Myelodysplasias

Incidence and prognostic significance of karyotype abnormalities in de novo primary myelodysplastic syndromes: a study on 331 patients from a single institution

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Abstract

The impact of clinical parameters, International Prognostic Scoring System (IPSS) scores/cytogenetic categories, and some single cytogenetic defects on overall survival (OS) and time to myelodysplastic syndromes (MDS)/AML progression (progression-free interval (PFI)) was evaluated in 331 MDS patients. Statistical analysis demonstrated that OS and PFI were significantly affected by all these parameters. Since single 7q- showed a better survival than the poor IPSS cytogenetic category (P=0.009), it was considered as a new prognostic entity (‘modified IPSS categories’). In multivariate analysis OS was significantly influenced by age, marrow blast cell percentage, number of cytopenias and either modified or standard IPSS cytogenetic categories; hazard ratios for MDS/AML progression were influenced by all the former, except for age and cytopenias. Multivariate analysis of del(7)(q31q35) confirmed the results of univariate analysis, but the Akaike Information Criterion showed no difference in evaluating OS and PFI between the modified and standard IPSS cytogenetic grouping. In conclusion, (i) chromosome defects as grouped by IPSS and blast cell percentage are the most relevant parameters for predicting OS and PFI; (ii) the prognostic power of the IPSS cytogenetic grouping is not ameliorated by the introduction of del(7)(q31q35) as a new entity; (iii) complex karyotypes have a prognostic value independent of blast cell percentage.

Introduction

Myelodysplastic syndromes (MDS) are malignant heterogeneous stem cell disorders characterized by hypercellular marrow with ineffective hemopoiesis resulting in peripheral cytopenias.1 In 1982 the French-American-British (FAB) group2 developed a morphological classification which subdivides MDS into five subtypes. Chromosome abnormalities are detected in about 40–70% of de novo MDS, confirm the clonality of the disorder, and, except for the 5q- syndromes, are not specific for any FAB subtype.3, 4, 5 In addition, in the 1980s, various studies have demonstrated the prognostic relevance of chromosome abnormalities.6, 7, 8, 9 Following the FAB classification, five scoring systems based on clinical and laboratory findings have been developed in order to better define overall survival (OS) and the time to MDS/AML progression (PFI) in MDS patients.10, 11, 12, 13, 14 Among these systems two recognize the prognostic value of chromosome defects.13, 14 In 1997, the International Prognostic Scoring System (IPSS) confirmed that in MDS patients, karyotype, blast cell percentage and number/types of peripheral blood cytopenias are the most important prognostic factors, and allow the subdivision of patients into four prognostically different categories.15

The goals of our study were to establish the incidence of chromosome abnormalities in a large series of de novo MDS patients (331 consecutive), to correlate chromosomal defects with FAB subtype and peculiar clinical–biological findings, to confirm the value of IPSS cytogenetic subgroups and to assess the impact of single defects with a still ill-defined prognosis on OS and on the time to MDS/AML progression.

Materials and methods

Diagnosis

All of the 331 consecutive de novo MDS patients were diagnosed at the Division of Hematology, Policlinico San Matteo IRCCS, Pavia, between January 1990 and December 2001. MDS diagnosis was made according to FAB criteria. Perl's staining was applied in all refractory anemia (RA) patients in order to establish a diagnosis of refractory anemia with ringed sideroblasts (RARS). None of the 331 patients had a white blood cell (WBC) count above 12 × 109/l. Patients with a diagnosis of chronic myelomonocytic leukemia (CMML), those previously treated with chemo-radiotherapy for other cancers or for nonmalignant disorders (eg autoimmune diseases) and those previously exposed to environmental carcinogens were excluded from the study. For every patient, bone marrow examination was an integral part of the diagnostic work-up and was repeated when necessary. As far as follow-up is concerned, patients were seen at our outpatient clinic every 2–3 months, unless any change in their clinical condition occurred. In particular, a MDS/AML progression was easily recognized since the family physicians submitted their patients to peripheral blood counts with differentials every 15 days. In case of evolution patients were immediately referred to our ward. Therefore, we are very confident that no MDS/AML progression occurred in any patient who died at home.

Cytogenetic studies

Chromosome studies were performed on bone marrow cells at diagnosis, using a trypsin-Giemsa banding technique. Metaphase cells were obtained from short-term unstimulated cultures. Whenever possible, at least 20 metaphases were analyzed and 10 fully karyotyped. Chromosome identification and karyotype description were made in accordance with the International System for Chromosome Nomenclature (ISCN, 1995).16 More than three abnormalities were necessary to define the karyotype as complex.

