New Agents Transform Treatment of Non-Hodgkin Lymphoma

Mitchell Smith, MD

Rapid advancements in non-Hodgkin lymphoma (NHL) have transformed the field in recent years. In the past few months, several new agents have made significant strides while others continue to show promise.

These include ibrutinib (Imbruvica), which was approved in March 2016 for the frontline treatment of patients with chronic lymphocytic leukemia (CLL), based on data from the RESONATE-2 trial.

In the trial, an independent review committee found that ibrutinib, compared with chlorambucil, led to an 84% reduction in the risk of progression or death (HR, 0.16; 95% CI, 0.09-0.28).

At a median follow-up of 18.4 months, the median progression-free survival (PFS) rate was not yet reached with ibrutinib versus 19 months with chlorambucil (P <.0001). The median 18-month PFS rates were 94% and 45%, respectively.

Ibrutinib was previously approved by the FDA for pretreated CLL, pretreated mantle cell lymphoma, and Waldenström's macroglobulinemia.

Venetoclax (ABT-199), an agent that targets Bcl-2, has also made headlines, as it received a priority review by the FDA in January 2016 for use in adults with CLL, including patients with a 17p deletion.

The review is based on the phase II M13-982 study, in which venetoclax elicited responses in nearly 80% of relapsed/refractory patients with CLL who have a 17p deletion. The FDA is expected to make a decision on venetoclax within the next 6 months. The first-in-class agent is also being investigated in combination with anti-CD20 monoclonal antibodies, including rituximab (Rituxan) and obinutuzumab (Gazyva).

Chimeric antigen receptor (CAR)—modified T-cell therapies are also generating excitement in the NHL.

In a recent phase I study conducted by the National Cancer Institute, allogeneic anti-CD19 CAR T-cell therapy induced complete remissions in 30% of patients with advanced progressive B-cell malignancies without causing graft-versus-host disease (GVHD).

The overall response rate with the CAR T-cell therapy was 40%, consisting of 2 partial remissions and 6 complete remissions. Patients with acute lymphoblastic leukemia (ALL) experienced the most promising responses.

OncLive: What impact do you see venetoclax making in NHL?

To learn more about these and other advancements in the field of NHL, OncLive interviewed Mitchell Smith, MD, in the Department of Hematology and Oncology at Cleveland Clinic.Smith: I think venetoclax is going to be a groundbreaking drug. For years, we have asked, “Why do cells not die?” We try to kill them with chemotherapy or some of the newer medicines, and they just don’t die.

There is a mechanism that relies on the protein Bcl-2 to prevent cell death, and venetoclax attacks that. It is a totally new pathway; there is no drug like it. It looks to be very remarkable in the treatment of CLL. It is very well tolerated and it is an oral regimen, so there are no chemotherapy side effects.

CAR T-cell therapies have generated tremendous excitement in the field. What role do you see them playing in NHL?

I see this as a game-changer. It will be able to be added to just about any other drug. We can add it to anything we are using to kill cancer cells, and it should make it work better.We are all excited about CAR T-cell therapy; it works spectacularly in ALL—mostly in children&mdash;but in some adults, as well.

It also works in CLL, and we are opening trials in diffuse large B-cell lymphoma and mantle cell lymphoma. These are diseases that, when they come back, they are very difficult to treat.

Therefore, we are very excited about the opportunity to participate in these trials and offer them to our patients. For years, immunotherapy was the “holy grail.” Why can’t we teach our immune system to attack cancer? Now, for the last few years, this has become a reality.

How have newer agents, such as ibrutinib and idelalisib, revolutionized the treatment of CLL?

We watch patients receiving CAR T-cell therapy in the hospital for about 1 week after we infuse the engineered cells. Most patients do fine, while a few have some acute side effects. It is a one-time treatment. These cells remain in the body. If any cancer cells start to come back, they will attack them. In the future, perhaps we can target other things besides B cells. However, right now, the focus is on targeting B cells in ALL and CLL.We are very excited about the development of ibrutinib, idelalisib (Zydelig) and that whole family of drugs. Both of those drugs are now approved in CLL and idelalisib is approved in indolent lymphoma that has returned after initial treatment.

These are pills that are well tolerated and are very effective. They attack pathways that the B cells rely on to tell the cells to proliferate and not to die. It is a dramatic and easy treatment.

It doesn’t cure the disease so, eventually, the disease becomes resistant and we have to do something else. These are great additions. The next step would be to combine them. They could potentially be combined with venetoclax, which works on a different pathway, or they could be combined with chemotherapy.

The next steps include how to use these better and determine why patients become resistant so we can prevent that. That will be the future of these agents.

Do you see potential for obinutuzumab?

We are also looking at maintenance therapy. Perhaps we can get a patient into remission with standard treatment, and then not let it replace and instead give them these drugs and prevent relapse. Perhaps we can turn this into lifelong chronic condition.Obinutuzumab is a drug that binds to CD20 cells. We have had rituximab for almost 20 years, and that has really changed the landscape for B-cell lymphomas.

For years, we have wanted to find a better rituximab and it appears that obinutuzumab may be that. It has some features that make it a little bit different than rituximab. I don’t think it is a game-changer, because we already have rituximab. However, it is an option for patients when rituximab doesn’t work. It has been approved for use in frontline CLL. There is an art to which one should use it, but it is always nice to have more tools in our toolbox.