Original Article
Prognostic Subgroups in B-Cell Chronic Lymphocytic Leukemia Defined by Specific Chromosomal Abnormalities
N Engl J Med 1990; 323:720-724September 13, 1990
- Abstract
- Abstract
Background and Methods.
Specific chromosomal abnormalities have been shown to affect the overall survival of patients with acute leukemia, but the possibility that specific chromosomal defects may influence the course of B-cell chronic lymphocytic leukemia (CLL) is controversial. We assessed this possibility as follows: blood mononuclear cells from 433 patients with B-cell CLL in five European centers were cultured with B-cell mitogens, and banded metaphases were studied.
Results.
Three hundred ninety-one patients could be evaluated cytogenetically, and 218 had clonal chromosomal changes. The most common abnormalities were trisomy 12 (n = 67) and structural abnormalities of chromosome 13 (n = 51; most involving the site of the retinoblastoma gene) and of chromosome 14 (n = 41). Patients with a normal karyotype had a median overall survival of more than 15 years, in contrast to 7.7 years for patients with clonal changes. Patients with single abnormalities (n = 113) did better than those with complex karyotypes (P<0.001). Patients with abnormalities involving chromosome 14q had poorer survival than those with aberrations of chromosome 13q (P<0.05). Among patients with single abnormalities, those with trisomy 12 alone had poorer survival than patients with single aberrations of chromosome 13q (P = 0.01); the latter had the same survival as those with a normal karyotype. A high percentage of cells in metaphase with chromosomal abnormalities, indicating highly proliferative leukemic cells, was associated with poor survival (P<0.001). Cox proportional-hazards analysis identified age, sex, the percentage of cells in metaphase with chromosomal abnormalities, and the clinical stage of the disease (Binet classification system) as independent prognostic variables.
Conclusions.
Chromosomal analysis provides prognostic information about overall survival in addition to that supplied by clinical data in patients with B-cell CLL. (N Engl J Med 1990; 323:720–4.)
Media in This Article
Figure 1
Patients with Cytogenetic Abnormalities (Both Numerical and Structural) Involving Specific Chromosomes, Patients with Normal Karyotypes, and Patients with Karyotypes That Could Not Be Evaluated (NE).Figure 2
Overall Survival According to Karyotype.Article Activity
- Article
CHROMOSOMAL analysis in malignant disease has increased in importance during the past decade. Analysis of the Philadelphia chromosome in chronic myelocytic leukemia1 and of the (14;18) translocation in follicular lymphomas2 has led to the identification of tumor-specific hybrid genes3 , 4 with highly probable pathogenetic roles.3 , 5 Furthermore, nonrandom chromosomal abnormalities in acute leukemias have been shown to define subgroups with specific clinical characteristics and prognoses.6 , 7
In B-cell chronic lymphocytic leukemia (CLL), stimulation with specific mitogens is required to achieve suitable metaphases for chromosomal analysis — a factor that has limited the amount of data available. The typical abnormality in CLL is trisomy 12 and not a translocation with specific breakpoints8; thus, it has not yet been possible to identify specific genes of pathogenetic importance. Patients with CLL are long lived; however, it has been demonstrated that patients with CLL who have clonal chromosomal abnormalities have poorer survival than those in whom no clonal abnormality is found9 , 10 and that trisomy 12 indicates the presence of aggressive disease that requires treatment.10 11 12 To achieve a better correlation between chromosome status and survival, the fourth international workshop on CLL13 recommended a multicenter collaboration. This is the first analysis of data from five collaborating European centers, comprising more than half of all patients with CLL with previously reported abnormal karyotypes (for a review, see reference 14).
