Novel Combinations Seek to Build Off Lenalidomide/Rituximab Backbone in Indolent Lymphoma


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Paolo Strati, MD, discusses novel combinations for the treatment of indolent B-cell lymphoma, emphasizes the primary goal of improving the efficacy of immunotherapy and providing patients with chemotherapy-free treatment options, and highlights ongoing trials are investigating various approaches to enhance the activity of lenalidomide/rituximab

Paolo Strati, MD

Paolo Strati, MD

Ongoing trials in the field of indolent B-cell lymphoma, including in patients with follicular lymphoma or marginal zone lymphoma (MZL), evaluating the addition of novel agents to lenalidomide (Revlimid) alone or the combination of lenalidomide and rituximab (Rituxan) could help bring immunotherapy to earlier settings and improve outcomes for these patient populations, according to Paolo Strati, MD.

“We know that patients [with indolent lymphoma], unfortunately, are generally older and frail, and being able to completely shy away from chemotherapy [in the frontline setting] with novel combination strategies would be a major achievement,” said Strati, who presented on novel combination in indolent lymphoma at the 2023 SOHO Annual Meeting.

In an interview with OncLive®, Strati, discussed novel combinations for the treatment of indolent B-cell lymphoma, emphasized the primary goal of improving the efficacy of immunotherapy and providing patients with chemotherapy-free treatment options, and highlighted ongoing trials are investigating various approaches to enhance the activity of lenalidomide/rituximab. Strati is an assistant professor in the Department of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center, in Houston, Texas.

OncLive: How could novel combinations better utilize immunotherapy in the treatment of patients with indolent lymphoma?

Strati: The goal of [my SOHO] presentation was to provide an outline of ongoing clinical trials that are trying to investigate novel combination for patients with indolent B-cell lymphoma, including follicular lymphoma and MZL. My focus was on combinations trying to increase the efficacy of immunotherapy and provide patients with indolent B-cell lymphoma with a chemotherapy-free treatment option.

Currently, the combination of lenalidomide and rituximab is the only immunotherapy formally approved by the FDA in the United States for patients with relapsed follicular lymphoma and MZL. Recently, bispecific antibodies such as mosunetuzumab-axgb [Lunsumio] have also been approved.

The problem is that, historically, we've been trying to move immunotherapy into the frontline space. One thing to keep in mind is that patients with indolent B-cell lymphoma tend to be elderly at the time of diagnosis. They tend to be 70 [years of age] or older. As such, these patients may also have comorbid health conditions that may limit our ability to utilize chemoimmunotherapy as a frontline strategy. This has been attempted historically in the phase 3 RELEVANCE trial [NCT01476787; NCT01650701], which was a randomized trial comparing chemoimmunotherapy [R-CHOP] vs lenalidomide/rituximab in patients with previously untreated follicular lymphoma. The study was designed as a superiority study, and unfortunately, lenalidomide/rituximab was not superior, which is why it is currently not approved by the FDA as a frontline option for patients with follicular lymphoma.

However, clearly, lenalidomide/rituximab was not inferior. As such, you can now find lenalidomide/rituximab as an option in the National Comprehensive Cancer Network Guidelines as a frontline treatment. However, penetration in the community is still very limited because we need to see better efficacy. That's where these novel trials come into play.

Could you highlight some of these novel combinations being evaluated in ongoing trials?

Ongoing trials in the follicular lymphoma space looking into novel combinations are based on trying to increase the activity of lenalidomide/rituximab specifically. They are trying to do this in a biologically rational way. The most interesting trials currently are those trying to combine lenalidomide or rituximab to agents that can increase T cell engagement, such as mosunetuzumab or epcoritamab-bysp [Epkinly].

There is currently the randomized phase 3 Celestimo trial [NCT04712097] comparing mosunetuzumab plus lenalidomide to lenalidomide/rituximab. There's also the ongoing phase 1/2 EPCORE NHL-2 trial [NCT04663347] looking into the combination of epcoritamab and lenalidomide/rituximab for patients with relapsed or previously untreated indolent B-cell lymphoma.

[Another] interesting [strategy] to try to increase the activity of immunotherapy is by favoring repolarization or tumor-associated macrophages to a more antitumoral phenotype, which could be achieved with BTK inhibitors. There have been multiple trials looking into combining lenalidomide/rituximab with BTK inhibitors, such as acalabrutinib [Calquence].

Finally, what I find exciting is the possibility to shy away not only from chemotherapy, but also from lenalidomide/rituximab itself, by combining BTK inhibitors with anti-CD20 monoclonal antibodies. The phase 2 ROSEWOOD trial [NCT03332017] compared zanubrutinib [Brukinsa] plus obinutuzumab [Gazyva] vs obinutuzumab alone [in patients with relapsed/refractory follicular lymphoma] and showed significantly increased progression-free survival [with the combination]. That is very promising for our patient population, because we may be able to offer, in addition to chemotherapy and standard immunotherapy, novel biological regimens that were not previously available.

Are there any safety concerns for adding additional agents to the lenalidomide/rituximab backbone?

Every time we add agents that could increase the activity of immunotherapy, the concern of immunotherapy-related toxicities might also increase. This may bring life-threatening complications, which has happened in the past when, for example, trying to combine lenalidomide to PI3K inhibitors. Luckily, so far, in phase 1/2 trials combining mosunetuzumab, epcoritamab, acalabrutinib, or tazemetostat [Tazverik] to lenalidomide, we haven't seen a significant increase in typical immune-related adverse effects of lenalidomide.

Of course, when we use bispecifics, something to keep in mind is that these can be associated with cytokine release syndrome [CRS].In [a phase 1/2 trial (NCT04246086) evaluating mosunetuzumab plus lenalidomide in patients with follicular lymphoma], the incidence of CRS was quite high; however, the CRS rate didn't seem to be higher than what we would expect with a single-agent bispecific. Most importantly, CRS tended to be mostly low grade and usually [occurred] during the first few cycles. Despite the initial biological concerns, clinical evidence from trials supports the continuation of these combinations in an experimental setting.

What could the emergence of novel combinations mean for patients with indolent lymphoma?

Keep in mind that there are ongoing clinical trials that could increase the efficacy of immunotherapy. As a next step, these studies could lead to approval of novel combinations for patients who relapse after frontline chemotherapy and may lead to the development of new randomized phase 3 trials where novel combinations will be compared with standard chemoimmunotherapy in the frontline setting.

For our patient population and us as oncologists, [developing novel combination strategies] would be a major win. We know that these patients, unfortunately, are older and frail, and being able to completely shy away from chemotherapy with these novel strategies would be a major achievement.


Strati P. Novel combinations in indolent lymphoma. Presented at: 2023 SOHO Annual Meeting; September 6-9, 2023; Houston, TX.

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