Better Prognosis for Patients With Del(7q) Than for Patients With Monosomy 7 in Myelodysplastic Syndrome

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1 Better Prognosis for Patients With Del(7q) Than for Patients With Monosomy 7 in Myelodysplastic Syndrome Iris Cordoba, MD 1 ; José R. González-Porras, MD 1 ; Benet Nomdedeu, MD 2 ; Elisa Luño, MD 3 ; Raquel de Paz, MD 4 ; Esperanza Such, MD 5 ; Mar Tormo, MD 6 ; Teresa Vallespi, MD 7 ; Rosa Collado, MD 8 ; Blanca Xicoy, MD 9 ; Rafael Andreu, MD 10 ; Juan A. Muñoz, MD 11 ; Francesc Solé, MD 12 ; Jose Cervera, MD 5 ; Consuelo del Cañizo, MD 1 ; and On behalf of the Spanish Myelodysplastic Syndrome Registry BACKGROUND: Abnormalities involving chromosome 7 are frequent in myelodysplastic syndrome (MDS) and suggest a poor prognosis. METHODS: The authors examined the hypothesis that the clinical features and survival associated with isolated deletion (del) of part of the long arm of chromosome 7 (7q) in MDS are different from those associated with isolated monosomy 7 (complete loss of chromosome 7). In total, 133 patients with a diagnosis of de novo MDS (according to the World Health Organization [WHO] classification) and chromosome 7 abnormalities in the Spanish MDS Registry were evaluated retrospectively. Four karyotypic groups were identified: isolated del(7q) (n ¼ 29), isolated monosomy 7 (n ¼ 27), del(7q) with additional abnormalities (n ¼ 24), and monosomy 7 with additional abnormalities (n ¼ 53). RESULTS: Isolated del(7q) was more frequent in patients with less advanced MDS according to the WHO classification or the International Prognostic Scoring System. In addition, isolated del(7q) was associated with fewer blasts in bone marrow than other cytogenetics groups. Survival was significantly superior in patients with isolated del(7) than in those with isolated monosomy 7, del(7q) with additional abnormalities, or monosomy 7 with additional abnormalities. On multivariate analysis, age, the percentage of blasts in bone marrow, and other chromosome 7 abnormalities apart from isolated del(7q) were identified as independent risk factors for survival. CONCLUSIONS: The current results demonstrated that patients who had MDS with isolated del(7q) had some distinct clinical-pathologic characteristics as well as better survival than patients who had MDS with isolated monosomy 7. Cancer 2012;118: VC 2011 American Cancer Society. KEYWORDS: myelodysplastic syndrome, monosomy 7, cytogenetic, del(7q), survival. Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, dysplastic changes in bone marrow and peripheral blood, and the risk of transformation to acute myeloid leukemia (AML). 1-3 Previous studies have clearly demonstrated the prognostic impact of chromosomal abnormalities in patients with MDS. 4-7 In addition, the most commonly used prognostic tool for evaluating patients with MDS, the International Prognostic Scoring System (IPSS), takes into account 3 refined, risk-based cytogenetic subgroups (good risk, intermediate risk, and poor risk). In accordance with the IPSS, patients with a complex karyotype (>3 abnormalities) and chromosome 7 anomalies, present either as a single anomaly or in combination with other anomalies, were assigned to the poor-risk karyotype group. 8 Abnormalities involving chromosome 7 occur in Corresponding author: José R. González-Porras, MD, Hospital Universitario de Salamanca, Paseo de San Vicente, , Salamanca, Spain; Fax: (011) ; jfgp@usal.es 1 Department of Hematology, Salamanca University Hospital, Salamanca, Spain; 2 Department of Hematology, Hospital Clinic, Barcelona, Spain; 3 Department of Hematology, Asturias University Hospital Center, Oviedo, Spain; 4 Department of Hematology, La Paz University Hospital, Madrid, Spain; 5 Department of Hematology, La Fe University Hospital, Valencia, Spain; 6 Department of Hematology, Valencia Hospital Clinic, Valencia, Spain; 7 Department of Hematology, Vall d Hebron Hospital, Barcelona, Spain; 8 Department of Hematology, University General Hospital, Valencia, Spain; 9 Department of Hematology, Germans Trias i Pujol Hospital, Badalona, Spain; 10 Department of Hematology, Dr. Peset University Hospital, Valencia, Spain; 11 Department of Hematology, Puerta del Mar University Hospital, Cadiz, Spain; 12 Department of Hematology, Del Mar Hospital, Barcelona, Spain We thank V. Marco, S. Bonanad, L. Benlloch, D. Costa, J. Bueno, T. Bernal, and all members of the Spanish MDS Registry along with Phil Mason for their excellent technical assistance. DOI: /cncr.26279, Received: March 15, 2011; Revised: April 21, 2011; Accepted: April 21, 2011, Published online June 29, 2011 in Wiley Online Library (wileyonlinelibrary.com) Cancer January 1,

