Expert Discusses Frontline Bortezomib in MCL

Andrew Evens, DO, MSc

Late last year, the FDA approved bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to be used as a frontline treatment in patients with mantle cell lymphoma (MCL).

The decision was based on findings from the phase III LYM-3002 study that compared VR-CAP with standard R-CHOP in previously untreated patients with MCL. In the study, VR-CAP improved progression-free survival (PFS) by 37% compared with standard R-CHOP. Data from the study were recently published in The New England Journal of Medicine.

To gain new insight on this pivotal study and bortezomib’s use in the frontline MCL setting, OncLive interviewed Andrew Evens, DO, MSc, director of the Tufts Cancer Center and chief of the Division of Hematology/Oncology at Tufts University School of Medicine.

What was the rationale behind this study?

MCL is a subtype of non-Hodgkin lymphoma that is very treatable but is often aggressive and not curable. Despite being able to give patients treatment and obtain remission, these remissions are often short-lived. There is a need to find tolerable treatments that can extend the time that patients are in remission or even find a cure.

This study represents another step in that process. There have been a few studies over the years that have tried to improve upon the natural history of MCL, but we have not had many breakthroughs for patients with newly diagnosed disease. There are several new targeted agents that have been approved by the FDA for patients with relapsed or refractory MCL, but there had really been none approved for patients with newly-diagnosed or untreated disease.

Bortezomib is one agent that’s been approved for patients with relapsed or refractory disease. The hope is not to wait for a relapse, but rather, to bring it to the frontline or untreated patient population. In this study, the research team replaced vincristine with bortezomib in frontline therapy with R-CHOP.

What did the study find?

The study really hit all of its endpoints in terms of response and PFS. Median PFS was 14.4 months among patients receiving the standard R-CHOP, and it was 24.7 months among patients in the bortezomib arm.

On the bortezomib arm, there was an increased risk of hematologic toxicity. It’s known that vincristine is associated with neurologic toxicity. How do these toxicities compare?

We don’t want to increase any toxicity, but in treating these lymphomas, we are very used to managing hematologic toxicities. These toxicities are not life-threatening— they’re manageable. Patients usually don’t feel hematologic toxicities. They’re just blood numbers. However, a neurologic toxicity can really affect a patient’s quality of life.

How are these hematologic toxicities managed?

In the control arm, there was an increased incidence of thrombocytopenia. This is usually managed with observation. If it dips too low, the patient would need a platelet transfusion. In this case, though, only a small percentage needed this procedure.

What does the approval of frontline bortezomib mean for practicing oncologists/hematologists?

This is an important breakthrough in the treatment of newly diagnosed MCL. We now have a novel therapeutic agent that, when integrated into standard frontline therapy, can benefit meaningful endpoints.

Is this practice changing now?

I think this is potentially practice changing. When these studies are designed, they are designed with an understanding of the science at that time.

When the trial started, R-CHOP was a fairly standard regimen. Now, we still use R-CHOP, but we’ll then give 2 years of rituximab maintenance. The unanswered question here is, “Would these patients who benefitted from bortezomib benefit in the same way when given rituximab as maintenance?” There are studies ongoing right now that are addressing this.

E1411 should really define and potentially be practice changing, given the current standard of rituximab maintenance.

[E1411 is a phase II four-arm study of patients with untreated MCL. The study is comparing rituximab plus bendamustine followed by rituximab consolidation; rituximab plus bendamustine and bortezomib followed by rituximab consolidation; rituximab plus bendamustine followed by lenalidomide plus rituximab consolidation; and rituximab plus bendamustine and bortezomib followed by lenalidomide plus rituximab consolidation.]

What questions remain in newly diagnosed MCL?

I think the whole platform is integrating targeted therapeutic agents with agents we already have. We’re still figuring out out the impact of adding bortezomib and lenalidomide, but what about ibrutinib? How do we integrate ibrutinib into practice? We might use ibrutinib with chemotherapy or we could use it with other targeted agents.

Immune checkpoint inhibitors have not had as big of an impact yet in MCL, but they’re not a priority yet.

We could get to a point in the next decade when we use all targeted agents in this space. That’s where oncology is moving in general, not just in MCL.