B-Cell Receptor Signaling Activity Portends Inferior Outcomes in MCL

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B-cell receptor (BCR) signaling properties were associated with poor clinical outcomes in patients with mantle cell lymphoma (MCL), according to findings from a study published in Scientific Reports.

Patients with MCL who were grouped in the high responder BCR group (n = 11) experienced a median progression-free survival (PFS) of 15 months compared with 40 months among patients in the low responder BCR group (n = 19; log-rank P = .042); the median overall survival (OS) was 27 months vs 52 months, respectively (log-rank P = .041). When the analysis was restricted to samples collected from patients with lymphoma at first diagnosis, the median PFS in the high responder and low responder groups was 8 months vs 63 months, respectively (log-rank P = .036), and the median OS was 14 months vs 30 months, respectively (log-rank P = .001).

“We identified BCR signaling properties associated with poor clinical outcome and resistance to ibrutinib [Imbruvica], thus highlighting the prognostic and predictive significance of BCR activity and advancing our understanding of signaling heterogeneity underlying clinical behavior of MCL,” Simona Gambino, of the Department of Engineering for Innovation Medicine, Section of Biomedicine, at the University of Verona in Italy, and coauthors wrote.

To conduct their study, investigators collected and cryopreserved peripheral blood mononuclear cell samples from 30 patients with MCL and 10 age-matched healthy donors at a single site in Italy. Additionally, peripheral blood samples were collected at diagnosis before treatment (n = 19) and at relapse at least 6 months after the latest therapy and before any additional therapy (n = 11).

Study authors characterized BCR signaling by determining the phosphorylation status of proteins downstream of BCR signaling: SYK, LCK, BTK, PLCγ2, p38, ERK1/2, AKT, NF-κB p65, and STAT5. The proteins were analyzed at the single-cell level in the samples via phospho-specific flow cytometry in combination with fluorescent cell barcoding. Phosphorylation of the BCR signaling proteins was measured in the basal condition and under modulation of the BCR with anti-IgG, anti-IgD, anti-IgM antibodies, or a combination of the 3; circulating B cells from the healthy donors served as the controls.

At baseline, patients with MCL had a median age of 76 years (range, 47-87) and a median white blood cell count of 9 x 109 cells per liter (range, 3-206). Patients had classical (n = 22), blastoid/pleomorphic (n =3), leukemic non-nodal (n = 4), and not determined (n = 1) disease. Most patients either had MCL international prognostic index intermediate (n = 14) or high-risk (n = 14) disease. The median Ki-67 index was 20% (range, 3%-80%). The median OS was 47 months (range, 1-176) and the median PFS was 38 months (range, 1-144).

Additional findings from the study revealed that phosphoprotein variance of pBTK was higher in MCL samples compared with healthy donor samples (σ2 = 0.14 vs 0.03, respectively); the same was true of pPLCγ2 (σ2 = 0.21 vs 0.12). Conversely, comparable variances of pSTAT5 were observed (σ2 = 0.10 vs 0.08). Each signaling protein was constitutively more phosphorylated in samples of patients with higher intrinsic BCR signaling compared with lower basal BCR signaling: SYK (P = .0014); LCK (P = .0015); BTK (P < .0001); PLCγ2 (P = .0003); p38 (P < .0001); ERK1/2 (P < .0001); AKT (P = .0003); NF-κB p65 (P < .0001); and STAT5 (P = .0032).

Phosphorylation response of SYK (P < .0001), LCK (P < .0001), BTK (P < .0001), PLCγ2 (P < .0001), p38 (P = .004), ERK1/2 (P < .0001), AKT (P = .029), and STAT5 (P < .0001) to BCR engagement was significantly higher in the high responder BCR group compared with the low responder BCR group. Additionally, the high responder samples displayed a higher BCR response in terms of SYK (P = .008), LCK (P < .0001), BTK (P < .0001), PLCγ2 (P < .0001), ERK1/2 (P = .0001), AKT (P = .002), and STAT5 (P < .0001) compared with the healthy donor samples.

Regarding ibrutinib resistance, higher levels of pAKT were correlated with a significantly higher resistance to the drug (P = .023) and was confirmed by logistic regression analysis. No association was observed between responses to anti-IgM modulation and response to ibrutinib.

“Overall, these data show that responsiveness profiles of signaling proteins to BCR stimulation, rather than the basal levels of protein phosphorylation, are correlated with disease progression in MCL,” study authors wrote in conclusion. “These findings agree with our previous data in chronic lymphocytic leukemia and with the concept that exposing cancer cell signaling to potentiating inputs, rather than relying upon the basal levels of protein phosphorylation alone, can identify unique cancer signaling profiles that correlate with disease outcome.”

“In conclusion, this study identifies BCR signaling profiles that are associated with poor clinical outcome and resistance to the BTK inhibitor ibrutinib, thus advancing our understanding of signaling heterogeneity underlying clinical behavior of MCL. Future challenges are to use BCR signaling data integrated with genetic signature to predict patient’s clinical behavior and drug response for a more personalized treatment approach.”

Reference

Gambino S, Quaglia FM, Galasso M, et al. B-cell receptor signaling activity identifies patients with mantle cell lymphoma at higher risk of progression. Sci Rep. 2024;14(1):6595. doi:10.1038/s41598-024-55728-9