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Ibrutinib plus bendamustine-rituximab for treatment naïve mantle-cell lymphoma

Results of the phase 3 SHINE trial show that ibrutinib in combination with bendamustine plus rituximab and rituximab maintenance therapy is an effective first-line treatment for patients with mantle-cell lymphoma who were 65 years of age or older and were considered to be unsuitable candidates for an autologous stem-cell transplantation.


Mantle-cell lymphoma (MCL) is an incurable subtype of B-cell non-Hodgkin’s lymphoma. Most patients with MCL are older and are unsuitable for aggressive treatment or autologous stem-cell transplantation, resulting in suboptimal clinical outcomes for these patients. Current guidelines recommend less-aggressive first-line therapy in older patients, such as bendamustine plus rituximab (BR), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), or VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone). Of these combinations, BR has become one of the most-used first-line regimens for MCL, mainly because of clinical trial data indicating a longer progression-free survival (PFS) with this combination than with R-CHOP. Furthermore, two observational studies showed an additional PFS and overall survival (OS) benefit with the addition of rituximab maintenance therapy after induction therapy with BR. Single-agent ibrutinib, an oral Bruton’s tyrosine kinase (BTK) inhibitor, has transformed the care of patients with relapsed or refractory mantle-cell lymphoma with its durable activity, particularly when it is used at first relapse. Building further on these data, the randomized, double-blind, phase III SHINE trial evaluated the combination of ibrutinib with BR and R maintenance therapy in older patients with untreated MCL.

Study design

SHINE randomly assigned 523 patients ≥ 65 years of age to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg/m2 body-surface area) and rituximab (375 mg/m2). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary endpoint of the trial consisted of PFS, with OS and safety as key secondary study objectives.


The median age of patients in the study was 71 years, with approximately 30% of patients being 75 years or older. At the data-cutoff date for the primary analysis, the median follow-up among all the patients was 84.7 months. In the ibrutinib group, 209 patients (80.7%) received all six cycles of induction therapy with BR, and 206 patients (78.9%) received at least one cycle of R maintenance therapy. In the placebo group, 215 patients (82.7%) received all six cycles of induction therapy with BR, and 210 patients (80.2%) received at least one cycle of R maintenance therapy. The median duration of the treatment period was 24.1 months (with ibrutinib and 34.1 months with placebo. At data cut-off, 220 patients (84.3%) in the ibrutinib group and 201 (76.7%) in the placebo group had discontinued all trial treatments. The most common reasons for discontinuation were an adverse event (in 39.5% of the patients in the ibrutinib group and in 24.0% of those in the placebo group) or progressive disease or relapse (in 10.7% and 34.7%, respectively).

Patients in the experimental arm experienced a significant 2.3 years improvement in PFS compared to patients in the control arm, with a median PFS of 80.6 and 52.9 years, respectively (HR[95%CI]: 0.75[0.59-0.96]; p= 0.011). This PFS was observed irrespective of sex, age, ECOG performances status and tumor bulk. Also in patients with a blastoid/pleomorphic histology and with a TP53 mutation, the addition of ibrutinib induced a clinically relevant prolongation of the median PFS. One exception consists of the subgroup of patients with a high risk simplified MIPI score at baseline in whom no benefit was observed from adding ibrutinib. The objective response rate (ORR) was comparable between both arms (89.7% vs. 88.5%), but a numerically higher percentage of patients obtained a complete response (CR) in the ibrutinib arm (65.5% vs. 57.6%, p= 0.057). Also the time to the next line of therapy was significantly longer in patients receiving ibrutinib compared to the control arm (median not reached vs. 92 months; HR[95%CI]: 0.48[0.34-0.66]). Results for OS were immature at the time of the analysis.

Adverse events of grade ≥ 3 occurred in 81.5% of the patients in the ibrutinib group and in 77.3% of those in the placebo group. The most common grade ≥ 3 adverse events being neutropenia (47.1% vs. 48.1%), pneumonia (20.1% vs. 14.2%), lymphopenia (16.2% vs. 11.9%) and anemia (15.4% vs. 8.8%). The incidence of atrial fibrillation, an expected adverse event with BTK inhibitors, was higher in the ibrutinib group (13.9%) than in the placebo group (6.5%). Hypertension, arthralgia, and major hemorrhage were observed at a similar incidence in the two trial groups over the prolonged follow-up.


Adding ibrutinib to standard chemoimmunotherapy significantly prolongs the PFS of previously untreated MCL patients. In addition, ibrutinib increased the CR rate and significantly delayed the time to next therapy. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. Results for OS were still immature.


M. Wang, et al. Primary results from the phase III SHINE study of ibrutinib in combination with bendamustine-rituximab and R maintenance as a first line treatment for older patients with mantle cell lymphoma. Presented at EHA 2022; Abstract S209.

Speaker Michael Wang

Michael Wang

Michael Wang, MD, University of Texas MD Anderson Cancer Center, Houston, TX, USA


See: Keyslides


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