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Journal of Clinical Oncology, Vol 23, No 31 (November 1), 2005: pp. 8126-8127 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.1690
Chronic Lymphocytic Leukemia: To Transplant or Not to Transplant... That Is the Question?Oncology Specialists, S.C.; Lutheran General Hospital Cancer Center, Division of Hematology and Oncology, Park Ridge, IL To the Editor: Since 1999, there have been a number of publications on the biologic aspects of chronic lymphocytic leukemia (CLL) and various prognostic factors that influence survival. The challenge that hematologists face lies in trying to integrate this information in the management of patients with CLL. Genomic aberrations, mutational status of the immunoglobulin variable heavy chain gene (IgVH), CD 38 expression, and overexpression of a tyrosine kinase, ZAP-70, have all been reported to be potential prognostic markers that may identify a subset of patients whose disease course is likely to be aggressive and potentially fatal.1-3 CLL patients with poor prognosis usually have the unmutated IgVH, chromosomal abnormalities such as 17p or 11q, and overexpress ZAP-70 and CD 38.4,5 The question is what is the best therapeutic strategy for such patients. In their recent article, Moreno et al6 propose that high-dose chemotherapy with allogeneic stem-cell transplant (alloSCT) may overcome the unfavorable effect of unmutated IgVH in patients with CLL. The authors analyzed retrospectively the outcome of autologous stem-cell transplant (auto-SCT) or alloSCT in patients with CLL who underwent such a procedure due to unfavorable prognostic factors. IgVH sequencing data were available on these patients, allowing for analysis of the impact of IgVH mutational status on SCT outcome. Moreno et al report that patients with unmutated IgVH who underwent auto-SCT progressed more often than those who had alloSCT; however the event-free survival (EFS) did not reach statistical significance (P = .06). In contrast, patients with mutated IgVH who presumably have a better prognosis and underwent alloSCT had statistically significant longer EFS than those who underwent auto-SCT (P = .0008). Overall survival was also better with alloSCT as opposed to auto-SCT in this subgroup of patients (P = .01). We believe that based on the data presented, their conclusion needs to be challenged. First, their conclusion that alloSCT overcomes the unfavorable effect of unmutated IgVH, is not necessarily supported by their own data. While there may be a trend toward better EFS, it has not reached statistical significance. Secondly, their data show that patients with mutated IgVH (who usually have a favorable outcome) fare better when undergoing alloSCT than auto-SCT. The fact that patients with favorable prognosis did better with alloSCT as opposed to auto-SCT may have been expected as graft versus leukemia effect could have a favorable impact on CLL patients.7 It is plausible that subjecting patients who have favorable prognosis to an aggressive regimen could enhance their outcome provided that treatment-related mortality is low. On the other hand, the lack of statistically significant EFS difference between allo and auto-SCT in patients with unmutated CLL could be interpreted in different ways. First, the small sample size precluded detecting a 30% to 40% difference. Second, there are now data showing that the status of IgVH may not accurately predict prognosis. Rassenti et al8 reported recently that ZAP-70 positive status is more accurate than IgVH. The discordance between ZAP-70 positivity and unmutated IgVH may be as high as 20% to 25%. Patients with more than 20% cells overexpressing ZAP-70 carry poor prognosis regardless of the mutational status of IgVH. This speaks in favor of choosing the correct surrogate marker in studying novel approaches in CLL. Once verified in additional studies, ZAP-70 may be a better prognostic marker than IgVH. Finally, Moreno et al should present any available data on minimal residual disease (MRD) detection in the patients they studied. Recent reports suggested that patients with negative MRD status have statistically significant longer overall survival compared with those with MRD positivity.9 The question is whether SCT adds any further advantage to patients who have already achieved MRD negative status. We believe that the data on MRD status are readily available on the patients reported by Moreno et al, since the same investigators reported on part of this data previously.10 Knowing whether patients with mutated or unmutated IgVH benefited from SCT based on MRD might give further insight into the benefit of auto or alloSCT in both patient populations. In addition, the induction chemotherapy may heavily influence the attainment of MRD negativity and should have been presented. We now realize that CLL is a heterogeneous disease with many variables that affect prognosis and could change our therapeutic strategy. Ideally, we need to identify the subset of patients who have adverse prognostic features and explore whether novel approaches with or without SCT could alter their outcome. We would advocate high-dose therapy with SCT only in patients who have detectable MRD by sensitive assays as long as they are young, fit, and able to tolerate the procedure. Patients with negative MRD status may be observed or enrolled on studies exploring maintenance programs. The data provided by Moreno et al suggest that alloSCT is more advantageous than auto-SCT in CLL, possibly due to graft versus leukemia effect. This retrospective analysis show that alloSCT leads to the best outcome in the subgroup of patients with good risk profile CLL, contradicting their conclusions and leaving the debate open as to why this aggressive strategy did not translate into improved outcome in the high-risk patients. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Damle RN, Wasil T, Fais F, et al: Ig V gene mutation status and CD 38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840-1847, 1999
2. 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
3. Chiorazzi N, Rai KR, Ferrarini M: Chronic lymphocytic leukemia. N Engl J Med 352:804-815, 2005
4. Dohner H, Stilgenbauer S, Benner A, et al: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910-1916, 2000
5. 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
6. Moreno C, Villamor N, Colomer D, et al: Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol 23:3433-3438, 2005
7. 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
8. Rassenti LZ, Huynh L, Toy TL, et al: ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 351:893-901, 2004
9. 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 10. 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[CrossRef][Medline]
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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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