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Journal of Clinical Oncology, Vol 24, No 28 (October 1), 2006: pp. 4634-4641 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.9492 Prospective Evaluation of Clonal Evolution During Long-Term Follow-Up of Patients With Untreated Early-Stage Chronic Lymphocytic Leukemia
From the Mayo Clinic College of Medicine, Department of Internal Medicine, Division of Hematology, Department Pathology, Division of Cytogenetics, Department of Immunology, Division of Biostatistics, Mayo Clinic, Rochester, MN Address reprint requests to Tait D. Shanafelt, MD, 200 First Street SW, Mayo Clinic, Rochester, MN 55905
PURPOSE: Retrospective studies suggest cytogenetic abnormalities detected by interphase fluorescent in situ hybridization (FISH) can identify patients with chronic lymphocytic leukemia (CLL) who will experience a more aggressive disease course. Other studies suggest that patients may acquire chromosome abnormalities during the course of their disease. There are minimal prospective data on the clinical utility of the widely used hierarchical FISH prognostic categories in patients with newly diagnosed early-stage CLL or the frequency of clonal evolution as determined by interphase FISH. PATIENTS AND METHODS: Between 1994 and 2002, we enrolled 159 patients with previously untreated CLL (83% Rai stage 0/I) on a prospective trial evaluating clonal evolution by FISH. Patients provided baseline and follow-up specimens for FISH testing during 2 to 12 years. RESULTS: Chromosomal abnormalities detected by FISH at study entry predicted overall survival. Eighteen patients experienced clonal evolution during follow-up. The rate of clonal evolution increased with duration of follow-up with only one occurrence in the first 2 years (n = 71; 1.4%) but 17 occurrences (n = 63; 27%) among patients tested after 5+ years. Clonal evolution occurred among 10% of ZAP-70–negative and 42% of ZAP-70–positive patients at 5+ years (P = .008). CONCLUSION: This clinical trial confirms prospectively that cytogenetic abnormalities detected by FISH can predict overall survival for CLL patients at the time of diagnosis, but also suggests that many patients acquire new abnormalities during the course of their disease. Patients with higher ZAP-70 expression may be more likely to experience such clonal evolution. These findings have important implications for both clinical management and trials of early treatment for patients with high-risk, early-stage CLL.
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, with an annual incidence of 2.5 to 5 per 100,000 and a median age at diagnosis of 65 years.1 Clinical CLL staging systems devised by Rai et al2 and Binet et al3,4 in the late 1970s effectively identify patients with short survival based on the presence of marrow failure (anemia, thrombocytopenia). Unfortunately, these staging systems do not predict which patients with early-stage disease (Rai 0/I, Binet A) will experience an aggressive disease course. Conventional G-banding analysis to detect chromosome abnormalities in CLL is of limited clinical value because a majority of CLL B cells are nondividing G0 cells.5-10 With the development of fluorescent in situ hybridization (FISH), it became possible to detect chromosome abnormalities in nondividing cells. Studies using interphase FISH analysis of CLL cells have shown that specific cytogenetic abnormalities identify CLL patients with a more aggressive (17p–, 11q–) or indolent clinical disease course (13q–).11-14 These studies were all retrospective and included patients with both early- and advanced-stage disease, many of whom were treated previously and had FISH testing performed many years after diagnosis.11-16 The clonal stability of malignant cells in CLL has also been the focus of intensive investigation. Several studies suggest that some patients with no detectable chromosomal abnormalities on initial analysis can acquire new abnormalities that may correlate with more aggressive disease behavior.17,18 This raises a question of whether retrospective studies on the prognostic utility of FISH relate to cytogenetic abnormalities present at diagnosis or acquired during the course of the disease. Early studies using conventional cytogenetic analysis suggested such clonal evolution was rare,19,20 but subsequent studies suggested it may be more common than originally believed.17,18 The relationship between clonal evolution and other prognostic markers such as ZAP-70 and IgVH gene mutation status is unknown. We report the results of a prospective study confirming the relationship between FISH results and overall survival (OS) in a cohort of untreated, predominantly early-stage patients with CLL/small lymphocytic lymphoma (SLL). This represents the first published prospective study reporting on the frequency of clonal evolution in a cohort of patients with previously untreated CLL using comprehensive FISH analysis.
Patients Between January 1994 and October 2002, we enrolled 167 patients with previously untreated B-cell CLL/SLL seen at Mayo Clinic (Rochester, MN, and Jacksonville, FL) onto a prospective trial evaluating the prognostic importance of cytogenetic abnormalities and clonal evolution as evaluated by FISH. The trial was approved by the Mayo Clinic Institutional Review Board and all patients signed written consent to participate.
