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© 2003 American Society for Clinical Oncology Binet’s Staging System and VH Genes Are Independent but Complementary Prognostic Indicators in Chronic Lymphocytic Leukemia
From the Institut Pasteur; Hôpital Pitié-Salpêtrière; Biostatistique, Unité L’Institut National de la Santé et de la Recherche Médicale 444 Hôpital St Louis; Hôtel-Dieu, Paris, France; Disciplina de Hematologia e Hemoterapia-Universidade Federal de São Paulo, São Paulo, Brazil; and Hospital Maciel, Facultad de Medicina, Montevideo, Uruguay. Address reprint requests to Guillaume Dighiero, MD, Unité d’Immuno-Hématologie, et d’Immunopathologie, Institut Pasteur, 28 Rue du Docteur Roux, 75015 Paris, France; e-mail: dighiero{at}pasteur.fr.
Purpose: Rai’s and Binet’s staging systems have contributed significantly to the identification of major prognostic groups in chronic lymphocytic leukemia (CLL), though they fail to accurately predict disease progression at the individual level. Biologic factors, such as the mutational status of the immunoglobulin heavy-chain variable genes (VH, cytogenetics, CD38 expression, and some serum markers, have recently improved prognostic assessment in CLL. In this study, we analyzed the prognostic value of VH mutational status within the different stages of Binet’s classification in 145 patients. Patients and Methods: Our series consisted of 83 VH mutated (MT) and 62 VH unmutated (UM) patients. MT cases predominated within Binet’s stage A (70%), whereas UM cases predominated among stages B and C (62%). Results: Median overall survival (OS) was 84 months for UM patients and was not achieved for the MT group (70% 12-year survival, P < .0001). Concerning Binet’s stage A, both median OS and progression-free survival were significantly shorter for UM patients when compared with those of MT patients (97 months v not achieved, P = .0017; and 42 v 156 months, P < .0001), which compared favorably with the classical A' and A'' substaging. The VH mutational profile could also segregate stage B and C patients into two groups with different survival patterns (median OS, 78 v 120 months for UM and MT patients, respectively; P = .002). Conclusion: The significant survival differences observed between the VH mutational groups, among stage A and stage B and C patients, indicate that Binet’s classification and VH genes are independent prognostic variables and are most likely complementary.
CHRONIC LYMPHOCYTIC leukemia (CLL) arises from a malignant clone of B cells with a characteristic phenotype.1,2 One third of patients never require treatment and have long survival; in another third, an initial indolent phase is followed by disease progression. The remaining patients exhibit aggressive disease at the onset and need immediate treatment.3 Rai’s4 and Binet’s5 staging systems have allowed allocation of patients into good, intermediate, and poor prognostic groups. Additional studies6,7 identified a subset of patients within Binet’s stage A and Rai’s stage 0 whose survival was close to that of a healthy sex- and age-matched population. However, neither system succeeds in predicting disease progression at an early stage for an individual patient. Cellular expression of CD388–10 and serum markers, such as beta2-microglobulin, lactate dehydrogenase, thymidine kinase, and soluble CD23, can predict disease activity,9 but genomic 11q or 17p aberrations10–12 and the absence of somatic mutations in immunoglobulin heavy-chain variable genes (VH genes) are stronger predictors of rapid progression and shorter survival.10–13 According to the mutational profile of VH genes, two variants of CLL were proposed, one displaying unmutated VH genes and a poor prognosis, the other with mutated VH genes and good outcome.8,13,14 We have studied the prognostic value of VH mutational status in 145 CLL patients. Although Binet’s classification still maintains an independent prognostic significance, our results confirm a pivotal role for VH mutational profile in predicting CLL prognosis, by clearly segregating patients within all stages.
Patients Peripheral-blood samples were collected from 145 typical CLL patients from our institutions after informed consent was obtained. According to Binet’s staging system, they were distributed as follows: stage A, 87 patients (60%); stage B, 35 patients (24%), and stage C, 23 patients (16%). This distribution was similar to our historical series.3,15 Stage A patients were also subclassified as A' (< 30 x 109 lymphocytes/L and hemoglobin  120 g/L) or A'' (either 30 x 109 lymphocytes/L or hemoglobin 100 and < 120 g/L).6 Clinical follow-up ranged from 1 to 432 months for all patients and from 6 to 432 months for live patients (n = 109), with corresponding median periods of 62 and 51 months, respectively. Stage A patients remained untreated until disease progression was observed, whereas stage B and C or progressive stage A patients16 mainly received chlorambucil or fludarabine as first-line therapy. Chronically relapsing and resistant patients were generally treated with fludarabine-based regimens. Patients who died during follow-up were categorized by either CLL-related or -nonrelated causes.
VH Gene Analysis
Statistical Analysis
Heterogeneous Distribution of Binet’s Stages Within VH Mutational Groups Patients’ characteristics are listed, according to either Binet’s staging system (Table 1  ) or to VH mutational status (Table 2). Our series consisted of 62 patients with unmutated (UM) and 83 with mutated (MT) VH genes (43% and 57%, respectively). In contrast to a previous report from Tobin et al,19 our series displayed only two patients expressing the VH3–21 gene (one MT and the other UM). According to Binet’s classification, the UM cohort comprised 26 stage A, 22 stage B, and 14 stage C patients, whereas the MT group comprised 61 stage A, 13 stage B, and nine stage C patients. As observed, the MT group contained 70% of stage A patients, whereas the UM population represented 62% of stage B and C patients (P < .001). Moreover, the A' and A'' subgroups corresponded to 65 and 22 patients, respectively, with a similar distribution in the VH mutational status: 20 A' and six A'' patients (31% and 28%, respectively) belonged to the UM cohort.
