|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2006.08.4194 on March 12 2007 © 2007 American Society of Clinical Oncology. Abdominal Computed Tomography Predicts Progression in Patients With Rai Stage 0 Chronic Lymphocytic Leukemia
From the Departments of Hematology and Radiology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Spain Address reprint requests to Emili Montserrat, MD, Department of Hematology, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain; e-mail: emontse{at}clinic.ub.es
Purpose: Whether computed tomography (CT) should be routinely included in the diagnostic work-up in patients with chronic lymphocytic leukemia (CLL) has not yet been determined. The aim of this study was to analyze the prognostic significance of abdominal CT in patients with CLL in Rai clinical stage 0. Patients and Methods: Abdominal CT was performed at diagnosis in 140 patients consecutively diagnosed with CLL in Rai stage 0 disease. Results: An abnormal abdominal CT was found in 38 patients (27%). Abnormal CT correlated with increased bone marrow infiltration (P = .024), high lymphocyte count (P = .001), increased ZAP-70 expression (P = .003), and short lymphocyte doubling time (LDT; P = .007). Patients with abnormal CT progressed more frequently and had a shorter time to progression than those with normal CT (median, 3.5 years v not reached, respectively; P < .001) and required earlier treatment intervention. In a multivariate analysis, only high ZAP-70 expression (relative risk = 3.60) and an abnormal abdominal CT (RR = 2.71) correlated with disease progression. Conclusion: In this series, an abnormal abdominal CT was a strong predictor of progression in patients with early-stage CLL. The inclusion of CT scans in the initial work-up of patients with early clinical stage on clinical grounds can, therefore, provide relevant clinical information.
Chronic lymphocytic leukemia (CLL) has a variable clinical course. Although the median survival of patients with this form of leukemia is approximately 10 years, the prognosis is extremely variable in individual patients, ranging from a very short to a normal life span.1 The clinical staging systems independently developed by Rai et al2 and Binet et al,3 based on easily obtainable biologic and clinical parameters, are extremely useful for assessing prognosis in patients with CLL. However, although reproducible and easy to apply, staging systems have some limitations, including that they do not allow differentiation between patients in early stage (nowadays, up to 80% of all patients at diagnosis) who are likely to progress, and those in whom the disease will remain stable for many years.1,4,5 Since the introduction of the staging systems, there has been a continuous effort to identify new prognostic factors in CLL.6,7 The clinical significance of abdominal lymphadenopathy in patients with CLL has not been formally assessed. To the best of our knowledge, the only published studies on the prognostic value of retroperitoneal lymphadenopathy in patients with CLL were published more than 20 years ago. In these two studies, lymph nodes’ size and their appearance were evaluated by lymphography, and the conclusion was that there was no correlation between the lymph node characteristics and disease stage or survival.8,9 Currently, CT scans are mandatory in the assessment of disease extension in the vast majority of chronic lymphoproliferative disorders.10,11 Although, according to the National Cancer Institute CLL Working Group (NCI/WG), CT scans are not necessary to routinely evaluate disease extension,12 imaging studies, including CT scans, are increasingly being performed in patients with CLL to assess disease extension and response to therapy. Moreover, the detection of lymphadenopathy has been related with high-risk cytogenetics abnormalities such as del11q, and also with poor response to treatment with alemtuzumab.13,14 Despite that, there are no studies addressing the overall prognostic significance of abnormal CT scans in patients with CLL, particularly in those with no palpable lymph nodes. Against this background, we investigated the clinical significance of abdominal CT in patients with CLL in early clinical stage with the hypothesis that the disease in patients in early Rai 0 clinical stage on clinical grounds but with detectable abdominal lymphadenopathy by CT scans would behave as would that in patients in more advanced stage than those in true Rai 0 disease.
