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Journal of Clinical Oncology, Vol 24, No 19 (July 1), 2006: pp. 3218-3219 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.1077
Cytogenetic Abnormalities Can Change During the Course of the Disease Process in Chronic Lymphocytic LeukemiaMayo Clinic College of Medicine, Rochester, MN To the Editor: We read with interest the article by Krober et al1 evaluating cytogenetic abnormalities and immunoglobulin variable region heavy chain (IgVH) family usage in chronic lymphocytic leukemia (CLL) patients with discordant results on IgVH gene mutation and zeta-associated protein 70 (ZAP-70) analysis. Their findings suggest unfavorable IgVH gene usage (VH 3-21) among mutated CLL B-cell clones explains ZAP-70 positive/IgVH mutated cases and unfavorable cytogenetic findings (17p–; 11q–) cluster among ZAP-70 negative/IgVH unmutated cases. The reproducibility of this observation is important since it suggests the combination of fluorescence in situ hybridization (FISH) and IgVH analysis or FISH and ZAP-70 analysis may be sufficiently precise to identify most CLL patients with high risk of disease progression.
We attempted to confirm these findings in an independent sample of 234 patients seen at Mayo Clinic who had FISH, IgVH gene mutation status (65% IgVH mutated; using
Unlike IgVH gene mutation status, cytogenetic abnormalities can change during course of the CLL disease process. In a prospective study of the chromosomal defects of malignant cells in 160 previously untreated patients with CLL, we found approximately 25% of patients acquired a new cytogenetic abnormality (clonal evolution) on repeat FISH analysis performed more than 5 years after baseline testing.4 The cytogenetic abnormality acquired during follow-up in these patients was frequently 17p– or 11q–. It is notable that in Krober's series, 36 (90%) of 40 patients with 17p– or 11q– had unmutated IgVH genes. The overall frequency of having 17p– or 11q– among IgVH mutated patients in our series was 9.8% compared with 24.4% in IgVH unmutated patients (P < .01). When considered with our findings on clonal evolution,4 the results of these two series suggest CLL patients with unmutated IgVH genes may have greater chromosomal instability and be at higher risk for acquiring unfavorable chromosomal defects such as 17p– or 11q– during the course of their disease. This possibility has important biologic, prognostic, and therapeutic implications5,6 and should be explored in future studies. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Krober A, Bloehdorn J, Hafner S, et al: Additional genetic high-risk features such as 11q deletion, 17p deletion, and V3-21 usage characterize discordance of ZAP-70 and VH mutation status in chronic lymphocytic leukemia. J Clin Oncol 24:969-975, 2006 2. 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 3. Orchard JA, Best OG, Ibbotson RE, et al: ZAP-70 by flow cytometry: Comparison of methodologies, and with IgVH mutation and ZAP-70 methylation status. Blood 106, 2005 (abstr 1181) 4. Shanafelt TD, Fink S, Witzig T, et al: Frequency of clonal evolution by FISH in untreated, early stage patients with CLL: A prospective longitudinal study with long clinical follow-up. Blood 106, 2005 (abstr 2098) 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. Byrd JC, Gribben JG, Peterson BL, et al: Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: Justification for risk-adapted therapy. J Clin Oncol 24:437-443, 2006
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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2% cutoff), and ZAP-70 analysis (69% ZAP-70 negative,using 
20% cut off) available. In our series, ZAP-70 and mutation status were concordant in 71% of patients when ZAP-70 was assessed using the Rassenti method.