Eight patients originally enrolled onto this study were found to be ineligible because of a diagnosis other than CLL/SLL (ie, mantle-cell lymphoma, CD5– lymphoproliferative disorder, T-cell lymphoproliferative disease) or prior treatment, and were excluded from the analyses. The remaining 159 patients had an absolute lymphocytosis and documentation of a B-cell population coexpressing CD5 along with B-cell antigens on immunophenotyping of peripheral blood or nodal tissue consistent with a diagnosis of CLL/SLL according to either the NCI CLL Working Group21 or WHO criteria.22 The diagnosis of mantle-cell lymphoma was excluded in all patients by FISH testing for the translocation (11:14). Before enrollment, 154 of 159 eligible patients had an absolute lymphocyte count more than 5.0 x 109/L and five patients had an absolute lymphocyte count (ALC) between 3.0 and 5.0 x 109/L. Three of the five patients with an ALC between 3.0 and 5.0 x 109/L at study entry later had an ALC Patients initially provided baseline blood specimens for FISH testing and follow-up specimens during the ensuing 24 months. Samples were processed immediately or stored at –70°C until studied. Subjects surviving as of last known follow-up were recontacted by mail in mid-2004 to request updated clinical data and determine willingness to provide an additional sample for FISH testing. Correct addresses were identified for 128 of 133 (96.2%) participants who were known to be living or whose vital status was unknown at the date of the survey. One hundred eight surveys were returned (response rate, 81.2%) by patients (n = 81) or surviving relatives (n = 27). Treatment and survival status as of last known follow-up were abstracted from clinical records for the remaining 25 individuals. Of the 81 surviving patients who responded to the survey, 68 agreed to provide a follow-up sample for cytogenetic analysis and 58 samples (85.3%) were collected and analyzed as of October 2005. Additional samples from other time points were also evaluated for enrolled subjects who had cells stored for research purposes at Mayo Clinic.
Chromosome Evaluation by FISH Testing
Prognostic Testing
Statistical Considerations OS was calculated as the date of diagnosis to date of death. Differences in OS between FISH risk groups were evaluated using standard Kaplan-Meier methods and log-rank statistics. Given that the interval from diagnosis to study entry was more than 1 year for some patients, we also calculated patient survival from the date of study entry/FISH testing. Cox models were used to evaluate the impact of multiple variables simultaneously on OS from diagnosis. To help ameliorate the issue of small numbers of patients in some of the groups, we also evaluated FISH results grouped as poor (17p–, 11q–) versus good/intermediate prognosis (13q–, normal, +12). This was done based on our own as well as other retrospective studies demonstrating the prognostic importance of such categorizations.12,13
Patient characteristics are shown in Table 1. Median patient age at diagnosis was 64 years (range, 37 to 87 years). Median time from diagnosis to study enrollment was 3.4 months (range, 0 to 19.7 years) with 102 patients (64.2%) enrolled within approximately 1 year of diagnosis (< 1.1 year) and 72 patients (45%) enrolled within 1 month of diagnosis. A majority of patients had Rai stage 0 or I disease (83%) at study entry; only 6% had advanced-stage disease. Median follow-up from diagnosis was 8.4 years (range, 0.3 to 23 years). Survival status was confirmed for all 159 patients and treatment status could be verified for 119 patients. Diagnosis date was missing for two patients who were omitted, therefore, from any OS analysis from time of diagnosis but included in analysis of survival from date of baseline FISH analysis. As of last follow-up, 59 patients (50%) had been treated and 56 patients (35%) had died. The estimated median survival from time of diagnosis for the entire cohort was 13.2 years (95% CI, 11.1 years to not yet reached).
Results of Baseline FISH Testing Chromosome abnormalities were detected by FISH testing at study entry in 120 of the 159 patients (75%; Table 2). Sixty-one patients had a single abnormality, 52 patients had two abnormalities, and seven patients had three or more abnormalities. All deletions were monoallelic except for the 13q14 region. In 41 (44%) of the 93 patients who had 13q– deletions there were biallelic or concomitant monoallelic and biallelic deletions of 13q–.
The number of individuals in each hierarchical FISH risk category as well as the median and 5-year OS according to the classification system of Dohner et al11 is listed in Table 3. Significant differences in OS from both the time of diagnosis (P = .021; Fig 1A) and date of baseline FISH analysis (P = .0008; Fig 1B) were observed by hierarchical FISH risk category. Differences in OS from diagnosis were also observed for the subset of patients enrolled within 1 year (P = .0164; Fig 1C) or 1 month of diagnosis (P = .000014). Patients with 11q– or 17p– on baseline FISH compared with other FISH categories had shorter expected OS from diagnosis and baseline FISH analysis (all P < .004; Figs 2A to 2C).