Methods
Retrospective data were obtained on 433 patients whose condition was diagnosed according to conventional criteria. B-cell clonality was confirmed by immunophenotyping. There were 139 patients from Bournemouth, United Kingdom, 137 from Edinburgh, 107 from Huddinge, Sweden, 26 from Ferrara, Italy, and 24 from Helsinki. Among these, 391 (90 percent) could be evaluated cytogenetically; 224 were men and 167 were women, and their ages at diagnosis ranged from 32.4 to 98.8 years (median, 67.3; mean, 66.1). On evaluation, 176 patients were classified in Rai15 Stage 0 (lymphocytosis only), 82 in Stage I (lymphocytosis with lymphadenopathy), 67 in Stage II (lymphocytosis with splenomegaly), 31 in Stage III (lymphocytosis with anemia), and 35 in Stage IV (lymphocytosis with thrombocytopenia). According to the Binet classification system,16 276 patients were in stage A (fewer than three involved lymph node areas), 49 were in stage B (three or more involved areas), and 66 were in stage C (anemia, thrombocytopenia, or both). Karyotypic data did not influence therapy. Patients with symptoms were treated, most with chlorambucil with or without prednisone or with combinations of cyclophosphamide, vincristine, and prednisone with or without doxorubicin. One hundred forty-six of the 391 patients died during the observation period (37 percent). The median survival of the patients who died was 4.3 years from diagnosis (mean, 5.0), and the median observation time of the surviving patients was 5.4 years (mean, 6.2). The mean age at diagnosis was 68.8 years for the patients who died and 64.4 years for the surviving patients.
Sampling for chromosomal analysis was performed at diagnosis in 29 percent of the patients, and the median time from diagnosis to sampling was 0.9 years. Blood mononuclear cells were cultured according to the protocols of the individual institutions. The B-cell mitogens used were Epstein–Barr virus, lipopolysaccharide from Escherichia coli, 12-O-tetradecanoylphorbol-13-acetate, cytochalasin B, pokeweed mitogen, and phytohemagglutinin.10 , 17 18 19 20 Banded metaphases were karyotyped, and clonal chromosomal abnormalities were defined according to conventional criteria.21 If no clonal abnormality was found in at least 10 cells in metaphase, the karyotype was considered normal, and if one or often more samples yielded less than 10 cells in metaphase, the karyotype was designated as not able to be evaluated. A balanced translocation was considered to be a single abnormality, despite the presence of two chromosomal breakpoints.
The statistical analyses included the log-rank test22 and Cox proportional-hazards analysis.23 Overall survival from the time of diagnosis was used as the end point.
Results
Chromosomal Aberrations
Figure 1Figure 1
Patients with Cytogenetic Abnormalities (Both Numerical and Structural) Involving Specific Chromosomes, Patients with Normal Karyotypes, and Patients with Karyotypes That Could Not Be Evaluated (NE). shows the numbers of patients with clonal chromosomal abnormalities involving specific chromosomes, with normal karyotypes, and with a karyotype that could not be evaluated. Trisomy 12, the most common abnormality in CLL,8 , 9 , 14 was found in 67 patients, and another 2 had duplications of parts of the long arm of chromosome 12.14 , 24 Structural aberrations most commonly affected the long arm of chromosome 13 (n = 51). Interstitial deletions involving band 13q14,25 the site of the retinoblastoma antioncogene,26 were found in 23 patients, and translocations with one breakpoint at 13q14 in 12 patients. Three additional patients had deletions of the long arm of chromosome 13 with unidentified breakpoints. Structural aberrations involving the long arm of chromosome 14 were found in 41 patients, mostly as 14q + markers resulting from translocations from various donor chromosomes to 14q32 (n = 24). Structural aberrations involving 11q13 were found in 12 patients, 10 of whom had t(11;14)(q13;q32).Prognosis
The overall survival of patients with clonal chromosomal aberrations was, as in previous studies,9 , 10 poorer than that of patients with a normal karyotype (P<0.001) (Table 1Table 1
Factors Affecting Survival among 391 Patients Evaluated Cytogenetically.); however, specific chromosomal findings were significantly associated with poorer survival, and others with better survival. Patients with structural aberrations involving the long arm of chromosome 14 were found to have a poor prognosis, whereas those with structural aberrations involving 13q survived longer (P<0.05 by the log-rank test) (Fig. 2Figure 2Overall Survival According to Karyotype.). Figure 3Figure 3
Overall Survival among 35 Patients with an Abnormal Karyotype in Which Band 13q14 Was Deleted or Involved as a Breakpoint in Translocation and 24 Patients with an Abnormal Karyotype Involving Translocation to 14q32, Forming a 14q+ Chromosome. shows survival among patients with chromosomal abnormalities specifically involving bands 13q14 and 14q32. Patients with trisomy 12 had an intermediate prognosis among patients with abnormal karyotypes (Fig. 2). To assess the importance of a specific aberration without the influence of additional abnormalities, we analyzed patients with single aberrations separately. Those with trisomy 12 alone had the poorest survival, significantly poorer than those with aberrations of chromosome 13q (P = 0.01) (Fig. 4Figure 4
Overall Survival According to Karyotype among All 113 Patients with Single Aberrations, 24 Patients with Single Aberrations of Chromosome 13q, and 31 Patients with Trisomy 12 (+12) as a Single Aberration.). Altogether, patients with single aberrations did better than those with three or more aberrations (P<0.001) (Fig. 5Figure 5
Overall Survival According to the Number of Chromosomal Aberrations: None (Normal Karyotype; N = 173), One (N = 113), Two (N = 52), or Three or More (N = 53).). Also, patients with clonal chromosomal abnormalities in all evaluated cells in metaphase had poor survival, whereas those with higher percentages of cells in metaphase with no abnormalities did better (P<0.001) (Fig. 6Figure 6
Overall Survival According to the Percentage of Evaluated Cells in Metaphase Found to Have Clonal Chromosomal Aberrations.).Cox proportional-hazards analysis23 was performed to study the association of chromosomal results and clinical data with overall survival from the time of diagnosis. This analysis is especially suitable for continuous variables and is also useful to establish whether variables are independent or interrelated. Several cytogenetic variables were found to be significant in the univariate analysis. Age was the prognostic variable with the greatest significance, followed by the percentage of cells in metaphase with clonal aberrations and by clinical stage according to the Binet staging system (Table 1). The multivariate analysis incorporated these three variables and sex into the model, showing that they were independent prognostic variables.
