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Originally published as JCO Early Release 10.1200/JCO.2007.15.8584 on November 10 2008 © 2008 American Society of Clinical Oncology.
In Reply
Leeds Teaching Hospitals National Health Service Trust, St James Institute of Oncology, Leeds, United Kingdom Unfortunately, the correspondence of Oberoi and Jawde reveals some confusion in the interpretation of the 1996 National Cancer Institute (NCI) criteria for chronic lymphocytic leukemia (CLL)1 and of the literature. First, the observation that only one third of patients in the CAM307 trial had cytopenia (Rai stage III or IV) indicates that this study is similar to other recently published frontline studies, such as the Leukemia Research Fund CLL4 trial,2 in which only 30% of patients were Binet stage C; and the German CLL4 trial,3 in which 40% of patients were Rai stage III or IV. Second, computed tomography (CT) scans are not required for staging of patients or for the assessment of response, according to the NCI criteria. Therefore, to suggest that CT scans should be used to assess the time to progression is not appropriate. This is because CLL is largely a disease affecting the blood and bone marrow, and when there is nodal disease it is usually palpable. There is no evidence that regular CT scans have a major impact on the assessment of the time to progression. Such an approach would also be associated with numerous CT scans, which carries a potential risk to the patient and certainly has resource implications. Also, the analysis of the bone marrow has no significance for staging patients with CLL, and the pattern of infiltration by CLL in the marrow is of no prognostic importance. Thus, the statement, "this can lead to understaging of the patients involved in the study and potentially overestimating of the reported benefits of treatment" is inaccurate and misleading. While Oberoi and Jawde are correct to state that the comparison of responses between trials is not entirely valid, it is a fact that the complete remission (CR) rate for alemtuzumab in our trial (24% by Independent Review Panel, and 30% by the investigator) is higher than the fludarabine monotherapy CR rate in other large trials (LRF CLL4 fludarabine arm, investigators assessment, CR = 15%; and German CLL Study Group CLL4 fludarabine arm, investigators assessment, CR = 6.7%). In addition, the eradication of minimal residual disease is not reported with fludarabine monotherapy, but was seen in 7.4% of patients treated with alemtuzumab. The combination of fludarabine plus rituximab is not a fair comparator as it cannot be considered monotherapy. Oberoi and Jawde have failed to appreciate the principle advantages of alemtuzumab over fludarabine-based treatment, which may indicate where the role of the drug will lie earlier in the patient's treatment. First, the mechanism of alemtuzumab is p53-independent and because p53 deletion and/or mutation is the most common mechanism of resistance in CLL, this is an important feature. Second, alemtuzumab can eradicate detectable minimal residual disease, and this is associated with prolonged remission and improved survival. Therefore, in our opinion, the comparison of alemtuzumab monotherapy to fludarabine alone (proven to be less effective than fludarabine plus cyclophosphamide combination therapy) or to fludarabine plus rituximab (a therapy for which there is no randomized, controlled data to support its use) is inappropriate. Our study in fact demonstrates that alemtuzumab is relatively safe compared with chlorambucil, and we believe that alemtuzumab should be used in a much more intelligent manner than simply as a comparison with another nonstandard therapy. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Peter Hillmen, Bayer Healthcare Research Funding: Peter Hillmen, Genzyme, Bayer Healthcare Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on November 10, 2008. REFERENCES
1. 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 2. Catovsky D, Richards S, Matutes E, et al: Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): A randomised controlled trial. Lancet 370:230-239, 2007[CrossRef][Medline] 3. Eichhorst BF, Busch R, Hopfinger G, et al: Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 107:885-891, 2006
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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