We next used multivariable Cox regression models to evaluate how FISH categories associated with survival when accounting for other relevant factors such as Rai stage at study entry and age at diagnosis. For the purposes of these analyses, a patient with an initial FISH diagnosis of 17p– or 11q– was categorized as having a poor FISH prognosis. Similarly, patients with a FISH classification of normal, 13q–, or +12 were categorized as having a good/intermediate FISH prognosis. Each factor was associated significantly with OS from diagnosis when evaluated in a univariate manner (poor v good FISH, P = .004; age at diagnosis, P = .0006; Rai stage, P = .0026). When all factors were included in the survival model, each still remained associated significantly with OS (poor v good FISH, P = .00022; age at diagnosis, P = .000024; Rai stage, P = .00012).
Results of Sequential FISH Testing to Evaluate Clonal Evolution Eighteen patients had clonal evolution as evidenced by detection of a new cytogenetic abnormality during follow-up. In five patients, the newly acquired cytogenetic abnormality changed their classification from a lower hierarchical FISH risk category to a higher FISH risk category using the Dohner system (Table 4). Only one case of clonal evolution was observed in the first 2 years of follow-up (n = 71; 1.4%); however 17 of 63 (27%) patients with samples at least 5 years after baseline had clonal evolution. The median time from baseline FISH testing to the development of a new cytogenetic abnormality among these patients was 7.8 years (range, 1.9 to 11 years). Treatment status was known for 17 of 18 patients with clonal evolution, 12 (71%) of whom were treated before developing clonal evolution.
We next evaluated the ZAP-70, CD38, and IgVH gene mutation status of the 63 patients who had samples at least 5 years apart to determine if clonal evolution was more common among patients in different prognostic groups. ZAP-70 and CD38 results were available for 60 of these 63 patients. Using the traditional 20% threshold to classify ZAP-70 status and 30% threshold to classify CD38 status, 31 of 60 patients were ZAP-70 positive and 14 of 60 patients were CD38 positive. Clonal evolution was present in 13 of 31 ZAP-positive patients compared with three of 29 ZAP-negative patients (42% v 10%; P = .008). Clonal evolution was present in five of 14 CD38+ patients compared with nine of 46 CD38– patients (36% v 24%; P = .49).
The IgVH genes could be sequenced and classified as mutated (> 2% difference from germline) or unmutated (
This is the first published study that examines prospectively the correlation between OS and hierarchical FISH risk category in CLL using the classification system devised by Dohner et al.11 Consistent with the original German study, we found shorter survival among patients with 17p– and 11q–, and longer survival for those with 13q–. In addition to being a prospective validation, this finding is important because all subjects were untreated at study entry and the vast majority were early-stage patients enrolled shortly after diagnosis. Remarkably, despite differences in study design and patients sampled, the OS by FISH risk category is similar to that in the German series (Table 5). 11
In addition to the pioneering work by Dohner et al,11 at least two other retrospective series have evaluated the relationship of comprehensive cytogenetic evaluation by FISH and OS.15,16 Oscier et al15 also reported a relationship between cytogenetic abnormalities and OS in 205 patients with untreated CLL. Given that the primary emphasis of their analysis was to evaluate correlations between FISH and IgVH mutation status, the authors limited their analysis to individuals whose immunoglobulin heavy chain genes could be sequenced, which excluded 50% of the patients from the analysis and introduced potentially significant selection bias. Cytogenetic abnormalities in this series were evaluated through a combination of FISH and conventional chromosome banding, confounding interpretation further because the prognostic implications of detecting abnormalities using these two methods differs and conventional chromosome analysis does not detect the typical microscopic deletions of 13q–.7,11,26-29 Chevallier et al16 retrospectively correlated comprehensive cytogenetic analysis by FISH with OS in a convenience sample of 111 patients with CLL who were studied because they had stored specimens available for testing. Twenty-six percent of patients in this series had advanced-stage disease and 5% were treated previously. Although on univariate analysis patients with 17p– or 11q– in this series had shorter OS compared with those with other cytogenetic abnormalities, this difference was not significant on multivariate analysis controlling for disease stage and CD38 status. A preliminary report from the prospective German CLL Study Group CLL1 trial suggest that individuals in a pooled unfavorable FISH category (+12, 17p–, or 11q–) have shorter progression-free survival; however, results of this trial have not been published and the significance of the individual FISH categories and their relationship to OS is not yet available.30,31 Preliminary results of the prospective Medical Research Council CLL4 trial also suggest a relationship between 17p– and survival, but this trial enrolled patients requiring treatment rather than at the time of diagnosis.32 How to combine FISH optimally with other prognostic markers such as IgVH gene mutations status,33,34 expression of CD38,34-36 and expression of ZAP-7037-41 is also being evaluated prospectively as part of these trials.30,31 