We also performed a multivariate analysis using the Cox proportional-hazards model on data for the patients with clonal chromosomal aberrations only. This again showed that more prognostic information can be achieved from karyotyping than merely the identification of an abnormal clone. Interestingly, among patients with clonal abnormalities, the multivariate analysis identified the same four variables as significant as had the multivariate analysis of all patients; another variable, structural aberrations of chromosome 14, may yield additional information (P = 0.06).
Discussion
The present study demonstrates that specific chromosomal abnormalities in CLL predict overall survival. Patients without clonal chromosomal aberrations have a very long overall survival, with a median of more than 15 years. Patients with clonal aberrations do worse9 , 10; however, within this group survival among those with structural aberrations of chromosome 13 is almost as good as that among patients with a normal karyotype, whereas those with structural aberrations of chromosome 14 have poor survival.27 Furthermore, increasing complexity of the karyotype is associated with poorer survival.10 These prognostic differences were found by two independent statistical methods, the log-rank test22 and Cox proportional-hazards analysis.23 We were able to show that cytogenetic data have prognostic importance independent of age, sex, clinical stage, and blood leukocyte count28; in this study only age had greater prognostic importance.
Overall survival was chosen as an end point, since the true cause of death in CLL is often difficult to determine accurately. Survival was analyzed from the time of diagnosis and not from the date of karyotyping, since longitudinal studies have shown that in contrast to chronic myelocytic leukemia29 and follicular lymphoma,30 , 31 the karyotype in CLL is usually very stable throughout the course of the disease.32 , 33 Furthermore, chromosomal analysis was performed in most patients within a year of diagnosis, and analyses of survival from the time of karyotyping did not change the results significantly.
Recurrent chromosomal abnormalities may provide clues to genes of specific pathogenetic importance. Trisomy 12 is the most common chromosomal change in CLL,8 9 10 , 14 and structural aberrations involving the long arm of chromosome 13 are also frequent.14 , 17 , 18 , 25 , 34 The finding that trisomy 12 and aberrations of chromosome 13q were present as single aberrations in almost half the cases in which they were observed (Fig. 1) increases the likelihood that they play a part in the pathogenesis of the disease. Analysis in the literature of clonal structural abnormalities affecting chromosome 12 may indicate that the important genes are localized on bands q13 to q22.14 On chromosome 13 the retinoblastoma gene26 may be involved, since most of the aberrations were deletions of q14 and adjacent bands, or translocations involving 13q14.25 In contrast, structural abnormalities of 14q occurred as single aberrations in only one fifth of the cases, and this group of abnormalities seems less specific for CLL. Because chromosomal translocations occur in connection with the physiologic rearrangement of the immunoglobin heavy-chain gene at 14q32 in cells of the B lineage, 14q+ chromosomes are common in all B-cell tumors.
This study confirms that trisomy 12 is a marker for poor prognosis. This has previously been shown for treatment-free survival10 11 12 , 28 , 35 and has now proved true for overall survival. However, the association with survival was found only in patients with single aberrations (Fig. 4), whereas the presence of trisomy 12 in complex karyotypes was not prognostically important (Fig. 2). This suggests that the effect of trisomy 12 may be overwhelmed by other markers in patients with a poor prognosis. Also, the adverse prognostic effect of aberrations of chromosome 14q seems due in part to their frequent occurrence in complex karyotypes.
