Geographic differences in the incidence of cytogenetic abnormalities of acute myelogenous leukemia (AML) in Spain

Leukemia Research 30 (2006) 943–948

Geographic differences in the incidence of cytogenetic abnormalities of acute myelogenous leukemia (AML) in Spain ´ Magdalena Sierra a,b , Alvaro Alonso c , M. Dolores Odero d , M. Bel´en Gonzalez a,b , Idoia Lahortiga d , Jos´e J. P´erez a,b , Juan L. Garc´ıa a,b , Norma C. Guti´errez a,b , Mar´ıa J. Calasanz d , Jes´us F. San Miguel a,b , Jes´us M. Hern´andez a,b,∗ a

Servicio de Hematolog´ıa, Hospital Universitario de Salamanca, Paseo San Vicente 58-182, 37007 Salamanca, Spain b Centro de Investigaci´ on del C´ancer, Universidad de Salamanca, Spain c Departamento de Medicina Preventiva y Salud P´ ublica, Universidad de Navarra, Spain d Departamento de Gen´ etica, Universidad de Navarra, Spain Received 3 August 2005; received in revised form 10 November 2005; accepted 27 December 2005 Available online 28 February 2006

Abstract The incidence of chromosomal abnormalities in acute myeloid leukemia (AML) differs according to geographical regions in Spain. We analyse 1271 consecutive patients diagnosed of AML between 1995 and 2002 in three different regions of Spain: northern, central and southern. There were 624 males (55%) and 505 females (45%). Age ranged between 1 month and 94 years with a median of 61 years. Abnormal karyotypes were observed in 64% of cases. Numerical abnormalities as sole cytogenetic changes were detected in 15% of patients, while structural aberrations were present in 28% of cases, and both abnormalities were found in 22% of patients. A significantly higher proportion of t(15;17) was observed in the south of Spain (21.6%) than in the central (17%) or northern regions (12.6%) (p = 0.03). By contrast, patients from the south of Spain showed lower incidence of t(8;21) (0%, compared to 1.6% and 3.6% in central and northern areas, respectively, p = 0.04). These differences were maintained in the age-adjusted analysis. Trisomy 8 showed similar incidence in southern and central areas, while the incidence in the northern area was lower (14% and 10%, respectively, p = 0.04). Other chromosomal abnormalities, such as inv(16) or 11q23 rearrangements, were found at similar frequencies in the three regions. © 2006 Elsevier Ltd. All rights reserved. Keywords: Differences; Incidence; Karyotype; AML

1. Introduction Acute myeloid leukemia (AML) is a heterogeneous disease with diverse morphological, immunophenotypic, cytogenetic and clinical characteristics [1]. AML can be classified into homogeneous biological subgroups using chromosomal aberrations and leukemia-specific molecular gene rearrangements [2]. However, descriptive epidemiological reports on AML consider the disease as a single entity [3,4]. ∗ Corresponding author at: Servicio de Hematolog´ıa, Hospital Universitario de Salamanca, Paseo San Vicente 58-182, 37007 Salamanca, Spain. Tel.: +34 923 291384; fax: +34 923 294624. E-mail address: [email protected] (J.M. Hern´andez).

0145-2126/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2005.12.025

The epidemiological study of acute leukemia has been focused on adults exposed to occupational and environmental agents (ionizing radiation, petrochemical industry, pesticides or benzene), factors that increase the risk of leukemia [5–7]. Other epidemiological studies have shown differences in age and ethnicity [8,9]. In children, an association between AML and genetic syndromes (Down syndrome, Bloom syndrome, neurofibromatosis, Schwachman syndrome, ataxia telangiectasia and Klinefelter’s syndrome) or familial aggregation (familial monosomy 7) has been demonstrated [6]. In AML the genetic changes can vary between countries [10]. Thus, the high incidence of acute promielocytic leukemia in Latin populations or t(8;21) in the Japanese population supports the view that there may be geographic

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variations in tumor-associated genetic aberrations in hematologic malignancies [1,8,11–13]. However, little is known about the molecular epidemiology of AML between regions within the same country. We have surveyed a large population of patients with newly diagnosed AML from three regions of Spain, in order to investigate differences in the incidence of genetic abnormalities in AML.

