Alemtuzumab (Campath-1H) for chronic lymphocytic leukemia: a drug in search of its optimal schedule

Alemtuzumab (Campath-1H) is a fully humanized immunoglobulin G1 (IgG1)-type monoclonal antibody directed against CD52, an antigen expressed primarily on T and B lymphocytes. It was originally developed and designed by Waldmann and colleagues for depletion of normal T cells from donor bone marrow to combat graft versus host disease [1]. Additional disorders for which this antibody has been given as therapy, or is under investigation, include: vasculitis, multiple sclerosis, autoimmune disorders, and T-cell lymphoproliferative diseases. The first studies relating to its activity in chronic lymphocytic leukemia (CLL) were reported in 1996 by Osterborg et al., who determined the mode of administration, giving alemtuzumab as a 30 mg 2 h intravenous (IV) infusion thrice weekly for a period of 12 weeks [2,3]. Its IV use has been associated with a high rate of side effects such as ‘flu like’ symptoms, and as a result patients required a slow titration of the dose to be administered during the first week of therapy. These initial studies led to several other clinical trials which compared the IV route of administration to subcutaneous (SC) injection of the drug [3,4]. These observations confirmed non-inferiority of the SC route of administration in terms of efficacy, and also showed that it was possible to achieve similar blood concentrations of alemtuzumab after SC injection as with the IV route, but with fewer systemic side effects [4]. In 2000, based on all the above data, the drug received orphan status and fast-track approval by the US Food and Drug Administration (FDA) [5]. Thereafter, alemtuzumab was shown to have activity in patients with CLL failing fludarabine-based therapy [6], and these observations led to the subsequent open-label, international, multicenter, randomized trial of previously untreated patients with CLL [7]. The positive results of this study brought the US FDA in 2007 to grant regular approval and expand labeling for alemtuzumab as single-agent therapy for B-CLL [8].

Since its successful use in this disease, alemtuzumab raised new hopes for the treatment of patients with refractory and aggressive CLL, including those who carry the p53 mutation [9]; however, this was associated with a high cost of toxicity, mainly infectious complications. On the other hand, even after the encouraging results reported with this impressive drug as long as 15 years ago [3], it has still not fulfilled its early and obvious promise in an optimal manner.

In recent years, several attempts have been made to improve these results by using alemtuzumab not as a monotherapy but in combination with other drugs. Campath-1H has been given with fludarabine, the so-called ‘FLU-CAM’ regimen [10], or with high-dose methylprednisolone for patients with a p53 defect [11], but often at the price of high toxicity, or in combination with rituximab [12] or filgrastim [13]. None of the above combinations have been universally accepted as common practice and they are still not used routinely.

Another approach to be utilized in the search for the optimal use of alemtuzumab in CLL relates to exploiting the drug for different clinical stages of the disease: as first line therapy [14], as a salvage regimen, for disease consolidation [15], or for the control of minimal residual disease after primary therapy [16]. Furthermore, it has also been exploited for different indications, as it clearly has impressive activity in autoimmune phenomena accompanying CLL, such as hemolysis [17]. The classic dosing schedule proposed initially was developed empirically in the absence of pharmacokinetic data, but later on changes were also made in the schedule of drug administration, starting from 12 weeks of therapy and expanding to 18 weeks, or even using monthly injections of alemtuzumab [18]. The latter studies were supported by pharmacokinetic and pharmacodynamic analyses, which demonstrated that higher serum levels were associated with better treatment responses [19].

In this regard, the study by Bezares et al., which appears in the current issue of Leukemia and Lymphoma, is intriguing, as they describe an interesting strategy to improve upon the toxicity profile by utilizing subcutaneous administration of alemtuzumab at a reduced dose, and during a prolonged period of time, for newly diagnosed patients with CLL [20]. They started therapy with a conventional dose of 30 mg, but only twice weekly instead of three times a week. This was followed by injection every other week for 10 weeks, then every 4 weeks for four doses followed by four injections every 6 weeks. Using this schedule they report an overall response rate of 95%, with a complete response rate of 50.7%, and with lower toxicity compared to all previous reports [20]. Indeed, this article reports a promising schedule that needs to be taken into consideration seriously and should be tried out in a larger cohort of patients in order to verify the slow toxicity and high efficacy reported by the authors.

This novel and interesting schedule of giving alemtuzumab may pave the way for a new concept of ‘tailoring alemtuzumab therapy,’ designing the doses given and the schedule of administration based on the level of the absolute lymphocyte count and clinical response. Although this was not performed here in the current study, it will probably be reasonable to attempt to combine this agent with determinations of blood concentrations of the drug during its administration to investigate whether this prolonged schedule is capable of maintaining an acceptable therapeutic level of alemtuzumab.

One should bear in mind that a new drug not always brings us to the brink of a new era, but in most cases it is the optimal mode of administration, together with the best dose scheduling for the correct disease, which makes all the difference, leading to the eventual achievement of improved responses. In this regard, alemtuzumab is still in search of its optimal schedule, but in the mean time it advances one more step forward with the study reported by Bezares and colleagues in this issue of Leukemia and Lymphoma [20].

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