Patients Between March 1992 and December 2004, 140 patients consecutively diagnosed with CLL in Rai stage 0 disease in our institution were enrolled onto the study. The key inclusion criteria were the following: (1) diagnosis of CLL according to the NCI/WG criteria12; (2) abdominal CT scan performed at diagnosis; (3) Rai stage 0 at the time of the CT examination; (4) no previous treatment; (5) more than 1 year of follow-up. Progression was defined as the change to a more advanced clinical stage or treatment requirement, considering that patients were treated according to the NCI/WG criteria.12 In addition to patients in Rai stage 0, a series of 86 patients consecutively diagnosed with CLL in Rai stage I during the same period of inclusion was also analyzed. Informed consent was required from all the patients in accordance with the local ethics committee guidelines. Fluorescence in situ hybridization (FISH) analysis was performed in 107 patients with the probes LSI D13S319 (13q14.3), CEP12, LSI ATM (11q22.3), and LSI p53 (17p13.1) following standard methods.15 ZAP-70 expression was analyzed by flow cytometry in 120 patients following the method described by our group.16
Abdominal CT Evaluation Two expert radiologists (C.A. and P.A.) independently evaluated abdominal CT scans, not having any information of the clinical status or disease evolution. In the 10% of cases in which there was disagreement in their evaluation of the CT scan images, a consensus diagnosis was achieved. The assessment of normality of nodal groups was based on size criteria.17 The maximum short-axis dimension of lymph nodes was measured because it is accepted as being the most helpful measurement because it is the most reproducible.18 To better classify the areas involved, the following five abdominal lymphoid areas were considered: diaphragmatic, celiac, mesenteric, iliac, and retroperitoneal (the latter including periaortic, interaortocaval, and pericaval chains). Following international standard criteria, lymph nodes more than 10 mm in diameter were considered abnormal. Furthermore, lymph nodes were also considered abnormal if multiple nodes smaller than 10 mm in the short-axis diameter were seen in a single region.19 Finally, spleen enlargement was analyzed in all the cases and considered another involved lymph node region. Splenomegaly was considered when significant enlargement of the spleen was present changing the normal relationship with the other abdominal viscera. CT was defined as abnormal when one or more anomalous lymph node regions, including spleen enlargement, were observed (Fig 1).
Statistical Analysis The Fisher's exact or t tests were used to analyze the association between the presence of an abnormal abdominal CT and the main initial clinical characteristics.20 Survival time and time to progression (TTP) were calculated from the time of the CT and analyzed using the Kaplan-Meier method,21 and curves were compared by means of the log-rank test. Multivariate analysis to ascertain variables predicting progression was performed using the Cox model by including statistically significant variables at the univariate analysis determined in the great majority of patients, along with abdominal CT results. All statistical tests were two sided, and the significance level was .05. Statistical analysis was performed using the SPSS statistical package, version 13.0 (SPSS Inc, Chicago, IL).
Patient Characteristics The most important patient features at the time of inclusion in the study are listed in Table 1. Eighty-six patients (61%) were male and the median age was 67 years (range, 43 to 89 years). The mean leukocyte count was 14.8 x 109/L and the median hemoglobin level was 13.9 g/dL (range, 11.1 to 17.9 g/dL). All patients included in this series were in Rai stage 0, and the vast majority of them were asymptomatic at the time of the CT. ZAP-70 expression was available in 120 patients, with 30 (25%) of them having high expression (  20%) in peripheral tumor cells. Lymphocyte doubling time was shorter than 12 months in 9% of the patients. Sixty-six (62%) of 107 patients presented with abnormalities in the FISH analysis. Abdominal CT was defined as pathological in 38 patients (27%). Detailed distribution of abdominal nodal involvement was as follows: retroperitoneal, 23 (61%); iliac, 24 (63%); celiac, 16 (42%); mesenteric, 10 (26%); spleen enlargement, 13 (34%); and diaphragmatic, two (5%). All but five patients presented with abdominal lymph nodes of 2 cm or less in diameter, and more than half of the patients with abnormal CT (n = 23) had more than one involved lymph node region, including spleen.
Abnormal CT and Clinical Variables Among the main initial characteristics, a pathologic abdominal CT at the time of diagnosis correlated with blood lymphocyte count of 30 x 109/L or higher (P = .001), lymphocyte doubling time of 12 months or less (P = .007), lymphoid bone marrow infiltration of 50% or higher (P = .024), and ZAP-70 expression of 20% (P = .003) or higher. Sixteen (53%) of 30 patients with high expression of ZAP-70 had an abnormal abdominal CT at the time of diagnosis. As per the genetic abnormalities, no correlation was observed between abnormal CT and FISH aberrations such as del17p, del11q, del13q, or trisomy 12 (Table 2). After a median follow-up of 5.1 years, 38 patients (27%) eventually experienced disease progression. Overall progression rate of the whole series was 30% at 5 years (median TTP not reached). Time to progression was significantly shorter in patients with an abnormal CT than in those with a normal CT (median TTP, 3.5 years v not reached, respectively; P < .001; Fig 2). In the univariate analysis, five additional variables were associated with a shorter TTP: high ZAP-70 expression ( 20%; P < .0001), high leukocyte count ( 30 x 109/L; P < .0001), high serum lactate dehydrogenase (P = .029), elevated lymphocyte bone marrow infiltration ( 50%; P = .001), and lymphocyte doubling time shorter than 12 months (P = .0001). In the Cox multivariate analysis for progression including newer biologic prognostic variables such as ZAP-70 and FISH abnormalities, only high ZAP-70 expression (P = .001; relative risk [RR] = 3.60; 95% CI, 1.74 to 7.43) and an abnormal abdominal CT (P = .007; RR = 2.71; 95% CI, 1.31 to 5.61) predicted disease progression.