Statistical analysis

Descriptive statistics were reported as the mean and standard deviation (s.d.) or median and interquartile range (IQR) for continuous variables, and as absolute frequencies and percentages for categorical variables. For the purpose of the analysis, continuous variables were dichotomized according to values reported in the literature.15 Median follow-up was computed according to the ‘reverse Kaplan–Meier’ method. Censoring occurred in cases of: study completion, death, start of intensive chemotherapy, or allo-BMT (depending on which occurred first). Median time to the event (either death or time to MDS/AML progression) was also reported. Survival was estimated by using the Kaplan–Meier method.17 Univariate and multivariate Cox proportional hazard models were used to identify possible predictors of events. Hazard ratios (HR) and their 95% confidence intervals (95% CI) were computed; the corresponding P-values were also reported. The assumption of proportional hazards was verified. A modified IPSS cytogenetic grouping, which considered del(7)(q31q35) as a new prognostic entity, along with the standard IPSS cytogenetic categories, was analyzed. Variables of clinical relevance were included in a Cox multivariate model. Competing models were informally compared by means of the Akaike Information Criterion (AIC): the lower the AIC, the better the model. Stata 8 (StataCorp, College Station, TX, USA) was used for computation. A two-sided P-value <0.05 was considered statistically significant.

Results

Patients

The clinical characteristics, FAB classification and IPSS score of the 331 patients who entered the study are listed in Table 1. In all, 251 patients received supportive treatment (transfusions and hemopoietic growth factors), 11 differentiation-inducing agents, eight immunosuppressive treatments, 22 low-dose chemotherapy aimed at reducing the WBC count, 30 various regimens of intensive chemotherapy. A total of 14 patients were submitted to an allogeneic bone marrow transplantation (allo-BMT). Nine of them had previously received supportive treatment and five had been submitted to various schedules of intensive chemotherapy. This last induced a complete remission (CR) in three patients and a partial remission (PR) in the remaining two.

Table 1 Patients' clinical characteristics

Median follow-up based on the reverse Kaplan–Meier method was 37.6 months (IQR=15.6–82.3). At the time of the analysis 194 patients were alive, while 137 had died. Median survival time was 62.8 months (IQR=19.3–193.8). For the 137 patients who died, median time to death was 16.1 months (IQR=7.5–34.1). In all, 15 patients (4.5%) progressed to advanced MDS, while 90 (27.1%) evolved into AML. Median PFI was 173.3 months (IQR=17.0–not reached). For the 105 patients who progressed, median time to progression was 8.2 months (IQR=3.9–21.9).

Cytogenetic studies

The overall incidence of clonal chromosome abnormalities was 62.2%. Their frequency in relation to FAB subtype and IPSS score, the chromosomes most frequently rearranged or present as single defects are listed in Table 2. Del(5q), independent of the interstitial deletion breakpoints, del(20q) and +8, were more commonly observed in RA and RARS, −7 and del(7)(q31q35) in all MDS FAB subtypes, 3q rearrangements and complex karyotypes in advanced MDS.

Table 2 Patients' cytogenetic features

Identification of prognostic factors

The statistical relevance of clinical and cytogenetic parameters of the 331 patients on 2-and 5-year survival with their respective HRs, 95% confidence intervals and P-values, and on HRs for MDS/AML progression are reported in Table 3. OS in relation to IPSS scores and modified IPSS cytogenetic categories are shown in Figures 1a and b, and PFI in relation to these variables in Figures 2a and b. All the parameters listed in Table 3 significantly affected survival probabilities, while only some of them significantly influenced the HRs for MDS/AML progression. Considering chromosome abnormalities, patients with del(5q) with one additional defect, miscellaneous defects, 3q abnormalities, −7, del(7)(q31q35) and complex karyotypes showed a survival probability lower than those of patients with a normal chromosome pattern. Patients with +8, miscellaneous defects, 3q abnormalities, −7, del(7)(q31q35) and complex karyotypes more frequently experienced MDS/AML progression than patients with a normal chromosome pattern (HRs, 95% CI and P-values listed in Table 3). No statistical difference in clinical outcome was detected when some of the single abnormalities included in the intermediate IPSS category (del(5q) and one additional defect, +8, del(12p)) were compared to the remaining set of abnormalities within this IPSS category. In contrast, 3q abnormalities, also included within this same IPSS cytogenetic category, presented a survival probability significantly inferior to those of the good and intermediate IPSS cytogenetic category (HR=5.6 (95% CI=2.6–12.4) with P=0.001 and HR=0.3 (95% CI=0.1–0.8) with P=0.01 respectively) and similar to that of the poor IPSS cytogenetic category (HR=1.1 (95% CI=0.5–2.4) with P=0.7) when it was considered as a new cytogenetic subgroup. In addition, 3q abnormalities presented a HR for MDS/AML progression that was three times that of patients included in the good IPSS cytogenetic category (HR=2.9 (95% CI=1.0–8.4) with P=0.04) and similar to that of patients included in the intermediate IPSS cytogenetic category (HR=0.9 (95% CI=0.3–2.5) with P=0.8). However, due to the small number of patients, these results could not be confirmed by multivariate analysis.

