To ascertain the frequency of treatment-related acute myeloid leukemias and myelodysplastic syndromes (t-AML/t-MDS) in an unselected series, we have identified all adult cases analyzed in our department from 1976 to 1993. Further aims were to compare karyotypic features of t-AML/t-MDS with de novo AML/MDS, in our material as well as in 5098 unselected, cytogenetically abnormal, published cases, and to analyze associations between type of prior therapy and karyotype. Among our 372 AML and 389 MDS, 47 (13%) were t-AML and 62 (16%) were t-MDS. Clonal abnormalities were significantly more common in t-AML and t-MDS than in de novo disease (68% vs 50%, P Ͻ 0.05 and 84% vs 45%, P Ͻ 0.001, respectively). Among the available 4230 AML and 1629 MDS (the present series and published cases), 14% were t-AML and 15% were t-MDS. In t-AML/t-MDS, the number of anomalies and the ploidy levels differed significantly from de novo cases, with complex and hypodiploid karyotypes being more common in t-AML/t-MDS. In t-AML, unbalanced changes in general, t(1;3), der(1;7), 3p−, −5, 5q−, −7, 7q−, t(9;11), t(11;19), t(11q23), der(12p), −17, der(17p), −18, and −21 were significantly more frequent than in de novo AML. In t-MDS, −5, −7, 7q−, 13q−, der(17p), and −18 were significantly more common. Type of prior treatment correlated significantly with number of anomalies in t-AML and with ploidy levels in t-AML/t-MDS. The frequencies of several aberrations varied with type of therapy, eg, 5q− was more frequent in radiotherapyassociated t-MDS, monosomy 7 was more common in t-AML and t-MDS after treatment with alkylators, and t(11q23) in t-AML was associated with topoisomerase II inhibitors. Abnormalities significantly more common in de novo disease were +8 as a sole anomaly, balanced changes in general, t(8;21), t(9;22), t(15;17), inv(16), and t(21q22) in AML, and −Y, 5q−, and 20q− as sole anomalies and +8 in MDS. The results emphasize the strong association between previous genotoxic exposure and karyotypic features. Leukemia (2002) IntroductionEver since the mid-1970s, when the first case reports describing chromosomal abnormalities in treatment-related acute myeloid leukemias (t-AML) were published, 1,2 the cytogenetic features of t-AML and of therapy-associated myelodysplastic syndromes (t-MDS) have received much attention. 3,4 To date, two distinct karyotypic patterns that correlate with specific types of chemotherapeutic agents have emerged. Previous chemotherapy (CT) with alkylators (alk) has been strongly linked to the development of t-MDS/t-AML harboring unbal- anced changes, mainly whole or partial losses of chromosomes 5 and 7, often in complex, hypodiploid karyotypes, 5-9 whereas prior CT with DNA topoisomerase II inhibitors (topo II) has been associated with t-AML characterized by, in particular, translocations involving chromosome band 11q23 resulting in MLL gene rearrangements. 4,[10][11][12] It has been debated, but remains to be settled, whether prior radiotherapy (RT) alone or exposure to CT other than alk/topo II may correla...