2 Table 1. Frequency of Chromosome 7 Abnormalities Among Different Variables Variable All Patients, n Karyotype Group Isolated Aberration Chromosome 7 Abnormality With Additional Abnormalities Group A Group B Group C Group D Del(7q), n , n 5 29 Del(7q), n , n 5 53 Age: Mean SD, y NS Sex, % Men Women P [Groups Compared] WHO classification: No. of patients (%) <.001 [A vs B], <.001 [A vs C],.002 [A vs D] RA 7 (5) 4 (15) 2 (6) 1 (2) RARS 4 (3) 2 (7) 2 (4) RCMD 28 (21) 13 (48) 6 (21) 1 (4) 8 (15) RCMD-RS 6 (4) 1 (4) 2 (8) 3 (6) RAEB-1 30 (23) 1 (4) 6 (21) 8 (33) 15 (28) RAEB-2 58 (44) 6 (22) 15 (52) 13 (55) 24 (45) Hemoglobin level: Mean SD, g/dl [A vs C] Neutrophil level: Mean SD, 10 9 /L [A vs D] Platelet count: Mean SD, 10 9 /L [A vs B],.018 [A vs C],.005 [A vs D] Blasts in BM: Mean SD, % [A vs B],.001 [A vs C],.017 [A vs D] LDH level: Mean SD, IU [A vs C],.048 [A vs D] IPSS score: No. of patients (%).020 [A vs B],.001 [A vs C],.001 [A vs D] Intermediate-1 24 (18) 13 (48) 4 (14) 1 (4) 6 (11) Intermediate-2 60 (45) 9 (33) 16 (55) 11 (46) 24 (45) High 49 (37) 5 (18) 9 (31) 12 (50) 23 (43) Abbreviations: BM, bone marrow; Del(7q), deletion of part of the long arm of chromosome 7; IPSS, International Prognostic Scoring System; LDH, lactate dehydrogenase; NS, nonsignificant; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RARS, refractory anemia with ringed sideroblasts; RCMD, refractory cytopenia with multilineage dysplasia; RCMD-RS, refractory cytopenia with multilineage dysplasia and ringed sideroblasts; SD, standard deviation; WHO, World Health Organization. NS approximately 20% of patients with MDS and clonal cytogenetic abnormalities 9 and usually include deletion (del)ofpartofthelongarmofchromosome7(7q), total loss of chromosome 7 (monosomy 7), or translocations involving chromosome 7. Recent reports argue that patients who have del(7q) as a single abnormality overall tend to have a better prognosis than those who have isolated monosomy 7. These findings tend to suggest that patients who have MDS with isolated del(7q) should not be classified in the same group as those who have MDS with single monosomy However, those studies involved a very limited number of patients with MDS and chromosome 7 anomalies, and the observed differences in survival between isolated del(7q) and single monosomy 7 were not statistically significant. In the current study, we tested the hypothesis that patients who have MDS with del(7q) may have clinical features that differ from those in patients who have MDS with monosomy 7. To address this hypothesis, we reviewed the cases of chromosome 7 abnormalities in adult primary MDS patients in the Spanish Registry and compared the clinical and prognostic findings of del(7q) and monosomy 7 in patients with MDS. MATERIALS AND METHODS In total, 133 patients (aged 18 years) who had a diagnosis of de novo MDS and chromosome 7 abnormalities in the Spanish MDS Registry ( ) were evaluated retrospectively. The diagnosis was made on the basis of the World Health Organization (WHO) classification, 2 and 128 Cancer January 1, 2012

3 Chromosome 7 Abnormalities in MDS/Cordoba et al patients were assessed according to IPSS criteria. Patients and disease characteristics, including age, sex, hemoglobin levels, platelet counts, absolute granulocyte counts, percentage of bone marrow blasts, lactate dehydrogenase levels, duration of MDS, and previous therapies, also were recorded. Bone marrow samples were analyzed cytogenetically at the individual centers according to standard procedures. At least 20 metaphases were analyzed in each case. Chromosomes were identified and karyotypes described according to the International System for Chromosome Nomenclature. 