Table 3 Clinical and cytogenetic parameters related to survival and hazard ratios for MDS/AML progression
Figure 1
figure1

Overall survival: (a) in relation to IPSS; (b) in relation to modified IPSS cytogenetic categories.

Figure 2
figure2

Progression-free survival: (a) in relation to IPSS; (b) in relation to modified IPSS cytogenetic categories.

Del(7)(q31q35) showed a survival probability better than those of the remaining set of abnormalities included within the poor IPSS category and similar to those of the intermediate IPSS category. The HR for MDS/AML progression was similar to that of both the poor and the intermediate IPSS cytogenetic categories (Table 3). Therefore, del(7)(q31q35) was introduced as a new variable within the classic IPSS cytogenetic categories (‘modified IPSS cytogenetic categories’).

The multivariate Cox model included age (for survival only), bone marrow blast cell percentage, number of cytopenias and standard IPSS cytogenetic categories. For comparison, a second multivariate model was fitted by using the modified IPSS cytogenetic categories (Table 4), which included del(7)(q31q35) as a new entity distinct from the poor IPSS cytogenetic category and a third model including age and IPSS score only. According to the AIC, the model including the modified IPSS cytogenetic categories was the best (AIC=1057) when evaluating survival, although not much better in comparison to the standard IPSS cytogenetic categories (AIC=1063), but definitely better than the third model with the IPSS score only (AIC=1101). Considering the PFI models, the AIC was 992 for the model with the standard IPSS cytogenetic categories, 994 for that with the modified IPSS cytogenetic categories and 1000 for that with IPSS only. In multivariate analysis del(7)(q31q35) showed an OS significantly better than that of the IPSS poor cytogenetic category (P=0.009) and similar to that of both the IPSS intermediate and good IPSS categories (P=0.96 and 0.16 respectively), whereas it showed a HR for MDS/AML progression similar to that of both the IPSS poor and intermediate categories (P=0.19 and 0.63, respectively).

Table 4 Multivariate analysis of survival and AML evolution

Discussion

In our series clonal chromosome abnormalities had an incidence of 62.2%, a frequency similar to that of other reports.3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 18, 19, 20, 21, 22, 23, 24, 25, 26 Chromosome defects were more common in RAEB and RAEB-t than in RARS and RA. Deletions or gains of entire chromosomes had an incidence of 60.4% and translocations of only 1.8%. Except for single del(5q), which was associated with RA, no other defect was specific for any FAB subtype.

Numerous reports have demonstrated that MDS karyotype abnormalities significantly affect OS and the risk of MDS/AML progression,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 18, 19, 20, 21, 22, 23, 24, 25, 26 even in patients undergoing intensive chemotherapies.27, 28 Therefore, in 1997 the IPSS15 grouped MDS patients (either untreated or submitted to low-dose chemotherapy or growth factors only) into three prognostically different cytogenetic categories and included the chromosome pattern in a new scoring system which has been validated by various reports.23, 24, 29, 30 One of the aims of the present study was to check whether IPSS scores and IPSS cytogenetic categories significantly influenced OS and HRs for MDS/AML progression in a series of 331 MDS patients from a single Institution. In order to achieve these goals, we analyzed a patient population similar to that included in the IPSS study; otherwise the two studies could not be compared. Therefore, since it is well known that intensive chemotherapy and allo-BMT may significantly change the natural course of MDS, the OS and HRs for MDS/AML progression, data from these patients were collected until the time when they were submitted to these treatments. In addition, patients with a WBC >12 × 109/l, as well as those with a diagnosis of CMML (nowadays no longer recognized as an MDS entity), were excluded from the study. When Cox regression was applied, the statistical significance of clinical parameters, IPSS scores and IPSS cytogenetic categories on either OS or HRs for MDS/AML progression became apparent (Table 3). In addition, when evaluating survival, the two multivariate Cox models which included age, bone marrow blast cell percentage, number of cytopenias and either standard or modified IPSS cytogenetic categories showed AIC scores of 1057 and 1063, respectively, definitely better than that of the Cox model which included age and IPSS scores only, AIC=1101. The same datum was obtained when evaluating HRs for MDS/AML progression. The AIC scores for the two former models were 992 and 994, respectively, while that for the model which included IPSS scores was 1000.

