Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis

Abstract

Advanced marginal zone lymphoma (MZL) is an incurable B-cell malignancy dependent on B-cell receptor signaling. The phase 2 PCYC-1121 study demonstrated the safety and efficacy of single-agent ibrutinib 560 mg/d in 63 patients with relapsed/refractory MZL treated with prior rituximab (RTX) or rituximab-based chemoimmunotherapy (RTX-CIT). We report the final analysis of PCYC-1121 with median follow-up of 33.1 months (range: 1.4-44.6). Overall response rate (ORR) was 58%; median duration of response (DOR) was 27.6 months (95% confidence interval [CI]: 12.1 to not estimable [NE]); median progression-free survival (PFS) was 15.7 months (95% CI: 12.2-30.4); and median overall survival (OS) was not reached (95% CI: NE to NE). Patients with prior RTX treatment had better outcomes (ORR: 81%; median DOR: not reached [95% CI: 12.2 to NE]; median PFS: 30.4 months [95% CI: 22.1 to NE]; median OS: not reached [95% CI: 30.3 to NE]) vs those with prior RTX-CIT treatment (ORR: 51%; DOR: 12.4 months [95% CI: 2.8 to NE]; PFS: 13.8 months [95% CI: 8.3-22.5]; OS: not reached [95% CI: NE to NE]). ORRs were 63%, 47%, and 62% for extranodal, nodal, and splenic subtypes, respectively. With up to 45 months of ibrutinib treatment, the safety profile remained consistent with prior reports. The most common grade ≥3 event was anemia (16%). Exploratory biomarker analysis showed NF-κB pathway gene mutations correlated with outcomes. Final analysis of PCYC-1121 demonstrated long-term safety and efficacy of ibrutinib in patients with relapsed/refractory MZL, regardless of prior treatment or MZL subtype. This trial was registered at www.clinicaltrials.gov as #NCT01980628.

Primary Pulmonary B-Cell Lymphoma: A Review and Update

“…Novel therapeutic strategies are being currently explored in ongoing clinical trials. Noy et al recently reported on long-term safety and efficacy of single agent ibrutinib, a Bruton’s tyrosine kinase inhibitor, in a cohort of relapsed/refractory MZLs previously treated with rituximab, alone or in combination [ 81 ]. Preliminary clinical evidence indicated that PI3K inhibitors copanlisib and umbrasilib showed excellent activity in MZL [ 82 ].…”

Chemotherapy-Free Management of Follicular and Marginal Zone Lymphoma

“…Grade ≥ 3 AEs occurred in 71% of patients including grade ≥ 3 infection in 22%. 109 Most adverse events were grade 1/2, and grade ≥3 events included also anemia (16%), pneumonia (8%) and fatigue (6%). Ibrutinib is thus an excellent option for older patients whose MZL is refractory to rituximab monotherapy.…”

“…In MZL, the use of ibrutinib is more compelling, as it attains 58% ORR (81% for those pre-treated with rituximab only) with a median PFS of 16 months and median duration of response of 28 months. 108 , 109 It is now FDA-approved for use in relapsed/refractory MZL. Ibrutinib is tolerable among older patients, with the oldest patient enrolled in a phase 2 trial being 92 years old.…”

How we treat mature B-cell neoplasms (indolent B-cell lymphomas)

“…In MZL, the frequency of MYD88 mutation is less than 5% while ORR to ibrutinib 48%, suggesting that responses are independent of MYD88 mutation status [ 204 , 205 ]. Notwithstanding, in a recent analysis in R/R MZL, patients with TNFAIP3 mutations had better responses to ibrutinib and those with MYD88L265P mutations had longer PFS [ 206 ]. Conversely, patients with mutations in KMT2D and CARD11 derived less benefit from treatment.…”