Expert Emphasizes Need to Enhance Treatment Strategies for Indolent Lymphomas

Allison C. Rosenthal, DO

Investigators are exploring therapy options for patients with indolent lymphomas—including follicular lymphoma, marginal zone lymphoma (MZL), and small lymphocytic lymphoma (SLL)—as rituximab (Rituxan) regimens are proving to not be a long-term option for many patients, explains Allison C. Rosenthal, DO.

In follicular lymphoma, for instance, an ongoing phase II trial is testing the first-line combination of rituximab plus ibrutinib (Imbruvica) in patients with advanced disease (NCT02451111). The primary endpoint of the randomized study is complete response.

A supplemental new drug application (sNDA) for ibrutinib as a treatment for patients with MZL was submitted to the FDA in September 2016. The application was based on the open-label phase II PCYC-1121 trial, which investigated the BTK inhibitor in patients with MZL following at least 1 prior therapy (NCT01980628).

OncLive: Can you provide an overview of your lecture on indolent lymphomas?

In an interview during the 2016 OncLive State of the Science Summit on Treatment of Hematologic Malignancies, Rosenthal, a hematology consultant at Mayo Clinic, shared her insight on the need for updated treatment options for patients with indolent lymphomas, ongoing progress in the field, and the challenges oncologists are still facing in this space.Rosenthal: My presentation covered what exists now as an indolent lymphoma, including things such as follicular lymphoma, SLL, and MZL. The key points include, what do we currently have as treatment options for patients with follicular lymphoma? What kind of clinical trials are currently in progress to try and find targeted options for patients, or new ways of combining treatments that we already have? It took a look at what trials are in progress, what should we be looking for at national meetings this year, as far as updates go, and what might be the next wave of treatments available for these patients.

What are the current treatment strategies?

Other indolent lymphomas include Waldenström’s macroglobulinemia, some cutaneous lymphomas, and some non-Hodgkin lymphomas, as well.Currently, our first-line treatment for most people who need therapy for indolent lymphomas includes rituximab alone, or rituximab in combination with chemotherapy. However, those strategies aren’t great for everyone. Some people have comorbidities or have reasons as to why they would want other strategies.

What are some of these newer targeted therapies?

Also, not everyone responds to chemotherapy. It’s a great short-term option, but not a great long-term option that can be repeated for a lot of patients. Some of the targeted therapies that are new are oral and it is hopeful that they will be long-term options for patients that are tolerable and keep their disease under control for longer periods of time. So far, they are pretty new and we don’t have the experience yet to understand what they are going to offer patients in the long-term.Idelalisib (Zydelig) has already been approved for the treatment of patients with relapsed/refractory follicular lymphoma. Some patients do have good responses, but the toxicities can be pretty significant—hepatic toxicities, colitis, diarrhea, pneumonitis, and even some infections in patients who are severely immunocompromised. Therefore, where exactly that fits is a little bit unclear, and what safe combinations are out there are what we are exploring now.

Do BCL-2 inhibitors, such as venetoclax (Venclexta), have any potential in these patient populations?

In MZL, a new drug application was submitted for ibrutinib. What impact could that potential approval have on the field?

What are some ongoing clinical trials in this space?

There are some other trials now looking at other new PI3K inhibitors, as well as targeting the BTK pathway and some other novel drugs such as selective inhibitors like selinexor (KPT-330), and some new CD20 antibodies. We are looking at new and improved versions of rituximab for patients who are unable to receive it or are refractory to it.Venetoclax, while it has been approved so far in treatment of chronic lymphocytic leukemia and SLL, it still being studied in combinations for other indolent lymphomas. Surprisingly, in something such as follicular lymphoma, where BCL-2 is commonly expressed, it doesn’t really do the job on its own. We will probably see it coming in combination with other agents to get the best effect that we can out of it.So far, we have no drugs approved specifically for MZL. For years in that disease, data has been extrapolated from studies where it was included as part of all indolent lymphomas being treated. It is exciting to think that there could be a drug specifically approved for patients with nodal MZL, which is a small subset of our patients—but one that deserve good therapies, too. We will have to see with the new updates coming, and whether or not the application is approved, if that becomes an option. However, it would be the first approved option, specifically, for patients with MZL.There are updates coming from the GALLIUM trial, which should be survival updates. The GADOLIN trial is looking at the combination of bendamustine (Treanda) with or without obinutuzumab (Gazyva) followed by obinutuzumab maintenance, and whether or not that strategy would become one that’s important for patients with follicular lymphoma, in particular.

Why might some people not be able to receive long-term treatment with rituximab?

When that study was designed, bendamustine wasn’t something we were using in the frontline setting, so where exactly this will come into the sequence of therapies we choose for patients is a little bit unknown. This is looking at relapsed/refractory patients, but my guess is people will make a leap and consider using it in the frontline setting, if possible.Rituximab is generally pretty well tolerated. However, the problem is that patients who are treated and retreated with rituximab will sometimes become refractory. While it has really improved outcomes for patients with indolent lymphoma, there are patients for whom it doesn’t work forever.

What are the biggest challenges that oncologists still face in patients with indolent lymphomas?

Newer drugs, such as obinutuzumab, are helpful in that space because there are patients who will respond to that when they have stopped responding to rituximab. It allows us to still offer patients immunotherapy where, in older patients who maybe wouldn’t tolerate full chemotherapy, it might still get some responses and disease control.In indolent lymphoma, one of the big problems we have is that we have some prognostic factors we have put together, as far as stage of disease, what abnormalities they have, and age of the patient that give us an idea of what the risk might be. But in indolent lymphoma, we don’t have a good predictor yet of what some genetic aberrations might be for predicting poor response or high-risk disease.

We have this FLT7 that has been proposed. It is looking at 7 different genes that are commonly altered in follicular lymphoma and common mutations that are found. It will likely be looked at in future studies to see how applicable it is to clinical practice, but that would be the first combined clinical plus genomic type prognosticator we have for follicular lymphoma. That would help us maybe identify patients upfront who might not be good candidates for chemotherapy or that it might only be a short-term solution for them.

Will transplant always have a role in this field?

The biggest challenge is probably identifying who this high-risk group is. Who is going to do poorly with chemotherapy? We know people who are diagnosed younger with an incurable, even indolent lymphoma are probably going to run out of therapies unless we push boundaries and find new ways to treat them. It helps us also identify what patients might be considered for transplant early on, because that’s still a little bit of a grey zone in terms of who gets referred or who doesn’t.It is hard to say. It does have a role now for some patients with follicular lymphoma—those who have earlier relapse in disease after they have had their first or second course of chemotherapy. If it lasts less than 2 years, you’re probably not going to buy a whole lot of time with the other therapies we have.

What are the most important things community oncologists should take away from your lecture?

Young patients really do get some decent benefit with the autologous transplants. The big challenge is, for patients who are chemotherapy refractory, an autologous stem cell transplant is probably not going to buy them a lot of time or disease-free intervals. Then, we are really looking at things such as allogeneic transplant that come with a whole other set of genetic risk factors. We want to be able to select those patients carefully.I would like for them to leave with a little more comfort, as far as being able to collaborate with us on difficult patients and challenging cases. For example, some of these targeted therapies can look pretty intimidating on the box warnings. It is tough to know when to pull back and when to push through some of these side effects. This can be a good resource for some thing like that. We participated in some of the clinical trials that led to approvals of some of these drugs, so we probably have a little more experience.

It is also important for them to know what clinical trials options are out there for their patients, so they know what new drugs are hopefully going to be available for their patients who are going to hopefully be living longer with these indolent lymphomas.