2. Patients and methods 2.1. Patients Between 1995 to 2002, a total of 1271 consecutive patients with newly diagnosed AML, regardless of age, were registered in databases of the Genetic Department of the University of Navarra and the Hematology Department of the University of Salamanca, Spain. Morphological diagnosis was made according to the French–American–British (FAB) criteria for AML (M0–M7) [14]. Patients without a sufficient number of metaphases for the genetic study were excluded (n = 142, 11%). All cases were centrally review in both Institutions (Navarra and Salamanca). Cytogenetic studies were successfully performed on 1129 patients: 665 cases were from the northern region of Spain (14 hospitals included), and 376 from the central area (nine hospitals included). In addition, 88 patients from the south (three hospitals included) were also studied (Fig. 1). Median age was 61 years (range 1–94). Patients from the southern region were slightly younger (median age 50 years, range 1–81) than the other two regions: in the central area, patients had a median age of 65 years (range 6–94 years), while in the north they had a median of 60 years (range 2–92 years) (p = 0.001). There were 624 males (55%) and 505 females (45%). No significant differences in the sex distribution of AML patients according to geographical region were observed (Table 1). A total of 51 patients had previous toxic exposure (4.5%) including chemotherapy (n = 39), occupational (n = 11) and environmental agents (n = 1). The antecedent of hematologic disorder were observed in 19 out of the 51 patients, including aplastic anemia (n = 1), myeloproliferative disorders (n = 3), lympho-

Fig. 1. Distribution of geographic regions: grey clear: northern region: 665 cases from 14 hospitals, grey dark: central area: 376 patients from nine hospitals and black: southern region: 88 AML from three hospitals.

proliferative disorders (n = 12), Fanconi anemia (n = 2), and paroxysmal nocturnal hemoglobinuria (n = 1). Three patients had secondary acute promyelocytic leukemia, one of them was treated with chemotherapy for a colon carcinome and the remaining two cases had a previous toxic exposure (chemical industry). 2.2. Cytogenetic studies Chromosome analysis of bone marrow cells was performed at diagnosis using short-term (24–48 h) unstimulated cultures. At least 20 metaphases were analyzed. Definitions of cytogenetic clonality and karyotypic descriptions were in accordance with ISCN guidelines (1995) [15]. Complex karyotype was defined by the presence of a clone with at least three unrelated cytogenetic abnormalities following the SWOG criteria or five unrelated cytogenetic abnormalities according to MRC criteria [16,17]. Numerical cytogenetic abnormalities were defined as the loss and/or gain of a whole chromosome. Structural abnormalities involve changes in the structure of one or more chromosomes. In addition, fluorescence “in situ” hybridization (FISH) studies were performed by standard techniques to confirm

Table 1 Patient characteristics of 1129 cases of AML

No. of patients (n) Age: mean Median Range Sex (M/F) (%) Toxic exposure: n (%) Chemotherapy Other

Northern

Central

Southern

Total

665 56 60 2–92 54/46 29 (4.3) 23 (3.4) 6 (0.9)

376 59 65 6–94 57/43 20 (5.3) 16 (4.2) 4 (1)

88 48 50 1–81 59/40 2 (2.2) 2 (2.2) 0

1129 56 61 1–94 55/45 51 (4.5) 41 (3.6) 10 (0.8)

NS: no significance. * Pearson’s chi-squared test for categorical variables and one-way ANOVA for continuous variables.

p* <0.001

NS NS

M. Sierra et al. / Leukemia Research 30 (2006) 943–948

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Table 2 Karyotypic characteristics of 1129 cases of AML Northern (%)

Central (%)

Southern (%)

Total (%)