To ascertain whether Rai stage 0 with abnormal CT had a similar clinical behavior to Rai stage I, the TTP of patients with abnormal CT was compared with that TTP observed in a series of 86 patients diagnosed on clinical grounds as having disease in Rai stage I. The TTP was not significantly different between these two groups of patients (P = .11; Fig 3).
The overall survival of the series was 79% at 5 years. Six variables significantly correlated with a poorer survival in the univariate analysis: high ZAP-70 expression (P = .002), del17p (P = .017), increased serum lactate dehydrogenase (P = .042) and β2-microglobulin (P = .022), age older than 65 years (P = .001), and high lymphocyte bone marrow infiltration (P = .002). Regarding CT scans, there was a trend for a worse survival in those patients showing a higher number of involved lymph nodes. However, these differences did not reach statistical significance (P = .32; Fig 4).
The clinical staging systems independently developed by Rai et al2 and Binet et al3 are the backbone for assessing prognosis in patients with CLL. However, staging systems are not devoid of some limitations, among the most significant of which is the lack of recognition of early-stage patients who will progress.22 For these reasons, several efforts have been made to identify groups of patients with CLL in early stage with a high risk of disease progression.15,16,23-25 In contrast with the majority of chronic lymphoproliferative disorders,10 CT scans and other imaging studies are not routinely recommended in the diagnostic work-up of patients with CLL and, to the best of our knowledge, there are no studies investigating the clinical significance of CT scans in CLL. Against this background, we hypothesized that patients with early Rai 0 CLL with abnormal abdominal CT scans could have a different natural history and prognosis compared with those with normal CT. We therefore analyzed the prognostic value of abdominal CT scan at diagnosis in 140 patients with CLL in Rai 0 stage with a median follow-up of 61 months. Abdominal CT was abnormal in 27% patients. The percentage of occult lymphadenopathy could, however, be underestimated. Thus, CT of the mediastinal area was not contemplated in the initial design of the study because its involvement in CLL cases is usually considered to be low,26 although this has not been investigated in a systematic way and by using modern imaging techniques.19,27,28 Abnormal CT scans were associated with some variables reflecting the bulk of the disease, such as blood lymphocyte count and the degree of bone marrow infiltration by lymphocytes. Although several groups have reported more frequent lymph node involvement with high-risk karyotype, such as del11q,13,29,30 in our series, with 107 patients studied with FISH, no statistical correlation has been found between abnormal abdominal CT scans and cytogenetic aberrations. This may be caused by the relatively small number of patients in whom FISH analysis was performed. Importantly, TTP was shorter for patients with one or more lymph node regions involved in abdominal CT compared with those with normal CT. Of note, TTP in patients with Rai 0 disease with abnormal CT scan was not different from that of patients with Rai I disease. Interestingly, multivariate analysis for progression showed that ZAP-70 expression and abnormal abdominal CT scan were the only two variables independently associated with progression. The lack of correlation between cytogenetic abnormalities and disease progression is in contrast with other studies13,15 and could result from the smaller number of patients in whom cytogenetic abnormalities could be evaluated, as well as the fact that we focused on patients in early Rai 0 disease. Taken together, these results indicate that, among patients with Rai stage 0 CLL, abdominal lymphadenopathy or splenomegaly, as detected by CT, predict disease progression. Moreover, the herein-mentioned results suggested that disease in patients with Rai 0 disease and an abnormal abdominal CT scan behaves much more like that in patients in Rai stage I disease than that in patients in true Rai 0 disease (including absence of abdominal lymphadenopathy). No statistical differences were found on survival on the basis of CT findings, which is probably explained by the relatively short follow-up of the series and particularly early treatment intervention in patients with abnormal CT scans (data not shown). Although our results provide a basis for performing abdominal CT scans in patients with CLL in early stage, it would be premature to either recommend that CT studies be performed on a routine basis or to make treatment decisions on the basis of CT findings. Nevertheless, the prognostic significance of CT scans, along with other new prognostic factors, in patients with CLL warrants further evaluation in clinical trials.
The authors indicated no potential conflicts of interest.
