Ibrutinib With Bendamustine and Rituximab Prolongs PFS in Treatment-Naïve MCL

Frontline treatment with ibrutinib, bendamustine, and rituximab showed a prolongation in progression-free survival along with a good response rate in older patients with mantle cell lymphoma.

Ibrutinib (Imbruvica) combined with bendamustine, and rituximab (Rituxan) demonstrated improvement in progression-free survival (PFS) compared with placebo in patients with previously untreated mantle cell lymphoma (MCL), according to published results from the SHINE clinical trial (NCT01776840).1

The median PFS observed with the ibrutinib combination was 80.6 months (95% CI, 61.0 months-not evaluable [NE]) compared with 52.9 months (95% CI, 43.7-71.0 months) in the placebo arm (HR, 0.75; 95% CI, 0.59-0.96; P =.01). Notably, the PFS result was longer than previously shown with rituximab (Rituxan) plus cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) combined with rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP), and bendamustine in a phase 3 study of patients with newly-diagnosed MCL.2

Moreover, the PFS benefit of the ibrutinib combination was observed across most prespecified subgroups.1

“The separation of the progression-free survival curves occurred within the first year after the initiation of treatment, and the benefit was durable throughout the median follow-up of 7 years,” wrote the study authors led by Michael L. Wang. MD, professor in the department of Lymphoma & Myeloma at the University of Texas MD Anderson Cancer Center.

The Bruton’s tyrosine kinase inhibitor, ibrutinib, has transformed the treatment landscape for relapsed or refractory MCL considering its durable activity in the patient population. In an earlier phase 1b study, ibrutinib added to bendamustine plus rituximab showed was deemed safe and tolerable and achieved an objective response rate (ORR) of 76%. Investigators sought to further explore the combination of ibrutinib, bendamustine, and rituximab in the SHINE study.

The study included 523 patients with previously-untreated MCL and randomly assigned 261 to the ibrutinib combination arm and 262 to the placebo arm. The median age in the ibrutinib group was 71 years (range, 65-86 years), and in the placebo group, the median age was 71 years (range, 65-87 years). More patients (62.1%) were ≥ 70 years old in the ibrutinib combination arm compared with the placebo arm (58.8%). Contrarily, more patients in the placebo arm (31.3%) were ≥ 75 years old compared with the ibrutinib arm (28.4%). The population was largely male, and most were either White or Asian.

The median time from the initial diagnosis to treatment was 1.4 months (range, 0.2-116.1 months) in the ibrutinib group vs 1.5 months (range, 0.1-66.1) in the placebo group. Most patients had an ECOG performance score of 0, stage IV disease, and intermediate-risk disease. Bone marrow involvement was found in 75.9% of the ibrutinib group vs 76.3% of the placebo group. For histologic features, many patients in both treatment arms had nonblastoid or nonpleomorphic tumors. Over 85% of patients in both arms had extranodal disease. Tumor bulk was < 5 cm in largest diameter for more than 60% of patients in each arm. Tumor bulk was ≥ 5 cm in largest diameter in greater than 30% of patients in each arm. Most patients in the study had unknown tp53 status, but among those with known tp53 status, more than 40% in each arm were tp53 unmutated.

Patients included in the SHINE study were assessed for the primary end point of PFS. The key secondary end points of the study included overall survival (OS), complete response (CR) rate, time to next treatment, the percentage of patients with an overall response, minimal residual disease (MRD)-negative response rate, time to worsening in the Lymphoma Subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym), duration of response, duration of complete response, time to response, and the number of patients with treatment-emergent adverse events (TEAEs).

Results from the SHINE study showed that the 7-year OS rate in the ibrutinib-treated patients was 55.0% compared with 56.8% in the placebo arm (HR 1.01; 95% CI, 0.81-1.40), showing no significant difference between the 2 arms. The CR rate was 65.5% with the ibrutinib combination vs 57.6% with placebo (P =0.06). The percentage of patients with an objective response was 89.7% in the ibrutinib arm vs 88.5% in the placebo arm. Following treatment, MRD was undetectable in 62.1% of the ibrutinib group compared with 56.5% in the placebo group.

Any-grade AEs occurred in all patients in the ibrutinib group compared with 98.8% of the placebo group. Grade 3 or 4 AEs occurred in 81.5% of the ibrutinib arm vs 77.3% of the placebo arm. The most common grade 3/4 AEs observed with ibrutinib vs placebo, respectively were neutropenia (47.1% vs 48.1%), pneumonia (20.1% vs 14.2%,), lymphopenia 16.2% vs 11.9%), anemia (15.4% vs 8.8%), thrombocytopenia (12.7% vs 13.1%), rash (12.0% vs 1.9%), and leukopenia (10.0% vs 11.2%).

The AEs of clinical interest included atrial fibrillation, hypertension, diarrhea, major hemorrhage, and arthralgia. One patient in each arm experienced pneumocystis pneumonia, and aspergillus infection was seen in 4 patients treated with the ibrutinib combination vs 1 in the placebo group. AEs were the main cause of death for 28 patients in the ibrutinib group vs 16 in the placebo arm. Other deaths were caused by either cardiac disorder or coronavirus.

Patient-reported outcomes according to the FACT-Lym scale showed no significant difference in time to worsening between the 2 groups (HR 1.02; 95% CI, 0.83-1.26).

Overall, Wang et al consider front-line ibrutinib with bendamustine and rituximab maintenance therapy to be an effective option for patients with MCL who 65 years of age or older and who are not suitable for stem cell transplantation.


1. Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med. 2022; 386:2482-2494. doi.10.1056/NEJMoa2201817

2. Robak T, Jin J, Pylypenko H, et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2022;19(11):1449-1458. doi:10.1016/S1470-2045(18)30685-5

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