Allogeneic Stem-Cell Transplantation May Overcome the Adverse Prognosis of Unmutated VH Gene in Patients With Chronic Lymphocytic Leukemia
http://www.100md.com
《临床肿瘤学》
the Department of Hematology and the Hematopathology Unit, Institute of Hematology and Oncology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer
Department of Hematology, Hospital de Sant Pau, Barcelona, Spain
ABSTRACT
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.
INTRODUCTION
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.
PATIENTS AND METHODS
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
High molecular weight DNA was extracted from mononuclear cells according to standard procedures. The VH gene family used by each clonal CLL population was determined by polymerase chain reaction (PCR), as previously described.11
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
Comparison between the two groups was performed by the corrected 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)12 and compared by the Gray method,13 considering death in complete response (CR) and relapse as competing events for each variable, respectively.
RESULTS
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
As shown in Table 2, 21 of 23 allo-SCT patients achieved a CR and two died as a result of NRM before day +100. In auto-SCT, 24 of 27 achieved CR, whereas PR was achieved in the remaining three patients. During the follow-up, four allo-SCT patients died: two as a result of late NRM (overall NRM, 17%) and two as a result of relapse. Sixteen patients in the auto-SCT group died: 12 as a result of relapse, two as a result of late NRM, and two as a result of other causes (Epstein-Barr virus-positive Hodgkin's disease, and liver cirrhosis, respectively). No differences in response rate and NRM after SCT were observed according to the VH mutational status. Chronic graft-versus-host disease was seen in 11 (52%; five limited and six extensive) of the 21 allo-SCT patients at risk.
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).
DISCUSSION
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.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
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 Jose Carreras International Leukemia Foundation grant Nos. EM-04; CR-04. C.M. is a recipient of a grant from the Fundación Espaola 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.
REFERENCES
Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333:1052-1057, 1995
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
Hamblin TJ, Davis Z, Gardiner A, et al: Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94:1848-1854, 1999
Wendtner CM, Eichhorst BB, Hallek MM: Advances in chemotherapy for chronic lymphocytic leukemia. Semin Hematol 41:224-233, 2004
Ritgen M, Lange A, Stilgenbauer S, et al: Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia. Blood 101:2049-2053, 2003
Dreger P, Stilgenbauer S, Benner A, et al: The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: A risk-matched analysis based on the VH gene mutational status. Blood 103:2850-2858, 2004
Ritgen M, Stilgenbauer S, von Neuhoff N, et al: Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy chain gene status: Implications of minimal residual disease measurement with quantitative PCR. Blood 104:2600-2602, 2004
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
Esteve J, Villamor N, Colomer D, et al: Stem cell transplantation for chronic lymphocytic leukemia: Different outcome after autologous and allogeneic transplantation and correlation with minimal residual disease status. Leukemia 15:445-451, 2001
Esteve J, Villamor N, Colomer D, et al: Different clinical value of minimal residual disease after autologous and allogenic stem cell transplantation for chronic lymphocytic leukemia. Blood 99:1873-1874, 2002
van Dongen JJ, Langerak AW, Bruggemann M, et al: Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 17:2257-2317, 2003
Pepe MS, Mori M: Kaplan-Meier, marginal or conditional probability curves in summarizing competing risks failure time data Stat Med 12:737-751, 1993
Gray RJ: A class of K-sample test for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988
Shanafelt TD, Geyer SM, Kay NE: Prognosis at diagnosis: Integrating molecular biologic insights into clinical practice for patients with CLL. Blood 103:1202-1210, 2004
Montserrat E: Classical and new prognostic factors in chronic lymphocytic leukemia: Where to now Hematol J 3:7-9, 2002