Conception and design: Francesc Bosch, Emili Montserrat Provision of study materials or patients: Francesc Bosch Collection and assembly of data: Ana Muntañola, Francesc Bosch, Eduardo Arellano-Rodrigo, Eva Giné, Carol Moreno, Francesc Cobo Data analysis and interpretation: Ana Muntañola, Francesc Bosch, Pau Abrisqueta, Armando López-Guillermo Manuscript writing: Ana Muntañola, Francesc Bosch, Armando López-Guillermo, Emili Montserrat Final approval of manuscript: Emili Montserrat Other: Pedro Arguis, Carmen Ayuso, Marta Crespo, Francesc Cobo
published online ahead of print at www.jco.org on March 12, 2007. Supported by grants from the Spanish Ministry of Health (05/0213), Marató de TV3 (05/1810), Deutsche José Carreras Leukämie-Stiftunge (D-1643), and Red Temática de Investigación Cooperativa en Cáncer (RTICC) 2006. A.M. holds a contract from Asociación Española contra el Cáncer. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333:1052-1057, 1995 2. Rai KR, Sawitsky A, Cronkite EP, et al: Clinical staging of chronic lymphocytic leukemia. Blood 46:219-234, 1975 3. Binet JL, Auquier A, Dighiero G, et al: A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48:198-206, 1981[CrossRef][Medline] 4. Molica S, Levato D: What is changing in the natural history of chronic lymphocytic leukemia? Haematologica 86:8-12, 2001 5. Rozman C, Bosch F, Montserrat E: Chronic lymphocytic leukemia: A changing natural history? Leukemia 11:775-778, 1997[CrossRef][Medline] 6. Bosch F, Montserrat E: Refining prognostic factors in chronic lymphocytic leukemia. Rev Clin Exp Hematol 6:335-349, 2002[CrossRef][Medline] 7. Montserrat E: Classical and new prognostic factors in chronic lymphocytic leukemia: Where to now? Hematol J 3:7-9, 2002[CrossRef][Medline] 8. Auclerc MF, Desprez-Curely JP, Maral J, et al: Prognostic value of lymphograms in chronic lymphatic leukemia. Cancer 53:888-895, 1984[CrossRef][Medline] 9. Grellet J, Curet P, Laemmel MG, et al: Correlation between lymphographic grouping and anatomic and clinical stages in chronic lymphoid leukemia. AJR Am J Roentgenol 133:797-803, 1979[Abstract] 10. Armitage JO: Staging non-Hodgkin lymphoma. CA Cancer J Clin 55:368-376, 2005 11. Mavromatis BH, Cheson BD: Pre- and post-treatment evaluation of non-Hodgkin's lymphoma. Best Pract Res Clin Haematol 15:429-447, 2002[Medline] 12. Cheson BD, Bennett JM, Grever M, et al: National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 87:4990-4997, 1996 13. Dohner H, Stilgenbauer S, James MR, et al: 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood 89:2516-2522, 1997 14. Moreton P, Kennedy B, Lucas G, et al: Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 23:2971-2979, 2005 15. Dohner H, Stilgenbauer S, Benner A, et al: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910-1916, 2000 16. Crespo M, Bosch F, Villamor N, et al: ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 348:1764-1775, 2003 17. Dorfman RE, Alpern MB, Gross BH, et al: Upper abdominal lymph nodes: Criteria for normal size determined with CT. Radiology 180:319-322, 1991 18. Vinnicombe SJ, Reznek RH: Computerised tomography in the staging of Hodgkin's disease and non-Hodgkin's lymphoma. Eur JNucl Med Mol Imaging 30 Suppl 1:S42-S55, 2003 19. Sutinen E, Jyrkkio S, Varpula M, et al: Nodal staging of lymphoma with whole-body PET: Comparison of. J Nucl Med 41:1980-1988, 2000 20. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline] 21. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 22. Montserrat E: Assessing prognosis in patients with chronic lymphocytic leukemia a quarter of a century after Rai and Binet staging systems. Ann Oncol 15:1450-1451, 2004 23. Damle RN, Wasil T, Fais F, et al: Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840-1847, 1999 24. Montillo M, Hamblin T, Hallek M, et al: Chronic lymphocytic leukemia: Novel prognostic factors and their relevance for risk-adapted therapeutic strategies. Haematologica 90:391-399, 2005 25. Oscier DG, Thompsett A, Zhu D, et al: Differential rates of somatic hypermutation in V(H) genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities. Blood 89:4153-4160, 1997 26. Berkman N, Polliack A, Breuer R, et al: Pulmonary involvement as the major manifestation of chronic lymphocytic leukemia. Leuk Lymphoma 8:495-499, 1992[Medline] 27. Brennan DD, Gleeson T, Coate LE, et al: A comparison of whole-body MRI and CT for the staging of lymphoma. AJR Am J Roentgenol 185:711-716, 2005 28. Karam M, Novak L, Cyriac J, et al: Role of fluorine-18 fluoro-deoxyglucose positron emission tomography scan in the evaluation and follow-up of patients with low-grade lymphomas. Cancer 107:175-183, 2006[CrossRef][Medline] 29. Austen B, Powell JE, Alvi A, et al: Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL. Blood 106:3175-3182, 2005 30. Neilson JR, Auer R, White D, et al: Deletions at 11q identify a subset of patients with typical CLL who show consistent disease progression and reduced survival. Leukemia 11:1929-1932, 1997[CrossRef][Medline] Submitted July 28, 2006; accepted January 19, 2007. This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
