High CXCL13 level at baseline strongly predicts the achievement of PR or better following one year of ibrutinib therapy for Waldenström Macroglobulinemia

On 10th August, Josephine M. Vos from St. Antonius Hospital, Nieuwegein, The Netherlands, et al. published in Haematologica their investigation into the serum cytokine profiles of Waldenström Macroglobulinemia (WM) patients based on MYDD88 and CXCR4 mutation status, and how serum cytokine levels change in response to therapy with ibrutinib.

Firstly, samples from 86 patients off-therapy (first-line = 52; Relapsed/Refractory [R/R] = 34; MYD88L265P/CXCR4WT = 45; MYD88L265P/CXCR4MUT = 32; MYD88WT/CXCR4WT = 9) were compared to samples from age and gender matched Healthy Donors (HD; n = 20). Following this, samples were analyzed from 29 R/R WM patients who had received ibrutinib on a prospective clinical trial and had baseline and post-treatment serum samples taken one year after therapy initiation (MYD88L265P/CXCR4WT = 19; MYD88L265P/CXCR4MUT = 9; MYD88WT/CXCR4WT = 1).

Overall, 24 cytokines were analyzed and included the known WM biomarker CD27.

Key Highlights:
WM patients versus HDs:
  • In the initial 86 pts: median age = 63 years (range, 31–94); median Bone Marrow (BM) infiltration = 58% (range, 3–95%); median IgM level = 3,632mg/dL (range, 134–7,400); male = 74% (64/86)
  • In HDs: median age = 57 years (38–80); male = 75% (15/20)
  • Regardless of previous therapy status, levels of the following cytokines were significantly higher in WM pts versus HDs: CXCL10 (+1.7 fold; P = 0.004), IL10 (+13.9; P < 0.001), IL2RA (+4.3 fold; P < 0.001), CXCL13 (+33.8 fold; P < 0.001), and sCD27 (+174.1 fold; P < 0.001)
  • In WM pts, serum levels of CXCL13, IL2RA, and sCD27 strongly correlated with hemoglobin levels with correlation coefficients of -0.55, -0.55, and -0.47, respectively (P < 0.001 for all three)
  • In WM pts, serum levels of CXCL13 (rho = 0.56; P < 0.001) and sCD27 (rho = 0.46; P < 0.001) correlated with BM infiltration
  • MYD88L265P/CXCR4WT pts had significantly higher levels of IL6 versus HDs (+1.8 fold; P = 0.001)
  • In MYD88L265P, IL2RA (+2.2 fold; P = 0.025), IL1RA (+1.5 fold; P = 0.003), CXCL10 (+1.5 fold; P = 0.026), and sCD27 (+1.7 fold; P = 0.016) levels were higher in CXCR4WT pts versus CXCR4MUT pts
  • No differences in cytokine levels were found in patients with symptomatic compared to asymptomatic disease
Cytokine levels in response to ibrutinib:
  • After one year on ibrutinib, 12/24 (50%) of cytokines showed a significant change
  • The most significant decreases were documented for TNFα (-1.6 fold), IL2RA (-2.2 fold), and CXCL13 (-38.2 fold); P < 0.001 for all three
  • CXCL13 was associated with the achievement of major response after one year on ibrutinib: CXCL13 was 451.6 fold higher in pts who achieve major responses compared to those who did not (P = 0.049)
  • After one year of treatment, a significantly greater decrease in CXCL13 levels was reported in patients who achieved major response (-306.9 fold) compared to those without major response (-2.3 fold); P = 0.019)
  • Levels of CXCL13 were not different based on CXCR4 mutational status (P = 0.199)
  • Changes in level of CXCL13 correlated with changes in hemoglobin (rho = -0.64; P = 0.005) and serum IgM levels (rho = 0.68; P = 0.002)

The authors state that their findings are the first to be published regarding changes in cytokine levels after ibrutinib therapy for WM. The group drew attention to the fact that their results mirror what has been previously found for Chronic Lymphocytic Leukemia (CLL) treated with ibrutinib, primarily changes in CXCL13, IL8, CXCL10, CCL4, CCL11, IL1RA, and TNFα. They hypothesize that these changes could be due to on-target tumor effects resulting in reduced cytokine production by lymphoplasmacytic lymphoma cells or the impact of ibrutinib on cells of the microenvironment e.g. T-cells, macrophages, etc.

It was also found that a high CXCL13 level at baseline strongly predicted the achievement of PR or better following one year of ibrutinib therapy, and deep suppression of CXCL13 was associated with major responses. To their knowledge, the authors state that there are currently no published findings of CXCL13 as a predictor of response to ibrutinib in CLL or other B-cell malignancies.

In conclusion, this group’s findings indicate a that CXCL13 has a key role in the tumor biology of WM, as well as in sensitivity to treatment with ibrutinib therapy. It is recommended that the accuracy and plausibility of CXCL13 as a biomarker for ibrutinib therapy, as well as a potential therapeutic target, is investigated in the future.



  1. Vos J.M. et al. CXCL13 levels are elevated in patients with Waldenstrom's Macroglobulinemia, and are predictive of major response to ibrutinib. Haematologica. 017 Aug 10. pii: haematol.2017.172627. DOI: 10.3324/haematol.2017.172627. [Epub ahead of print].