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, cyto- genetically 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 < 0.05 and 84% vs 45%, P < 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 radiotherapy-associated 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.
Ever 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 unbalanced changes, mainly whole or partial losses of chromosomes 5 and 7, often in complex, hypodiploid karyotypes,5,6,7,8,9 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 correlate with specific chromosomal abnormalities.13,14 Another issue that needs to be clarified concerns the true frequency of treatment-related cases among AML and MDS. In the literature, quite variable frequencies, from a few percent to 27%, have been reported,15,16,17,18,19,20,21,22,23,24,25,26,27,28 discrepancies that may well be due to the fact that few of the series were population-based. Furthermore, detailed statistical analyses comparing cytogenetic findings in larger series of t-AML/t-MDS and de novo AML/MDS have not been performed. Such studies are imperative for determining whether some karyotypic patterns/chromosomal abnormalities may be significantly associated with previous iatrogenic genotoxic exposure as such or with certain types of CT.
In the present study, we have identified all t-AML/t-MDS in a population-based, consecutive series of AML/MDS analyzed in our department between 1976 and 1993 in order to ascertain the frequencies of such cases. Two further aims of the investigation were to compare the cytogenetic features of t-AML/t-MDS with de novo AML/MDS, in our material as well as in published cases, and to analyze possible associations with type of prior therapy.
Materials and methods
The study is based on a consecutive series of 1500 adult (⩾20 years) patients with suspected or confirmed hematologic malignancy, successfully cytogenetically analyzed at the Department of Clinical Genetics, Lund University Hospital, Sweden, between 1976 and 1993. This center is the only one performing cytogenetic analyses in southern Sweden, a region with a population of approximately 1.5 million people. The basic demographic, morphologic, cytogenetic and survival data on the present 372 AML and 389 MDS cases have been reported previously.29,30,31 The diagnoses were based on the morphologic findings present at the time of karyotypic investigation. Survival was calculated from the time of diagnosis of t-MDS/t-AML until date of last follow-up (18 May 2001). The date of cytogenetic analysis was also used to calculate the latency period between prior CT/RT and the development of t-AML/t-MDS. Data on previous RT and/or CT were obtained from patient records and interviews. The reasons for including only patients diagnosed between 1976 and 1993 were that cytogenetic data could not be reliably ascertained before this time-period, the method of fluorescence in situ hybridization was introduced in routine practice in 1994 (and inclusion of such cases would have introduced a cytogenetic bias), and that interview data were not available for patients diagnosed after this time-period.
Cases ascertained from the literature
The Mitelman Database of Chromosome Aberrations in Cancer32 was used to ascertain previously published, cytogenetically abnormal AML and MDS, de novo as well as t-AML/t-MDS, among adult patients. The search was performed in May 2001 at which time the database encompassed 6657 adult AML and 2777 adult MDS cases. Only unselected series, ie, studies where the AML/MDS cases were not reported because of specific/unusual karyotypic features, were retrieved, yielding a total of 5098 AML/MDS cases from other departments. However, for some calculations, we also included information from selected series, thereby increasing the number of cases that could be investigated as regards specific types of topo II (see Results). All cases published as treatment-related were identified, and data on type of previous therapy were extracted from the original articles.
Five treatment groups were considered: (1) RT alone, (2) alk +/− RT, (3) topo II +/− RT, (4) alk + topo II +/− RT, and (5) other agents +/− RT. For the literature cases, the latter group also included a handful of reported t-MDS/t-AML where the CT was unspecified. The following drugs were designated as alk: busulfan, carmustine (BCNU), chlorambucil, cisplatin, cyclophosphamide, lomustine (CCNU), mechlorethamine, melphalan, mustine, procarbazine, thiotepa, and treosulfan. The topo II group consisted of the non-intercalating agents etoposide and teniposide, and the intercalating agents aclarubicin, amsacrine, dactinomycin, daunorubicin, doxorubicin, 4-epidoxorubicin, mitoxantrone, pirarubicin, and streptonigrin. Other agents included azathioprine, 5-fluorouracil, hydroxyurea, methotrexate, pipobroman, vinblastine, vincristine, and cytosine arabinoside.
