Functional Evidence that Ibrutinib Blocks Leukemia Cell Proliferation and Trafficking and Promotes Leukemia Cell Death
Ibrutinib is a BTK inhibitor whose clinical efficacy in patients with CLL is thought to be a result of the inhibition of B-cell receptor and chemokine receptor signaling, resulting in redistribution lymphocytosis and leukemic cell death (Herman SEM, et al. Blood. 2014;123:3286-3295). However, these mechanisms of action have not formally been documented in patients with CLL. At ASH 2014, Burger and colleagues reported on a study in which they assessed the impact of ibrutinib on CLL cell proliferation, trafficking, and death (Blood. 2014;124. Abstract 326). In their study, previously untreated patients with CLL were asked to drink deuterated water to label proliferating CLL cells with deuterium (2H), and the effects of subsequent ibrutinib treatment on leukemia cell kinetics (proliferation and death rates), as well as the mobilization of cells from lymphoid tissues (trafficking) were measured.
A total of 30 patients with early-stage (Rai stages 0-II, N = 16) or advanced-stage (Rai stages III-IV, N = 14) CLL were treated with 70% 2H2O according to an established protocol, and after a 6-week to 12-week washout phase were given ibrutinib on 28-day cycles. At a median follow-up of 13 months, 28 of the 30 patients continued therapy without disease progression (93% achieved PR, 3% achieved CR, and 3% had stable disease, for an ORR of 97%).
The average CLL cell birth rate determined before ibrutinib therapy was 0.42% daily (range, 0.32%-1.42%). After initiating ibrutinib, there was a rapid increase in absolute lymphocyte count in the blood in 26 of the 30 patients; this contained previously labeled CLL cells rather than newly divided unlabeled cells.
Over time, the proportion of circulating CLL cells that were labeled did not decrease appreciably, despite a concomitant fall in circulating lymphocytes, indicating that newly divided cells were not entering the circulation and strongly suggesting that ibrutinib had a major inhibitory effect on leukemia cell proliferation. In 3 of the 4 patients in whom there was a rapid influx of unlabeled cells with the onset of ibrutinib, the maintenance of circulating labeled cells concomitant with a significant fall in circulating lymphocytes suggested that the proliferation of CLL cells was inhibited with extended treatment. Because both cell proliferation and efflux from the blood were markedly reduced after ibrutinib therapy, the elimination rate should equal the death rate. Notably, with treatment, the elimination rate of CLL cells was much faster than before ibrutinib, revealing a “true” death rate of 1.48% of the leukemic clone daily.
These are the first data shown directly in patients with CLL that ibrutinib significantly inhibits leukemia cell proliferation, leads to an efflux of CLL cells from the tissue into the blood, and promotes a high death rate of CLL cells, likely as a result of the interruption of survival signals from the B-cell receptor and other receptors engaged in lymphoid tissues.