37.9

35

32.6

36.5

12 28 22.1

17.8 26.6 21.8

21.6 30.7 15.9

14.7 27.7 21.5

No. of chromosomes >48 <45 45–48

4.8 5.1 52

5.3 3.5 57.4

5.7 6.8 55.7

5 4.7 54.1

Complex karyotype SWOG (>2)a MRC (>4)b

20.9 13.8

16 10.4

21.6 11.4

19.3 12.5

Karyotype Normal Abnormal Numerical changes Structural changes Both

a b

According to SWOG criteria (more than two changes). According to MRC criteria (more than four changes).

criteria, and 13% by MRC criteria. No statistical differences were observed in the three geographical regions (Table 2). The frequency of chromosomal abnormalities is shown in Table 3. The most frequent cytogenetic abnormality was t(15;17) (14.8%), followed by +8 (11.4%), −5/del(5q) (9.1%), −7/del(7q) (8.6%), 11q23 (3.3%), 3q (3.2%), +21 (2.8%), inv(16) (2.7%), t(8;21) (2.7%), +11 (2.3%) and 11p (2.3%). The incidence of other abnormalities was less than 1% in each category. A statistically significant difference in the distribution of t(15;17) was observed between the three regions whereby 21.6% displayed t(15;17) in the south, as compared to 17% in the central region and 12.6% in the north (p = 0.03). Differences were even more significant after age-adjustment (p = 0.006). In addition, t(8;21) also displayed a different incidence according to the region with no cases observed in the south, but 1.6% of patients in the central area and 3.6% of the patients in the north (p = 0.04). These differences were maintained in the age-adjusted analysis. Inv(16) and 11q23 abnormalities did not show differences by geographical area or by age.

conventional cytogenetics or morphological suspicion (M3, M4eo), as previously reported [18]. 2.3. Statistical analysis Data from different regions were compared using Pearson’s chi-squared test and Fisher exact test for categorical variables and ANOVA for continuous variables. Analyses were performed using SPSS 10.0 (SPSS Inc, Chicago, IL, USA).

3. Results 3.1. Cytogenetics Karyotypic analysis was available in 1129 cases. Clonal abnormalities were observed in 64% of cases (Table 2). Numerical changes were found in 15% of patients, while 28% showed structural changes, and both abnormalities were present in 21% of patients. Complex karyotypes were detected in 19% of patients according to SWOG

Table 3 Comparison of the incidence of chromosomal abnormalities in three Spanish regions

t(15;17) t(8;21) inv(16) −5/del(5q) −7/del(7q) +8 +21 +11 11p 11q23 3q * **

Northern (%)

Central (%)

Southern (%)

Total (%)

p*

p** for trend

12.6 3.6 2.7 9.6 8.4 9.5 2.7 1.7 2.9 2.9 3.3

17 1.6 2.7 8.4 9.4 14.4 2.9 3.5 0.8 4.3 2.9

21.6 0 3.4 8.0 6.9 13.6 2.3 2.3 4.5 2.3 3.4

14.8 2.7 2.7 9.1 8.6 11.4 2.8 2.3 2.3 3.3 3.2

0.03 0.04 0.92 0.75 0.73 0.04 0.94 0.17 0.04 0.41 0.94

0.007 0.01 0.81 0.46

Pearson’s chi-squared test. Linear chi-squared test for categorical variables and linear regression analysis for continuous variables.

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Fig. 2. Incidence by age in good-risk AML: t(15;17): 22% of patients between 35 and 44 years; t(8;21): 25% of cases between 25 and 34 years; inv(16) peak of incidence under 15 years.

