Flinn Sheds Light on Advances in MCL and Other Lymphomas

Ian W. Flinn, MD, PhD

The FDA approval of axicabtagene ciloleucel (axi-cel; Yescarta) in October 2017 for patients with non-Hodgkin lymphoma was one of the most exciting advancements in years for the lymphoma community.

Investigators are building on this breakthrough by exploring combination regimens with the CAR T-cell therapy. Results from the phase I/II ZUMA-6 trial presented at the 2017 ASH Annual Meeting showed that the combination of axi-cel with the PD-L1 inhibitor atezolizumab (Tecentriq) was highly active with a manageable safety profile in patients with refractory diffuse large B-cell lymphoma (DLBCL).

Looking specifically to the area of mantle cell lymphoma (MCL), additional therapeutic options have also emerged for this subtype of non-Hodgkin lymphoma, notes Ian W. Flinn, MD, PhD. Aside from 2 BTK inhibitors available in the second-line setting—ibrutinib (Imbruvica) and acalabrutinib (Calquence)—combination strategies, such as rituximab (Rituxan) with lenalidomide (Revlimid), have shown encouraging findings, as well.

OncLive: What are some exciting advancements in lymphoma?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Flinn, director of the Blood Cancer Research Program at Sarah Cannon Research Institute, discussed the impact of CAR T-cell therapy on the field of lymphoma and highlighted emerging options for the treatment of patients with MCL.Flinn: CAR T cells are front and center in our thoughts for the treatment of patients with lymphoma. We have the approval from Kite Pharma with their anti—CD19 CAR T-cell therapy axi-cel that showed durable remissions in patients with refractory large cell lymphoma. There were follow-up data presented at the 2017 ASH Annual Meeting regarding that approval. Almost 40% of patients will remain in a complete remission for a considerable period of 6 to 9 months after receiving CAR T cells.

In other studies, we have seen patients who have remained in remission for years. These are patients who have failed everything and are not eligible for transplant, but are seeing durable remissions.

Will we start to see more combinations with CAR T-cell therapy?

We saw other CAR T-cell products with data that are less mature than what we saw with the KITE product. Some patients are receiving therapy on an outpatient basis. We are learning how to deliver this therapy in a safer manner. Some of the new products may include less toxicity, so this is an area that is moving fast in lymphoma.We are already seeing data with the combination of CAR T-cell therapy and checkpoint inhibitors. At first, there was apprehension about combination strategies. We are thinking about what we have seen with graft-versus-host disease, allogeneic stem cell transplant, cytokine release syndrome, and the neurotoxicities in CAR T cells.

Moving onto MCL, we saw the approval of acalabrutinib in October 2017. What significance does that approval have on the treatment landscape?

The studies are premature but suggest that they can be safely combined. This could add to the persistence of the cells and remissions. We are seeing much higher remission rates, but some patients are progressing despite achieving complete remission rates. Adding some immunomodulatory agents to CAR T cells is exciting. We are in the early days of exploring acalabrutinib. Acalabrutinib is a second-generation BTK inhibitor that has cleaner kinase activity and does not hit many of the off-target toxicities that we see with ibrutinib. Patients are seeing durable remissions with acalabrutinib. We are still in the early days, and this drug does not make a difference for patients with relapsed/refractory disease.

We saw long-term data with ibrutinib in MCL at the 2017 ASH Annual Meeting. Can you speak to the durability of this agent?

However, combinations with acalabrutinib are moving earlier in the disease course. Perhaps combining it with conventional chemotherapy might demonstrate an improvement in survival and PFS. There is a lot more to come in that setting.It depends on the disease. In chronic lymphocytic leukemia, we are seeing durable remissions of 5 years and an impressive median PFS. However, the curve is declining. While we are seeing some durable remissions in MCL, the majority of patients are relapsing before 3, 4, or 5 years.

Could the combination of rituximab and lenalidomide be an option for patients with MCL who progress on acalabrutinib or ibrutinib?

We have changed the natural history of this disease. When I was coming out of my training, MCL had a median survival of 3 years. Now, patients are living much longer than that with the help of combination therapies and other novel strategies. It would be fantastic to see our curves continue to incline and not have patients relapse.We are still unsure. There is data with lenalidomide and rituximab in the frontline setting for patients with MCL. It has been hard to duplicate, but those data suggest that it is [not] for everyone. For many patients and doctors, a more aggressive course of therapy with a transplant in the frontline setting is useful. The combination of lenalidomide and rituximab has a place for patients with MCL, whether that is before or after a BTK inhibitor. In my own practice, I would use a BTK inhibitor as a second-line therapy for patients and perhaps use the combination regimen for the third-line setting.

Locke FL, JR Westin JR, Miklos DB, et al. Phase 1 results from ZUMA‑6: axicabtagene ciloleucel (axi-cel; KTE-C19) in combination with atezolizumab for the treatment of patients with refractory diffuse large B cell lymphoma. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 2826.