Dreger P, Van Biezen A, Brand R, et al: Prognostic factors for survival after autologous stem cell transplantation for chronic lymphocytic leukemia (CLL): The EBMT experience. Blood 96:482a, 2000 (abstr 2071)
Montserrat E: Role of auto- and allotransplantation in B-cell chronic lymphocytic leukemia. Hematol Oncol Clin North Am 18:915-926, 2004
Jabbour E, Keating MJ, Champlin RE, et al: Stem cell transplantation for chronic lymphocytic leukemia: Should not more patients get a transplant Bone Marrow Transplant 34:289-297, 2004
Pavletic ZS, Bierman PJ, Vose JM, et al: High incidence of relapse after autologous stem-cell transplantation for B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. Ann Oncol 9:1023-1026, 1998
Mattsson J, Uzunel M, Remberger M, et al: Minimal residual disease is common after allogeneic stem cell transplantation in patients with B cell chronic lymphocytic leukemia and may be controlled by graft-versus-host disease. Leukemia 14:247-254, 2000
Schetelig J, Thiede C, Bornhauser M, et al: Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: The Cooperative German Transplant Study Group. J Clin Oncol 21:2747-2753, 2003
Dreger P, Brand R, Hansz J, et al: Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning. Leukemia 17:841-848, 2003
Khouri IF, Keating MJ, Saliba RM, et al: Long-term follow-up of patients with CLL treated with allogeneic hematopoietic transplantation. Cytotherapy 4:217-221, 2002
Horowitz MM, Montserrat E, Sobocinski K, et al: Hematopoietic stem cell transplantation for chronic lymphocytic leukemia. Blood 96:522a, 2000 (abstr 2245)
Michallet M, Brand R, Dreger P, et al: Analysis of prognostic factors on the outcome of autologous and allogeneic stem cell transplantation (SCT) for chronic lymphocytic leukemia (CLL). Blood 98:859a, 2001 (abstr 3568)
Esteve J, Montserrat E, Dreger P, et al: Stem cell transplantation (SCT) for chronic lymphocytic leukemia (CLL): Outcome and prognostic factors after autologous and allogeneic transplants. Blood 98::482a, 2001 (abstr 2013)
Stilgenbauer S, Ritgen M, Bullinger L, et al: Genomic aberrations in the CLL3 trial of the German CLL Study Group: Deletion 11q23 identifies patients with molecular disease persistence after autologous high-dose therapy. Blood 98::763a-764a, 2001 (abstr 3180)
Krober A, Seiler T, Benner A, et al: V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 100:1410-1416, 2002(Carol Moreno, Neus Villam)
Department of Hematology, Hospital de Sant Pau, Barcelona, Spain
ABSTRACT
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.
INTRODUCTION
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.
PATIENTS AND METHODS
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
High molecular weight DNA was extracted from mononuclear cells according to standard procedures. The VH gene family used by each clonal CLL population was determined by polymerase chain reaction (PCR), as previously described.11
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
Comparison between the two groups was performed by the corrected 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)12 and compared by the Gray method,13 considering death in complete response (CR) and relapse as competing events for each variable, respectively.
RESULTS
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
As shown in Table 2, 21 of 23 allo-SCT patients achieved a CR and two died as a result of NRM before day +100. In auto-SCT, 24 of 27 achieved CR, whereas PR was achieved in the remaining three patients. During the follow-up, four allo-SCT patients died: two as a result of late NRM (overall NRM, 17%) and two as a result of relapse. Sixteen patients in the auto-SCT group died: 12 as a result of relapse, two as a result of late NRM, and two as a result of other causes (Epstein-Barr virus-positive Hodgkin's disease, and liver cirrhosis, respectively). No differences in response rate and NRM after SCT were observed according to the VH mutational status. Chronic graft-versus-host disease was seen in 11 (52%; five limited and six extensive) of the 21 allo-SCT patients at risk.
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).
DISCUSSION
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.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
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 Jose Carreras International Leukemia Foundation grant Nos. EM-04; CR-04. C.M. is a recipient of a grant from the Fundación Espaola 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.
