Ibrutinib for the treatment of relapsed/refractory mantle cell lymphoma: extended 3.5-year follow up from a pooled analysis

The first-in-class, once-daily Bruton tyrosine kinase (BTK) inhibitor ibrutinib is one of the preferred standards of care for patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL), which has a median overall survival (OS) of 4-5 years. We previously reported a pooled analysis of 370 patients with R/R MCL treated with ibrutinib in three studies (phase II PCYC-1104 and SPARK, phase III RAY) with a median 2-year follow up. Here, we present extended 3.5-year follow up. Patients treated with ibrutinib in second line and those achieving a complete response (CR) gained the greatest benefit from ibrutinib, without new long-term safety concerns. Analysis included patients enrolled between 2011 and 2013 who received oral ibrutinib 560 mg QD. Tumor response was evaluated using revised response criteria for malignant lymphoma. Positron emission tomography (PET) scans were not conducted routinely but were required to confirm CR suspected on computed tomography scan. TP53 mutational status was determined by DNA sequencing using formalin-fixed paraffin-embedded slides. Progression-free survival (PFS), duration of response (DOR), and OS were analyzed by number of prior lines of therapy and best tumor response; DOR and PFS were further analyzed for second-line ibrutinib patients with a time to next treatment (TTNT) ≥2 years in front-line treatment, with TTNT serving as an approximation for DOR. Multivariate analysis was performed to identify predictors of PFS and OS. Grade ≥3 or serious treatment-emergent adverse events (TEAEs) were analyzed over time and by number of prior lines of therapy. All analyses are descriptive. Baseline characteristics for the pooled dataset were published previously. Nearly one-third (31.8%) of the 370 patients had high-risk disease per simplified Mantle Cell Lymphoma International Prognostic Index (sMIPI), 48.9% had bulky disease (≥5 cm), 11.9% had blastoid variant, and 73.2% had received ≥2 prior lines of therapy (median 2; range, 1-9). Baseline cardiac risk factors included hypertension in 176 (47.6%) and history of atrial fibrillation (AF) or arrhythmia in 53 (14.3%) patients. Eighty-seven (23.5%) patients benefiting from ibrutinib after completion of the original study rolled over to an open-label access study (CAN3001), 58.6% of whom were receiving ibrutinib at the time of this analysis. Across the overall population, estimated median duration of follow up was 41.4 months [95% confidence interval (CI): 37.3-43.9 months] and median treatment exposure 11.1 months (range, 0.03-76.9 months). Approximately one-third (n=115, 31.1%) of patients received ibrutinib for ≥2 years, including 83 (22.4%) and 62 (16.8%) patients receiving treatment for ≥3 and ≥4 years, respectively. Treatment discontinuation rates due to disease progression, AEs, and death were 59.2%, 10.3%, and 5.1%, respectively. Overall, median PFS and OS were 12.5 (95%CI: 9.816.6) and 26.7 (95%CI: 22.5-38.4) months, respectively (Table 1). Response rates, DOR, PFS, and OS, overall and by subgroups, are summarized in Table 1. Patients receiving ibrutinib in second line had better outcomes than those treated in later lines (>1 prior line): median PFS and OS were 25.4 months (95%CI: 17.557.5) and not reached [NR; 95%CI: 36.0-not estimable (NE)], respectively (Table 1 and Figure 1). Overall response (ORR; 77.8%) and CR (37.4%) rates were higher in second versus later lines, and the median DOR of 35.6 months was twice as long with earlier versus later use (Table 1). Multivariate analyses of PFS and OS were