Trisomy 8 showed similar incidence in southern and central areas, while the incidence in the north was lower (14% and 10%, respectively, p = 0.04); but this pattern was not maintained in age-adjusted analysis. Other chromosomal abnormalities were found at similar frequencies in the three regions. In terms of age, t(15;17) was most frequent in patients between 35 and 44 years old (22% of acute promyelocytic leukemia occurred in this age group). The peak of incidence was earlier for t(8;21) (25% of cases in the 25–34 years old age-group) and inv(16) (35% younger than 15 years) (Fig. 2). Patients younger than 44 had higher probability of good risk karyotype, especially in those aged between 24 and 44 years old (>40%) (p < 0.0001). Interestingly, an association between MLL rearrangements and previous toxic exposure was observed. Thus, 16.2% of cases with 11q23 abnormalities showed previous toxic exposure (five patients were previously treated with chemotherapy and one had a previous exposure to chemical products), compared to only 4.2% of AML patients showing 11q23 rearrangements without previous toxic exposure. No differences in age or toxic exposure according to the region were presented (Table 1).

4. Discussion The present study showed geographical differences in the incidence of chromosomal abnormalities in acute myeloblastic leukemias in three regions of Spain. Thus, the incidence of t(15;17) was significantly higher in the south of Spain, with lower incidence in northern regions. An increased frequency has been reported for Latino patients as compared to Caucasians [2,8]. Therefore, the race could be one of the reason for the different incidence of AML [1,2,8,9]. In Spain, immigration level had been low in last centuries, and this situation is only changing in the last years. According to the results observed in the present study, the incidence of cytogenetic abnormalities in the Spanish population from north region is similar to that found in Caucasian race or in Europeans [17]. By contrast, acute myelogenous leukemias from the south region show similarities to latin population [12].

This could be a possible explanation of the differences found in the study, although we cannot exclude another possibilities such as environmental exposures or differences in body mass index (BMI) [7,13]. The contrary was observed in t(8;21), with higher incidence in northern regions and lower in the south of Spain. Geographical differences have also been reported for t(8;21), with a high frequency in Japanese (13%) and African–American (17%) [1,9] (Table 4). The present study showed that t(15;17) was the most frequent karyotypic abnormality in AML in Spain while the other good-risk abnormalities, such as inv(16) or t(8;21) were infrequent [1,9,11,16,17,19]. The differences between our distribution of karyotypic abnormalities and those reported in previous studies could reflect diverse eligibility selection criteria, specifically related to the upper age limit and possible restriction to “de novo” AML. Here, unselected patients with “de novo” or secondary leukemias and no age limits were included. Thus, complex karyotypes were detected in 19% and 13% of patients analyzed by SWOG or MRC criteria, respectively, a higher frequency than previously reported [9,16,17]. But when our results are compared with patients from MRC AML 11, which included older adults, the incidence are similar [20]. Karyotypic abnormalities associated with older age or dysplasia, −5/del(5q) and −7/del(7q), showed higher frequency in our series (9.1% and 8.6%, respectively) than in the MRC AML 10 trial (3.3% and 5.7%, respectively) [17], but similar to those observed in other large series without age limitations (7.1% and 7.8%, respectively) [19]. In accordance with recent reports trisomy 8 was the most frequent numerical aberration in our series and the second most frequent abnormality (11.4%) [16,17,19,21]. AML with 11q23 abnormalities is a heterogeneous group due to the different partner chromosomes [22]. In addition, MLL rearrangements have been reported in leukemia secondary to topoisomerase II inhibitors [6]. The incidence of 11q23 AML was higher in patients with a history of previous toxic exposure than in the rest of AML patients (16% versus 4%), in line with previously reports [11,22]. Good-risk AML subgroups are more common in younger adults. In the present series, a peak of APL incidence was observed in the group of 35–44 year olds and for t(8;21) at a slightly younger age (24–34 years old) [2,7,23,24]. This makes it difficult to evaluate the prognostic impact of these abnormalities in elderly patients [24]. Inv(16) had an earlier peak of incidence than in other large series of patients, with 35% of cases occurring in patients younger than 15 years old, compared to 19% of patients within the same age group in a French study [25]. The combination of all this data reveals that the most favorable changes are more infrequent in older patients [20]. In summary, this study describes differences in the incidence patterns of AML by age and geographic distribution. t(15;17) is the most frequent abnormality in AML in Spain and differences have been observed in the distribution of good-risk karyotypic abnormalities, with a higher prevalence