REFERENCES
Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333:1052-1057, 1995
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
Hamblin TJ, Davis Z, Gardiner A, et al: Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94:1848-1854, 1999
Wendtner CM, Eichhorst BB, Hallek MM: Advances in chemotherapy for chronic lymphocytic leukemia. Semin Hematol 41:224-233, 2004
Ritgen M, Lange A, Stilgenbauer S, et al: Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia. Blood 101:2049-2053, 2003
Dreger P, Stilgenbauer S, Benner A, et al: The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: A risk-matched analysis based on the VH gene mutational status. Blood 103:2850-2858, 2004
Ritgen M, Stilgenbauer S, von Neuhoff N, et al: Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy chain gene status: Implications of minimal residual disease measurement with quantitative PCR. Blood 104:2600-2602, 2004
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
Esteve J, Villamor N, Colomer D, et al: Stem cell transplantation for chronic lymphocytic leukemia: Different outcome after autologous and allogeneic transplantation and correlation with minimal residual disease status. Leukemia 15:445-451, 2001
Esteve J, Villamor N, Colomer D, et al: Different clinical value of minimal residual disease after autologous and allogenic stem cell transplantation for chronic lymphocytic leukemia. Blood 99:1873-1874, 2002
van Dongen JJ, Langerak AW, Bruggemann M, et al: Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 17:2257-2317, 2003
Pepe MS, Mori M: Kaplan-Meier, marginal or conditional probability curves in summarizing competing risks failure time data Stat Med 12:737-751, 1993
Gray RJ: A class of K-sample test for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988
Shanafelt TD, Geyer SM, Kay NE: Prognosis at diagnosis: Integrating molecular biologic insights into clinical practice for patients with CLL. Blood 103:1202-1210, 2004
Montserrat E: Classical and new prognostic factors in chronic lymphocytic leukemia: Where to now Hematol J 3:7-9, 2002
Dreger P, Van Biezen A, Brand R, et al: Prognostic factors for survival after autologous stem cell transplantation for chronic lymphocytic leukemia (CLL): The EBMT experience. Blood 96:482a, 2000 (abstr 2071)
Montserrat E: Role of auto- and allotransplantation in B-cell chronic lymphocytic leukemia. Hematol Oncol Clin North Am 18:915-926, 2004
Jabbour E, Keating MJ, Champlin RE, et al: Stem cell transplantation for chronic lymphocytic leukemia: Should not more patients get a transplant Bone Marrow Transplant 34:289-297, 2004
Pavletic ZS, Bierman PJ, Vose JM, et al: High incidence of relapse after autologous stem-cell transplantation for B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. Ann Oncol 9:1023-1026, 1998
Mattsson J, Uzunel M, Remberger M, et al: Minimal residual disease is common after allogeneic stem cell transplantation in patients with B cell chronic lymphocytic leukemia and may be controlled by graft-versus-host disease. Leukemia 14:247-254, 2000
Schetelig J, Thiede C, Bornhauser M, et al: Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: The Cooperative German Transplant Study Group. J Clin Oncol 21:2747-2753, 2003
Dreger P, Brand R, Hansz J, et al: Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning. Leukemia 17:841-848, 2003
Khouri IF, Keating MJ, Saliba RM, et al: Long-term follow-up of patients with CLL treated with allogeneic hematopoietic transplantation. Cytotherapy 4:217-221, 2002
Horowitz MM, Montserrat E, Sobocinski K, et al: Hematopoietic stem cell transplantation for chronic lymphocytic leukemia. Blood 96:522a, 2000 (abstr 2245)
Michallet M, Brand R, Dreger P, et al: Analysis of prognostic factors on the outcome of autologous and allogeneic stem cell transplantation (SCT) for chronic lymphocytic leukemia (CLL). Blood 98:859a, 2001 (abstr 3568)
Esteve J, Montserrat E, Dreger P, et al: Stem cell transplantation (SCT) for chronic lymphocytic leukemia (CLL): Outcome and prognostic factors after autologous and allogeneic transplants. Blood 98::482a, 2001 (abstr 2013)
Stilgenbauer S, Ritgen M, Bullinger L, et al: Genomic aberrations in the CLL3 trial of the German CLL Study Group: Deletion 11q23 identifies patients with molecular disease persistence after autologous high-dose therapy. Blood 98::763a-764a, 2001 (abstr 3180)
Krober A, Seiler T, Benner A, et al: V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 100:1410-1416, 2002(Carol Moreno, Neus Villam)