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Originally published as JCO Early Release 10.1200/JCO.2005.04.531 on April 4 2005 © 2005 American Society of Clinical Oncology. Allogeneic Stem-Cell Transplantation May Overcome the Adverse Prognosis of Unmutated VH Gene in Patients With Chronic Lymphocytic LeukemiaFrom the Department of Hematology and the Hematopathology Unit, Institute of Hematology and Oncology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer; and Department of Hematology, Hospital de Sant Pau, 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: To investigate whether allogeneic stem-cell transplantation (allo-SCT) may overcome the negative impact of unmutated VH genes in the outcome of patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: We analyzed the outcome of patients who underwent SCT according to their VH mutational status. RESULTS: Thirty-four patients (14 allo-SCT and 20 autologous SCT [auto-SCT]) presented unmutated VH genes and 16 patients presented mutated VH genes (nine allo-SCT and seven auto-SCT). Tumoral burden pre-SCT was significantly higher in the allo-SCT patients independent of the VH mutational status. The risk of relapse was significantly higher after auto-SCT (5-year risk, 61%; 95% CI, 44% to 84%) than after allo-SCT (5-year risk 12%, 95% CI, 3% to 44%; P < .05). In the unmutated group, 13 of 20 auto-SCT and two of 14 allo-SCT patients experienced disease progression, with a risk of relapse at 5 years of 66% (95% CI, 48% to 93%) v 17% (95% CI, 5% to 60%), respectively (P = .01). CONCLUSION: These results show that allo-SCT may overcome the unfavorable effect of unmutated VH genes in patients with CLL.
Chronic lymphocytic leukemia (CLL) has a variable clinical course.1 The mutational status of the variable region of the immunoglobulin heavy chain gene (VH) identifies two clinical forms of CLL. Whereas patients with mutated VH genes (mutated CLL) tend to have indolent disease and may not require therapy for long periods of time, those with unmutated VH genes (unmutated CLL) have progressive disease and a shorter survival.2,3 CLL remains incurable with standard treatments.4 Because of this, stem-cell transplantation (SCT) is increasingly being considered in patients with CLL and poor prognosis. A recent study has shown that patients with unmutated CLL who have undergone auto-SCT have a poor outcome,5 although these patients may still have longer survival rates than those who are treated conventionally.6 Whether unmutated VH genes also confer poor prognosis in patients receiving allogeneic SCT (allo-SCT) is being investigated. Recently it has been suggested that nonmyeloablative allo-SCT could benefit patients with unmutated CLL.7 This article analyzes the outcome in a series of patients with CLL undergoing SCT according to their VH mutational status.
Patient Characteristics Fifty patients diagnosed with CLL with adverse prognostic factors (ie, advanced clinical stage, diffuse bone marrow infiltration, short doubling time, massive or progressive lymphadenopathy, poor-risk cytogenetics) who underwent SCT (27 auto-SCT, 23 allo-SCT) between 1986 and October 2002 in two institutions and who had available VH sequences were included. As a rule, auto-SCT was proposed for patients with a chemosensitive disease, whereas allo-SCT was performed mostly in young CLL patients who had not responded to therapy and for whom an HLA-identical sibling was available. The response was assessed according to National Cancer Institute criteria.8 Clinical results of some of the patients included in this study have been reported elsewhere.9,10 Informed consent was required from all patients in accordance with ethics committee guidelines from both participating institutions.
Sequence of Patient-Specific VH Segment Rearrangement and Mutational Status of VH Genes PCR products were purified using a rapid PCR purification system (Marligen, Biosciences, Ijamsville, MD) and directly sequenced (in both directions to avoid misreading errors) with the appropriate specific VH primer using the Big Dye Terminator Cycle Sequencing 1.1 and 3.1 (Applied Biosystems, Foster City, CA) in an automated DNA sequencer (ABI PRISM 3100; Applied Biosystems). The sequences obtained were aligned and compared with the published germ line VH gene segments using the IgBLAST database (http://www.ncbi.nlm.nih.gov/igblast). VH sequences showing a mismatch of more than 2% from the corresponding germline gene were defined as mutated.
Statistical Analysis
Patient Characteristics Fifty patients with CLL who underwent SCT have been analyzed according to the VH mutational status. Characteristics of the patients according to the type of SCT are listed in Table 1. There were no significant differences in the clinical characteristics of patients such as age, sex, and interval between diagnosis and transplantation. Furthermore, no differences in the known prognostic factors such as clinical stage, lymphocyte count, beta2-microglobulin level, degree of bone marrow infiltration, and cytogenetic alterations were observed. However, at the time of transplantation, patients undergoing allo-SCT had significantly higher tumoral burden (advanced clinical stage, and degree of peripheral blood and bone marrow involvement) compared with auto-SCT patients.
VH Mutational Status Thirty four patients (68%; 14 allo-SCT and 20 auto-SCT) had unmutated VH genes, whereas 16 patients (32%) had somatically hypermutated VH genes (nine allo-SCT and seven auto-SCT). The only significant difference between unmutated and mutated CLL was the higher prevalence of unfavorable cytogenetic features in the unmutated group (35% v 0%; P = .005). No differences in tumoral burden pre-SCT were observed between the two groups.
