Background Ibrutinib is a Bruton's tyrosine kinase inhibitor with high response rates in CLL. The quality of response improves with duration of treatment following an initial redistribution of CLL cells from lymph nodes to the peripheral blood (PB). The IcICLLe trial(ISRCTN 12695354) is a feasibility study to investigate the biological response to ibrutinib and identify changes that may impact the design of therapeutic strategies. Method 40 participants with CLL requiring treatment receivedibrutinib (420 mg/day) until either achievement of<0.01% residual disease in bone marrow (BM) ordisease progression. A large panel of markers were assessed on PB & BM taken at -0.5 (screening), 1 & 6 months with additional PB at 0 (baseline), 4 hours, 1, 2, 7, & 14 days and 2, 9, & 12 months (M). Results B-cell counts increased immediately after the first dose, peaked at two weeks, and returning to baseline by month 2.CLL cells Ki67 expression initially increased, peaking at 24 hours and then declined below quantifiable levels (<0.5%) in 15% of patients by week 1 and in more than 90% of patients at subsequent time points. Also CLL Ki67 expression was not detectable in most patients' marrow after 1 month of treatment. Decreases in proliferation-associated markers (CD5/CD23/CD38/CD49d/IRF4), changes in molecules involved in CLL cell trafficking and adhesion (increased CXCR4/CD24& decreasedCCR7/CD31/CD11a), and reduced expression in potential therapeutic targets (CD20/ BCL2) followed the same kinetics as cell cycle arrest, i.e. differences emerged after 1-2 weeks of treatment and then stabilised during subsequent treatment. Conclusion The redistribution of CLL cells during ibrutinib happens much more rapidly than any changes in proteins associated with proliferation, cell trafficking or adhesion. The majority of changes in CLL cells correlate with the loss of the proliferative fraction, mostly stabilising after one month of treatment.
|Publication status||Published - Nov 2015|