Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Taking over the Atlas
Dear Colleagues,
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Jean-Loup Huret
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Refractory anemia (RA)


ICD-Morpho 9980/3 Refractory anemia
Note This disorder is part of the heterogeneous category of myelodysplastic syndrome (MDS). According to the FAB classification of MDS, RA includes those patients with refractory cytopenia with multilineage dysplasia (RCMD), the latter category having been recognised as a distinct entity by the WHO classification (vide infra). Also, the 5q- syndrome is part of the RA in the FAB classification.
In this card, the FAB classification will be used, because the majority of available data on cytogenetic anomalies was derived from studies published before WHO classification.

Clinics and Pathology

Phenotype / cell stem origin RA is a clonal disorder originating from a totipotent stem cell or from a multipotent myeloid progenitor cell, characterized by ineffective hemopoiesis and diserythropoiesis.
Epidemiology There are few data on the epidemiology of RA, which may account for 30-40% of all MDS cases. MDS is predominantly diagnosed in the elderly population. The global incidence of all MDS was comprised between 3,5 and 12,6 new cases / year / per 100,000 in some studies. The incidence may rise from 0,5 MDS cases per year in the 40 years age-group to 89 cases per year in the >80 age-group.
Clinics RA usually presents with hypercellular bone marrow (BM) and anemia. There may be leukopenia and/or and thrombocytopenia, but these features do not represent a diagnostic requirement.
In the WHO classification RA shows anemia, no or rare blasts in the peripheral blood, isolated erythoid dysplasia with <5% blasts and <15% ringed sideroblasts in the BM. RCMD shows cytopenias (bicytopenia or pancytopenia) in the peripheral blood plus dysplasia in more than 10% of the cells in 2 or more myeloid lineages.
Cytology Criteria for the recognition of dysplastic features of BM cells were published by the FAB group. Dyserythropoiesis includes megaloblastoid changes of erythroid precursors, multinuclearity, nuclear fragmentation, unstained area in the cytoplasm (dysemoglobinization).
Pathology The bone biopsy may be useful in some cases of MDS with BM fibrosis and allows for the demonstration of the so called "abnormal localization of immature precursors" (ALIP) which may represent a prognostic factor.
Treatment Treatment of this condition is largely supportive, including blood transfusion in patients with symptomatic anemia. Anemic patients with low serum erythropoietin (EPO) levels may benefit of the administration of rHu-EPO.
Evolution This is a preleukemic condition, carrying a 10-20% probability of evolving into leukemia. The probability of RA to transform into AML may be lower when including the 5q- syndrome and excluding RCMD, but prospective studies are lacking. In a study 25% of the patient developed acute myeloid leukemia (AML) within 5 years.
Prognosis Median survival of RA may fall in the 27-50 month range. As noted above, heterogeneity of patient population may account for inter-study variability in median survival. The best outcome is usually observed in RA with isolated 5q- (5q- syndrome of the WHO classification) and in those patients without multilineage dysplasia, corresponding to the RA category in the WHO classification.
Chromosomal abnormalities have independent prognostic significance and are to be included in risk assessment at diagnosis. Favourable cytogenetic features are normal karyotype, 5q- or 20q- isolated; unfavourable features are complex karyotype (i.e. 3 or more clonal anomalies) and abnormalities of chromosome 7q; other abnormalities identify patients in the intermediate cytogenetic-risk group.


Cytogenetics Morphological There is no specific chromosome marker for patients with RA, 70 to 80% of whom may show a normal karyotype. More sensitive techniques such as fluorescence in situ hybridization (FISH) failed to increase the percentage of abnormal cases in this category of MDS.
The 5q- chromosome may be found in as many as 70% of RA with a clonal aberrations. Usually, but not invariably, the breakpoints involve the bands q13 and q33. When the 5q- is the sole change and it is associated with hypolobated megakaryocytes in the BM, with macrocytic anemia, with normal or increased platelet count then the patient should be diagnosed as having the "5q- syndrome". The 5q- can be present in other subsets of MDS.
A chromosome 20q deletion if found in 5% of all MDS and in 10-15% of RA with abnormal karyotype.
Other chromosome aberrations in RA include trisomy 8 in 10% of cytogenetically abnormal cases -7/7q- or 11q- in < 5% of the abnormal cases.
A number of very rare chromosome aberrations were described in single reports.

Other genes implicated (Data extracted from papers in the Atlas)

Genes ETV6 ZMYND10

Translocations implicated (Data extracted from papers in the Atlas)


Myelodysplastic syndromes: recent advances.
Alessandrino EP, Amadori S, Cazzola M, Locatelli F, Mecucci C, Morra E, Saglio G, Visani G, Tura S
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PMID 11694400
Proposals for the classification of the myelodysplastic syndromes.
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British journal of haematology. 1982 ; 51 (2) : 189-199.
PMID 6952920
Two types of acquired idiopathic sideroblastic anaemia (AISA)
Gattermann N, Aul C, Schneider W
British journal of haematology. 1990 ; 74 (1) : 45-52.
PMID 2310696
Prognostic factors of myelodysplastic syndromes--a simplified 3-D scoring system.
Goasguen JE, Garand R, Bizet M, Bremond JL, Gardais J, Callat MP, Accard F, Chaperon J
Leukemia research. 1990 ; 14 (3) : 255-262.
PMID 2319806
International scoring system for evaluating prognosis in myelodysplastic syndromes.
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J
Blood. 1997 ; 89 (6) : 2079-2088.
PMID 9058730
Life expectancy in primary myelodysplastic syndromes: a prognostic score based upon histopathology from bone marrow biopsies of 569 patients.
Maschek H, Gutzmer R, Choritz H, Georgii A
European journal of haematology. 1994 ; 53 (5) : 280-287.
PMID 7813708
Clinical importance of interphase cytogenetics detecting occult chromosome lesions in myelodysplastic syndromes with normal karyotype.
Rigolin GM, Bigoni R, Milani R, Cavazzini F, Roberti MG, Bardi A, Agostini P, Della Porta M, Tieghi A, Piva N, Cuneo A, Castoldi G
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2001 ; 15 (12) : 1841-1847.
PMID 11753603
Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in Japan.
Toyama K, Ohyashiki K, Yoshida Y, Abe T, Asano S, Hirai H, Hirashima K, Hotta T, Kuramoto A, Kuriya S
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1993 ; 7 (4) : 499-508.
PMID 8464227
The World Health Organization (WHO) classification of the myeloid neoplasms.
Vardiman JW, Harris NL, Brunning RD
Blood. 2002 ; 100 (7) : 2292-2302.
PMID 12239137
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed


Written11-2003Antonio Cuneo, Gianluigi Castoldi


This paper should be referenced as such :
Cuneo, A ; Castoldi, GL
Refractory anemia (RA)
Atlas Genet Cytogenet Oncol Haematol. 2004;8(1):33-34.
Free journal version : [ pdf ]   [ DOI ]

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