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Table 4 Review of previous reports of incidence in AML by cytogenetics groups Spain (%)

United Kingdom (%)

Japan (%)

Australia (%)

USA (%)

USA (%)

USA (%)

USA (%)

a

MRC 10 trialb

MRC 11 trialc

d

d

SWOGe

CALGBf

Caucasian raceg

African–American raceg

N

1129

1612

1065

438

230

609

NA

2300

270

Age Median Range

56 1–94

35

66 44–91

Mean 51 16–91

Mean 51 16–86

39 16–55

52 15–86

54 16–86

48 17–86

t(15;17) inv(16) t(8;21) −5/del5q −7/del7q +8 11q23

14.8 2.7 2.7 9.1 8.6 11.4 3.3

12 3.5 7.5 3.3 5.7 9.1 3.7

4 1 2 13 13 10 1

11.2 2.7 13.2 NA NA NA 2.2

11.7 6.0 5.2 NA NA NA 2.6

4 9 8 6 9 9 7

NA 7.9 6.7 7.1 7.8 10 5.5

4.7 8.1 5.8 NA 4.9 11.2 NA

8.3 5.7 17 NA 7.1 15.6 NA

Complex k >2 >4

19 12

NA 6

NA 14

NA NA

NA NA

12 9

NA NA

10.5

12.8

NA: not available. a AML consecutive patients without age limitation. b Grimwade et al.: include children and adults, mostly up to 55 years of age. Secondary AML were entered too [17]. c Grimwade et al.: older adults, include de novo and secondary AML [20]. d Nakase et al.: adult patients (older than 15 years) with newly diagnosed untreated AML [1]. e Slovak et al.: three intensive postremission therapies for adult patients (age 16–55) with previously untreated AML. [16]. f Byrd et al.: CALGB group: five sequential treatment studies. Patients with a prior history of myelodyspasia, other antecedent hematologic malignancies, prior nonsteroidal cytotoxic chemotherapy or radiation therapy, preexisting liver disease, or uncontrolled infection were excluded. Two studies excluded patients who were 60 years or older and one study excluded patients under the age of 60. Cases with t(15;17) or t(9;22) have been excluded from the analysis too [19]. g Sekeres et al.: retrospective study with de novo AML who were eligible to receive intensive chemotherapy as part of one of seven studies. Only one include patients with prior MDS or patients who had received prior cytotoxic chemotherapy [9].

of t(15;17) in southern regions and t(8;21) in northern regions of Spain.

Acknowledgements The authors wish to thank Abelardo Barez (Avila), Lourdes Hermos´ın (Jerez de la Frontera, C´adiz), Fernando Ramos (Le´on), Inmaculada Heras (Morales Meseguer, Murcia), Fernando Ortega (Palencia), Guillermo Mart´ın (Plasencia, C´aceres), Josefina Galende (Ponferrada, Le´on), Sonia P´erez (Segovia), Rebeca Cuello (Valladolid), Mercedes Romero (Valladolid), Roberto Hern´andez (Vitoria) and Alejandro Mart´ın (Zamora), which have contributed with the inclusion of patients. We also thank to Dr. B. Johansson from the University of Ulm for the critical review and to Mark Anderson from the University Technology Transfer Office and M ´ Angeles Hern´andez, Amador Crego, Ana Sim´on, and Teresa Prieto for technical assistance. Partially supported by Grants from Ministerio de Ciencia y Tecnolog´ıa (SAF2001-1687), FIS FEDER 02/1358, Proyectos de Biomedicina del Sacyl and LAIR Foundation (no. 50602); M.B.G. is supported by a Grant from the “Programa Juan de la Cierva”; J.L.G. is supported by a Grant from the “Fondo de Investigaciones Sanitarias” (01/3153).

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