Observation of Prognostic Differences Within All Binet’s Stages According to VH Genes Median OS was 84 months for UM patients and was not achieved for MT patients (70% 12-year survival; hazard ratio [HR], 0.4; 95% CI, 0.278 to 0.575; P < .0001; Fig 1A ). In stage A patients, both median OS and PFS were significantly shorter for UM patients when compared with those of MT patients: 97 months versus not achieved, respectively (HR, 0.45; 95% CI, 0.277 to 0.731; P = .0017) and 42 versus 156 months (HR, 0.47; 95% CI, 0.330 to 0.668; P < .0001; Fig 1B and 1C). When compared with classic A' and A'' substaging (Fig 1D), VH genes were advantageously discriminative in predicting prognosis.
Eleven UM stage A patients (42%) exhibited no disease progression, although nine of these 11 patients were observed only for a short follow-up period (< 3 years), and the two other patients were observed for 71 and 96 months, respectively. In contrast, 40 MT stage A patients (66%) remained stable during a median follow-up of 99 months. Progression was observed for 21 MT stage A patients: eight before 4 years, seven between 4 and 8 years, and six after 8 years of follow-up. In contrast, 12 of 15 progressive UM stage A patients progressed before 4 years, whereas two patients progressed between 4 and 8 years and only one progressed after 8 years from diagnosis. Moreover, we noted six (10%) and eight (33%) CLL-related deaths among MT and UM stage A cases, respectively. In both groups, all deaths were preceded by disease progression.
VH genes also segregated stage B and C patients (Fig 2A
Improvement of Binet’s Staging by Inclusion of Mutational Profiles of VH Genes According to the VH mutational profile, Binet’s staging can be stratified into four prognostic groups (Fig 2D  ). The first group includes MT stage A patients (42%), with a 12-year survival of 75% and a median PFS of 156 months. The second group comprises MT stage B and C patients (15%), with a median OS of 120 months. The third group consists of UM stage A patients (18%), with a median OS of 97 months and median PFS of 42 months. Finally, the worst prognostic group contains UM stage B and C patients (25%), with a median OS of 79 months. In addition, we compared different mutational cutoffs (98% v 97% and 98 v 95%) for VH genes. In our study, 98% remained the most discriminative cutoff (data not shown).
Binet’s stage A corresponds to a good prognostic group, comprising almost 65% of CLL patient cases. During the course of the disease, 25% died from CLL-related causes, 40% progress to stages B and C, and 50% ultimately require treatment.3 In addition, a small subset of stage B and C patients display an indolent disease course. Thus, early recognition of aggressive stage A and indolent stage B and C disease should provide better rationale for treatment strategies. The mutational profile of VH genes, as well as genomic aberrations and CD38 expression, independently predict disease outcome.8,10–13 Because VH and cytogenetic analysis have been considered cumbersome, serum levels of thymidine kinase,20 CD38 cellular expression,8 and, more recently, zeta-chain–associated protein 7021 have been proposed as surrogate markers of VH genes’ mutational status. However, the VH mutational profile remains constant during disease course, which contrasts with CD38 expression, genomic aberrations, and serum markers. In addition, 11q23 or 17p13 deletions are associated with poor outcome9–11 and with a UM VH profile. These deletions have been found in approximately one third of UM patients,11 but their occurrence as a second oncogenic event cannot be ruled out. In addition, advances in sequencing techniques permit complete VH analysis within reasonable time and at reasonable cost, allowing its extension to routine practice. Our results confirm the strong prognostic value of the VH mutational profile, which delineates prognostic groups within all Binet’s stages. Because MT and UM groups display different prognosis when comparing stage A with stage B and stage C cases, both Binet’s staging and VH genes retain their independent prognostic significance in CLL. Indeed, they are most likely complementary. The association of Binet’s stage A with the VH MT profile isolates a group accounting for more than 40% of CLL patients, with very good prognosis (< 10% of CLL-related deaths) and long PFS. For these patients, a watch-and-wait approach is justified. Given the possibility of a second oncogenic event, it is unclear whether early identification of the small group of stage A MT patients who will display disease progression during disease course is possible. However, wide recognition of UM VH patients among Binet’s stage A (or Rai’s indolent forms) should provide a means of testing the putative benefits for early treatment, in the frame of prospective randomized trials. In addition, our results suggest that when either VH sequencing techniques or an adequate surrogate becomes routinely available, the A' and A'' substaging could be discontinued. Finally, the prognostic differences observed among stage B and C patients according to VH mutational status raise the question of whether therapy could be tailored for these patients—a question that should also be tested in prospective clinical studies.
The authors indicated no potential conflicts of interest.
Supported in part by a fellowship from the Brazilian government agency CAPES (Y.V.).
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
