Clinical Advances in Mantle Cell Lymphoma

Bruce D. Cheson, MD

A Shift Toward Less-Aggressive Treatment

The long-term prognosis for most patients with mantle cell lymphoma (MCL) is poor, with median overall survival rates of 3 to 5 years.¹Because treatment is not curative, almost all patients will experience a relapse or find that their disease is refractory to treatment.²In this relapsed or refractory population, treatment success is rare.³Therefore, even though MCL is one of the rarest forms of non-Hodgkin lymphoma, the need for new treatments that will lead to improvements in patient outcomes is great.“Mantle cell lymphoma is a relatively uncommon form of non-Hodgkin lymphoma, and it has been treated traditionally with combination chemotherapy, which achieves a high response rate—but the responses have not tended to be durable, and the disease has remained incurable,” said Bruce D. Cheson, MD, professor of Medicine, deputy chief of Hematology/Oncology, and head of Hematology at the Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC. Many of the chemotherapy approaches today are very aggressive. One of the problems with an aggressive strategy is that, according to Cheson, “Patients with mantle cell lymphoma present with a median age in their 60s, and they can’t tolerate some of the aggressive regimens very well. Less-intensive regimens like R-CHOP are not terribly effective. So now we have the opportunity to have well-tolerated, oral, highly effective therapies for a disease for which previous treatments have been very intensive, very aggressive, and suboptimal.”

Ari M. Melnick, MD, on Emerging Therapies

Melnick is the Gebroe Professor of Hematology/Oncology at the Weill Cornell Medical College.

Approved Targeted Therapies

The opportunity of which Cheson speaks is with newer targeted therapies. “The goal is to reduce the intensity of therapy,” he said. “The concept ‘more is better’ is not valid. ‘Different is better’ is the operative hypothesis. We’re going away from aggressive regimens like hyper-CVAD and stem cell transplants, and moving in the direction to taking some fairly innocuous pills. It is a major seismic shift that is occurring now in the treatment of mantle cell lymphoma, and it’s not that far away. Within a matter of just a couple of years, I expect that these drugs will become an important part of the treatment of mantle cell lymphoma, replacing very aggressive, intensive regimens.”The first of these drugs to hit the market was the injectable proteasome inhibitor bortezomib, which received FDA approval in 2006.^4,5Bortezomib’s approval was based on a single-arm, single-agent study in 155 patients with relapsed, progressive mantle cell lymphoma following one or two prior therapies. The overall response rate was 31% with a median duration of response of 9.3 months, and the complete response rate was 8% with a median duration of response of 15.4 months. The most common adverse event (AE) that caused discontinuation was neuropathy. Overall, AEs caused 30% of patients to discontinue the study medication.⁵

“Bortezomib is approved in this space, but the activity is modest and the long-term benefit is relatively limited. Thus, bortezomib is an active drug but it is uncertain how it fits into the treatment schema without additional data,” said Andrew D. Zelenetz, MD, PhD, vice chair of Medicine for Medical Informatics and attending physician on the Lymphoma Service at Memorial Sloan-Kettering Cancer Center in New York City.

As of June 2013, patients in the United States whose disease has relapsed or progressed after two prior therapies (including bortezomib) can now use the oral immunomodulator lenalidomide.⁶A pooled analysis of data in relapsed or refractory mantle cell lymphoma that was presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting showed that single-agent lenalidomide produced an overall response rate of 32% with a median duration of response of 16.6 months. The estimates for median progression-free survival (PFS) and overall survival (OS) were 5.4 and 23.9 months, respectively.⁷

Andrew D. Zelenetz, MD, PhD

Novel Agents: Ibrutinib

“Lenalidomide is a funny drug with multiple mechanisms of action,” Zelenetz said. “It certainly has direct-acting effects on the tumor, but it also has an important impact on the microenvironment. What you get is a revved up immune environment, probably enhancing antibody-dependent cell-mediated cytotoxicity. You’re hitting both the tumor directly as well as improving the host ability to fight the tumor.”In addition to bortezomib and lenalidomide, there are many newer agents that are of great interest to the mantle cell lymphoma community. According to Zelenetz, “The most exciting area in mantle cell lymphoma is clearly the emergence of some small molecule inhibitors. Probably the single most exciting [one] is ibrutinib. This is a tyrosine kinase inhibitor that targets Bruton’s tyrosine kinase. It’s a component of the signaling pathway downstream of the B-cell receptor. It turns out that a number of tumors, including mantle cell lymphoma, are quite dependent on chronic signaling through the B-cell receptor. If you interrupt this chronic signaling, the cells die.”

