Toward chemotherapy-free treatment of CLL.

F irst, the most important and biggest subgroup of CLL patients—the elderly, who are usually neglected in clinical trials—is studied. Second, the authors were ambitious enough to design a nonchemotherapeutic first-line treatment approach for these patients. Third, they included carefully preplanned correlative analysis not only focusing on the usual biologic disease characteristics but also on topics of specific relevance for the treatment modality chosen. Fourth, they chose a wise dosing schedule that anticipated a schedule that was later established by clinical phase-1 testing. Fifth, although recently accrued, the population has a complete and almost maximal follow-up time documenting the overall excellent data quality. Major breakthroughs have been made in CLL in recent years.2,3 Among the biggest steps forward are: (1) the introduction of chemoimmunotherapy with FCR (fludarabine, cyclophosphamide, and rituximab, or similar regimens), which appears to improve overall survival4,5; and (2) the identification of subgroups of patients (deletion 17p, TP53 mutation) that do not benefit as much as others from this approach and are prime candidates for novel treatment options.3,5 However, these advances are largely limited to young and physically fit CLL patients, which constitute a minority of all patients. Progress has been much more difficult in the elderly with a considerable degree of comorbidity. Only very little data are available regarding treatment approaches for CLL patients of advanced age and with comorbidities.6,7 In fact, chlorambucil can still be considered the standard treatment for these patients. However, chlorambucil leads to an unsatisfactory overall response rate of 50%60% with virtually no complete responses and short progression-free survival as well as overall survival.6,7 It is of note that the data reported by Badoux and colleagues here point to very similar efficacy of lenalidomide as a single agent in CLL with a slow but steady improvement over time.1 Not unexpectedly, the major side effect of treatment was hematotoxicity, but this was accompanied by a lower-than-expected rate of severe infection. Most likely, both aspects result from the particular mechanisms of action of lenalidomide in CLL, which appear to be much more related to its immunomodulatory properties than in other diseases. Lenalidomide has pleiotropic effects and multiple molecular targets, depending on the cellular context.8 In multiple myeloma, it has direct cellular toxicity, which does not seem to be the case for CLL cells. Lenalidomide impacts on several signaling pathways, on the intercellular cross-talk and hematopoietic tissue composition. In CLL, the therapeutic effects are possibly caused by targeting the interaction of the leukemic cells with their microenvironment and even by the induction of a cellular and humoral antitumor response. One of the intracellular Effects of lenalidomide on CLL cells in vivo. Treatment with lenalidomide impacts PI3K, NFAT, and NFkB signaling, thereby inducing expression of CD154 that allows interaction of the CLL cells with T cells and activation of these T cells. At the same time, the chemoattractants CCL3 and CCL4 are deregulated on treatment with lenalidomide, with patients responding to therapy showing a down-regulation. Together with the observed induction of antibody production in CLL patients after therapy with lenalidomide, probably produced by nonmalignant B cells, these effects point toward re-establishment of a functional microenvironment by lenalidomide. The role of BCR signaling in this process is underlined by the fact that patients with unmutated IGHV genes and potentially active BCR signaling show a better response to lenalidomide treatment. However, patients with del(17p) had a poor outcome when treated with lenalidomide in the current study,1 suggesting that the major well-defined cause of treatment resistance in CLL (TP53 deletion/mutation) is not overcome.