In its deliberations, the Hematology Disease Site Group (DSG) places particular emphasis on the following: (a) results from published randomized controlled trials (RCTs) (where available), (b) the recognition of a hierarchy of outcomes that should influence treatment decisions, with priority given to therapies found to extend life or improve quality of life, and (c) the potential toxicities associated with treatment, with particular emphasis on those toxicities seen in the patients most likely to make up the eventual population treated. The members of the Hematology DSG had considerable difficulty reaching consensus on the appropriate wording of the recommendation for a potential indication for alemtuzumab in patients with chronic lymphocytic leukemia (CLL); the recommendation went through multiple iterations (see section 3, Guideline Development and External Review—Methods and Results in the original guideline document). Based on their review of the evidence provided in this systematic review, the DSG considered several interpretations for the use of alemtuzumab in patients with CLL.
The DSG regards alemtuzumab as an active agent for the treatment of patients with relapsed or chemotherapy-refractory CLL. This conclusion is based on response data from single-arm studies that report partial responses in approximately one third of patients and recognizes that complete remissions are uncommon. From a perspective of drug and/or multi-agent regimen development, these data are extremely promising and warrant further testing of alemtuzumab.
In their deliberations, the DSG cited the following factors leading to the above recommendation: (a) a lack of data from properly designed RCTs, (b) a paucity of comparative data suggesting improved response duration, quality of life, or improved overall survival compared with alternative treatment approaches, and (c) significant potential toxicity, particularly infection-related morbidity and mortality. Given the anticipated toxicity, data from RCTs demonstrating improvement in clinically meaningful outcome measures (e.g., time-to-progression, quality of life, or overall survival) are required before recommendations permitting the routine use of alemtuzumab in this patient population can be made.
The practice guidelines published by European Society for Medical Oncology (ESMO) and the United Kingdom Chronic Lymphocytic Leukemia (UK CLL) Forum made recommendations regarding the use of alemtuzumab in previously treated patients. The ESMO guideline recommended alemtuzumab as an option for patients with refractory disease following first-line therapy, based on the lowest level evidence (American Society of Clinical Oncology [ASCO] level V evidence: small case-series). In addition, the UK CLL Forum guideline recommended alemtuzumab for use in patients without bulky lymphadenopathy (<5 cm), who were previously treated with alkylating agents and refractory to fludarabine. The evidence informing the UK CLL Forum recommendation was similar to the evidence contained in this report and was comprised of data from a smaller selection of single-arm studies. The German CLL Study Group determined that definitive recommendations could not be made regarding alemtuzumab use and indicated that further testing in clinical trials would be preferred. The Keating et al. guideline did not make explicit recommendations regarding the appropriateness of alemtuzumab use in CLL patients, but implied that alemtuzumab is appropriate in fludarabine-refractory patients. Keating et al. also stated that advanced age should not be a contraindication for alemtuzumab use.
The DSG considered the above recommendations to be based on low levels of evidence and, initially, was not convinced that these recommendations would inform the basis of a best clinical practice. Instead, the DSG initially concluded that potential benefits (response rates in a minority of patients, uncertain benefit in terms of response duration, overall survival, and quality of life) were offset by the potential for significant toxicity. Therefore, an initial recommendation was developed to indicate that there were insufficient data to support the routine use of alemtuzumab in patients with CLL. The DSG acknowledged the potential controversy that could result from issuing a "non–permissive" recommendation regarding alemtuzumab use and the potential implications such a recommendation might have for drug availability. The DSG was aware that its recommendations differed from those of other existing practice recommendations, including those published by ESMO and the UK CLL Forum.
The DSG was also aware that within the response data described from the literature reviewed were responses of a magnitude that reporting authors, and members of the DSG, considered to be clinically important. While the precise frequency of these responses were uncertain, and the best estimate was that they would be infrequent, the DSG acknowledged that an opportunity for such a response, even with substantial risks of toxicity, may be highly desired by some patients. The DSG attempted to reflect this sentiment by indicating that, after balancing the benefits and risks of treatment, certain patients may wish to consider a trial of therapy. While the DSG had concerns with issuing an unclear and potentially conflicting set of recommendations, it initially considered this option to represent the best available alternative and offered the following guidance: For patients with CLL, there is insufficient evidence to recommend the use of alemtuzumab outside of clinical trials. The DSG recognizes that, in highly selected cases, after thorough consideration of the risks and benefits, a trial of alemtuzumab might be considered. Section 3 of the original guideline document details the subsequent Practitioner Feedback and notes that responding clinicians were generally in agreement with the synthesis and interpretation of the available literature and the resulting recommendation. However, a small number of respondents commented on the lack of clarity associated with the recommendations. As a result, the DSG continued its consensus process in an effort to develop a clearer statement and issued a new set of recommendations. The redeveloped recommendation states, "Treatment with alemtuzumab is a reasonable option for patients with progressive and symptomatic CLL that is refractory to both alkylator-based and fludarabine-based regimens." In order to account for the continued concern about the level of evidence supporting this recommendation and the potential adverse risk-benefit profiles of this therapy, a detailed set of Qualifying Statements were also developed.
