Waldenström macroglobulinemia (WM) patients with high CXCR4S338X clonality had worse clinical outcomes after ibrutinib therapy compared with patients who had low CXCR4S338X clonality, according to the results of a single-institution study recently reported in Blood Advances.1

The study included 147 patients with WM who were consecutively identified between May 2012 and January 2018 and received ibrutinib monotherapy. Among those patients, 37 patients had a CXCR4S338X mutation and 110 did not.

Patients with a CXCR4S338X mutation had a worse major response rate (62% vs 85%; P = 0.001) and very good partial response rate (11% vs 35%; P = 0.006) compared with patients with wild-type CXCR4.

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In addition, the presence of a CXCR4S338X mutation was correlated with a significantly shorter progression-free survival (PFS; 44.1 months vs not reached) and higher likelihood of disease progression or death (hazard ratio [HR], 5.03; 95% CI, 1.91-13.2; P =.001) compared with the presence of a CXCR4 wild-type.

The 37 patients with a CXCR4S338X mutation were then grouped based on clonality. A total of 23 patients had high clonality (≥ 25%) and 14 patients had low clonality (< 25%).

Patients with high CXCR4S338X clonality had a significantly higher likelihood of disease progression or death compared with patients with CXCR4 wild-type (HR, 10.44; 95% CI, 3.43-31.8; P =.0001). In contrast, patients with low CXCR4S338X clonality did not (HR, 0.90; 95% CI, 0.13-6.44; P =.92).

In addition, patients with high CXCR4S338X clonality had a significantly worse median PFS (39.9 months; P =.0001) compared with both patients with low clonality (not reached) or CXCR4 wild-type (not reached).

“In summary, high CXCR4S338X clonality adversely impacts clinical outcomes to ibrutinib therapy in WM patients,” the study authors wrote. “Clonality assessment represents a novel biomarker for predicting outcomes on ibrutinib in WM patients carrying CXCR4S338X nonsense mutations.”


  1. Gustine JN, Xu L, Tsakmaklis N, et al. CXCR4 S338X clonality is an important determinant of ibrutinib outcomes in patients with Waldenström macroglobulinemia. Blood Adv. 2019;3:2800-2803.