Novel Agents: Idelalisib

Further Down the Pipeline

So far, the ibrutinib data have far surpassed the modest response rates seen with bortezomib and lenalidomide. “What really caught the interest and imagination of the audience was Michael Wang’s presentation at ASCO of the data with ibrutinib in relapsed or refractory mantle cell lymphoma, where response rates were in the range of 65% to 70%-plus,” said Cheson. “And the longer they followed the patients, the higher the response rates seemed to go. These data were very exciting with a couple of caveats: One, we obviously don’t have long-term follow-up, and two, we don’t yet know why some patients respond and why others don’t. Clearly, an understanding of the differences between patients will be critical to the further development and proper use of these drugs.”^8,9Therefore, although the ibrutinib data are encouraging, more research is needed to confirm its place in mantle cell lymphoma.“The other small molecule that has been interesting is idelalisib, also known as CAL-101 or GS-1101. This is a PI3 kinase inhibitor. It’s specific for the δ isoform of PI3 kinase. In the early studies, there seemed to be substantial activity in mantle cell lymphoma, but unfortunately, the durability of these responses has been relatively short,” said Zelenetz. “In data presented at ASCO, idelalisib was combined with rituximab, bendamustine, or everolimus for patients with MCL; however, the activity was not as striking as when idelalisib was combined with other agents in the indolent non-Hodgkin lymphomas.”^10,11To explain this unexpected phenomenon, Zelenetz said, “We know something about why mantle cell might escape from response to idelalisib. There have been data published now that the α isoform of PI3 kinase is expressed in mantle cell lymphoma and may be upregulated in tumors that have been exposed to idelalisib, and so it provides an escape mechanism by providing an alternative isoform of the PI3 kinase to allow tumor escape. So I’m less excited about idelalisib in mantle cell lymphoma.”¹²There may be some hope for PI3 kinase as a target, however. “There is a PI3 kinase inhibitor that is a dual α and δ inhibitor,” Zelenetz said. “That drug might actually be a perfect drug for mantle cell lymphoma because it hits the primary pathway as well as the escape pathway.” The PI3 kinase inhibitor is GDC-0941, which has been found to be significantly more active against mantle cell lymphoma lines than idelalisib.¹³

In addition, a dual δ and γ PI3K inhibitor, IPI-145, is also in the early days of development for lymphoma. It has been shown to be active in patients with relapsed or refractory advanced B- and T-cell lymphomas, and, in Cheson’s opinion, there is a signal that “mantle cell lymphoma may be an appropriate target.”¹⁴

“The other agent that’s really exciting in mantle cell lymphoma is a BH3 inhibitor called ABT-199 or GDC-199. This is a BH3 selective inhibitor of the Bcl-2 protein. This drug in very early results has been very active in mantle cell lymphoma,” said Zelenetz.¹⁵He added that, “It’s very early days with ABT-199. The drug has a dose-limiting tumor lysis syndrome in [CLL], which put the clinical development on hold for a while until this could be sorted out. But when your drug toxicity is tumor lysis, you know you have an active drug.”¹⁶

Multiple Pathways Could Be the Key

The Path Toward Individualized Therapy

Another possible class of drug targets PD-1/PD-L1. “They have shown impressive activity in solid tumors and are now being looked at in a number of hematologic malignancies,” Cheson said. “Killer cells get suppressed by the immune system and by the patient’s own tumor. These drugs allow the suppression to be reversed so the killer cells can attack their appropriate target. It’s a very exciting new possibility.” The anti-PD-1 agent nivolumab, for example, is being studied in melanoma, hematologic malignancies, and solid tumors.^17-19“I think the responses with ibrutinib are very exciting. It’s a real game changer. The question though is: How can we improve upon the single agent activity?” said Stephen E.F. Spurgeon, MD, assistant professor of Medicine at the Center for Hematologic Malignancies, Knight Cancer Institute at Oregon Health & Science University. “Ideally we would want to see a trial combining idelalisib and ibrutinib with each other or with additional signaling inhibitors. With this in mind, there are some preclinical data in abstract form looking at the combination of the Syk [spleen tyrosine kinase] inhibitor GS9973 with idelalisib in CLL. It looks like there may be synergy, but we don’t know what that means clinically or for MCL. The rationale here is to target multiple pathways in B-cell signaling,”20 Therefore, we may be seeing many more combination therapy studies of agents that target different pathways, including Syk, in the future.There is a long way to go, according to Cheson, though, before the ideal combinations are found. “We’re combining agents more or less empirically at the present time, which is not optimal. Hopefully in the future, as we better understand the biology of the cells and the best way to deliver these drugs, we’ll develop more rational combinations, the goal eventually being individualized therapy, because it’s highly likely that each patient will have a different pattern of pathway activation that would require different drugs to target that specific patient’s lymphoma abnormalities.”

Now that there are a few targeted therapies available for the treatment of mantle cell lymphoma and many agents targeting many different pathways in development, it may someday become feasible to change the goal of treating mantle cell lymphoma from the current aggressive, systemic approach to a less-intensive regimen that can be tolerated by a greater number of patients in this population.

References

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