12 We defined 4 cytogenetic groups: isolated del(7q), isolated monosomy 7, del(7q) with additional abnormalities, and monosomy 7 with additional abnormalities. Additional abnormalities were defined as those cytogenetic changes accompanying del(7q) or monosomy 7. Instances of balanced or unbalanced translocation t(1;7) with del(7q) or monosomy 7 were not observed in our series. This analysis was performed in accordance with the Declaration of Helsinki as amended in Edinburgh in The study was performed according to the guideline of the institutional review boards of the participating centers. A descriptive statistical analysis was performed after including all the data in an Excel spreadsheet (Microsoft Corp., Redmond, Wash). The results are expressed as percentages for categorical variables and as medians (and standard deviations) for continuous variables. Differences in clinical measurements between groups were evaluated with the statistical software package SPSS 17.0 (SPSS Inc., Chicago, Ill). Demographic and clinical covariates were compared using Student t tests for continuous variables and Pearson chi-square tests for categorical variables. Overall survival (OS) and leukemia-free survival (LFS) were estimated by using the Kaplan-Meier method, and statistical differences between curves were assessed by using logrank tests. OS was defined as the time elapsed between diagnosis and death or last follow-up, and LFS was defined as the time elapsed between diagnosis and progression to acute leukemia or last follow-up. Patients who underwent allogeneic stem cell transplantation or who received azacitidine were censored at the time of the therapeutic procedure. Survival analysis was performed comparing isolated del(7q) versus isolated monosomy 7, isolated del(7q) versus del(7q) with additional abnormalities, and del(7q) with additional abnormalities versus monosomy 7 with additional abnormalities. A Cox proportional hazards regression model was developed (using stepwise, forward conditional variable selection) to determine the impact of potential risk factors on survival and LFS. Statistical significance of all tests was concluded for values of P <.05. Figure 1. Overall survival is illustrated for 133 patients who had myelodysplastic syndromes and chromosome 7 abnormalities. RESULTS The main demographic and hematologic features of the 133 patients with de novo MDS and chromosome 7 abnormalities (deletion 7q and monosomy 7; ages years; 67% men) are listed in Table 1. The WHO subgroups were as follows: Seven patients (5%) had refractory anemia (RA), 4 patients (3%) had RA with ringed sideroblasts, 28 patients (21%) had refractory cytopenia with multilineage dysplasia (RCMD), 6 patients (4%) had RCMD with ringed sideroblasts, 30 patients (23%) had RA with excess blasts 1 (RAEB-1), and 58 patients (44%) had RAEB-2. With respect to IPSS, 24 patients (18%) had intermediate- 1 risk scores, 60 patients (45%) had intermediate-2 risk scores, and 49 patients (37%) had high risk scores. In total, we identified 27 patients who had isolated del(7q), 29 patients who had isolated monosomy 7, 24 patients who had del(7q) with additional abnormalities, and 53 patients who had monosomy 7 with additional abnormalities. There was no statistically significant age or sex predominance among any of the 4 karyotypic groups. Isolated del(7q) was more frequent in patients with lower WHO and IPSS risk subtypes than in the other 3 karyotypic groups. In addition, platelet counts were significantly higher and the percentages of blasts in bone marrow were lower in the group with isolated del(7q) than in the other 3 karyotypic groups. The impact of chromosome 7 abnormalities on the natural course of MDS was analyzed. For this purpose, 19 Cancer January 1,

4 patients who received azacitidine and 9 patients who underwent allogeneic stem cell transplantation were censored at the time of the therapeutic procedure. After a median follow-up of 13 months (range, months), the median OS in our cohort of patients with chromosome 7 abnormalities was 11 months (95% confidence interval [CI], months) (Fig. 1). A significant difference in OS was observed between patients with isolated del(7q) and patients with isolated monosomy 7. The median OS for patients who had isolated del(7q) was 40.8 months compared with 16 months for patients who had isolated monosomy 7 (Kaplan-Meier estimate; P ¼.011; log-rank test) (Fig. 2, top). The most common 7q-deleted regions were 7q22 (n ¼ 11), 7q31-35 (n ¼ 10), and other unspecific break points (n ¼ 6). The OS in these break-point groups did not differ significantly (P ¼.521; log-rank test). Patients who had chromosomal abnormalities in addition to del(7q) tended to have poorer survival. Patients who had isolated del(7q) had significantly better OS (median OS, 40.8 months; 95% CI, months) compared with patients who had del(7q) with additional abnormalities (median OS, 7.2 months; 95% CI, months; Kaplan-Meier estimate; P <.001; log-rank test) (Fig. 2, middle). There was no statistically significant difference between del(7q) with additional abnormalities and monosomy 7 with additional