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Letters to the Editor
Modulated expression of adhesion, migration and activation molecules may predict the degree of response in chronic lymphocytic leukemia patients treated with ibrutinib plus rituximab
B-cell receptor (BCR) signaling has emerged as a pivotal pathway in the pathogenesis and progression of chronic lymphocytic leukemia (CLL) and the introduction of small molecules targeting the BCR signalosome has dra- matically changed the treatment landscape of CLL. Among such molecules, ibrutinib, a potent and selective inhibitor of the Bruton tyrosine kinase (BTK) protein, a central mediator of BCR signaling, has been associated with high efficacy and an acceptable toxicity profile in patients with CLL, including those with high-risk genetic features who respond poorly to chemoimmunotherapy.1
Ibrutinib, as well as other BCR inhibitors, produces an early redistribution of tissue-resident CLL cells into the blood, resulting in a transient, treatment-induced lym- phocytosis.2 Previous in vitro studies have shown that this phenomenon is correlated to the direct effect of the drug on B-cell adhesion and migration which leads to attenu- ated microenvironment retention and homing of CLL cells.3 A significant downmodulation in the gene expres- sion and plasma concentration of tissue-homing chemokines has also been observed in vivo following combination therapies with ibrutinib and anti-CD20 monoclonal antibodies, currently being explored to improve patients’ clinical outcome.4 No data are, howev- er, available on the modulation of CLL cell surface mark- ers in this context. In the present study (ClinicalTrials.gov
identifier NCT02232386), we analyzed the in vivo effects of ibrutinib on the expression of adhesion, migration and activation molecules in peripheral blood samples collect- ed from 119 CLL patients enrolled in the GIMEMA LLC 1114 phase II front-line ibrutinib plus rituximab (IR) trial. In particular, the mean fluorescent intensity (MFI) of CD11a, CD18, CD38, CD40, CD43, CD44, CD49d, CD62L, CD69, CD80, CD81, CD86, CD154, CD184 and CD185 on leukemic B cells was evaluated on day 0 (D0) and day 14 (D14) of IR therapy. The CLL patients’ char- acteristics and experiments are detailed in Online Supplementary Table S1 and in the Online Supplementary Methods, respectively.
We found that 14 days of IR therapy were sufficient to induce a significant change in the levels of expression of the majority of the markers analyzed (10/15, 66.7%). As shown in Figure 1, among the antigens that were modu- lated, nine were downmodulated while only one was upmodulated after in vivo treatment. We observed a sig- nificant downmodulation of CD62L (467±437 vs. 162±134, P<0.00001), a key molecule in CLL cell migra- tion, adhesion and transendothelial migration.5 The expression of the CXCL13 chemokine receptor CD185, another mediator of CLL tissue homing, also decreased significantly after in vivo treatment with IR (1396±1340 vs. 810±679, P<0.00001), while we unexpectedly observed upmodulation of the CXCL12 chemokine receptor CD184 (2309±1951 vs. 3127±1799, P<0.00001). These data are consistent with recent reports of both a greater dependency of CD184low CLL cells on microenvi- ronmental stimuli for survival and a correlation between
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Figure 1. Effects of ibrutinib plus rituximab in vivo treatment on the expression of chronic lymphocytic leukemia cell adhesion molecules, chemokine recep- tors and activation markers. Box plots show the comparison between the expression levels for each of the antigens analyzed on primary leukemic B cells before and after 14 days of in vivo treatment with ibrutinib plus rituximab. Data are presented as mean fluorescent intensity values obtained with specific monoclonal antibodies compared with values given by isotype controls. Significant differences are indicated as ****P<0.00001, ***P<0.0001, **P<0.001, *P<0.01; NS: not significant (paired Student t-test). D0: before treatment, D14: after 14 days of treatment; MFI: mean fluorescent intensity.
haematologica | 2021; 106(5)