Karyotypic patterns and chromosomal abnormalities investigated
For our own de novo and treatment-related cases, an initial cytogenetic dichotomy separated the AML/MDS into those with a normal and those with an abnormal karyotype. Only disorders with cytogenetic aberrations are registered in the Mitelman Database of Chromosome Aberrations in Cancer.32 The cases with chromosomal changes were subgrouped according to number of anomalies (1, 2, ⩾3) and ploidy level, ie hypodiploidy (35–45 chromosomes), pseudodiploidy (46 chromosomes), hyperdiploidy (47–57 chromosomes), or tri-/tetraploidy (58–103 chromosomes). In addition, the frequencies of the following aberrations/aberration types were calculated and compared between de novo and treatment-related cases as well as among the various treatment groups: unbalanced changes as such, −Y (as a sole anomaly), der(1;7)(q10;p10), 3p−, −5, 5q− (also as a sole anomaly), −7 (also as a sole anomaly), 7q−, loss of 5 and/or 7, +8 (also as a sole anomaly), 11q−, der(12p), 13q−, −17, der(17p), −18, 20q− (also as a sole anomaly), and −21, and balanced changes as such, t(1;3)(p36;q21), inv(3)(q21q26)/t(3;3)(q21;q26), t(6;11) (q27;q23), t(6;9)(p23;q34), t(8;16)(p11;p13), t(8;21) (q22;q22), t(9;11)(p22;q23), t(9;22)(q34;q11), t(11;19) (q23;p13), t(11q23), t(15;17)(q22;q12), inv(16)(p13q22)/ t(16;16)(p13;q22), and t(21q22).
For comparing independent groups of observation by significance testing, we used the chi-square test and Fisher's exact test. The Kruskal–Wallis test was used to compare latency periods. The P-values reported are two-sided, and we considered P < 0.05 as significant. When an aberration was significantly more common among t-AML/t-MDS, we calculated the attributable fraction (AF), ie the fraction of the aberration occurrence among all AML/MDS that can be explained by previous treatment. AF is often interpreted as the fraction of disease in a population that might be avoided by reducing or eliminating exposure to an etiologic agent, provided that it is causative.33
Analyses of the present material
Among the 372 AML and 389 MDS cases analyzed in our department from 1976 to 1993, there were 47 (13%, 95% confidence interval, CI 9–16%) t-AML and 62 (16%, 95% CI 12-20%) t-MDS. The clinical and the cytogenetic features of these 109 t-AML/t-MDS are given in Table 1. The t-AML group comprised 35 female and 12 male patients between 31 and 86 years of age (median 66), and the t-MDS group consisted of 35 female and 27 male patients between 23 and 83 years of age (median 68). The median age for all 109 patients was 68 years.
The primary disorders were arthrosis/arthritis (14 patients), breast cancer (14), chronic myeloproliferative disorder (13), ovarian cancer (12), uterine cancer (11), multiple myeloma (10), non-Hodgkin lymphoma (9), Hodgkin disease (6), thyreotoxicosis (3), glomerulonephritis (2), lung cancer (2), nevus (2), neuroglial tumor (2), seminoma (2), vasculitis (2), and single cases of adenocarcinoma of unknown origin, amyloidosis, bladder cancer, connective tissue disease, kidney transplantation, larynx cancer, lip cancer, menorrhagia, psoriasis, urethral cancer, and Wegener disease (Table 1). Some patients had more than one primary diagnosis. Hence, the total number of primary disorders exceeds 109.