Response to Treatment
Disease Progression In the allo-SCT group, after a median follow-up of 62 months (range, 17 to 215 months), three patients had experienced disease relapse (at 37, 53, and 117 months, respectively). In the auto-SCT patients, after a median follow-up of 54 months (range, 11 to 101 months), 15 of the CR patients had experienced disease relapse and the three patients with PR had experienced disease progression with a median time to progression of 28 months (range, 5 to 112 months). Therefore, only five of 27 auto-SCT patients were alive and in CR at the last follow-up. Overall, the risk of relapse was significantly higher after auto-SCT (5-year risk of progression, 61%; 95% CI, 44% to 84%) than after allo-SCT (5-year risk of progression,12%; 95% CI, 3% to 44%; P < .05; Fig 1A). EFS was also significantly better for allo-SCT patients compared with auto-SCT patients (EFS at 5 years, 17% for auto-SCT patients and 71% with a plateau in allo-SCT; P = .0002; Fig 1B). Significantly longer survival was observed in patients after allo-SCT (P = .02; Fig 1C).
Patients With Unmutated CLL When considering patients with unmutated CLL, 13 of 20 auto-SCT patients experienced disease progression (5-year risk of progression, 66%; 95% CI, 47% to 93%), with a median time to progression of 28 months, compared with two of 14 patients undergoing allo-SCT (5-year risk of progression, 17%; 95% CI, 5% to 60%, P = .01; Fig 2A). Although the difference in EFS between the auto-SCT and allo-SCT groups did not achieve a significant level (median, 22 months v not reached; P = .06), a trend for a longer EFS with a plateau was observed after allo-SCT (Fig 2B). There was no difference in the OS of the two groups (P = .33), with median survival of 6 and 4 years after allo-SCT and auto-SCT, respectively (Fig 2C).
Patients With Mutated CLL In those with mutated CLL, clinical progression was observed in five of seven auto-SCT patients, with a median time of 20 months, compared with one of nine patients in the allo-SCT group (P = .0008; Fig 3A). EFS was significantly better in mutated CLL patients who underwent allo-SCT (not reached v 22 months; P = .0002; Fig 3B). Significantly longer survival was observed in patients after allo-SCT (median survival, not reached v 3 years after auto-SCT; P = .01; Fig 3C).
Prognostic factors in patients with CLL who are candidates to receive SCT warrant investigation, particularly in the light of new biologic prognostic factors.14,15 The outcome after auto-SCT is better in those patients who undergo transplantation early in the course of the disease, are not extensively pretreated, are without poor cytogenetic features [ie, del(11q)], and have achieved response before transplantation.16-19 Recently, it has been shown that the outcome of patients with unmutated CLL who undergo auto-SCT is poor,5 although according to a retrospective matched-pair analysis, survival might be improved in some of these patients.6 Conversely, there are data that support that a fraction of patients with allografted CLL can actually be cured—a fact most likely related to a graft-versus-CLL effect.9,20-22 Prognostic factors in patients with CLL who undergo allo-SCT have not been studied extensively, although patients' age, interval between diagnosis and transplantation, HLA-identical sibling donor, and the status of the disease before transplantation are important variables.17,23 Recently, it has been suggested that in patients with unmutated CLL, the graft-versus-leukemia effect after nonmyeloablative allo-SCT might be able to control the disease.7 In our series including 50 patients, 34 (68%) displayed unmutated VH genes, whereas 16 patients showed somatically hypermutated VH genes. No significant differences were observed between auto- and allo-SCT in most of the clinical characteristics of patients, including those that have been shown to have an impact on the outcome after SCT.23-27 However, patients who underwent allo-SCT had a significantly higher tumoral burden pre-SCT compared with patients who underwent auto-SCT, indicating that patients receiving allo-SCT had poorer pre-SCT factors than those who underwent auto-SCT. Regarding unmutated and mutated CLL, the higher prevalence of unfavorable cytogenetic features was the only significant difference between both groups, in agreement with the well-established relationship between VH mutational status and cytogenetic features.28 Our results showed no differences in the CR rate between type of transplantation and VH mutational status. Nevertheless, after a median follow-up of 5 years, auto-SCT results in a significantly higher relapse rate than allo-SCT in both VH mutational status groups. Focusing on the aim of this study, disease progression and EFS were analyzed in the auto- and allo-SCT groups according to the VH mutational status. Interestingly, our data show that in patients with unmutated CLL who receive an auto-SCT, the relapse rate is high, whereas in those who receive an allo-SCT, the relapse rate is significantly lower. These data suggest that the graft-versus-tumor effect may overcome the negative impact of unmutated VH gene in the outcome of patients with CLL. If confirmed in other series, this information would have an important clinical impact when transplantation modality is decided in patients with CLL.
The authors indicated no potential conflicts of interest.
Supported by grant No. 01/1581, Red de Genómica de Cáncer grant No. 03/10, and Red Estudio de Neoplasias linfoides grant No. 03/179, Instituto Nacional de Salud Carlos III-Ministerio de Sanidad from Fondo de Investigaciones Sanitarias (Spain) and the José Carreras International Leukemia Foundation grant Nos. EM-04; CR-04. C.M. is a recipient of a grant from the Fundación Española de Hematología y Hemoterapia. Presented at the 45th meeting of the American Society of Hematology, San Diego, CA, December 6–9, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. Time of relapse was estimated from the date of transplantation to morphologic or clinical relapse (complete responders) or clinical progression (patients achieving partial response [PR]), and the event-free survival (EFS) was calculated from the date of transplantation until relapse or death as a result of any cause. Overall survival (OS) and EFS curves were calculated by the Kaplan-Meier method and comparison between subgroups was performed using the log-rank test with SPSS software (version 10.0.6; SPSS Inc, Chicago, IL). The risk of relapse and nonrelapse mortality (NRM) were estimated by the cumulative incidence method (marginal probability)
