Exposure to myelotoxic agents and myelodysplasia: case–control study and correlation with clinicobiological findings

Abstract

Summary.To better define the role of exposure to myelotoxic agents in the genesis of myelodysplastic syndrome (MDS), we carried out (a) a case-control study for the determination of the relative risk (RR) of developing MDS, including 178 consecutive patients and 178 sex-and age-matched controls; (b) a study of clinicobiological features in MDS arising after occupational exposure to myelotoxic agents and in MDS in 'non-exposed' patients. The definition of the 'exposure' status was based on a predetermined questionnaire, with calculation of an 'exposure' index (hours/ day × days/year × years). Cumulative exposure to pesticides or to organic solvents, for >2400 h, was recorded in 48 and 25 MDS patients, respectively, compared to 27 and four controls (P < 0·00001; RR 3·74; 95% confidence interval 2·02-5·37). Older age and an excess of refractory anaemia with ringed sideroblasts and refractory anaemia with excess of blasts was noted among 'exposed' MDS-patients (group 1), compared to non-exposed MDS-patients (group 2). 68·3% patients in group 1 had clonal chromosome changes, compared with 43·2% patients in group 2. Complex karyotypes, ¹7/7q¹, ¹5/5q¹, þ8, 7p and 17p aberrations were seen more frequently in group 1, whereas a normal karyotype, isolated 5q¹ or 20q¹ occurred more frequently in group 2. The association of exposure to myelotoxic agents with older age at presentation and with unfavourable chromosome changes accounted for the shorter survival observed in 'exposed' patients. These data show that occupational exposure to pesticides and organic solvents in our region resulted in an increased RR of developing MDS and that a distinct cytogenetic profile was associated with MDS in 'exposed' patients. These findings provide strong indirect evidence that these agents may play a role in the pathogenesis of MDS, preferentially targeting some of the chromosome regions which are frequently involved in therapy-related myeloid neoplasias.

Clinical importance of interphase cytogenetics detecting occult chromosome lesions in myelodysplastic syndromes with normal karyotype

“…Around 40-65% of de novo MDS patients in fact present at diagnosis a normal karyotype, whereas among secondary or therapy-related MDS the proportion of patients with normal karyotype is only 20%. [1][2][3][4][5][6][7][8] Cytogenetic data in this analysis confirmed this observation, with a figure of 48.1% of normal karyotypes in a series of 210 MDS patients observed in a 10-year period.…”

“…5,10,11 All patients were classified in accordance with French-American-British (FAB) group criteria. 12 Patients who had previously received chemotherapy or those with secondary MDS were not included in this analysis.…”

“…Cytogenetic studies, using standard techniques, were performed as part of the diagnostic work up. 5 Whenever possible, at least 20 metaphases were analyzed in all patients with normal karyotype. Clonal abnormalities were defined as two or more cells with the same additional whole chromosome or chromosome rearrangements or three or more cells with the same chromosome missing.…”

“…5,8 For these reasons, further studies are warranted in order to define biological variables allowing for the identification of MDS patients with normal karyotypes who are at high risk of progression.…”

“…4 At diagnosis, 40 to 65% of MDS patients present normal karyotypes when assessed by conventional cytogenetic analysis (CCA) [1][2][3][4][5][6][7][8] and these patients are therefore classified, according to IPSS criteria, in the low-risk cytogenetic group.…”