The second novel aspect of our study is the prospective evaluation of clonal evolution using a comprehensive panel of FISH probes. Nearly all previous evaluations of clonal evolution in CLL have used conventional karyotype banding17-19 or evaluated only single cytogenetic abnormalities by FISH.27,42 We saw only one patient (< 2% of patients) with clonal evolution by FISH during the first 2 years of follow-up, but identified evolution in 27% of patients with samples more than 5 years after baseline. Notably, after 5 or more years of follow-up, ZAP-70–positive patients were four times more likely to experience clonal evolution (P = .008). Although similar trends were observed for patients with unmutated IgVH genes, this association did not reach statistical significance, possibly due to the small sample size. All patients with mutated IgVH who experienced clonal evolution developed favorable cytogenetic defects (13q–), whereas the majority of unmutated patients with clonal evolution acquired a 17p– or 11q–. These results suggest patients with high ZAP-70 expression or unmutated IgVH genes may have greater chromosomal instability and be at greater risk of acquiring chromosomal defects that confer biologically aggressive disease behavior during the course of their disease. Larger studies evaluating the frequency of clonal evolution by molecular features (ZAP-70, mutation status, telomerase activity) of the leukemic cell are needed to confirm these findings. Approximately 70% of patients who experienced clonal evolution had been treated before developing new cytogenetic abnormalities, suggesting that in some individuals treatment may be selecting a resistant clone.43 Clonal evolution involved acquisition of a 17p– or 11q– in roughly one third of patients: cytogenetic abnormalities associated with poor response to alkylating agents and purine nucleoside analogs.9,14,44,45 In the absence of curative therapy, this finding emphasizes the importance of delaying therapy until patients meet accepted criteria for treatment43 unless patients are participating in clinical trials. The finding also suggests that if assessment can be standardized, ZAP-70 may be the optimal marker to select early-stage patients for trials of early intervention because it seems to identify individuals at greater risk for acquisition of cytogenetic abnormalities known to influence the efficacy of treatment,45 but permits administration of therapy before such abnormalities develop. We report here the first published prospective validation of the prognostic significance of FISH-detectable cytogenetic abnormalities with relationship to OS in patients with untreated early-stage CLL using the hierarchical FISH classification scheme of Dohner et al.11 FISH is widely available and, in our opinion, should be a standard part of the initial prognostic work-up for patients with CLL.46,47 Importantly, despite the prognostic utility of FISH at diagnosis, 27% of patients in our series developed new cytogenetic abnormalities at chromosome sites of known prognostic importance during the course of their disease. Patients with high ZAP-70 expression seem to be more likely to experience such clonal evolution and to acquire unfavorable cytogenetic abnormalities. Given that there is evidence to suggest certain FISH abnormalities may predict patients’ response to treatment9,14,44,48 or risk of relapse,45 patients with a long interval between diagnosis and therapy could benefit from repeat FISH analysis before treatment. These findings have potentially important implications for both the prognosis and treatment of patients with CLL.
The authors indicated no potential conflicts of interest.
Supported by grants from Vysis Inc, Des Plaines, IL (G.D., R.J., T.W.), and Grants No. NCI K12 CA90628 and NCI Lymphoma SPORE CA97274 (S.F.). Presented at the 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 10-13, 2005. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Haematologica 87:44-51, 2002 43. Rosenwald A, Chuang EY, Davis RE, et al: Fludarabine treatment of patients with chronic lymphocytic leukemia induces a p53-dependent gene expression response. Blood 104:1428-1434, 2004 44. el Rouby S, Thomas A, Costin D, et al: p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression. Blood 82:3452-3459, 1993 45. Byrd JC, Gribben JG, Peterson BL, et al: Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: Justification for risk-adapted therapy. J Clin Oncol 24:437-443, 2006 46. Shanafelt TD, Geyer S, Kay N: Prognosis at diagnosis: Integrating molecular biologic insights into clinical practice for patients with CLL. Blood 103:1202-1210, 2004 47. 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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5.0 x 109/L during follow-up. No follow-up ALC was available for the other two patients whose initial ALC was less than 5.0 x 109/L (baseline ALC for these two patients was 4.4 and 4.6 x 109/L, respectively). 
2% difference from germline) in 43 of these 63 patients including 15 of the 17 patients who had clonal evolution. Of these patients, 19 (44%) had unmutated IgVH genes and 24 (56%) had mutated IgVH genes. Clonal evolution occurred in nine of 19 (47.4%) patients with unmutated genes compared with six of 24 (25%) patients with mutated genes (P = .198). Notably, in all six IgVH mutated patients with clonal evolution, the newly acquired cytogenetic abnormality was a new or additional 13q–. Among the nine patients with unmutated IgVH with clonal evolution, the newly acquired cytogenetic abnormality was a 17p– in four patients and an 11q– in one patient. 
