TY - CONF
T1 - The LLR TAP IcICLLe trial
T2 - Assessing biological response to ibrutinib in CLL: immediate disease redistribution precedes cell cycle arrest by 2 weeks with reduced bone marrow infiltration by 6 months
AU - Rawstron, Andy C
AU - Munir, Talha
AU - Dalal, Surita
AU - de Tute, Ruth M
AU - Brock, Kristian
AU - Fox, Christopher
AU - MacDonald, Donald
AU - Fegan, Christopher
AU - Bloor, Adrian
AU - Hillmen, Peter
PY - 2015/11
Y1 - 2015/11
N2 - 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.
AB - 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.
M3 - Abstract
ER -