The primary treatment modalities (Table 1) were RT in 70 patients (RT alone in 38) and CT in 71 patients (CT alone in 39). In the CT group, 50 had received alk not combined with topo II, 16 had received alk and topo II together, and five had received other agents only. None had received topo II alone. The used compounds in decreasing frequency were melphalan (22 patients), cyclophosphamide (21), chlorambucil (18), vincristine (17), doxorubicin (14), azathioprine (8), procarbazine (8), vinblastine (8), busulfan (7), cisplatin (6), CCNU (5), methotrexate (5), BCNU (4), mustine (4), 5-fluorouracil (2), hydroxyurea (2), 4-epidoxorubicin (1), etoposide (1), mitoxantrone (1), and thiotepa (1).
The median latency in months from start of previous therapy to diagnosis of t-AML/t-MDS was 96 (range 7–775; the latency of 775 months was exceptional; the next longest latency was 465 months). Grouped according to type of prior treatment, the corresponding latencies were 207 (range 17–775) for RT alone, 63 (range 7–173) for alkylators alone or in combination with RT and/or other agents except topo II (calculated from start of alk), 19 (range <1–127) for topo II in combination with alk, calculated from start of topo II (when calculated from start of alk 35, range 12–127), and 20 (range 14–43) for other agents alone or in combination with RT (calculated from start of CT). These latency intervals differed significantly (P < 0.001). The exceptionally long latencies were seen only for RT, with 22 of 70 cases having latencies longer than 240 months.
Survival after diagnosis of t-AML/t-MDS was generally short, with a median of 4 months (range <1–93) for t-AML and 7 months (range <1–97) for t-MDS. The median survival for the entire patient group was 5 months. Two patients, one with MDS and 5q− and one with AML who underwent allogeneic bone marrow transplantation, were still alive at 89 and 93 months, respectively (Table 1).
Clonal chromosomal abnormalities were more common in t-AML than in de novo AML (68% vs 50%, P < 0.05) and in t-MDS than in de novo MDS (84% vs 45%, P < 0.001). Among the 47 t-AML, an abnormal karyotype was more frequent after CT (alk alone or alk + topo II) than after RT (86% vs 39%, P < 0.01). No such difference was discerned in the t-MDS group (82% vs 90%).
Analyses of the pooled material
In the analyses regarding number of anomalies, ploidy levels, unbalanced and balanced changes as such as well as specific chromosomal abnormalities, the cytogenetically abnormal AML/MDS in our material were combined with the 5098 unselected adult AML/MDS cases reported in the literature from other laboratories, yielding a total of 4230 AML, of which 581 (14%) were t-AML (Table 2), and 1629 MDS, including 252 (15%) t-MDS (Table 3). An analysis focusing solely on the frequencies of common AML/MDS-associated translocations and inversions, which for all practical purposes are mutually exclusive, in relation to type of CT and type of topo II is given in Table 4, which includes data from selected as well as unselected series. Hence, the number of cases per abnormality listed in Table 4 is larger than the corresponding figures in Table 2.
To the best of our knowledge, the present single-center material of 372 AML and 389 MDS, encompassing 47 t-AML and 62 t-MDS, is the largest population-based, consecutive series addressing in detail the frequencies of t-AML and t-MDS in an unselected adult patient cohort. Previous investigations have generally been based on smaller, and usually more selected materials, and have reported rather wide frequency ranges, varying from a few percent to 27%.15,16,17,18,19,20,21,22,25,26,28 In addition, some studies do not distinguish between AML secondary to MDS and AML secondary to prior treatment,23,24,27 making it even more difficult to draw firm conclusions regarding the impact of previous iatrogenic genotoxic exposure on the incidence of AML. Merging the cases with abnormal karyotype in our own series with data from previously published unselected series of cytogenetically abnormal AML and MDS32 yielded frequencies of 14% t-AML among a total of 4230 AML and 15% t-MDS among 1629 MDS (Tables 2 and 3).
