High surface IgM levels relative to the low level typically found expressed by chronic lymphocytic leukemia (CLL) cells were associated with faster disease progression and need for the next line of treatment, according to a study published in Blood Advances.

Overall, CLL cells have a low surface IgM signaling capacity, but CLL cells with a higher signaling capacity is associated with faster disease progression. The aim of this study was to determine if time to new treatment (TTNT) after ibrutinib was associated with surface IgM signaling capacity among CLL cells.

The study retrospectively evaluated treatment outcomes of 70 patients with CLL. Pretreatment surface IgM levels and signaling capacity were assessed by intracellular calcium mobilization. The median follow-up was 66 months.

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In this cohort, the median surface IgM level prior to ibrutinib initiation was 65 and the median intracellular calcium mobilization was 47%. Higher pretreatment intracellular calcium mobilization in vitro was significantly associated with higher serum IgM levels (r =0.70; P <.0001).

A shorter TTNT was also significantly associated with higher surface IgM levels, with 36% and 8% of patients demonstrating disease progression (P <.008). Higher levels of intracellular calcium mobilization was also significantly associated with shorter TTNT, with 36% of patients demonstrating disease progression compared with 13% of patients whose cells demonstrated a low level of mobilization (P =.022).

Inhibition of surface IgM signaling by ibrutinib was lower in cells with higher surface IgM-mediated signaling in vitro (r =-0.68; P =.01). Downstream signaling of BTK was also associated with higher surface IgM expression (P <.05).

The authors concluded that these data “set the rationale for the need for combinatorial therapeutic approaches to target these cells, which have been heavily selected and appear to carry more dangerous potentials than the tumor population existing prior to the start of single-agent ibrutinib.”


Chiodin G, Drennan S, Martino EA, et al. High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL. Blood Adv. 2022;6:5494-5504. doi: 10.1182/bloodadvances.2021006659