Expert Covers Burgeoning Advancements in Follicular Lymphoma and MCL

Narendranath Epperla, MD

Clinical trials exploring novel combination regimens continue to advanced the treatment landscape for patients with follicular lymphoma and mantle cell lymphoma (MCL).

For example, the phase III GALLIUM trial combined obinutuzumab (Gazyva) with chemotherapy in the first-line setting and reduced the risk of disease progression or death by 34% versus rituximab (Rituxan) in patients with follicular lymphoma.

“Obinutuzumab continues to remain a very strong treatment modality in treatment of [patients with] follicular lymphoma, either in the relapsed/refractory setting or in the upfront setting,” said Narendranath Epperla, MD.

In the obinutuzumab arm of the GALLIUM study, the overall response rate was 88.5% versus 86.9% in the rituximab cohort. The 3-year progression-free survival (PFS) rate was 80% in the obinutuzumab arm versus 73.3% in the rituximab arm.

OncLive^®: Can you please provide an overview of your lecture?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Epperla, assistant professor of internal medicine, Department of Medicine, Division of Hematology, The Ohio State University, discussed the evolving treatment landscape for patients with follicular lymphoma and MCL.Epperla: The GALLIUM study looked at using obinutuzumab plus chemotherapy versus rituximab and chemotherapy. Obinutuzumab and chemotherapy had improved response rates and PFS. However, one needs to note that it was obinutuzumab plus chemotherapy followed by obinutuzumab maintenance, or rituximab plus chemotherapy followed by rituximab maintenance. One should be aware of the side effect profile when giving obinutuzumab and chemotherapy as an infusion, but it is an exciting time in the field.

Are there any ongoing studies in the follicular lymphoma field that you are excited to see the results of?

Finally, even in the relapsed/refractory setting, especially in the rituximab-refractory setting, we have seen impressive data with obinutuzumab/bendamustine followed by obinutuzumab maintenance compared with bendamustine monotherapy. In my clinical practice, for patients in the rituximab-refractory setting, I use obinutuzumab with bendamustine and obinutuzumab maintenance.We will see the primary results of the phase III RELEVANCE study, which compares rituximab plus lenalidomide (Revlimid) to rituximab plus chemotherapy in the upfront setting.

Do you think immunotherapy will continue to have a role in this landscape?

Switching gears to MCL, what role might modern immunotherapy have in this landscape?

I am also interested or curious to see what the follow-up data on the GALLIUM study would be. I am looking forward to novel agents using BTK combinations and PI3-kinase combinations in the relapsed, indolent non-Hodgkin lymphoma setting, as well as in MCL.There are some ongoing trials with checkpoint inhibitors in follicular lymphoma, which are being tested in the relapsed/refractory setting. However, we must await those results as none of the data are out yet. There might be a role for checkpoint inhibitors, but the more interesting question is, “How are we going to sequence when we have so many agents?” When we have the data, we will have to consider the baseline characteristics of each study to figure out how to best sequence them.There are many changes in the treatment armamentarium for MCL, which have been happening over the past few years. Most of the data that we have today are in the relapsed/refractory setting. I'm excited about some combinations, such as rituximab plus lenalidomide, as well as PI3K combinations in the relapsed/refractory setting.

Is there any potential with chimeric antigen receptor (CAR) T-cell therapy?

What should be done for patients who are intolerant to ibrutinib or have relapsed on ibrutinib?

There are also ongoing trials in the upfront setting that the Eastern Cooperative Group is undertaking, but these trials have just started enrolling patients to determine whether we still need autologous stem cell transplant in 2017. I'm curious to see what the results will be but we will have to wait a few more years for results.We don’t currently have enough data yet for CAR T-cell therapy in MCL. Based on the impressive data in the diffuse large B-cell lymphoma setting, I will not be surprised if CAR T-cell therapy will continue to have impressive results in MCL. An important question is, “When are we going to use CAR T-cell therapy? Is it pre- or post-allogeneic transplant or pre- or post-ibrutinib (Imbruvica)?” There are still some remaining questions that need to be investigated.The data are very dismal for patients who fail ibrutinib. There are published data showing the median overall survival was only a few months. Currently, there is a lot of interest to figure out the resistance mechanism so that we can improve upon it. However, we do not have any breakthrough treatments for patients who fail ibrutinib, which remains to be an urgent unmet need.

We currently have a few ongoing trials where we are trying to combine certain agents, such as CDK4/6 inhibitors with ibrutinib to see if that can overcome the resistance, but we don't know the data yet.

What is important for physicians to know about the field of MCL and its future over the next couple of years?

In my practice, I place the patient on ibrutinib and once they have achieved a response, I send them to allogeneic transplant. I use ibrutinib more as a bridge than a definitive therapy in patients who are transplant eligible so they can achieve the durable responses.As of today, the treatment for MCL continues to be induction therapy followed by autologous transplant, based on long-term follow-up data. The [pivotal] trial had almost 15 years of follow-up data that were published with very impressive PFS rates. Recent data presented at the 2016 ASH Annual Meeting showed that using rituximab maintenance after induction and autologous transplant led to impressive PFS. The upfront treatment for MCL is induction, incorporating rituximab and chemotherapy combination, followed by autologous transplant, and, with the recent data, rituximab maintenance.

In the relapsed/refractory setting, we have many agents to choose from. We have BTK inhibitors, PI3-kinase inhibitors, and combinations of immunomodulatory agents with rituximab. One can mix and match treatments, and enrollment in clinical trials will be important in the relapsed/refractory setting.

Hiddemann W, Barbui AM, Canales Albendea MA, et al. Immunochemotherapy with obinutuzumab or rituximab in previously untreated follicular lymphoma in the randomised phase III GALLIUM study: analysis by chemotherapy regimen. Hematological Oncology. 2017;35(S2):117—119. doi: 10.1002/hon.2437_106.