In the present cohort (Table 1), the antecedent diseases were solid tumors in 47 instances (43%) and hematologic malignancies in 38 (35%) (15 Hodgkin disease/non-Hodgkin lymphoma, 13 chronic myeloproliferative disorders, and 10 multiple myeloma). In 24 (22%, 95% CI 15–31%) cases, t-AML/t-MDS followed non-neoplastic conditions, mainly autoimmune disorders, treated with CT and/or RT. The fact that approximately a quarter of t-AML/t-MDS seems to be attributable to treatment for non-malignant diseases is noteworthy. In the majority of other reports, the percentages of previous non-neoplastic diseases have generally been lower, varying from 2 to 13%.6,7,8,9,16,19,44,45,46,47,48,49,50
The pooled analysis of the cytogenetic features of t-AML/t-MDS, including data from unselected series in the literature,32 revealed several significant differences between treatment-related and de novo disorders (Tables 2 and 3). In t-AML/t-MDS, the number of anomalies and the ploidy levels differed from de novo cases, with complex karyotypes and hypodiploidy being more common in t-AML/t-MDS. Some chromosomal abnormalities were significantly more common in both t-AML and t-MDS than in de novo AML/MDS, ie monosomies of 5 and 7, deletions of 7q, aberrations involving 17p, and monosomy 18 (Tables 2 and 3), all of which were previously associated with prior CT/RT.9,51,52 By distinguishing between t-MDS and t-AML and analyzing them separately in the present study, it was possible to identify cytogenetic patterns/ abnormalities that may be characteristic for only one of the disease entities. For example, unbalanced changes as such, a whole-arm translocation between chromosomes 1 and 7, deletions of 3p and 5q, and monosomies of 17 and 21 were significantly more common only in t-AML, whereas deletion of 13q was more frequent only in t-MDS (Tables 2 and 3). However, it should be stressed that the distinction between MDS and AML is somewhat arbitrary, and the differences observed should thus be interpreted with some caution. As regards balanced chromosomal abnormalities, too few MDS cases with such changes have been reported to allow meaningful statistical analyses. In AML, however, the present analysis revealed that t(1;3), t(9;11), t(11;19), and translocations involving 11q23 in general are significantly more common in treatment-related cases (Table 3). To the best of our knowledge, an association between t(1;3) and t-AML has not been emphasized previously, whereas various 11q23 translocations are well known to be associated with t-AML.4,41 It should be stressed that, although several abnormalities were significantly more frequent in t-AML/t-MDS as compared to de novo disease (Tables 2 and 3), the present analysis of the attributable fraction (AF) disclosed quite large variations among the different abnormalities. For example, 54% (95% CI 29–79%) of der(1;7)(q10;q10) in AML may be attributed to prior iatrogenic genotoxic exposure, but the corresponding fraction for 5q− is only 11% (95% CI 6.2–17%; Table 2). Because AF is usually interpreted as the fraction of disease in a population that might be avoided by reducing or eliminating exposure to an etiologic agent,33 the observed AFs would, for example, indicate that 54% of all t-AML with der(1;7) would have been avoided if no CT had been given (Table 2). Hence, the use of AF definitely provides more information as regards the impact of exposure than do P values alone.
