Mantle cell lymphoma (MCL) is a rare B-cell lymphoma that is clinically and biologically heterogeneous. Some individuals present with indolent disease that can be observed for years, or with highly aggressive disease with significant disease burden and urgent need for therapy. Most patients present with advanced-stage disease including frequent involvement of extranodal sites such as the gastrointestinal system and/or peripheral blood. The median age of diagnosis is in the early 60s, and there is a male predominance. Historically, MCL was associated with a poor prognosis, with a median overall survival (OS) of three to five years.1
Traditionally, the most common frontline approach has been chemotherapy, the intensity of which is driven by patient fitness. For patients who could tolerate an intensive, cytarabine-based induction, high-dose therapy and autologous stem cell transplantation followed by three years of maintenance rituximab (R) resulted in progression-free survival (PFS) and OS rates of 83 percent and 89 percent at four years.2 However, for less fit patients, R-bendamustine is a preferred frontline option given its superior PFS (though no difference in OS) and a more favorable safety profile compared to R plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in previously untreated indolent lymphoma and MCL.3 Though there is a clear role for maintenance R following R-CHOP, or R-cytarabine–based induction and autologous stem cell transplantation, the role for R maintenance following R-bendamustine is less clear.
Fortunately, major therapeutic advances have been possible due to an enhanced understanding of B-cell biology, including how malignant B cells exploit the B-cell receptor signaling pathway to their survival advantage. Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor and mediator of the B-cell receptor signaling pathway, is an effective targeted agent with a response rate of 68 percent (complete response rate of 21%) in relapsed or refractory MCL.4 A phase I study showed that the addition of ibrutinib to R-bendamustine was safe, and 76 percent achieved a complete response, supporting further study of this triplet combination.5
The SHINE study is a randomized, double-blind, phase III trial evaluating the combination of ibrutinib with R-bendamustine compared with placebo with R-bendamustine in older patients (≥65 years; median, 71 years) with untreated MCL. Ibrutinib (560 mg) or placebo was administered orally once daily until disease progression or unacceptable toxicity. Patients received six cycles of R (375 mg/m2) plus bendamustine (90 mg/m2 on days 1 and 2 of each cycle), and responding patients received R maintenance (every 8 weeks for up to 12 doses). The primary end point was PFS as assessed by the investigators.
At a median follow-up of 84.7 months, the median PFS was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (p=0.01). OS was no different. Forty-one patients (39%) in the placebo group received a second-line BTK inhibitor. Adverse events leading to death during the treatment period occurred in 10.7 percent in the ibrutinib group and 6.1 percent in the placebo group. The authors concluded that ibrutinib in combination with standard chemoimmunotherapy significantly prolonged PFS in previously untreated patients with MCL with no new safety signals.
In Brief
There are some important observations when we shine the light on the SHINE study. There is no difference in OS observed, and the addition of ibrutinib to R-bendamustine resulted in higher rates of toxicity. Therefore, is it necessary to pursue the triplet or can we continue to sequence therapy? Would a better-tolerated BTK inhibitor have been a more attractive combination partner? Is PFS the most clinically impactful end point when continuous therapy is only pursued in the experimental arm? A nonchemotherapy arm with rational partners might have been a more attractive strategy for the experimental arm to move away from chemotherapy in older patients. Despite these limitations, the authors should be commended for completing a randomized study in a subgroup of a rare tumor type.
Competing Interests
Dr. Nastoupil indicated no relevant conflicts of interest.
