Hows J, Tichelli A, Ljungman P, McCann SR, Frickhofen N, Van’t Veer-Korthof E, Gluckman E (1993) Malignant tumors occurring after treatment of aplastic anemia. European Bone Marrow Transplantation—Severe Aplastic Anaemia Working Party. N Engl J Med 329:1152–1157
Kojima S, Ohara A, Tsuchida M, Kudoh T, Hanada R, Okimoto Y, Kaneko T, Takano T, Ikuta K, Tsukimoto I (2002) Risk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children. Blood 100:786–790
Maciejewski JP, Risitano A, Sloand EM, Nunez O, Young NS (2002) Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood 99:3129–3135
Bagby GC, Meyers G (2007) Bone marrow failure as a risk factor for clonal evolution: prospects for leukemia prevention. Hematology Am Soc Hematol Educ Program 2007:40–46
Kaito K, Kobayashi M, Katayama T, Masuoka H, Shimada T, Nishiwaki K, Sekita T, Otsubo H, Ogasawara Y, Hosoya T (1998) Long-term administration of G-CSF for aplastic anaemia is closely related to the early evolution of monosomy 7 MDS in adults. Br J Haematol 103:297–303. doi:10.1046/j.1365-2141.1998.01014.x
Ohara A, Kojima S, Hamajima N, Tsuchida M, Imashuku S, Ohta S, Sasaki H, Okamura J, Sugita K, Kigasawa H, Kiriyama Y, Akatsuka J, Tsukimoto I (1997) Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia. Blood 90:1009–1013
Kojima S, Hibi S, Kosaka Y, Yamamoto M, Tsuchida M, Mugishima H, Sugita K, Yabe H, Ohara A, Tsukimoto I (2000) Immunosuppressive therapy using antithymocyte globulin, cyclosporine, and danazol with or without human granulocyte colony-stimulating factor in children with acquired aplastic anemia. Blood 96:2049–2054
Imashuku S, Hibi S, Bessho F, Tsuchida M, Nakahata T, Miyazaki S, Tsukimoto I, Hamajima N (2003) Detection of myelodysplastic syndrome/acute myeloid leukemia evolving from aplastic anemia in children, treated with recombinant human G-CSF. Haematologica 88:ECR31
Teramura M, Kimura A, Iwase S, Yonemura Y, Nakao S, Urabe A, Omine M, Mizoguchi H (2007) Treatment of severe aplastic anemia with antithymocyte globulin and cyclosporin A with or without G-CSF in adults: a multicenter randomized study in Japan. Blood 110:1756–1761. doi:10.1182/blood-2006-11-050526
Camitta BM, Thomas ED, Nathan DG, Santos G, Gordon-Smith EC, Gale RP, Rappeport JM, Storb R (1976) Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood 48:63–70
Zheng Y, Liu Y, Chu Y (2006) Immunosuppressive therapy for acquired severe aplastic anemia (SAA): a prospective comparison of four different regimens. Exp Hematol 34:826–831. doi:10.1016/j.exphem.2006.03.017
Vardiman JW, Thiele J, Arber DA et al (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114:937–951. doi:10.1182/blood-2009-03-209262
Socie G, Mary JY, Schrezenmeier H, Marsh J, Bacigalupo A, Locasciulli A, Fuehrer M, Bekassy A, Tichelli A, Passweg J (2007) Granulocyte-stimulating factor and severe aplastic anemia: a survey by the European Group for Blood and Marrow Transplantation (EBMT). Blood 109:2794–2796. doi:10.1182/blood-2006-07-034272
Rosenfeld S, Follmann D, Nunez O, Young NS (2003) Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA 289:1130–1135
Gurion R, Gafter-Gvili A, Paul M, Vidal L, Ben-Bassat I, Yeshurun M, Shpilberg O, Raanani P (2009) Hematopoietic growth factors in aplastic anemia patients treated with immunosuppressive therapy—systematic review and meta-analysis. Haematologica 94:712–719. doi:10.3324/haematol.2008.002170
Sloand EM, Yong AS, Ramkissoon S, Solomou E, Bruno TC, Kim S, Fuhrer M, Kajigaya S, Barrett AJ, Young NS (2006) Granulocyte colony-stimulating factor preferentially stimulates proliferation of monosomy 7 cells bearing the isoform IV receptor. Proc Natl Acad Sci USA 103:14483–14488. doi:10.1073/pnas.0605245103
Ol’shanskaia IuV, Mikhaĭlova EA, Domracheva EV, Udovichenko AI, Davidian IuR, Vodinskaia LA, Zakharova AV, Kokhno AV, Kaplanskaia IB, Tikhonova LIu, Tsvetaeva NV, Parovichnikova EN, Savchenko VG (2006) Clonal chromosomal aberrations in patients with aplastic anemia at the disease onset and transformation. Ter Arkh 78(31–34):36–37
Kearns WG, Sutton JF, Maciejewski JP, Young NS, Liu JM (2004) Genomic instability in bone marrow failure syndromes. Am J Hematol 76:220–224. doi:10.1002/ajh.20101
Najean Y, Haguenauer O (1990) Long-term (5 to 20 years) evolution of nongrafted aplastic anemias. The Cooperative Group for the Study of Aplastic and Refractory Anemias. Blood 76:2222–2228
