New research suggests that a combination therapy could be an effective approach to treating chronic lymphocytic leukaemia (CLL) when ibrutinib alone is ineffective.
Researchers at the CRO Aviano National Cancer Institute, Italy, and Paracelsus Medical University in Salzburg, Austria, has reported that ibrutinib is less effective at targeting CLL tumour cells expressing adhesive protein CD49d.
The team suggest that combining ibrutinib treatment with drugs that block CD49d activation could prevent the tumour cells from sheltering in lymphoid organs.
Ibrutinib promotes lymphocytosis, the reallocation of CLL cells from lymph nodes into the blood by inhibiting Bruton's tyrosine kinase (BTK), a key enzyme in the B-cell receptor (BCR) signalling pathway.
BCR signalling promotes the survival and differentiation of normal, healthy B-cells in several ways, including by activating the adhesion receptor VLA-4, which attaches B-cells to other, supportive cells within lymph nodes.
CD49d is a subunit of VLA-4 and is highly expressed in about 40% of CLL patients. It is established that these individuals have significantly poorer outcomes than patients that do not express it, however until now the reason for this was unclear.
Writing in the Journal of Experimental Medicine, the researchers, led by Antonella Zucchetto and Valter Gattei in Italy and Tanja Nicole Hartmann in Austria, say that BCR signalling can activate VLA-4 in CD49d-expressing CLL cells, enhancing the cells' adhesiveness.
Even though ibrutinib treatment impaired BCR signalling in these cells, it was unable to hinder the activation of VLA-4, they found.
The teams analysed three different cohorts of CLL patients from Italy and the USA and found that in all three, individuals who expressed higher levels of CD49d showed reduced responses to ibrutinib treatment.
"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 Ms Zucchetto.
"This activation leads to enhanced retention of VLA-4-positive CLL cells in tissue sites, thereby affecting patient outcome."
BCR signalling can also proceed through phosphatidylinositide 3-kinase (PI3K) and the researchers found that simultaneously inhibiting both BTK and PI3K completely blocked 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," added Dr Gattei.
Source: Tissino et al. Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia. Journal of Experimental Medicine. 2018 Jan 4:jem-20171288.
Link: http://jem.rupress.org/cgi/doi/10.1084/jem.20171288
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