Treating chronic lymphocytic leukemia with a combination of rituximab and alemtuzumab: a “successful couple,” but are they still relevant together?

In this issue of the journal, Frankfurt et al. present the short- and long-term results of frontline treatment in 30 previously untreated patients with chronic lymphocytic leukemia (CLL) using a combination of alemtuzumab and rituximab (AR) [1]. As the authors point out, these two approved monoclonal antibodies act on different molecular targets and also have individual preferred sites of biological activity that justify the rationale for their use in combination for patients with CLL.

This study is an interesting contribution to the present ongoing discussion regarding how best to approach chemotherapy-free treatment of CLL, particularly in view of the emerging new therapies, including new monoclonal antibodies, kinase inhibitors [2] and bcl-2 inhibitors [3]. However, the very pertinent question posed by Frankfurt et al., regarding the combination of R with A, still remains open [1]. From both a clinical and biological point of view, a possible additive or synergistic effect of these antibodies cannot be taken for granted by the treating physician. Both antibodies work via complement- (CDC) and antibody-dependent (ADCC) cytotoxicity, and it is indeed possible that they both compete for complement, or that A may also inhibit effector cells, thereby interfering with achieving an optimal response when they are used together. However, in vitro studies of A used together with another type-I antibody, ofatumumab, show that there is enhancement of the CDC effect on CLL cells in vitro [4], which is encouraging, and implies that we may see the same effect after combination AR.

Regarding effector cells, recent research in multiple sclerosis suggests that following the administration of A the repopulating T cells differ from their pretreatment counterpart subsets, favoring the return of regulatory T cells as opposed to the conventional CD4 and CD8 cells [5]. Similar results were also reported on the immune effect of R when given for the treatment of autoimmune disease [6]. Nevertheless, more studies are needed to evaluate the combined immune effect of these two immune-regulatory drugs, both on their short-term effect and on the timing of immune B and T cell reconstitution.

Clinically, we already have impressive results obtained from first-line trials using single-agent A as well as from other trials combining both A and R with chemotherapy [7–9]. In a large phase III trial of A versus chlorambucil [7], Hillmen et al. found that 12 weeks of A (30 mg intravenously three times per week [i.v. TIW]) led to an overall response rate (ORR) of 83%, complete response rate (CRR) of 23% and a minimal residual disease (MRD)-negative complete response (CR) in 7% with a median progression-free survival (PFS) of 14.6 months, which was superior to that of chlorambucil. In 2002 in a smaller phase II trial, Lundin et al. gave alemtuzumab 30 mg subcutaneously (s.c.) TIW for 18 weeks, and obtained an ORR and CRR of 87% and 19%, respectively, and a similar median PFS of 14 months [8].

Thus, the main difference between the above results and those of Frankfurt et al. reported here [1] is the longer PFS of 24 months in the latter, but with a quite broad confidence interval (6–73 months), as recorded by the authors. This is very compatible with the PFS of 14 months reported by Hillmen et al. [7] as well as Lundin et al. [8]. Regarding immunochemotherapy, Parikh et al. [9] treated high-risk CLL with the CFAR regimen (fludarabine, cyclophosphamide [FC], A and R), and reported an ORR of 92% and a CRR of 70% with a median PFS of 38 months. In comparison, identical results were also obtained with FC with R alone (FCR) in high-risk (immunoglobulin heavy chain variable gene [IGHV]-unmutated) CLL, leading to an ORR of 90% and median PFS of 40 months [10]. It is of interest to note that half of the eight patients in the AR study with bulky disease responded with a partial response (PR), but this is not too surprising, as in the study by Hillmen and co-workers, 25 of 33 such patients (76%) responded after A alone. By six-color flow cytometry, using standard criteria (< 0.1% CLL cells), AR led to MRD-negative CR in 20% (95% confidence interval [CI] ∼6–34%), again comparable to the 7.4% (3–11%) achieved by A alone in the CAM307 trial [7]. In this report 12 of the 30 patients had trisomy 12, an aberration often associated with NOTCH1 mutation. While patients with NOTCH1 mutations do not benefit from R [11], they clearly benefit from A [12], just like patients with CLL with trisomy 12, not studied for NOTCH1 mutations [13].

In conclusion, what does the study by Frankfurt et al. [1] add to the current knowledge regarding the combined regimen AR? First, the authors do not in fact document increased efficacy of AR compared to A alone. They do, however, reinforce earlier results, and provide details on toxicity and side effects including infections, and how they are managed when AR is used by an expert CLL team. Finally, they confirm that A is an effective drug against CLL, but there is still search for an optimal partner and an effective schedule [14]. It is indeed highly likely that new clinical trials exploring the use of A in combination with novel agents such as anti B-cell receptor signaling agents or anti Bcl-2 mimetics will eventually lead to better clinical responses, with improved PFS and safety profile, in the near future. However, in this context, one may pose the interesting question relating to how relevant Campath is or will continue be, in the current rapidly developing era of novel therapy for CLL.

Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.