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Ibrutinib (Imbruvica)
New research appears to explain why ibrutinib may be less effective in certain patients with chronic lymphocytic leukemia (CLL).
It seems the Bruton’s tyrosine kinase (BTK) inhibitor has a diminished capacity to delocalize and kill tumor cells expressing an adhesive protein called CD49d.
But combining ibrutinib with drugs that block CD49d activation could prevent CLL cells from sheltering in lymphoid organs.
Valter Gattei, MD, of CRO Aviano National Cancer Institute in Aviano, Italy, and his colleagues reported these findings in the Journal of Experimental Medicine.
The team noted that CD49d, the α chain of the CD49d/CD29 integrin heterodimer very late antigen 4 (VLA-4), is expressed in about 40% of CLL cases.
These patients tend to have poorer outcomes than patients who do not express CD49d, but the role of VLA-4 in CLL was unclear.
With this study, researchers found that B-cell receptor (BCR) signaling can activate VLA-4 in CD49d-expressing CLL cells, thereby enhancing the cells’ adhesiveness.
Even though ibrutinib treatment impaired BCR signaling in these cells, it was unable to fully prevent the pathway from activating VLA-4 and enhancing cell adhesion.
The researchers analyzed 3 cohorts of CLL patients and found that patients expressing higher levels of CD49d had reduced responses to ibrutinib.
The BTK inhibitor appeared less able to displace tumor cells from lymph nodes into the blood, resulting in decreased lymph node shrinkage and shorter progression-free survival times.
“Our results suggest that VLA-4-expressing CLL cells residing in the secondary lymphoid organs can receive BCR-mediated stimuli that can activate VLA-4 even in the presence of ibrutinib,” said study author Antonella Zucchetto, ScD, also of CRO Aviano National Cancer Institute.
“This activation leads to enhanced retention of VLA-4-positive CLL cells in tissue sites, thereby affecting patient outcome.”
Fortunately, the researchers found a way around this obstacle. Inhibiting BTK and phosphatidylinositide 3-kinase (PI3K) simultaneously completely blocked VLA-4 activation in CLL cells.
The researchers treated CLL cells with ibrutinib, the PI3K inhibitor idelalisib, or a combination of both.
Neither drug alone was able to fully block anti-IgM-induced VLA-4 activation. However, the team found that simultaneous inhibition of BTK and PI3K “completely abolished the integrin response to BCR triggering.”
The researchers also added idelalisib to ibrutinib-treated CLL cells (collected from patients at day 30 on ibrutinib) and observed a complete upset of anti-IgM–induced VLA-4 activation.
“Our data suggest that evaluation of CD49d expression in patients initiating ibrutinib therapy may identify those cases that would benefit from combination therapy approaches designed to completely block VLA-4 activation and VLA-4-mediated retention of leukemic cells in protective tissue compartments,” Dr Gattei said.