The Workshop identified 48 unselected patients with therapy-related myelodysplastic syndrome or acute myeloid leukemia (t-MDS/t-AML) and inv(16), and 41 patients with t(15;17) after chemotherapy (CT) and/or radiotherapy (RT) for a malignant or nonmalignant disease. The primary diseases were: breast cancer, 33 patients; lymphomas, 24 patients; various other solid tumors, 30 patients; and nonmalignant diseases, 2 patients. The general type of previous therapy was RT only in 10 patients with an inv(16) and in 12 patients with a t(15;17), alkylating agents plus topoisomerase II inhibitors in 24 patients with an inv(16) and in 18 patients with a t(15;17), topoisomerase II inhibitors only in 5 patients with an inv(16) and in 2 patients with a t(15;17), alkylating agents only in 6 patients in each subgroup, and other types of chemotherapy in 3 patients in each subgroup. Most CT-treated patients (69%) also received RT. The latency period to development of t-MDS/t-AML was short: a median of 22 months in patients with inv(16) and 29 months in patients with t(15;17). Twenty-six patients (54%) with an inv(16) and 17 patients (41%) with a t(15;17) had additional cytogenetic abnormalities, which were unrelated to age and survival in both subgroups. Trisomy of chromosomes 8, 21, and 22 and del(7q) were the most frequent additional abnormalities in the inv(16) subgroup, whereas +8, -5, and del(16q) were most frequent in the t(15;17) subgroup. The disease was overt t-AML in 38/48 patients (79%) with an inv(16) and in 38/41 patients (93%) with a t(15;17). Thirty-three of 39 intensively treated patients (85%) with an inv(16) obtained a complete remission, whereas 24 of 35 intensively treated patients (69%) with a t(15;17) obtained a complete remission. The median overall survival of intensively treated patients was 29 months in both cytogenetic subgroups. In the inv(16) subgroup, patients younger than 55 years of age had a longer survival when compared with older patients (P = 0.006). The study supports the observation that t-MDS/t-AML with inv(16) and t(15;17) is often associated with prior therapy with topoisomerase II inhibitors; however, a notable finding was the high frequency of treatment with only radiotherapy, 29% of t(15;17) and 21% of inv(16). Response rates to intensive chemotherapy in this study were comparable to those of de novo disease.

The purpose of this case-control study was to investigate tobacco smoking as a risk factor for myelodysplastic syndromes, emphasizing karyotypic aberrations as markers for exposure and risk differentiation with respect to morphology. We obtained smoking history by interview of 330 cytogenetically investigated adult myelodysplastic syndrome cases and 337 controls, matched with respect to sex, year of birth, and county of living. Smoking for at least 1 year at some time 20 years or less before diagnosis was associated with an elevated relative risk (RR) for primary myelodysplastic syndromes (odds ratio (OR) 1.8; 95% confidence interval (CI) = 1.2-2.7). The results indicated a relation with intensity and duration of smoking as well as a decrease in risk a few years after cessation of smoking. Smoking was associated with an increased RR for primary myelodysplastic syndromes with chromosome 7 abnormalities (OR 5.0; 95% CI = 1.1-23). Elevated RRs were also seen for refractory anemia (OR 2.5; 95% CI = 1.2-5.6) and for refractory anemia with ringed sideroblasts (OR 3.2; 95% CI = 0.88-12). The findings suggest that smoking is a risk factor for myelodysplastic syndromes.

Objectives-To investigate a broad range of occupational, hobby, and lifestyle exposures, suggested as risk factors for Philadelphia chromosome positive (Ph+) chronic myeloid leukaemia (CML). Methods-A case-control study, comprising 255 Ph+CML patients from southern Sweden and matched controls, was conducted. Individual data on work tasks, hobbies, and lifestyle exposures were obtained by telephone interviews. Occupational hygienists assessed occupational and hobby exposures for each subject individually. Also, occupational titles were obtained from national registries, and group level exposure-that is, the exposure proportion for each occupational title-was assessed with a job exposure matrix. The eVects of 11 exposures using individual data and two exposures using group data (organic solvents and animal dust) were estimated. Results-For the individual data on organic solvents, an eVect was found for moderate or high intensity of exposure (odds ratio (OR) 3.4, 95% confidence interval (95% CI) 1.1 to 11) and for long duration (15-20 years) of exposure (OR 2.1, 95% CI 1.1 to 4.0). By contrast, the group data showed no association (OR 0.69, 95% CI 0.27 to 1.8; moderate or high intensity versus no exposure). For extremely low frequency electromagnetic fields (EMFs), only individual data were available. An association with long occupational exposure to EMFs was found (OR 2.3, 95% CI 1.2 to 4.5). However, no eVect of EMF intensity was indicated. No significant eVects of benzene, gasoline or diesel, or tobacco smoking were found. OR estimates below unity were suggested for personal use of hair dye and for agricultural exposures. Conclusions-Associations between exposure to organic solvents and EMFs, and Ph+CML were indicated but were not entirely consistent. (Occup Environ Med 2001;58:722-727)

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