Another aim of our study was to test the prognostic impact of the single defects included in the different IPSS cytogenetic categories. As far as del(5q) is concerned, in our series patients with single del(5)(q13q33) and those with single del(5q) with different breakpoints presented similar 2- and 5-year survivals and similar HRs for MDS/AML progression (not statistically different from those of normal karyotypes (Table 3)). Similar results have also been reported by three independent studies,31, 32, 33 while conflicting findings have been obtained by one other.34 Recent data points to the fact that a relevant difference in survival does exist between patients with single del(5q) depending on whether their medullary blast cell percentage is < or >5%.32 It has been proposed that the latter patients should be excluded from the del(5q) syndrome. Our series confirms this finding. Considering all the isolated 5q-, the nine patients (seven RAEB and two RAEB-t) with a median blast cell percentage of 13 (range 7–31) presented a 5-year survival probability of 0.59% (95% CI=0.07–0.89), while the 21 patients (one RARS and 20 RA) with a blast cell percentage <5% showed a 5-year survival probability of 0.86% (95% CI=0.55–0.96) (HR=8.9 (95% CI=1.4–5.2) and P=0.02). Patients of the former group developed MDS/AML progression six times more frequently than those of the second group (HR=6.0 (95% CI=1.3–28.5) and P=0.02). The issue of whether the presence of del(5q) plus one additional defect predicts an unfavourable prognosis has been unanswered for a long time as several larger studies included only a few patients with this chromosomal anomaly and did not arrive at any firm conclusion.35, 36 In our series, patients with del(5q) plus one additional abnormality experienced a 5-year survival probability significantly inferior to that of normal karyotypes, but a similar HR for MDS/AML progression (Table 3). When the outcome of this defect was compared to that of the other abnormalities included within the IPSS intermediate cytogenetic category, no statistical difference was seen and del(5q) plus one additional defect could not be segregated from this IPSS cytogenetic category. Similar results were obtained for del(12p), +8. In contrast, 3q abnormalities presented a 2-year survival probability significantly inferior to that of the intermediate IPSS cytogenetic group and similar to that of the poor IPSS cytogenetic subgroup, while the HR for MDS/AML progression was similar to that of patients included in the intermediate IPSS cytogenetic category. A recent study which used an identical approach detected a trend towards a longer survival for patients with del(12p) and a shorter survival for patients with 1q abnormalities.24

Monosomy 7/7q deletion has been definitively associated with a poor prognosis in terms of either short survival from diagnosis or leukemic evolution;3, 13, 21, 37, 38 thus, the IPSS has included these defects in the poor cytogenetic category.15 Based on banding analysis, two broad critical regions, one at band 7q22 and the other at band 7q32–q35, seem to be targeted by the deletion, always defined as interstitial.39 From a prognostic viewpoint the last deletion seems to be correlated with the worst clinical outcome.38, 40 The present series confirms the adverse prognosis of monosomy 7 and shows that del(7)(q31q35), considered as a new IPSS cytogenetic category, presented a 5-year survival probability significantly better than that of the poor and similar to that of the intermediate IPSS cytogenetic category. Patients with del(7)(q31q35) had a HR for MDS/AML progression similar to that of both the IPSS cytogenetic categories (Table 3). Multivariate analysis confirmed these results (Table 4), but the modified and the standard IPSS cytogenetic groupings presented similar AIC scores for either OS and PFI, suggesting that they are equally effective for calculating the prognosis of MDS patients.

The prognostic relevance of complex karyotypes has been stressed by various reports3, 8, 13, 14, 23 and is confirmed by our data. In the present series RAEB and RAEB-t patients with this cytogenetic pattern presented a 1-year survival probability of 0.15% (95% CI=0.03–0.34) vs 0.77% (95% CI=0.66–0.85) (HR=6.6 (95% CI=3.5–12.4) and P=0.001) for those with other abnormalities. In addition, patients of the former group developed MDS/AML progression two times more frequently than those of the second group (HR=2.1 (95% CI=1.1–4.0) and P=0.03). This analysis could not be carried out in patients with RA or RARS, as none of them presented a complex karyotype.

In conclusion, (i) chromosome defects as grouped by IPSS and blast cell percentage are the most relevant parameters for predicting OS and HRs for MDS/AML progression in MDS patients; (ii) the definition of del(7)(q31q35) as a new prognostic subgroup does not add any prognostic power to the standard IPSS cytogenetic grouping; (iii) complex karyotypes have a prognostic value independent of blast cell percentage.

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Bernasconi, P., Klersy, C., Boni, M. et al. Incidence and prognostic significance of karyotype abnormalities in de novo primary myelodysplastic syndromes: a study on 331 patients from a single institution. Leukemia 19, 1424–1431 (2005) doi:10.1038/sj.leu.2403806

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Keywords

  • MDS
  • karyotype
  • chromosome abnormalities
  • prognostic scores
  • IPSS

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