Indolent Non-Hodgkin Lymphomas Still Require More Durable Treatment Options

For patients with indolent non-Hodgkin lymphomas (iNHL), such as follicular lymphoma (FL) and marginal zone lymphoma (MZL), the treatment landscape still lacks data on sequencing treatment in this patient population. The current standard in the relapsed setting remains either chemoimmunotherapy or the combination of rituximab (Rituxan) and lenalidomide (Revlimid; R²), which was recently approved by the FDA for the treatment of previously treated patients with FL and MZL.

The approval of this regimen in May 2019 was based on findings from the phase III AUGMENT trial, which demonstrated a reduction in the risk of disease progression or death by 54% compared with rituximab monotherapy. The median progression-free survival (PFS), overall survival (OS), complete response (CR) rate, and objective response rate (ORR) also saw improvement with the combination compared with the single-agent.

The phase III RELEVANCE trial also evaluated the use of R² in comparison with chemoimmunotherapy but, the trial did not demonstrate the superiority of the R² regimen. Data from this trial, however, demonstrated the survival associated with these 2 treatments were equivalent, which provides patients with an opportunity to use either chemoimmunotherapy or a chemotherapy-free regimen in the frontline setting.

In an interview with Targeted Oncology, Sonali M. Smith, MD, University of Chicago Medicine, discussed the treatment landscape for patients with iNHL. In particular, she highlighted the data supporting the use of R² in patients with FL and MZL.

TARGETED ONCOLOGY: What does prognosis look like for iNHL?

This refers to a group of different subtypes of B-cell lymphomas in general. The prototype is FL, but other types include MZL, lymphoplasmacytic lymphoma, and small lymphocytic lymphoma (SLL). Many trials group all of these diseases together. Of course, chronic lymphocytic leukemia and SLL get treated separately, but the other indolent lymphomas often get grouped, so we have very little data on, for example, MZL, that is distinct from the other indolent lymphomas.

That being said, there are some guiding principles for indolent lymphomas. It is important to remember that these are essentially chronic malignancies that patients can expect to live for a very long period of time [with]. When we have a patient with a very long expected survival, it is important to think about both short-term and long-term toxicities of the therapy we propose. One of the most important principles is that treating somebody before they need therapy does not help them live longer or better, at least based on any of the data that we have to date.

TARGETED ONCOLOGY: What are the frontline treatment options?

For patients who do need therapy for whatever reason that may be, we have a number of different options in the frontline setting. For low tumor burden patients, we often use monoclonal antibodies alone, such as rituximab. For many patients, when they do need therapy and they have high tumor burden, we have several options which include chemoimmunotherapy or lenalidomide plus rituximab.

TARGETED ONCOLOGY: Could you discuss the data supporting the use of R² in this patient population?

The RELEVANCE trial is a clinical trial that compared lenalidomide and rituximab head to head against chemoimmunotherapy for patients with FL that were in need of therapy, so these were all high tumor burden patients that required some type of therapy. The reason lenalidomide and rituximab were brought forth was based on several phase II trials showing synergy as well as a reasonable toxicity profile and significant efficacy. With the RELEVANCE trial, which has over 500 patients, patients were randomized 1:1 to receive lenalidomide plus rituximab versus chemoimmunotherapy. Practitioners were allowed to choose the chemoimmunotherapy that they wanted as the backbone. Surprisingly, two-thirds of the providers chose rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as the backbone. Only a quarter of providers chose bendamustine as their backbone.

Regardless, in the head to head comparison with the primary goal being the superiority of R² over chemoimmunotherapy, the study was essentially negative, meaning there was no difference. However, people have looked at this in different ways. On 1 hand, it is a negative trial and did not meet its end point of superiority. On the other hand, the efficacy in terms of CR rate, PFS, OS are all equivalent. This sets us up for equipoise where we can have a discussion with our patients and say would you prefer to have chemoimmunotherapy or would you prefer a technically chemotherapy-free option with R² knowing they have slightly different toxicity profiles, slightly different lengths of therapy, but equivalent outcomes.

TARGETED ONCOLOGY: What options are currently available for when a patient with iNHL relapses?

At the time of relapse for FL, there are a number of different options, but, unfortunately, do not have great data in terms of sequencing. However, there is 1 group that I usually pull aside, which is the early-progressors. Those patients who progress within 24 months of their frontline chemoimmunotherapy, we know they have a very poor survival. In fact, their 5-year survival is only 50%. This is a pool of patients that deserve and need extra attention.

There are several clinical trials addressing this. Other providers will offer an autologous stem cell transplant, but I do think those early-progressing patients really are in need of better options.

For other patients outside of the early-progressor status, we have other options, which include going back to chemoimmunotherapy, rituximab alone, or what was recently FDA-approved is the combination of lenalidomide plus rituximab. This is based on the AUGMENT trial, which was essentially a phase III randomized trial for patients with relapsed/refractory, mostly relapsed, with FL. They were randomized to either 1 year of R² or 1 year of rituximab monotherapy. It was interesting that not only was there improvement in the CR rate and the PFS, but there is even a small but real OS advantage, leading to R² being FDA-approved in the relapsed setting.

TARGETED ONCOLOGY: What are the unmet needs of this patient population?

There are a number of unmet needs and challenges for patients with indolent lymphomas. This includes better prognostication at diagnosis. For example, we have a number of prognostic indices, whether it is the FLIPI, the M7-FLIPI, or FLIPI2, but none of them have been validated or applicable to a specific individual. They are really helpful for groups of patients, so 1 unmet need is to how we can better prognosticate.

In terms of a wish list of what we could have is to have a limited duration of therapy that is well tolerated and, if we want to be incredibly grandiose, to try to get to cure.