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Updated: Sep 21, 2025
Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation
Published on: November 26, 2018
High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL
Giorgia Chiodin1, Samantha Drennan1,2, Enrica A Martino1,3
1School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
Insights
High surface IgM (sIgM) levels in chronic lymphocytic leukemia (CLL) cells correlate with faster disease progression and resistance to ibrutinib therapy. Targeting these sIgM-expressing cells may require combination approaches for better outcomes.
Area of Science:
- Hematology
- Oncology
- Immunology
Background:
- Chronic lymphocytic leukemia (CLL) cells exhibit variable surface IgM (sIgM) levels, influenced by antigen engagement.
- CLL with higher sIgM expression (CLLhigh) shows more rapid progression than CLL with lower sIgM (CLLlow).
- Ibrutinib therapy can lead to CLL cell redistribution and recovery of sIgM expression, potentially promoting recurrence.
Purpose of the Study:
- To investigate the correlation between pretreatment sIgM levels, signaling capacity, and time to new treatment (TTNT) in CLL patients receiving ibrutinib.
- To assess the in vitro and in vivo impact of ibrutinib on sIgM-mediated signaling in CLL cells.
- To determine if high sIgM expression contributes to ibrutinib resistance in CLL.
Main Methods:
- Analysis of TTNT in 70 CLL patients treated with ibrutinib, correlating with pretreatment sIgM levels and intracellular Ca2+ mobilization (iCa2+).
- In vitro assessment of ibrutinib's efficacy in inhibiting sIgM-mediated signaling based on sIgM and iCa2+ levels.
- Measurement of sIgM-mediated iCa2+ and ERK phosphorylation levels in patients before and during ibrutinib therapy.
Main Results:
- Pretreatment sIgM levels strongly correlated with signaling capacity (iCa2+) and shorter TTNT in CLL patients.
- 36% of CLLhigh patients required new treatment compared to 8% of CLLlow patients.
- Ibrutinib's inhibitory effect on sIgM signaling inversely correlated with sIgM levels and iCa2+; residual signaling was associated with high sIgM.
Conclusions:
- High sIgM levels in CLL cells are associated with more aggressive disease and reduced sensitivity to ibrutinib.
- Residual sIgM-mediated signaling downstream of BTK persists during ibrutinib therapy, particularly in high-sIgM CLL cells.
- Targeting high-sIgM CLL cell populations may necessitate combination therapies to overcome resistance and prevent disease recurrence.
Abstract:
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.
