Clinical Relevance of Cytogenetics Abnormalities in Adult Patients with Acquired Aplastic Anaemia.

Abstract

The clinical relevance of cytogenetics abnormalities in aplastic anaemia (AA) patients at time of diagnosis is unclear. We evaluated the clinical course of 81 AA patients with successful cytogenetics at diagnosis and treated with immunosuppressive therapy (IST) from January 1993 to March 2004. A cytogenetic study was considered to be successful if there were a minimum of 15 evaluable metaphases in the absence of a clonal abnormality. Response to IST, survival and later clonal complications in patients with an abnormal karyotype (n=10) was compared to those with a normal karyotype (n=71). The cytogenetic abnormalities at diagnosis consisted of trisomy 6 (n=2), trisomy 8 (n=2), trisomy 15 (n=2), monosomy 7 (n=1), add(10) (n=1), t(3;11) (n=1) and t(4;6) (n=1). Four out of five evaluable patients with a trisomy responded to a first or subsequent course of IST. One patient with monosomy 7 achieved a complete response and later developed haemolytic PNH but with no recurrence of the monosomy 7. None of the patients with a non-numerical karyotypic abnormality responded to IST. No significant differences in 4-year event-free survival (EFS) (54% vs. 30%, p=0.15), overall survival (OS) (84% vs. 80%, p=0.33) or later clonal disorders (PNH, MDS and AML) were observed between the patients with a normal karyotype and those with an abnormal karyotype. Advanced age (≥60 years) was the only independent poor prognostic factor for survival in a multivariate analysis. Among the patients with a normal karyotype (n=71), 6 patients later developed a clonal cytogenetic abnormality with a cumulative risk of 10% at 4 years. These abnormalities were trisomy 15 (n=2), trisomy 6(n=1), monosomy 7 (n=2) and t(13;15) (n=1). None of the three patients who acquired trisomies developed any clinically significant problem, while acquisition of monosomy 7 was associated with a transformation to MDS/AML. Our data show that AA patients with a trisomy cytogenetic clone at diagnosis show a similar response to IST, evolution to later clonal abnormalities and survival, compared to those AA patients with a normal karyotype.

Guidelines for the diagnosis and management of aplastic anaemia

“…As discussed previously (see section 2.8) an abnormal cytogenetic clone can be detected in up to 12% of patients with aplastic anaemia at diagnosis (Appelbaum et al, 1989;Socie et al, 2000;Gupta et al, 2006). The most frequently observed abnormalities include trisomy 8, trisomy 6, 5q-and anomalies of chromosomes 7 and 13.…”

“…Often the abnormal clone is small, comprising only a small proportion of total metaphases, and not infrequently, it may be transient and disappear spontaneously or after haematological response to immunosuppressive therapy (Mikhailova et al, 1986;Geary et al, 1999;Piaggio et al, 1999;Socie et al, 2000;Ishiyama et al, 2002;Gupta et al, 2006). From small reported series, the response rates to immunosuppressive therapy appear to be similar to patients with aplastic anaemia who lack an abnormal cytogenetic clone (Mikhailova et al, 1986;Geary et al, 1999;Ishiyama et al, 2002), with good response seen particularly in those patients with trisomies (Gupta et al, 2006). Maciejewski et al (2002) also reported a good response to immunosuppressive treatment in patients who acquired a trisomy 8 after treatment compared with a worse prognosis and high risk of leukaemic transformation for patients with monosomy 7.…”

“…In this situation, one should consider fluorescence in situ hybridization (FISH) analysis for chromosomes 5 and 7 in particular. It was previously assumed that the presence of an abnormal cytogenetic clone indicated a diagnosis of MDS and not aplastic anaemia, but it is now evident that abnormal cytogenetic clones may be present in up to 12% of patients with otherwise typical aplastic anaemia at diagnosis (Appelbaum et al , 1989; Tichelli et al , 1996; Gupta et al , 2006). The presence of abnormal cytogenetics at presentation in children, especially monosomy 7, should alert to the likelihood of MDS.…”