High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL

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Authors	CHIODIN Giorgia DRENNAN Samantha MARTINO Enrica A ONDRIŠOVÁ Laura HENDERSON Isla LUIS del Rio TRACY Ian D'AVOLA Annalisa PARKER Helen BONFIGLIO Silvia SCARF Lydia SUTTON Lesley-Ann STREFFORD Jonathan C FORSTER Jade BRAKE Oliver POTTER Kathleen N SALE Benjamin LANHAM Stuart MRÁZ Marek GHIA Paolo STEVENSON Freda K FORCONI Francesco
Year of publication	2022
Type	Article in Periodical
Magazine / Source	BLOOD ADVANCES
MU Faculty or unit	Central European Institute of Technology
Citation
Web	https://ashpublications.org/bloodadvances/article/6/18/5494/485430/High-surface-IgM-levels-associate-with-shorter
Doi	http://dx.doi.org/10.1182/bloodadvances.2021006659
Keywords	CHRONIC LYMPHOCYTIC-LEUKEMIAB-CELL RECEPTORCD38 EXPRESSIONRESISTANCEACTIVATIONPCI-32765IMMUNOGLOBULININHIBITIONMUTATIONSPATHWAYS
Description	Chronic lymphocytic leukemia (CLL) cells have variably low surface IgM (sIgM) levels/ signaling capacity, influenced by chronic antigen engagement at tissue sites. Within these low levels, CLL with relatively high sIgM (CLLhigh) progresses more rapidly than CLL with low sIgM (CLLlow). During ibrutinib therapy, surviving CLL cells redistribute into the peripheral blood and can recover sIgM expression. Return of CLL cells to tissue may eventually recur, where cells with high sIgM could promote tumor growth. We analyzed time to new treatment (TTNT) following ibrutinib in 70 patients with CLL (median follow-up of 66 months) and correlated it with pretreatment sIgM levels and signaling characteristics. Pretreatment sIgM levels correlated with signaling capacity, as measured by intracellular Ca2+ mobilization (iCa2+), in vitro (r = 0.70; P < .0001). High sIgM levels/ signaling strongly correlated with short TTNT (P < .05), and 36% of patients with CLLhigh vs 8% of patients with CLLlow progressed to require a new treatment. In vitro, capacity of ibrutinib to inhibit sIgM-mediated signaling inversely correlated with pretherapy sIgM levels (r = -0.68; P = .01) or iCa2+ (r = -0.71; P = .009). In patients, sIgM-mediated iCa2+ and ERK phosphorylation levels were reduced by ibrutinib therapy but not abolished. The residual signaling capacity downstream of BTK was associated with high expression of sIgM, whereas it was minimal when sIgM expression was low (P < .05). These results suggested that high sIgM levels facilitated CLL cell resistance to ibrutinib in patients. The CLL cells, surviving in the periphery with high sIgM expression, include a dangerous fraction that is able to migrate to tissue and receive proliferative stimuli, which may require targeting by combined approaches.