Combination Therapy May Benefit Subset of Patients With CLL Who Have Poor Response to Ibrutinib

A subset of patients with chronic lymphocytic leukemia (CLL) with highly expressed CD49d have poorer outcomes while on Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B-cell receptor (BCR) signals. However, a team of researchers may have found a way to treat these patients.

According to research published in the Journal of Experimental Medicine, combining ibrutinib with drugs that block CD49b activation could improve outcomes by preventing tumor cells from sheltering in lymphoid organs.

The researchers found that BCR signaling can activate the receptor VLA-4 in CD49d-expressing CLL cells, which reinforces the adhesive capabilities of CLL cells. They discovered that ibrutinib impaired BCR signaling but was unable to fully stop the VLA-4 from activating and enhancing cell adhesion. VLA-4 attaches B cells to other, supportive cells within lymph nodes

“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,” Antonella Zucchetto, ScD, of the CRO Aviano National Cancer Institute in Italy, said in a statement. “This activation leads to enhanced retention of VLA-4—positive CLL cells in tissue sites, thereby affecting patient outcome.”

Researchers from Italy and Austria analyzed 3 different cohorts of patients with CLL receiving ibrutinib as a single agent. One of the cohorts was in Italy, while the other 2 were in the United States. Patients in all 3 groups who had higher levels of CD49d had reduced responses to ibrutinib, which resulted in shorter progression-free survival times.

They determined that concomitant inhibition of BTK and phosphatidylinositide 3-kinase impairs VLA-4 activation in CLL cells.

“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,” said Valter Gattei, MD, of the CRO Aviano National Cancer Institute.