Ibrutinib Monotherapy in Symptomatic, Treatment-Naïve Patients With Waldenström Macroglobulinemia

Abstract

Purpose Ibrutinib is active in previously treated Waldenström macroglobulinemia (WM). MYD88 mutations ( MYD88) and CXCR4 mutations ( CXCR4) affect ibrutinib response. We report on a prospective study of ibrutinib monotherapy in symptomatic, untreated patients with WM, and the effect of CXCR4 status on outcome. Patients and Methods Symptomatic, treatment-naïve patients with WM were eligible. Ibrutinib (420 mg) was administered daily until progression or unacceptable toxicity. All tumors were genotyped for MYD88 and CXCR4. Results A total of 30 patients with WM received ibrutinib. All carried MYD88, and 14 (47%) carried a CXCR4. After ibrutinib treatment, median serum IgM levels declined from 4,370 to 1,513 mg/dL, bone marrow involvement declined from 65% to 20%, and hemoglobin level rose from 10.3 to 13.9 g/dL ( P < .001 for all comparisons). Overall (minor or more than minor) and major (partial or greater than partial) responses for all patients were 100% and 83%, respectively. Rates of major (94% v 71%) and very good partial (31 v 7%) responses were higher and time to major responses more rapid (1.8 v 7.3 months; P = 0.01) in patients with wild-type CXCR4 versus those with CXCR4, respectively. With a median follow-up of 14.6 months, disease in two patients (both with CXCR4) progressed. The 18-month, estimated progression-free survival is 92% (95% CI, 73% to 98%). All patients are alive. Grade 2/3 treatment-related toxicities in > 5% of patients included arthralgia (7%), bruising (7%), neutropenia (7%), upper respiratory tract infection (7%), urinary tract infection (7%), atrial fibrillation (10%), and hypertension (13%). There were no grade 4 or unexpected toxicities. Conclusion Ibrutinib is highly active, produces durable responses, and is safe as primary therapy in patients with symptomatic WM. CXCR4 status affects responses to ibrutinib.

CXCR4 S338X clonality is an important determinant of ibrutinib outcomes in patients with Waldenström macroglobulinemia

“…10,11 Prospective studies have also reported that CXCR4 mutations are associated with lower response rates, delayed response attainment, and shorter PFS on ibrutinib. [12][13][14][15] However, these studies included heterogenous groups of CXCR4-mutated patients, and were not large enough to discriminate the effect of individual somatic variants.…”

“…5,10,11 CXCR4 mutations also confer both in vitro and clinical resistance to ibrutinib, particularly nonsense variants such as CXCR4 S338X . [10][11][12][13][14][15][16] In WM patients, CXCR4 S338X constitutes the most common CXCR4 mutation identified. 3,5 CXCR4 S338X is primarily subclonal to mutated MYD88, but shows a highly variable clonal distribution.…”

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

“…Responses to ibrutinib and survival are not only impacted by MYD88 L265P but also by CXCR4 mutations [100]. A few drugs targeting CXCR4 are currently under investigation, as the response rates with ibrutinib alone are lower in the patient population with mutated CXCR4 compared to those who have the CXCR4 signature [127,128]. The CXCR4 antagonist ulocuplumab (BMS-936564/MDX1338) is a fully human IgG monoclonal antibody that is being evaluated in combination with ibrutinib in a phase 1/2 clinical trial for patients with relapsed or refractory WM (RRWM) only, who harbor a CXCR4 mutation (NCT03225716).…”

How I treat Waldenström macroglobulinemia

“…In previously untreated patients, ibrutinib monotherapy resulted in high response rates (no complete responses); these occurred slower in those carrying CXCR4 WHIM , but the follow-up is still short. 65 Ibrutinib is active in both rituximab-sensitive and rituximab-refractory patients. 62,63 In the initial phase 2 study, 5-year PFS was 60% and 5-year overall survival (OS) was 87%, but responses and PFS were better in patients with the MYD88 L265P /CXCR4 WT than the MYD88 L265P / CXCR4 WHIM genotype; among the few patients with MYD88 WT , the responses were minor and PFS short.…”