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Jeremy S. Abramson, MD, MMSc
Jeremy S. Abramson, MD, MMSc
Posted: Wednesday, July 20, 2022
Chronic lymphocytic leukemia (CLL) cells with high levels of surface immunoglobulin M (IgM) tend to be more resistant to ibrutinib therapy, and these cells are able to migrate into tissue to receive proliferative stimuli. These findings were reported by Francesco Forconi, MD, PhD, of the University Hospital Southampton NHS Trust, United Kingdom, and his colleagues in Blood Advances.
Researchers used data from 70 patients with CLL who were being followed at the University of Southampton. Phenotypic and immunogenic characteristics as well as the mutational profile of the patients’ cancers were recorded at the time of enrollment. All patients received 420 mg daily of ibrutinib until unacceptable toxicity and/or disease progression. The peripheral blood mononuclear cells were analyzed by flow cytometry before and during ibrutinib treatment to assess the levels of surface IgM. Anti-IgM–induced signaling capacity was measured by intracellular calcium mobilization and immunoblotting.
High levels of surface IgM were strongly correlated with a shorter time to new treatment (P < .05), and 36% of those with high levels of surface IgM experienced disease progression to a point where they required a new treatment. By comparison, 8% of patients with low levels of surface IgM needed a new treatment. In addition, increased signaling from surface IgM was found to be associated with a shorter time to disease progression (P = .022). After discontinuing ibrutinib therapy, surface IgM levels increased significantly compared with pretherapy levels in patients with progressive disease.
The pretreatment surface IgM levels correlated with signaling capacity (calcium mobilization) in vitro. In addition, the ability of ibrutinib to inhibit surface IgM–mediated signaling was inversely correlated with the pretherapy surface IgM levels and intracellular calcium signaling. Surface IgM–mediated intracellular calcium release and ERK phosphorylation levels were decreased by ibrutinib therapy but not completely inhibited. The residual signaling capacity downstream of Bruton’s tyrosine kinase was associated with a higher expression of surface IgM, and there was minimal activity when surface IgM expression was low.
Disclosure: The study authors reported no conflicts of interest.
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