Balzarotti Breaks Down New Developments in the Expanding DLBCL Paradigm

In recent years, rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has been the standard treatment for patients with diffuse large B-cell lymphoma (DLBCL), according to Monica Balzarotti, MD, but new approaches such as selinexor (Xpovio), bispecific antibodies, and CAR T-cell therapies are expanding the armamentarium.

“Notably, about 20% of patients with DLBCL have refractory disease. Some patients are not suitable for high-dose consolidation with autologous stem cell transplantation (ASCT) because there is no treatment that can guarantee a longer remission,” Balzarotti explained. “Whatever you use—chemotherapy, such as gemcitabine or oxaliplatin, polatuzumab vedotin (Polivy)/bendamustine, or even new experimental drugs—[we are not able to obtain] longer remissions. Looking forward, we must determine whether we can consolidate and maintain responses.”

In an interview with OncLive, Balzarotti, a hematologist in the Department of Hematology at the Institute for Research, Hospitalization, and Health Care (IRCCS) Humanitas Research Hospital, discussed the current treatment landscape of DLBCL, including the recent FDA approval of selinexor for the treatment of adult patients with relapsed/refractory disease.

OncLive: Could you discuss the current treatment landscape for DLBCL?

Balzarotti: In the first-line treatment of [patients with] DLBCL, R-CHOP is still the golden standard because no other regimen has been able to demonstrate superiority [over this approach]. However, there is some hope regarding the use of BTK inhibition in younger patients. The PHOENIX trial demonstrated the superiority of R-CHOP plus ibrutinib (Imbruvica) in younger patients; however, the primary end point concerned older patients. Thus, we don’t have a definitive [takeaway] from this trial. Another trial will examine acalabrutinib (Calquence) in younger patients that might help us to answer this question.

At relapse, [we use] high-dose consolidation with ASCT; this approach is reserved for younger patients aged up to 70 years. This strategy can cure about 50% of patients with relapsed disease, even the patients that experience relapse later on. In the case of primary refractory disease, or patients with very early progressive disease, even chemotherapy and ASCT is not enough to guarantee a high percentage of cure. Under 20% of these patients have the probability to survive 1 year.

Now, we have CAR T-cell therapy and we are very hopeful. This is a new strategy that is very promising, but I don't believe it will be able to cure all patients with relapsed/refractory disease. Thus, we need other drugs and more knowledge of the biology of the disease.

Could you expand on some of the later-line treatment approaches?

We have several therapies, many of which are concentrated [for use] in the subgroup of patients who are not suitable for ASCT. The majority of patients with DLBCL are not eligible for ASCT, because this disease mainly effects the elderly. Oftentimes, elderly patients do not receive an optimal treatment in the first-line setting. Sometimes they receive a reduced dose of R-CHOP and then they relapse, or they have a comorbidity that does not allow for them to receive full-dose chemotherapy.

As such, several therapies have been developed. One such therapy is lenalidomide (Revlimid), which can result in a 30% complete remission (CR) rate. This is higher in patient with the Germinal center B-cell like subtype. This is the only drug that has been approved for use worldwide.

Another agent is polatuzumab vedotin, which is a CD79b-directed antibody-drug conjugate (ADC); this drug has been approved for use in combination with bendamustinein the United States and it [will likely] be approved in Europe and Italy in the future. However, this has been delayed because of the novel coronavirus 2019 pandemic.

We also have several other drugs and strategies, such as the bispecific antibodies, ADCs, and monoclonal antibodies, such as cabozantinib (Cabometyx). We also have selinexor, CAR T-cell therapy, ASCT, and maybe some other drugs that are still in earlier phases of experimentation. We have many treatments, but we still need to learn how best to use them and how to sequence them appropriately.

What are the big unmet needs that still need to be addressed?

Oftentimes, DLBCL is not a good candidate for maintenance therapy because it does not have a molecular marker such BCL-2 which is used in follicular lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. However, when evaluating circulating tumor DNA and the identification of newer molecular markers, we may be able to proceed in that way. We have small experience with the consolidation and maintenance treatment, for example, with lenalidomide and other drugs, which is encouraging.

What ongoing studies are you most excited about?

In the first-line setting, the most highly anticipated results are those from the POLARIX trial, which compared R-CHOP with R-CHOP plus polatuzumab vedotin. We also anticipate results from another trial, which is comparing ASCT with CAR T cells in the setting of refractory disease. Other trials are in earlier stages and are currently accruing.

Could you speak to the recent FDA approval of selinexor in DLBCL?

Selinexor has shown encouraging activity with a high rate of both CR and overall remission. In the published trial, there were longer durations of complete and partial remissions. The fact that remission can be maintained is important, especially for the maintenance therapy that I mentioned earlier.

On the other hand, I know that selinexor is not an easy drug to manage, especially because of the high rate of nausea and vomiting. There are very aggressive protocols to contain these toxicities [but it] is a bit worrying for the European investigators; we are not used to administering these drugs. There is an agent in the United States that is used to help control these symptoms.

However, I believe this could potentially be problematic because, when prescribing a drug for a long period of time, the adverse effects may hinder a patient’s quality of life. We need to ensure that patients are taking the drug as directed.

Where should future research efforts be focused with this agent?

It’s important to learn how to manage selinexor [better]. When there is a new drug, you read the literature to better understand the activity of the drug, but only for a very selective group of patients. Then, there is the real world. We have real-world data on CAR T cells and it’s interesting to think about; this is better. We are now waiting for the real-world [data] of selinexor [to see what can be learned].

What is your take-home message to your colleagues treating patients with DLBCL?

The most important message is that patients with relapsed disease should be managed by the referral center, not because the conditions of the center are better, but because they usually have new drugs, strategies, and ways to approach patients.

In one center they may have selinexor, in another they may have ADCs, and another may have CAR T-cell therapy. You need a center or a collaborative group where you can find all of these strategies because this will help you choose the best therapy because you will have a better understanding of the risks and characteristics of the drug. Sometimes these strategies can be used in segments.