The pooled analysis also showed that type of prior treatment correlated significantly with number of anomalies in t-AML and with ploidy levels in both t-AML and t-MDS. Furthermore, the frequencies of several aberrations varied with type of therapy, eg, 5q− was most frequent in radiotherapy-associated t-MDS, monosomy 7 was more common in t-AML and t-MDS after alkylators, and translocations involving 11q23 in t-AML were associated with previous exposure to topo II (Tables 2 and 3). The associations observed between type of prior CT/RT and cytogenetic abnormalities fit well with previous reports, although there are some conflicting data as regards possible associations between prior RT and 5q−.4,8,45,47,52 In fact, the leukemogenic role of RT as well as the impact of RT on type of cytogenetic abnormalities in t-AML/t-MDS have been debated quite extensively.53,54,55,56
It is noteworthy that the frequencies of some abnormalities, although being significantly higher in t-AML and/or t-MDS, did not vary significantly among the treatment groups (Tables 2 and 3). For example, it should be stressed that 7q− was not associated with prior therapy with alkylators, neither in t-AML nor in t-MDS, emphasizing that total and partial losses of chromosome 7 should not be grouped together when analyzing the impact of exogenous factors on karyotypic patterns. Considering the fact that monosomy 5, but not 5q−, was more common in t-MDS (Table 3), it is also equally important to conclude that these changes should be analyzed separately. However, it should be stressed that the present review is based mainly on cases investigated by conventional chromosome banding techniques. Recently, several studies using multicolor fluorescence in situ hybridization have shown that complex karyotypes with monosomies of chromosomes 5 and 7 often harbor marker chromosomes containing material from these chromosomes and that many deletions, including 5q deletions, have been shown to be unbalanced translocations.57,58 Thus, the present conclusion concerning differences between whole and partial losses of chromosomes 5 and 7 may well be modified when more data based on molecular cytogenetics have been collected.
The chromosomal abnormalities shown to be more common in de novo disease were +8 as a sole anomaly, balanced changes as such, t(8;21), t(9;22), t(15;17), inv(16), and 21q22 translocations in general in AML (Table 2) and −Y, 5q−, and 20q− as sole anomalies and +8 in MDS (Table 3). The overrepresentation of these aberrations, many of which are associated with favorable prognosis, has been noted previously.8,35,52,59 However, chromosome changes in de novo disease may well be associated with non-iatrogenic exposure. For example, an association between exposure to organic solvents and trisomy 8 in AML has recently been reported.60 Considering the fact that it has repeatedly been suggested that several AML-associated translocations, other than 11q23 rearrangements, are associated with topo II,4,10,54,56,61,62 it may be surprising that we found no evidence for increased frequencies of these balanced abnormalities in AML after treatment with topo II (Table 2). This may well be due to only the inclusion of unselected series in the present literature review.
To address the above-mentioned issue further, an all-inclusive search for the most common translocations and inversions in AML and MDS was performed, after which we compared their frequencies in relation to treatment with or without topo II as well as in relation to the different types of topo II, ie intercalating and nonintercalating agents. As seen in Table 4, the majority of the investigated balanced abnormalities occur in de novo disease; only a handful of the translocations are treatment-related in more than 10% of the cases. When comparing the frequencies of the balanced changes in patients treated with topo II and in patients not receiving such drugs, only three abnormalities – t(9;11), t(11;19), and inv(16) – were significantly more common in the former group. Thus, we found no evidence for a significant association between t(15;17) or 21q22 translocations and previous exposure to topo II. Among the abnormalities reported after topo II treatment, significant frequency differences in relation to type of topo II were observed only for t(3;21), t(8;16), and t(9;11), with the two former translocations being strongly associated with intercalating drugs. It must be stressed, however, that the results presented in Table 4 should be interpreted with some caution. First, detailed data on previous genotoxic exposure may be lacking for some, or even several, of the literature cases. Second, some of the abnormalities are quite rare, making the results of the statistical analyses uncertain. This notwithstanding, the present detailed statistical analyses of all available cytogenetic data in AML and MDS emphasize the strong association between prior iatrogenic genotoxic exposure and karyotypic features.
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This study was supported by grants from the Swedish Cancer Society, the Swedish Council for Work Life Research, PREEM Research Foundation, Georg Danielsson's Fund, Gunnar, Arvid and Elisabeth Nilsson's Foundation, and Lund University Hospital Funds
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Mauritzson, N., Albin, M., Rylander, L. et al. Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976–1993 and on 5098 unselected cases reported in the literature 1974–2001. Leukemia 16, 2366–2378 (2002). https://doi.org/10.1038/sj.leu.2402713
- acute myeloid leukemia
- myelodysplastic syndromes
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