CXCR4^S338X Clonality Predicts Ibrutinib Outcomes in Waldenström Macroglobulinemia

Waldenström macroglobulinemia (WM) patients with high CXCR4^S338X clonality had worse clinical outcomes after ibrutinib therapy compared with patients who had low CXCR4^S338X 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 CXCR4^S338X mutation and 110 did not.

Patients with a CXCR4^S338X 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.

In addition, the presence of a CXCR4^S338X 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 CXCR4^S338X 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 CXCR4^S338X 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 CXCR4^S338X clonality did not (HR, 0.90; 95% CI, 0.13-6.44; P =.92).

In addition, patients with high CXCR4^S338X 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 CXCR4^S338X 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 CXCR4^S338X nonsense mutations.”

Reference

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.