Novel Combinations in Indolent Lymphoma

Paolo Strati, MD

In this video, Paolo Strati, MD, discusses chemotherapy-free approaches in the treatment of patients with indolent b-cell lymphoma, including early trials that are underway on the combination of lenalidomide and rituximab and the use of immunotherapy in a front-line setting. Dr Strati also discussed these topics during the session at the SOHO 2023 Annual Meeting titled “Novel Combinations in Indolent Lymphoma.”

Additional Resource:

Strati P. Novel combinations in indolent lymphoma. Talk presented at: The Eleventh Annual Meeting of the Society of Hematologic Oncology (SOHO 2023). September 6–9, 2023. Accessed September 7, 2023.

For more SOHO 2023 Annual Meeting coverage, visit the newsroom



Paolo Strati, MD: My name is Paolo Strati, and I'm an assistant professor in the Department of Lymphoma & Myeloma and in the Department of Translational Molecular Pathology at MD Anderson Cancer Center in Houston, Texas.

Consultant360: Please provide an overview of your session at SOHO 2023 titled “Novel Combinations of Indolent Lymphoma.”

Dr Strati: I've been tasked to present at the 2023 SOHO Conference a brief talk regarding novel combination indolent B-cell lymphoma. The therapeutic armamentarium for this subtype of B-cell lymphoma has meaningfully increased over the last few years. I've really tried to focus on chemotherapy-free approaches and in particular trying to understand what can be done to further increase the efficacy of immunotherapy for indolent B-cell lymphoma, follicular lymphoma being the most common subtype and less commonly marginal zone lymphoma, and try to achieve this goal by better understanding the biology and the pathophysiology of indolent B-cell lymphoma.

And so I tried to touch on what the historical background has been with very limited use currently of immunotherapy for follicular lymphoma and marginal zone lymphoma, except for patients who relapse, and what current early trials are being run trying to improve on the efficacy of R2, which is the combination of lenalidomide and rituximab by adding extra agents or substituting some of those and how these early trials are showing very promising safety and efficacy data and are progressively moving toward randomized phase three trials and hopefully, ultimately will result into FDA approvals of biological and more and more immunotherapy agents for indolent B-cell lymphoma.

C360: What learning objectives do you believe the audience took away from your session?

Dr Strati: Currently, the combination of lenalidomide and rituximab, of R2, is formally approved by the FDA only for patients with follicular, marginal zone lymphoma or relapse after frontline treatment. However, if you look into the NCCN guidelines, there's a compendium approval for this combination in frontline treatment, but despite this, its use in frontline both in academic and community environments is very limited. So what I really hoped the take-home message has been from my presentation at SOHO is that there's actually very good data supporting the use of R2 in frontline, both in terms of safety and efficacy. We now even have long-term data from the original phase two study that was actually developed here at MD Anderson, showing that up to 70% of patients with previously untreated follicular lymphoma may remain disease-free eight to 10 years after frontline R2.

But I also hope there will be more and more engagement both in academia and community in clinical trials based on immunotherapy and biological type of combination for these patients as clearly, these patients may shy away from the use of chemotherapy and may benefit from low toxicity agents such as biological and more targeted agents. This is very relevant in my opinion mainly for two reasons. The first reason to keep in mind is the median age for patients with follicular lymphoma tends to be quite old, 72 or older. And so it becomes very tricky to be able to use chemo-immunotherapy in this patient population. But CAR T cells, for example, are currently approved by the FDA for patients with follicular lymphoma who've relapsed after two lines of systemic treatment and hopefully will be also approved in the not-too-far future for marginal zone lymphoma. Previous treatments may impact response to CAR T cell therapy and probably even to bispecific antibodies that have been recently approved by the FDA in the same setting, so relapse after two lines of systemic therapy.

The standard treatment for follicular lymphoma or marginal zone lymphoma is currently represented by bendamustine, which is a very well-known lymphodepleting agent. And so the efficacy of both CAR T and bispecifics may be impacted by its use, though we're still waiting for more definitive data on this point. So I really hope my presentation will encourage the audience not only to increasingly prescribe immunotherapy in the frontline setting based on NCCN guidelines but also to utilize more and more clinical trials for this patient population.

C360: What are the benefits and pitfalls of these agents?

Dr Strati: We tend to use the term chemotherapy-free approach when we refer to immunotherapy or biological therapy or targeted agents for indolent B-cell lymphoma, but not everybody will agree on this term. Though these agents, including lenalidomide, mosunetuzumab, tafasitamab, are not formally chemotherapy agents, they're not toxicity-free. In my presentation, I try to emphasize as honestly as possible what the safety profile has been so far in early clinical trials and for some of them, even randomized phase three trials. So that's probably one of the pitfalls, which is very important to keep in mind.

