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In Reply

Division of Hematology-Oncology, The Ohio State University, Columbus, OH

In response to Drs Sirard and Trehu's letter, we provide the following comments. Since the publication of the CAM307 trial and our accompanying editorial in the Journal of Clinical Oncology, we have been contacted by many United States physicians with questions regarding the use of alemtuzumab as first-line therapy of chronic lymphocytic leukemia (CLL) based in part on a mail distribution of this article (in the absence of the editorial) by the marketing company of alemtuzumab.^1,2 At the present time, the most appropriate initial therapy for patients with symptomatic CLL is a moving target with fludarabine-based combination regimens being currently utilized for younger patients (< 65 to 70 years of age) and a variety of regimens including alkylator-based regimens such as chorambucil in those older than the age of 70. A recent German CLL study group failed to demonstrate the benefit of fludarabine over chlorambucil with respect to progression-free survival or overall survival in older patients with CLL. Thus, we agree with the authors that for elderly CLL patients (> 70 years of age), chlorambucil still is a reasonable comparative therapy for alternative therapies as noted in the National Comprehensive Cancer Network guidelines. However, the optimal schedule of chlorambucil is likely 0.8 mg/kg administered every 2 weeks or 10 mg/m² per day for 7 days every month as compared with the 40 mg/m² administered day 1 of an every 28 day cycle as administered in the CAM307 trial. As pointed out by Drs Sirard and Trehu, no single therapy in CLL has shown the ability to prolong survival. In our view, it is therefore necessary that new therapies, which could potentially adversely influence survival through late events (secondary malignancies, Richter's transformation, and opportunistic infections) need to be monitored for an extended period of time. Thus, while the CAM307 trial may not be powered to identify a statistical difference in favorable or adverse survival over time, these data should still be collected and updated periodically to provide assurances that alemtuzumab lacks adverse late adverse effects. It is unfortunate that we will never know the long-term complication rate (or absence thereof) in this uniform population of alemtuzumab-treated patients. The lack of long-term follow-up in CAM307 trial, increased cost of alemtuzumab as compared with other accepted agents, difficulty of administration, and potential short and long-term complications of alemtuzumab as a consequence of immune suppression therefore bring hesitancy in our recommendation for use of this agent in CLL. Specifically, we do not believe that alemtuzumab should be utilized either as monotherapy for the initial treatment of CLL outside of uncommon clinical situations such as symptomatic elderly patients who have del(17p13.1). Furthermore, we do not believe alemtuzumab should be used in any case for eradication of minimal residual disease after initial induction therapy with alternative CLL agents outside of an institutional review board–approved clinical trial.

The major focus of our editorial was to initiate academic dialog about important pivotal studies undertaken by pharmaceutical companies after receiving accelerated approval. As hematologists focused on the treatment of incurable diseases, we strongly endorse the accelerated approval process utilized by the US Food and Drug Administration. The process for determining comparator control arms in confirmatory licensing studies should be similar to that utilized by scientifically driven international study groups and also incorporate knowledge available at the time of such study initiation. At the US Food and Drug Administration Oncology Drug Advisory Committee (December 14, 2000) where a formal request for alemtuzumab accelerated approval was reviewed, detailed discussion occurred regarding the confirmatory phase III study. Recommendations by the US Food and Drug Administration at this time included a comparative phase III trial of fludarabine versus alemtuzumab in symptomatic patients who had not previously received fludarabine. At the time of this meeting and even currently, this would be a scientifically meaningful study based on the unpublished and un-reviewable marketing data outlined by Drs Sirard and Trehu noting that 30% to 40% of physicians in the United States still utilize chlorambucil as first-line therapy for CLL and "rates of single agent and specifically, chlorambucil, use are even higher in Europe." For such physicians utilizing chlorambucil as first-line CLL therapy, the benefit of fludarabine versus alemtuzumab therapy would now be known. In fact, this may be the more appropriate conclusion for Gemzyme's interpolation of progression-free survival comparisons of the CAM307 trial with the seminal work by Dr Rai³ demonstrating superiority of fludarabine over chlorambucil. Even in 2000, the recommendations by the Oncology Drug Advisory Committee included convening a scientific panel with perhaps US Food and Drug Administration collaboration to assist in determining the design of the confirmatory trial. For future drugs approved through the US Food and Drug Administration, we believe this process should be employed as part of the regulatory process.

Finally, the authors recognize the commitment of the pharmaceutical industry to bringing forth new therapeutics for patients with CLL and their commitment to clinical trials and diagnostic tests that support them. It is through the partnership of the pharmaceutical industry, US Food and Drug Administration, academic institutions, and cooperative groups that we will hopefully succeed in bringing more effective therapies forward for our patients.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

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[Abstract/Free Full Text]

2. Flynn JM, Byrd J: Have we forgotten the purpose of phase III studies? J Clin Oncol 25:5553-5555, 2007[Free Full Text]

3. Rai KR, Peterson BL, Appelbaum FR, et al: Fludarabine compared with chlorambucil as primary therapy for chromic lymphocytic leukemia. N Engl J Med 343:1750-1757, 2000[Abstract/Free Full Text]

Related Correspondence

• Hillmen Trial of Alemtuzumab in First-Line Chronic Lymphocytic Leukemia Still Provides Valuable Information
  Cynthia Sirard and Elizabeth G. Trehu
  JCO 2008 26: 2411-2412 [Full Text]

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