Andre Goy, MD
Lymphoma expert Andre Goy, MD, discussed the emerging landscape of mantle cell lymphoma (MCL) therapy at the 18th Annual International Congress on Hematologic Malignancies. Several novel agents are being tested in clinical trials for MCL. “This field is changing rapidly,” said Goy, who is chairman and director, and chief of the Lymphoma Division at John Theurer Cancer Center.
Improvement in Outcomes With High-Intensity Induction Chemotherapy
According to Goy, the progression-free survival (PFS) of more than 5 years that current patients with MCL can experience is attributed to intensive chemotherapy approaches, and particularly, regimens that incorporate a high-dose version of the chemotherapy agent cytarabine. A recent analysis of 167 patients aged <65 years treated with intense chemotherapy regimens who were not on a clinical trial showed that patients treated with a high-intensity regimen had improved PFS and overall survival (OS) compared with those treated with R-CHOP.1
For those patients who are younger, several studies have shown that an induction regimen containing high-dose cytarabine improves outcomes, with a 5-year event-free survival of 56% to 65%. A recent large European trial demonstrated that high-dose cytarabine in addition to R-CHOP significantly increased complete response rates and prolonged time to treatment failure from 46 months to 88 months (P
= .038) in patients aged <65 years.2
“This trial showed that the benefit of cytarabine is related to patients achieving minimal residual disease sooner and faster,” said Goy.
Still, there is a great need for novel therapies, as about 50% of patients are not eligible for intensive chemotherapies, and a relatively high relapse rate and chemoresistance persists. The MCL treatment scheme of chemotherapy followed by a transplant and more chemotherapy for those who relapse or become chemorefractory is not sufficient, said Goy, as the median duration of response in relapsed MCL is only 6 to 8 months with chemotherapy. “The new landscape is growing enormously and we have new options,” said Goy. “Agents are now being tested and approved in the relapsed and refractory setting and are slowly being moved into frontline treatment.”
One goal of new trials is to test whether the addition of novel therapies, such as bortezomib (Velcade) or ibrutinib (Imbruvica), to a chemotherapy backbone will achieve an earlier and deeper response in MCL. The second goal is to prevent relapse with either consolidation or maintenance therapy. A recent frontline study showed that adding bortezomib as either a maintenance or consolidation therapy improved 3-year PFS from 59% to 67% (P
= .0086) in a 151-patient trial.3
MCL Frontline Therapies for Elderly Patients
“R-CHOP alone is not enough for these patients,” said Goy. Researchers are evaluating whether bortezomib has a role in the frontline setting for elderly patients. Bendamustine (Treanda) plus rituximab (Rituxan) may be a new backbone that can be combined with novel agents, including bortezomib. Ongoing studies, such as the ECOG 1411 trial and a GOELAMS trial, are testing these combinations. Goy said that he believes that maintenance approaches will be part of routine MCL regimens in the future, based on improvement in survival of patients receiving maintenance after R-CHOP.
Novel Agents in Development in the Relapsed Setting
The goal of studies with newer agents is to get away from using chemotherapy in MCL. Bortezomib has been approved by the FDA since 2006 for treating MCL patients who had received one prior therapy. In 2009, updated results of the phase II PINNACLE trial, which involved 134 relapsed/refractory MCL patients, showed that single-agent bortezomib had an overall response rate of 33%, a complete response rate of 8%, and a median duration of response of 10 months.4
Since then, combination trials, such as bortezomib with rituximab and dexamethasone, have been building on the initial efficacy of bortezomib as a single agent. Currently, second-generation proteasome inhibitors, including carfilzomib (Kyprolis), are also in clinical trials in MCL.
Another group of agents being evaluated in relapsed/ refractory MCL are mTOR inhibitors. In a 162-patient phase III trial, the median PFS with temsirolimus (175 mg weekly for 3 weeks followed by 75 mg weekly) was 4.8 months compared with 1.9 months in the investigator’s choice arm.5
“The benefit was marginal but sufficient enough for approval in Europe in a relapsed setting based on this trial,” said Goy. Temsirolimus combined with rituximab could be a new treatment option and trials are ongoing in the frontline setting.