The cytogenetic measurement with the greatest prognostic importance was the proportion of cells in metaphase with chromosomal abnormalities in the sample.36 , 37 Patients with clonal abnormalities in all cells studied in metaphase had poorer survival than patients with a fraction of normal mitotic cells in the sample, and the greater the proportion of normal cells, the better the survival (Fig. 6). The results were the same whether different cutoff levels were arbitrarily chosen and analyzed with the log-rank test (Fig. 6) or the percentage of cells in metaphase with chromosomal abnormalities was used as a continuous variable in the Cox proportional-hazards model (Table 1). Interestingly, this measurement is in fact a marker for the mitogen-induced proliferation of tumor cells as compared with that of normal cells. Immune staining of cells in metaphase has been used to show that such cells with normal karyotypes in patients with clonal aberrations are nonleukemic cells.20 , 38 Also, studies of restriction-fragment–length polymorphism in cells from patients with trisomy 12 using probes for polymorphic genes on chromosome 12 have recently shown that almost all cells in the samples have trisomy 12 despite high numbers of cytogenetically normal cells in metaphase.39 These studies indicate that the malignant cells are not distributed equally in the cells in metaphase and in the cells in interphase. Thus, patients with CLL cells that divide more readily than normal lymphocytes on mitogenic stimulation in vitro do worse than patients with leukemic cells that are unresponsive to such stimulation. Also, these results are strongly corroborated by previous data on the prognostic effect of mitogen-induced proliferation of CLL cells in vitro.28 , 35 , 40 , 41
It would not have been possible for a single institution to accumulate the amount of data presented here. The collaborators currently include the three institutions that have reported the largest number of abnormal karyotypes in the international literature (for a review, see reference 14) and two additional centers. Collaborative data must be analyzed cautiously, however. The cell-culture conditions were not the same at each center, and there are also differences in the frequency of specific abnormalities. For instance, the incidence of 13q aberrations was higher in the United Kingdom centers, where mainly phorbol ester-induced cultures were studied; however, aberrations of chromosome 13q are also found in cells stimulated by Epstein–Barr virus and lipopolysaccharides.34 , 42
It is important to emphasize that the prognostic effect of specific karyotypes seems to be similar in different studies. A poorer prognosis in patients with clonal chromosomal aberrations,9 , 10 complex karyotypes,10 a high percentage of clonal metaphases,28 , 36 , 37 14q+ marker chromosomes,27 and trisomy 1210 , 11 , 14 has been reported previously, but there are also many reports in which some of these associations have not been statistically significant and were therefore rejected. However, the shape of the survival curves in relation to the number of patients studied in presentations from different institutions (reviewed by Juliusson and Gahrton14 and in unpublished presentations at the fourth international workshop on CLL13) is compatible with the data from the present study.
In chronic myelocytic leukemia and follicular lymphoma, chromosomal changes have prognostic importance because they predict transformation of the disease. In contrast to this, but in common with the findings in acute myelocytic leukemia6 and acute lymphoblastic leukemia,7 our study demonstrates that chromosomal analysis in CLL provides a tool for the identification of prognostic subgroups at the time of diagnosis. This is independent of other major prognostic indicators, such as age and clinical stage. Further studies are necessary to identify specific alterations at the level of the gene.
Source Information
From the Division of Clinical Hematology and Oncology, Department of Medicine, and the Department of Clinical Immunology, Karolinska Institute at Huddinge Hospital, Huddinge, Sweden (G.J., G.G.); the Department of Haematology, Royal Victoria Hospital, Bournemouth, and Oxford Regional Cytogenetic Laboratory, Oxford, United Kingdom (D.G.O., M.F.); Kay Kendall Leukemia Research Group, Medical Research Council, Human Genetics Unit, Western General Hospital, Edinburgh (F.M.R., G.S., M.J.M., A.C.P.); Cattedra di Ematologia, University of Ferrara, Ferrara, Italy (G.L.C., A.C.); and the Department of Medical Genetics, University of Helsinki, Helsinki, Finland (S.K., E.E.). Address reprint requests to Dr. Juliusson at the Department of Medicine, Huddinge University Hospital, S-141 86 Huddinge, Sweden.
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