Tiu R, Gondek L, O’Keefe C, Maciejewski JP (2007) Clonality of the stem cell compartment during evolution of myelodysplastic syndromes and other bone marrow failure syndromes. Leukemia 21:1648–1657. doi:10.1038/sj.leu.2404757
Parker CJ (2007) The pathophysiology of paroxysmal nocturnal hemoglobinuria. Exp Hematol 35:523–533. doi:10.1016/j.exphem.2007.01.046
Maciejewski JP, Rivera C, Kook H, Dunn D, Young NS (2001) Relationship between bone marrow failure syndromes and the presence of glycophosphatidyl inositol-anchored protein-deficient clones. Br J Haematol 115:1015–1022. doi:10.1046/j.1365-2141.2001.03191.x
Wang H, Chuhjo T, Yasue S, Omine M, Nakao S (2002) Clinical significance of a minor population of paroxysmal nocturnal hemoglobinuria-type cells in bone marrow failure syndrome. Blood 100:3897–3902. doi:10.1182/blood-2002-03-0799
Dunn DE, Tanawattanacharoen P, Boccuni P, Nagakura S, Green SW, Kirby MR, Kumar MS, Rosenfeld S, Young NS (1999) Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes. Ann Intern Med 131:401–408
Sugimori C, Chuhjo T, Feng X, Yamazaki H, Takami A, Teramura M, Mizoguchi H, Omine M, Nakao S (2006) Minor population of CD55-CD59- blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia. Blood 107:1308–1314. doi:10.1182/blood-2005-06-2485
Ishiyama K, Chuhjo T, Wang H, Yachie A, Omine M, Nakao S (2003) Polyclonal hematopoiesis maintained in patients with bone marrow failure harboring a minor population of paroxysmal nocturnal hemoglobinuria-type cells. Blood 102:1211–1216. doi:10.1182/blood-2002-12-3706
Paquette RL, Yoshimura R, Veiseh C, Kunkel L, Gajewski J, Rosen PJ (1997) Clinical characteristics predict response to antithymocyte globulin in paroxysmal nocturnal haemoglobinuria. Br J Haematol 96:92–97. doi:10.1046/j.1365-2141.1997.d01-1984.x
Broliden PA, Dahl IM, Hast R, Johansson B, Juvonen E, Kjeldsen L, Porwit-MacDonald A, Sjoo M, Tangen JM, Uggla B, Oberg G, Hellstrom-Lindberg E (2006) Antithymocyte globulin and cyclosporine A as combination therapy for low-risk non-sideroblastic myelodysplastic syndromes. Haematologica 91:667–670
Chen S, Jiang B, Da W, Gong M, Guan M (2007) Treatment of myelodysplastic syndrome with cyclosporin A. Int J Hematol 85:11–17
Killick SB, Mufti G, Cavenagh JD, Mijovic A, Peacock JL, Gordon-Smith EC, Bowen DT, Marsh JC (2003) A pilot study of antithymocyte globulin (ATG) in the treatment of patients with ‘low-risk’ myelodysplasia. Br J Haematol 120:679–684. doi:10.1046/j.1365-2141.2003.04136.x
de Latour RP, Mary JY, Salanoubat C, Terriou L, Etienne G, Mohty M, Roth S, de Guibert S, Maury S, Cahn JY, Socié G (2008) Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 112:3099–3106. doi:10.1182/blood-2008-01-133918
Gupta V, Brooker C, Tooze JA, Yi QL, Sage D, Turner D, Kangasabapathy P, Marsh JC (2006) Clinical relevance of cytogenetic abnormalities at diagnosis of acquired aplastic anaemia in adults. Br J Haematol 134:95–99. doi:10.1111/j.1365-2141.2006.06105.x
Mikhailova N, Sessarego M, Fugazza G, Caimo A, De Filippi S, van Lint MT, Bregante S, Valeriani A, Mordini N, Lamparelli T, Gualandi F, Occhini D, Bacigalupo A (1996) Cytogenetic abnormalities in patients with severe aplastic anemia. Haematologica 81:418–422
Brodsky RA (2008) Paroxysmal nocturnal hemoglobinuria: stem cells and clonality. Hematology Am Soc Hematol Educ Program 111–115
Rosenfeld C, List A (2000) A hypothesis for the pathogenesis of myelodysplastic syndromes: implications for new therapies. Leukemia 14:2–8
Acknowledgement
The authors thank all of the doctors and nurses in the Therapeutic Centre of Anemic Diseases and the researcher team of the Clinical Laboratory Centre including Cell Morphology, Cytochemistry, Cytogenetics, Cell Culture, Flow Cytometer, and Clinical Biochemistry for their professional assistance. The authors declared that they have no commercial, proprietary, or financial interest in the products or companies described in this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Li, Y., Li, X., Ge, M. et al. Long-term follow-up of clonal evolutions in 802 aplastic anemia patients: a single-center experience. Ann Hematol 90, 529–537 (2011). https://doi.org/10.1007/s00277-010-1140-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-010-1140-9