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Recently, a consensus International Prognostic Scoring System (IPSS) for predicting outcome and planning therapy in the myelodysplastic syndromes (MDS) has been developed. However, the intermediate-risk cytogenetic subgroup defined by the IPSS includes a miscellaneous number of different single abnormalities for which real prognosis at present is uncertain. The main aims of this study were to evaluate in an independent series the prognostic value of the IPSS and to identify chromosomal abnormalities with a previously unrecognized good or poor prognosis in 640 patients. In univariate analyses, cases with single 1q abnormalities experienced poor survival, whereas those with trisomy 8 had a higher risk of acute leukaemic transformation than the remaining patients (P = 0.004 and P = 0.009 respectively). Patients with single del(12p) had a similar survival to patients with a normal karyotype and showed some trend for a better survival than other cases belonging to the IPSS intermediate-risk cytogenetic subgroup (P = 0.045). Multivariate analyses demonstrated that IPSS cytogenetic prognostic subgroup, proportion of bone marrow blasts and haemoglobin level were the main prognostic factors for survival, and the first two characteristics and platelet count were the best predictors of acute leukaemic transformation risk. A large international co-operative study should be carried out to clarify these findings.
The myelodysplastic syndromes (MDS) constitute a heterogeneous group of haematological disorders characterized by peripheral blood cytopenia(s) in the presence of hypercellular bone marrow with features of ineffective haematopoiesis. MDS have been associated with a high risk of progression to acute myeloid leukaemia (AML) and an overall short survival, death being generally due to the consequences of cytopenias or to progression to AML ( Bennett et al, 1985 ). MDS are classified by the French/American/British (FAB) group, based on the percentage of bone marrow and peripheral blood blasts, the percentage of bone marrow ringed sideroblasts and the level of circulating monocytes, into five subtypes: refractory anaemia (RA); refractory anaemia with ringed sideroblasts (RARS); refractory anaemia with excess of blasts (RAEB); refractory anaemia with excess of blasts in transformation (RAEB-t); and chronic myelomonocytic leukaemia (CMML).
Although MDS are not associated with any specific chromosomal abnormalities, a high incidence of different abnormalities exist, such as deletion 5q, monosomy 7, deletion 7q, trisomy 8, deletion 11q, deletion 12p and deletion 20q, that are quite characteristic of these disorders ( Second International Workshop on Chromosomes in Leukemia, 1980; Knapp et al, 1985 ; Weh et al, 1987 ; Musilova & Michalova, 1988; Yunis et al, 1988 ; Nowell & Besa, 1989; Pierre et al, 1989 ; Suciu et al, 1990 ; Soléet al, 1992 , 1998; Morel et al, 1993 ; Toyama et al, 1993 ; Parlier et al, 1994 , 1995; Vallespíet al, 1998 ).
Several studies have demonstrated that the main prognostic factors in MDS are the percentage of bone marrow blasts, chromosomal abnormalities, the number and degree of cytopenias and, to a lesser extent, age ( Greenberg et al, 1997 ). As a result of these studies of prognostic factors, different scoring systems for predicting outcome in individual patients with MDS have been developed ( Mufti et al, 1985 ; Sanz et al, 1989 ; Morel et al, 1993 ). Recently, an international consensus score (International Prognostic Scoring System; IPSS), which has refined the prognostic subgroups defined by cytogenetics, has been published ( Greenberg et al, 1997 ). This scoring system is based on the percentage of bone marrow blasts (< 5%, 5–10%, 11–20% and 21–30%), karyotype [good, normal, −Y, del(5q), del(20q); poor, complex (≥ 3 abnormalities) or chromosome 7 abnormalities; intermediate, other abnormalities], and the degree of cytopenias (0/1 or 2/3). This score is gaining wide acceptance, but its prognostic value in independent series is disputed ( Estey et al, 1997 ).
The main goals of this study were to evaluate by multivariate analysis the prognostic value of the IPSS in an independent and large series of MDS patients and to try to identify chromosomal abnormalities with a previously unrecognized good or poor prognosis.
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- PATIENTS AND METHODS
The overall incidence of chromosomal abnormalities in this series of 640 patients with primary MDS was 51%, a figure very similar to other reported series ( Second International Workshop on Chromosomes in Leukemia, 1980; Knapp et al, 1985 ; Weh et al, 1987 ; Musilova & Michalova, 1988; Yunis et al, 1988 ; Nowell & Besa, 1989; Pierre et al, 1989 ; Suciu et al, 1990 ; Soléet al, 1992 , 1998; Morel et al, 1993 ; Toyama et al, 1993 ; Parlier et al, 1994 , 1995; Vallespíet al, 1998 ; Balduini et al, 1999 ). Our study confirms that RAEB and RAEB-t subtypes present the highest rate of chromosome abnormalities (61% and 70% respectively), and CMML and RARS the lowest (42% and 33% respectively).
As in other studies, the most common cytogenetic abnormalities found in this series included del(5q), monosomy 7/del(7q) and trisomy 8, del(5q) being the most frequent abnormality. Other chromosomal abnormalities frequently found included del(11q), del(12p), involvement of 12q, involvement of 13q, isochromosome 17q, del(20q), trisomy 21, monosomy 21 and loss of sex chromosomes. In MDS, chromosome loss accounts for about half of the chromosomal abnormalities. Among partial chromosome losses, del(5q) is the most common, followed by del(20q), del(11q) and del(7q) ( Third MIC Co-operative Study Group, 1988; Fenaux et al, 1996 Vallespíet al, 1998 ). In this series, the most frequent losses were del(5q), del(12p), del(7q) and del(20q).
