In the study under evaluation, Byrd et al. demonstrate that orally administered ibrutinib is well tolerated and induces significant objective responses in patients with CLL or SLL with relapsed or refractory disease. Generally, side effects were mild and despite the immunocompromised condition of the patients, who had received a median of four previous therapies, treatment with ibrutinib did not translate into increased incidence of grade 3–4 infections. This observation compares favorably with results of studies of relapsed or refractory CLL patients who received traditional therapy of salvage.
Fifteen patients (18%) in the study of Byrd et al. had more than 50% reduction in lymphadenopathy with residual lymphocytosis and were not considered as clinical progression but rather as a form of response described as 'PR with lymphocytosis'. Previous published studies have demonstrated that ibrutinib, likewise SYK and PI3K inhibitors, can mobilize CLL cells from tissues into the peripheral blood, interfering with their homing. From a clinical standpoint, Cheson et al. suggest to revise response criteria for CLL to correctly interpret results obtained with new agents with novel mechanisms of actions.
A relatively unexpected result was represented by better response to ibrutinib observed in patients without mutations of IGHV which does not translate, however, into a longer survival expectancy. Generally, the BCR in leukemic CLL cells with unmutated IGVH is competent and responds more rapidly to stimulation or inhibition, while those cells with mutated IGVH are typically unresponsive.
A novelty with ibrutinib as single agent is represented by its efficacy in relapsed/refractory patients with 17p deletion CLL. This observation suggests that ibrutinib should be further investigated alone or in combination in high-risk CLL patients, for instance, those patients with 17p deletion or mutations of the p53 gene who have poor outcomes when treated with FCR.[1–2]
Treatment of elderly with CLL is today an unmet clinical need. These patients, representing the majority of CLL population, frequently have major coexisting comorbidities. The use of an effective oral agent like ibrutinib whose efficacy does not translate into a high burden of toxicity should be considered in choosing the therapy in this subset of patients, especially when the end point is that of maintaining a good quality of life.
Finally, the study of Byrd et al. points out that the paradigma of CLL treatment is changing since we are moving from a chemotherapy-based approach to treatments targeting biologic mechanisms of disease. A challenging question is represented by cost–effectiveness of these new strategies that should be carefully weighed.
Expert Rev Hematol. 2013;6(5):543-546. © 2013 Expert Reviews Ltd.