Expert Discusses Combinations, Other Research for the Treatment of Indolent Lymphomas

Mitchell Smith, MD, PhD

Mitchell Smith, MD, PhD

Although a watch-and-wait strategy may work for many patients with indolent lymphomas, according to Mitchell Smith, MD, PhD, others require active treatment. Many new treatment options and combination approaches continue to emerge to treat patients with indolent lymphomas, aiming to give patients durable responses.

The combination of lenalidomide (Revlimid) and rituximab (Rituxan; R²), for example, has been used in hematologic malignancies and is now making its way into the treatment landscape for patients with indolent lymphomas. This combination was approved by the FDA in May 2019 for the treatment of patients with indolent lymphomas including preciously treated follicular lymphoma and marginal zone lymphoma. This update and data from other clinical trials has generated a lot of excitement around the idea of combining R²because of the tolerable safety profile that has been observed.

Another treatment option that is on the horizon for patients with indolent lymphomas includes venetoclax (Venclexta) and venetoclax in combination with other agents. This agent has shown promising results across hematologic malignancies and is being investigated in indolent lymphomas as well, and in combination with other agents.

“The next big wave of studies will be combinations,” Smith said. “I take a drug which blocks B-cell proliferation and add venetoclax or some drug like that which promotes cell death, and that combination looks active.”

Although new agents and combination regimens are under investigation for the treatment of indolent lymphomas, Smith concluded that in most patients, the best current approach is the watch-and-wait. If a patient is asymptomatic and feels fine, there is no reason to treat them right away.

“No study has ever shown an increase in survival, so I’m not going to make the patient live longer,” Smith said. “I’m going to give the patient adverse effects, and I’m not going to make the patient feel better, so there is no reason to treat it.” In these cases, patients can be monitored until the lymphoma grows to the point where treatment is necessary.

In an interview withTargeted Oncology, Smith, division director of hematology/oncology and associate cancer center director for clinical trials, George Washington University, discussed the most recent research and agents under investigation for the treatment of indolent lymphomas. He also highlighted how conversations transpire when discussing the watch-and-wait approach with his asymptomatic patients.

TARGETED ONCOLOGY:What are some targeted therapies that are on the rise for the treatment of indolent lymphomas?

Smith:In indolent lymphoma, most of the action has been on targeted therapies, small molecules, so either things that interfere with B-cell signaling—primarily PI3K inhibitors, of which several are approved now for indolent lymphomas in the relapsed setting—and BTK inhibitors like ibrutinib (Imbruvica) and acalabrutinib (Calquence), which are on the horizon. The [BTK inhibitors] don’t work as well in the indolent lymphomas as they do in chronic lymphocytic leukemia (CLL), so they are not approved in that setting, but people are studying these in combinations. The other exciting thing is venetoclax which promotes cell death, promotes apoptosis, and is very active in CLL and in certain lymphomas but is starting to play a role in the indolent lymphomas as well.

TARGETED ONCOLOGY:We’re hearing about venetoclax a lot across hematologic malignancies, but what is it about this drug has been so effective? Are there any other drugs you find particularly exciting?

Smith:I think the interesting thing about venetoclax is that it hits so many cancers. It hits a fundamental mechanism of cancer that the cells have forgotten how to die, or they are resistant to cell death. Whatever drives the cancer to grow, if you can make the cell die, you’d be ahead of the game. It seems to work across almost all hematologic cancers and now some solid tumors, so I think it just hits such a fundamental mechanism in cancer; that’s why it is so broadly applicable.

I’d like to spend some time talking about lenalidomide, which has been around for a very long time and is used a lot in multiple myeloma. In the last year and coming into the next year, we are seeing a lot of data on the combination of lenalidomide and rituximab in indolent lymphoma. A big frontline study comparing lenalidomide and rituximab (R²) versus rituximab and chemotherapy was recently presented, and it was actually a negative trial in the sense that the combination with lenalidomide was not any better. For our purposes, however, if it is less toxic with just different toxicities and if it’s at least as good, then it’s an area people are going to start to use. There’s a lot of excitement in using that combination to try and get to a chemotherapy-free approach; that’s 1 we can build on, so there is a lot of excitement about that, even though it was a negative trial.

TARGETED ONCOLOGY:How does the outlook of indolent lymphomas differ to those of the more high-risk lymphomas?

Smith:The key to when we call it an indolent lymphoma is that yes, it grows more slowly than the fast-growing, more aggressive, or high-grade lymphomas, but the big difference from a clinical standpoint is that as of yet, it is not curable. It grows slower, and you don’t often need to treat it. However, even with all these new agents and exciting new treatments, we get good response rates; the outcomes are much better in terms of overall survival than where they were 20 years ago, but we still don’t cure it. Indolent lymphoma is slow growing, you can watch and wait, don’t need to treat right away, but when you do treat it, you’ll get a response, just not a cure. We are always looking for better ways to approach it.

TARGETED ONCOLOGY:How many patients are able to or should receive a watch-and-wait approach?

Smith:In indolent lymphomas, a significant number of people do not need treatment when they present and walk in the door. They’ll have an asymptomatic lymph node that’s follicular lymphoma, and they are perfectly fine. It’s a long conversation, [we tell them] you have cancer, it’s stage IV, because almost everybody with lymphoma has it throughout their body, but we’re not going to treat you. If the patient feels fine, I’m not going to make them feel better by treating them. I could make the lymph node shrink and say, “wasn’t I smart? I was able to shrink your lymph node,” but I haven’t been able to make the patient feel any better. No study has ever shown an increase in survival, so I’m not going to make the patient live longer, I’m going to give the patient adverse effects, and I’m not going to make the patient feel better, so there is no reason to treat it.

TARGETED ONCOLOGY:Are patients skeptical at first when you say they have cancer, but you don’t want to treat it right now?

Smith:Absolutely. It’s a long conversation, you have to explain to them why you’re not treating it, and they’ll still say ask how come you’re not treating them. I’ll often see them back in a month, and we’ll see that they’re still fine. Then they get a little more comfortable, so I’ll see them in 2 months. They’re still fine. They sort of get used to it and see the picture. They’ll often go get other opinions from other oncologists and hear the same thing, but at least then they feel like you’re not crazy; it’s a learning process over those first few months.

TARGETED ONCOLOGY:Are there any other emerging therapies or new treatment approaches being investigated for indolent lymphomas right now?

Smith:I think there are a lot, and we’ve heard a lot about immunotherapy. Immunotherapy has not worked so well in the indolent lymphomas, but chimeric antigen receptor (CAR) T-cell therapies are starting to be studied. There’s a lot of studies on new antibodies; new antibodies themselves haven’t done so well, but antibody—drug conjugates (ADCs) have a lot of excitement. Radioimmunotherapy is active; it’s fallen off everyone’s radar, but we need to bring that back. There are antibody-based therapies, and all these new small molecules that hit these various pathways.

The next big wave of studies will be combinations. I take a drug which blocks B-cell proliferation and add venetoclax or some drug like that which promotes cell death, and that combination looks active. I think right now, the next stage won’t be so much new pathways, although we are still looking for those, but more of how to combine what we have and also if we can stop therapy. When can we stop therapy? How long do you need to be treated? What’s the endpoint? I think there are a lot of things we can learn, even without the excitement of new agents.