abnormalities (Kaplan-Meier estimate; P ¼.623; log-rank test) (Fig. 2, bottom). We evaluated the relation between OS and the number of additional chromosomal abnormalities observed in addition to del(7q) or monosomy 7. Regarding del(7q), patients who had del(7q) and 1 chromosomal abnormalities had an OS (8 months) similar to that of patients who had del(7) and 2 chromosomal abnormalities (OS, 7.2 months) and patients who had del(7q) and 3 chromosomal abnormalities (OS, 7.3 months; P ¼.763; log-rank test). In the same manner, there was no correlation between OS and the number of chromosomal abnormalities identified in addition to monosomy 7. Figure 2. Figure 2. These Kaplan-Meier curves illustrate survival according to karyotypic group. (Top) Overall survival (OS) is compared between patients who had isolated deletion (del) of part of the long arm of chromosome (7q) and patients who had isolated monosomy 7. (Middle) OS is compared between patients who had isolated del(7q) and patients who had del(7q) with additional abnormalities. (Bottom) OS is compared between patients who had del(7q) with additional abnormalities and patients who had monosomy 7 with additional abnormalities. 130 Cancer January 1, 2012

5 Chromosome 7 Abnormalities in MDS/Cordoba et al Table 2. Univariate and Multivariate Analyses of Prognostic Parameters for Survival Variable Univariate Analysis: P Multivariate Analysis: HR (95% CI) [P] Age ( ) [.03] Sex.714 Hemoglobin.004 Neutrophils.719 Platelet.224 Blast in BM < ( ) [.04] LDH.876 WHO subtype <.001 IPSS score <.001 Chromosome 7 abnormality <.001 [.001] Isolated del(7q) Reference Isolated monosomy ( ) [.04] Del(7q) with additional abnormalities 2.4 ( ) [.03] Monosomy 7 with additional abnormalities 3.7 ( ) [.04] Abbreviations: BM, bone marrow; CI, confidence interval; del(7q), deletion of part of the long arm of chromosome 7; HR, hazard ratio; IPSS, International Prognostic Scoring System; LDH, lactate dehydrogenase; WHO, World Health Organization. To establish the prognostic impact of these alterations, we analyzed standard variables with a known impact on OS (Table 2). In a univariate analysis of survival, the following characteristics were selected: age, hemoglobin, percentage blasts in bone marrow, WHO and IPSS subtypes, and karyotypic abnormality. In a multivariate analysis, advanced age, increased percentage blasts in bone marrow, and karyotypic group had an independent impact on survival. The risk of progression to AML also was evaluated in our cohort. Forty-one patients (31%) developed AML. The median time of progression to AML was 32 months (95% CI, months) (Fig. 3). Patients who had isolated del(7q) had a lower risk of evolution to acute leukemia than patients who had isolated monosomy 7, although the difference was not statically significant (Kaplan-Meier estimate; P ¼.094; log-rank test) (Fig. 4, top). In the isolated del(7q) group, the type of break point was not associated with significantly different AML transformation. However, LFS was significantly shorter in patients who had isolated del(7q) than in those who had del(7q) plus additional abnormalities (Kaplan-Meier estimate; P <.001; log-rank test) (Fig. 4, middle). However, we did not observe any statistically difference in LFS regarding the number of chromosomal abnormalities associated with del(7q) plus additional abnormalities. Finally, there was no significant difference in LFS between del(7q) with additional abnormalities and monosomy 7 with additional abnormalities (Kaplan-Meier estimate; P ¼.075; log-rank test) (Fig. 4, bottom). Multivariate analysis for AML progression (Table 3) indicated that the only factor influencing LFS was the percentage of blasts in bone marrow. Figure 3. Leukemia-free survival is illustrated for 133 patients with myelodysplastic syndromes and chromosome 7 abnormalities who developed acute myeloid leukemia (AML). DISCUSSION The IPSS introduced by Greenberg et al 8 more than 10 years ago is the most commonly used prognostic tool for evaluating patients with MDS. The IPSS classifies cytogenetic findings in MDS into 3 risk groups: good risk (normal, Y, del[5q]), poor risk (complex and/or any chromosome 7 abnormality), and intermediate risk (all other abnormalities). Karyotype abnormalities involving chromosome 7 (del[7q]/monosomy 7) are frequent in MDS (21% of clonal cytogenetic abnormalities). In accordance with IPSS criteria, del(7q) and monosomy Cancer January 1,

