Maria Demos

Purpose Ibrutinib is active in previously treated Waldenström macroglobulinemia (WM). MYD88 mutations ( MYD88 MUT ) and CXCR4 mutations ( CXCR4 MUT ) affect ibrutinib response. We report on a prospective study of ibrutinib monotherapy in symptomatic, untreated patients with WM, and the effect of CXCR4 MUT 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 MUT and CXCR4 MUT . Results A total of 30 patients with WM received ibrutinib. All carried MYD88 MUT , and 14 (47%) carried a CXCR4 MUT . 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 MUT , respectively. With a median follow-up of 14.6 months, disease in two patients (both with CXCR4 MUT ) 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 MUT status affects responses to ibrutinib.

Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM), including MYD88 (95%-97%), CXCR4 (30%-40%), ARID1A (17%), and CD79B (8%-15%). Deletions involving chromosome 6q are common in patients with mutated MYD88 and include genes that modulate NFKB, BCL2, Bruton tyrosine kinase (BTK), and apoptosis. Patients with wild-type MYD88 WM show an increased risk of transformation and death and exhibit many mutations found in diffuse large B-cell lymphoma. The discovery of MYD88 and CXCR4 mutations in WM has facilitated rational drug development, including the development of BTK and CXCR4 inhibitors. Responses to many agents commonly used to treat WM, including the BTK inhibitor ibrutinib, are affected by MYD88 and/or CXCR4 mutation status. The mutation status of both MYD88 and CXCR4 can be used for a precision-guided treatment approach to WM.

Key Points BTKCys481 mutations, including multiple mutated variants within individual patients are common in ibrutinib-progressing WM patients. BTKCys481 mutations were associated with mutated CXCR4 in WM patients progressing on ibrutinib.

Summary MYD 88 mutations are present in 95% of Waldenstrom Macroglobulinaemia ( WM ) patients, and support diagnostic discrimination from other IgM‐secreting B‐cell malignancies. Diagnostic discrimination can be difficult among suspected wild‐type MYD 88 ( MYD 88 WT ) WM cases. We systematically reviewed the clinical, pathological and laboratory studies for 64 suspected MYD 88 WT WM patients. World Health Organization and WM consensus guidelines were used to establish clinicopathological diagnosis. Up to 30% of suspected MYD 88 WT WM cases had an alternative clinicopathological diagnosis, including IgM multiple myeloma. The estimated 10‐year survival was 73% (95% confidence interval [ CI ] 52–86%) for MYD 88 WT versus 90% (95% CI 82–95%) for mutated ( MYD 88 MUT ) WM patients (Log‐rank P < 0·001). Multivariate analysis only showed MYD 88 mutation status ( P < 0·001) as a significant determinant for overall survival. Diffuse large B‐cell lymphoma ( DLBCL ) was diagnosed in 7 (15·2%) and 2 (0·76%) of MYD 88 WT and MYD 88 MUT patients, respectively (Odds ratio 23·3; 95% CI 4·2–233·8; P < 0·001). Overall survival was shorter among MYD 88 WT patients with an associated DLBCL event (Log‐rank P = 0·08). The findings show that among suspected MYD 88 WT WM cases, an alternative clinicopathological diagnosis is common and can impact clinical care. WM patients with MYD 88 WT disease have a high incidence of associated DLBCL events and significantly shorter survival versus those with MYD 88 MUT disease.

Summary Ibrutinib is associated with response rate of 90% and median progression‐free survival (PFS) in excess of 5 years in Waldenström macroglobulinaemia (WM) patients. CXCR4 mutations are detected in 30–40% of patients with WM and associate with lower rates of response and shorter PFS to ibrutinib therapy. Both frameshift ( CXCR4 FS ) and nonsense ( CXCR4 NS ) CXCR4 mutations have been described. The impact of these mutations on outcomes to ibrutinib have not been evaluated in WM patients. We studied consecutive patients with a diagnosis of WM, on ibrutinib therapy, for the presence of CXCR4 FS and CXCR4 NS mutations and evaluated the differences in response and PFS between groups. Of 180 patients, 68 patients (38%) had CXCR4 mutations; 49 (27%) had CXCR4 NS and 19 (11%) had CXCR4 FS mutations. In multivariate models, patients with CXCR4 NS had lower odds of major response (Odds ratio 0·25, 95% confidence interval [CI] 0·12–0·53; P < 0·001) and worse PFS (Hazard ratio 4·02, 95% CI 1·95–8·26; P < 0·001) than patients without CXCR4 mutations. CXCR4 FS was not associated with worse major response or PFS rates than patients without CXCR4 mutations. Our results suggest different response and PFS rates to ibrutinib for WM patients with CXCR4 NS and CXCR4 FS , and advocate in favour of CXCR4 mutational testing as well as CXCR4 ‐directed therapy.