Some of these toxicities, even if not the typical chemotherapy-associated adverse events such as nausea, vomiting, or hair loss, are still relevant for our patient population. To name some of them, with lenalidomide, patients may develop skin rash, severe fatigue, neutropenia, LFT elevation, and thrombotic events. With the more recently approved agents such as bispecific, patients can develop cytokine release syndrome, which is a potentially life-threatening condition. And then of course with CAR T cell therapy like Axi-cel or Tisa-cel, both of which are currently approved FDA in third-line or beyond for a patient with follicular lymphoma, immune cell-associated neurotoxicity syndrome can be observed, though the frequency is not as high as we see in large B-cell lymphoma, but this is also difficult to manage complication and a potentially life-threatening adverse event.

One other thing to keep in mind is the low-grade adverse events. So once again, even if these are chemotherapy-free approaches and relatively well-tolerated, they can come with low-grade but chronic adverse events. Thinking of BTK inhibitors currently approved for marginal zone lymphoma, not yet for follicular lymphoma, some of these patients can develop chronic fatigue, chronic low-grade diarrhea, and chronic low-grade hypertension, which does affect the meaningful quality of life in this patient population.

Finally, one thing to keep in mind is that the duration of treatment with immunological therapies, biological therapies, and targeted agents tends to be typically much longer than it is with chemotherapy, where typically it tends to be no more than six cycles, whereas this treatment can be as long as 18 cycles or lifelong. This can be inconvenient for some of our patients, and there's a constant effort looking into minimal residual disease eradication to try to minimize as much as possible this and aim for a fixed duration, MRD-driven, but we haven't got it yet. But despite keeping in mind all these limitations, I still think the ongoing effort in trying to invest in these types of agents for our patient population is very meaningful and should continue.

C360: What are the gaps in the research of novel agents in indolent lymphoma and what's next for research?

Dr Strati: I think when it comes to indolent B-cell lymphoma, it has become very clear the biological mechanism and the pathophysiology of this condition are closely related to apoptosis pathway, epigenetic changes, and a lymphocytic immune microenvironment. The hallmark of follicular lymphoma is the translocation between BCL2 and IgH that alters the apoptotic pathway, though BCL2 inhibitors have not really worked in follicular lymphoma and are not currently approved for either follicular lymphoma or marginal zone lymphoma. So it'll be very important to understand how other pro-apoptotic proteins, like BCL-XL or MCL1 may play a role in response to anti-apoptotic pathways and maybe develop agents targeting more than one pro-apoptotic protein. So that's definitely a gap in an area of research that may potentially bring to cure for follicular lymphoma.

We also know that this translocation is not present in every patient in, about 80-90 percent of patients, but it's not usually enough for the development of follicular lymphoma. So the additional hit is typically represented by epigenetic changes. And there's currently an agent approved by the FDA for follicular lymphoma, not for marginal zone lymphoma, called tazemetostat, which is an EZH2 inhibitor, but EZH2 is not only a relevant epigenetic gene dysregulated in this patient population. So research aimed at understanding how targeting epigenetics may result in better disease eradication and potential cure is relevant. Also, we know that these epigenetic changes may be responsible for the early onset of follicular lymphoma and for the early stages of this condition. So try to investigate more and more epigenetic targeting agents in patients who have low tumor burden disease before the amount of disease may hamper their activity I think would also be important and should be an area of research.

Finally, while there's a clear understanding of how T-cells are crucial for follicular and marginal zone lymphoma based on pivotal gene expression profiling study, and this is being exploited with multiple agents, lenalidomide, mosunetuzumab, CAR T cell therapy, there's still a limited understanding of how tumor-associated macrophages may play a role in these patients. Some recent data published by our group have clearly shown that an increase in pro-tumoral macrophages may be responsible for relapse after frontline R2. So trying to combine immunotherapy with agents that can favor repolarization of tumor-associated macrophages to a more antitumoral phenotype may help. We understand more and more that BTK inhibitors, for example, in addition to the more standard anti-CD47, antibodies may achieve this goal. So there's a lot of interest in using BTK inhibitors in combination with other agents in follicular lymphoma more than it was in the past.

I think that a good example is the ROSEWOOD study. Historically, single-agent BTK inhibitors have shown very limited activity in follicular lymphoma, but by combining novel BTK inhibitors that may act on tumor-associated macrophages with better anti-CD20 monoclonal antibodies such as obinutuzumab, that in preclinical studies have clearly worked, have clearly shown to provide better ADCP than rituximab may result in better efficacy. And again, in the ROSEWcOOD study, the combination of zanubrutinib and obinutuzumab performs significantly better than obinutuzumab alone. So I think that these are three important areas of research and gaps that we need to work on, but as we investigate more and more, looking into patient-derived samples, the biology of follicular lymphoma, and marginal zone lymphoma, more gaps and more area for improvement will open up.

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