6 7 should be considered poor-prognosis abnormalities, and several previous studies have demonstrated a poor prognosis in terms of either short survival from diagnosis or leukemic evolutioninpatientswithmonosomy7/del(7q). 4,13-15 By contrast, our results indicate that patients who have isolated del(7q) have a better prognosis than those who have isolated monosomy 7. These results are in close accordance with the findings from 2 recent studies of a small number of patients. 10,11 In a retrospective analysis of 2124 patients with MDS from the Austrian/German group, Hasse et al 9 observed a tendency toward better survival in patients with isolated del(7q) (n ¼ 18; OS, 19 months) than patients with isolated monosomy 7 (n ¼ 22; OS, 14 months), but the small number of patients with chromosome 7 abnormalities prevented any statistically significant difference. Brezinova et al 16 have confirmed high heterogeneity of the break points on 7q, suggesting that multiple genes are involved in the pathogenesis of myeloid disorders. Our current results reveled that the region 7q22 was most commonly deleted in patients with isolated del(7q). However, we were unable to demonstrate that the type of break point in del(7q) had prognostic value for OS or AML transformation. In the current analysis, patients who had MDS with isolated del(7q) had a distinct clinical-pathologic profile; it was more frequent in patients who had less advanced disease stages compared with those who had monosomy 7 or additional abnormalities. It is noteworthy that 20 of 27 patients (74%) who had isolated del(7q) had a low-risk WHO subtype. In addition, patients who had isolated del(7q) had significant fewer blasts in bone marrow than patients who had isolated monosomy 7. These features may explain the longer survival in patients with isolated del(7q). However, a multivariate analysis revealed that cytogenetic abnormality had a significant independent effect on prognosis with respect to OS. Our current results confirm that chromosome 7 abnormalities in MDS are not homogeneous with regard Figure 4. Figure 4. These Kaplan-Meier curves illustrate survival according to karyotypic group among patients who developed acute myeloid leukemia (AML). (Top) Leukemia-free survival (LFS) is compared between patients who had isolated deletion (del) of part of the long arm of chromosome (7q) and patients who had isolated monosomy 7. (Middle) LFS is compared between patients who had isolated del(7q) and patients who had del(7q) with additional abnormalities. (Bottom) LFS is compared between patients who had del(7q) with additional abnormalities and patients who had monosomy 7 with additional abnormalities. 132 Cancer January 1, 2012

7 Chromosome 7 Abnormalities in MDS/Cordoba et al Table 3. Univariate and Multivariate Analyses of Prognostic Parameters for Developing Acute Myeloid Leukemia Variable to clinical and prognostic features. In line with our report, Slovak et al 17 demonstrated that der(1;7) is associated with several clinically distinctive pathologic features compared with monosomy 7/del(7q). The presence of additional chromosomal abnormalities in patients with del(7q) shortened OS. However, we failed to observe a significant difference in OS between patients who had del(7q) and 1 chromosomal abnormality and patients who had del(7q) and 2 chromosomal abnormalities or del(7q) and 3 chromosomal abnormalities. It should be noted, however, that the limited number of patients in each group was not large enough to help us clarify this prognostic value. In summary, patients who have MDS with isolated del(7q) have some distinct clinical-pathologic characteristics as well as better survival than patients who have MDS with isolated monosomy 7. Therefore, isolated del(7q) should not be considered any longer in the same prognostic category as monosomy 7. Additional aberrations can worsen the prognostic consequences of del(7q). FUNDING SOURCES No specific funding was disclosed. Univariate Analysis: P Multivariate Analysis: HR (95% CI) [P] Age.451 Sex.640 Hemoglobin.911 Neutrophils.840 Platelets.345 Blasts in BM < ( ) [.001] LDH.425 WHO subtype <.001 IPSS score <.001 Chromosome abnormality Isolated del(7q) Isolated monosomy 7 Del(7q) with additional abnormalities Monosomy 7 with additional abnormalities Abbreviations: BM, bone marrow; CI, confidence interval; del(7q), deletion of part of the long arm of chromosome 7; HR, hazard ratio; IPSS, International Prognostic Scoring System; LDH, lactate dehydrogenase; WHO, World Health Organization. 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