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Journal of Clinical Oncology, Vol 26, No 14 (May 10), 2008: pp. 2411-2412 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.3782
Hillmen Trial of Alemtuzumab in First-Line Chronic Lymphocytic Leukemia Still Provides Valuable InformationClinical Research, Genzyme Corporation, Cambridge, MA
Oncology Medical Affairs, Genzyme Corporation, Cambridge, MA To the Editor: In their editorial accompanying the report by Hillmen et al1 of the first-line chronic lymphocytic leukemia (CLL) randomized trial (CAM307) of alemtuzumab (Campath; Genzyme Corporation, Cambridge, MA) versus chlorambucil, Drs Flynn and Byrd make some constructive recommendations regarding design of future phase III registration trials in CLL.2 They make some points about this particular study regarding the design, the patient population, and the progression-free and overall survival, however, to which it is important to add additional perspectives. First, we would like to comment on study design, specifically the choice of chlorambucil as the comparator and the decision to study single agent rather than combination therapy. Although it is true that data demonstrating superiority of fludarabine to chlorambucil was published shortly before the initiation of CAM307,3 fludarabine has never been approved in the United States for initial treatment of CLL either as a single agent or in combination therapy. Until the recent US Food and Drug Administration approval of alemtuzumab as a single agent for B-cell CLL based on the first-line CAM307 trial, chlorambucil remained the only agent approved broadly as therapy to treat patients with CLL. Our research indicates that 30% to 40% of community oncologists in the United States use single agents for initial therapy of CLL, and that chlorambucil accounts for the greatest proportion of that use (Genzyme Corp, data on file). The rates of single agent and specifically, chlorambucil, use are even higher in Europe. According to 2007 National Comprehensive Cancer Network guidelines, chlorambucil remains an acceptable standard of care as a first-line therapy for CLL. In addition, to demonstrate the superior efficacy of alemtuzumab compared with chlorambucil, CAM307 provided important data regarding the predictable and manageable adverse effect profile of alemtuzumab when used in previously untreated patients. Recognizing the trend toward combination therapy, Genzyme has also sponsored a second phase III trial comparing fludarabine plus alemtuzumab with fludarabine alone in patients with CLL in first relapse (CAM314), which is nearing completion of enrollment. This study will provide valuable information on the efficacy and safety of this combination of the two most active agents in CLL. CAM307 is the first randomized, phase III trial completed by a pharmaceutical sponsor of any therapy in CLL, and CAM314 will be our second. Genzyme, therefore, is not only one of few sponsors that have fulfilled postapproval commitments on time in such a rare disease population, but is also performing another phase III trial in the interest of moving the field of CLL therapy forward.
Second, we would like to address the patient population enrolled in the study. Flynn and Byrd2 describe the intended CAM307 patients as having "good performance and nonbulky lymph nodes." As described in the report by Hillmen et al,1 22.1% and 23% had adenopathy greater than or equal to 5 cm in the alemtuzumab and chlorambucil arms, respectively. Furthermore, CAM307 demonstrated significant activity in patients with bulky nodes, as evidenced by an overall response rate in patients with lymph nodes Third, we would like to discuss the "disappointing" median progression-free survival (PFS) in both arms of the study. We believe that it is important to focus on the difference between the alemtuzumab and the chlorambucil control arm, as factors such as differences in study population and conduct of the study (eg, use of an independent response review panel and more frequent measurements in CAM307) can lead to systematic differences across studies, which is one of the main reasons that randomized studies are the gold standard for establishing efficacy. We also believe that it is important to look at the entire Kaplan-Meier curve, rather than a single descriptive measure such as the median. It is useful to summarize PFS with a measure, such as the hazard ratio, which utilizes all of the survival information, as described in the report by Hillmen et al.1 Unfortunately the hazard ratio for PFS has not been commonly reported in other studies in this disease. An alternative method is to compare the estimated PFS rates across multiple time points, as these can be derived from the Kaplan-Meier curves commonly presented. Table 1 compares the estimated PFS at 12, 18, and 24 months for both alemtuzumab and fludarabine to chlorambucil (based on the data from Hillmen1 and Rai, 3 respectively). The relative difference between the comparator and chlorambucil in Table 1 is calculated as the ratio of PFS for chlorambucil to the PFS for alemtuzumab or fludarabine, respectively. Smaller differences indicate a greater improvement in PFS relative to chlorambucil. At both 18 and 24 months, the relative efficacy compared with chlorambucil is greater with alemtuzumab than with fludarabine.
Finally, with respect to overall survival, no randomized trials of first-line therapy for CLL have demonstrated an overall survival benefit, even with up to 5 years of follow-up. We note that the trial was not designed or powered to determine an effect on survival. If you assume optimistically that the improvement in survival should be similar to that assumed for PFS (hazard ratio of 0.67), you would need to continue the study until 190 deaths were observed to have 80% power. Subsequent therapies may also have the impact of diluting the treatment effect on survival. For example, if you assume that alemtuzumab improved survival by 20%, it would require a total of 631 deaths (more than twice as many randomly assigned in the Hillmen et al study). In fact, even if the Hillmen et al study were followed until all of the patients died (which would be expected to take over a decade), the power to see a 20% improvement in survival would be approximately 33%. Therefore, we believe that the high number of events needed, along with the confounding nature of subsequent therapies and their possible impact on an assumed treatment effect, would make it unlikely that this trial alone would provide definitive data. We do acknowledge that such follow-up could possibly help provide information more broadly in CLL if it could be combined with other trials. With regard to confirmatory trials, we agree that cooperative groups represent an excellent place for such trials to be designed and executed. However, a number of challenges still exist in assuring the extensive coordination required between industry sponsors, cooperative groups, and the US Food and Drug Administration in assuring such trials can be designed and initiated in a timely manner, particularly with respect to concurrent protocol review. We look forward to the opportunity to engage in dialogue that moves this process forward. In conclusion, it is our opinion that the CAM307 study has moved the field of CLL forward by providing important efficacy and safety data demonstrating that alemtuzumab is one of the most active agents in treatment of CLL. This study supports the use of single-agent alemtuzumab as an important alternative therapeutic option in patients with CLL, and provides the rationale for further investigation of this alemtuzumab in combination and consolidation strategies in this disease. 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: Cynthia Sirard, Genzyme Corporation (C); Elizabeth G. Trehu, Genzyme Corporation (C) Consultant or Advisory Role: None Stock Ownership: Cynthia Sirard, Genzyme Corporation; Elizabeth G. Trehu, Genzyme Corporation Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None
REFERENCES
1. Hillmen P, Skotnicki AB, Robak T, et al: Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 25:5616-5623, 2007 2. Flynn JM, Byrd J: Have we forgotten the purpose of phase III studies? J Clin Oncol 25:5553-5555, 2007 3. Rai KR, Peterson BL, Appelbaum FR, et al: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750-1757, 2000 Related Reply
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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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5 cm of 76% in alemtuzumab treated patients versus 44% in chlorambucil-treated patients (P = .0125). 