None of the cytogenetic abnormalities found in patients with MDS was specific to an FAB subtype. As in other series, certain chromosomal abnormalities showed some degree of association with the FAB subtype ( Yunis et al, 1988 ; Suciu et al, 1990 ; Toyama et al, 1993 ; Parlier et al, 1994 ). Monosomy 7/del(7q) and complex karyotypes were more frequently found in patients with excess of blasts (RAEB and RAEB-t). Deletion 5q as a sole anomaly, trisomy 8, del(20q) and loss of Y chromosome had a higher incidence in patients with RA. In patients with RARS, there was a noticeably high incidence of del(5q), trisomy 8 and del(20q). In CMML, the most frequent aberrations were trisomy 8, del(12p), monosomy 7/del(7q) and -Y.
Previous studies have shown the prognostic impact of chromosomal abnormalities in patients with MDS ( Second International Workshop on Chromosomes in Leukemia, 1980; Knapp et al, 1985 ; Weh et al, 1987 ; Musilova & Michalova, 1988; Yunis et al, 1988 ; Nowell & Besa, 1989; Pierre et al, 1989 ; Suciu et al, 1990 ; Benitez et al, 1991 ; Soléet al, 1992 ; Parlier et al, 1994 ), and two large series have demonstrated by multivariate analysis that karyotype has independent prognostic value ( Morel et al, 1993 ; Toyama et al, 1993 ). Recent evidence also shows that chromosomal abnormalities are the best predictors of outcome after intensive antileukaemic chemotherapy ( Estey et al, 1997 ). This series confirms the prognostic importance of cytogenetic findings in patients with primary MDS. The presence or absence of chromosomal abnormalities, the number of abnormalities, the IPSS cytogenetic prognostic subgroups and some single cytogenetic abnormalities were associated with outcome in univariate analyses. In a recent report by Pfeilstöcker et al (1999 ), a series of 386 patients were evaluated by different scoring systems to assess the power of cytogenetics. Differences in prognosis were found between evidence for no aberration, single aberrations excluding chromosomes 7 and 8, aberrations on chromosomes 5, 7 or 8, and complex aberrations. Multivariate analyses demonstrated that IPSS cytogenetic prognostic subgroups, proportion of bone marrow blasts and haemoglobin were the main prognostic factors for survival, and the first two characteristics and platelet count were the best predictors of acute leukaemic transformation risk.
One of the major aims of the present study was to evaluate in an independent and large series and by means of multivariate analysis the prognostic accuracy of the recently developed IPSS ( Greenberg et al, 1997 ). Our results clearly demonstrate that the IPSS is the most powerful prognostic indicator in MDS patients, both for survival and for risk of leukaemic evolution. In fact, when the IPSS was included in the multivariate analyses, no other characteristic added significant prognostic information.
One possible minor pitfall of the IPSS is the inclusion in the intermediate cytogenetic prognostic subgroup of a miscellaneous number of single chromosomal abnormalities and double abnormalities. Some of the single chromosomal abnormalities might well prove to be of good or poor prognosis when a large number of cases are properly analysed. In the present study, there was some suggestion that certain chromosomal abnormalities could be segregated from the IPSS intermediate-risk cytogenetic subgroup. Patients with single del(12p) experienced a similar survival to patients with a normal karyotype. In fact, single del(12p) showed in univariate analysis some trend for a better prognosis than other cases belonging to the IPSS intermediate-risk cytogenetic subgroup (P = 0.045). Rearrangements of 12p have been reported in about 10% of patients with CMML and in about 5% of patients with RAEB and RAEB-t, usually as deletions at 12p11–p13 ( Wilmoth et al, 1985 ; Berger et al, 1986 ). Interestingly, in this series, eight of the 13 patients with deletion 12p as a sole abnormality had RAEB, three of the patients had CMML, and only two of the patients had RA. These data suggest that the better survival of cases with del(12p) was not conditioned by their association with a good prognosis FAB subtype. In spite of the low number of patients with single involvement of 1q (only four patients), this group had a significantly poorer outcome when compared with the overall series of patients in univariate analysis (P = 0.004), and there was some trend for a statistically significant poorer survival than that observed in the remaining cases of the IPSS intermediate-risk cytogenetic subgroup (P = 0.013). Obviously, these results should be interpreted with caution. The possible prognostic impact of these single abnormalities, del(12p) and 1q involvement has not been previously recognized. In the present series, patients with single trisomy 8 experienced a significantly increased risk of leukaemic transformation (P = 0.009) and a shorter, but not statistically significant, survival than the overall series of MDS patients. This finding indicates that single trisomy 8 might be segregated from the intermediate-risk IPSS cytogenetic category. Obviously, all of these observations require confirmation in future in larger studies before being accepted and used in clinical practice.
To conclude, our results confirm the incidence and relationship with different FAB subtypes of distinct structural and numerical chromosomal abnormalities in primary MDS, demonstrate that the IPSS accurately predicts survival and leukaemic transformation risk in the individual MDS patient, and suggest that some specific chromosomal abnormalities, such as involvement of 1q, del(12p) and trisomy 8, may be segregated from the IPSS intermediate-risk cytogenetic prognostic subgroup. A very large co-operative study should be undertaken to clarify these issues.