FDA Approvals Augment Advances Made in the DLBCL Armamentarium

John M. Pagel, MD, PhD

In diffuse large B-cell lymphoma (DLBCL), it’s critical to understand the genetic risk of each individual patient, according to John M. Pagel, MD, PhD, who added that genetic risk can inform up-front and newly expanding options in the relapsed/refractory setting. 

“The most important thing is to really understand the genetic risk of each individual patient. Don’t miss if they have gene rearrangements that would lead to double-hit or triple-hit lymphoma,” said Pagel. “If you’re seeing these very aggressive, large cell lymphomas, follow them very closely and be prepared for the next type of treatment they may need.”

Such treatments now include CAR T-cell therapy, polatuzumab vedotin (Polivy), tafasitamab-cxix (Monjuvi) and selinexor.

On July 31, 2020, the FDA approved tafasitamab in combination with lenalidomide (Revlimid) for patients with relapsed/refractory DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant.¹

Selinexor received regulatory approval on June 22, 2020, for patients with relapsed/refractory DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy.²

In an interview with OncLive, Pagel, chief of the Hematologic Malignancies Program, and director of the Hematopoietic Cell Transplantation Program, at Swedish Cancer Institute, discussed current treatment approaches in frontline and relapsed/refractory DLBCL and provided insight on some of the agents that are generating excitement in the relapsed/refractory setting.

OncLive: Could you provide some insight on the current DLBCL treatment landscape?

Pagel: DLBCL has been, largely, a success story for us over the past years because we are now able to provide cures to at least 60% of patients with large cell lymphoma.

It is important to remember that not all large cell lymphoma is created equal; there are different subtypes of DLBCL. [The type of lymphoma] depends on the cell of origin. It’s important to understand if it’s a germinal center or non-germinal center large cell lymphoma because it’s important for prognosis and may be important for treatment and survival. The addition of rituximab (Rituxan) to standard CHOP–based chemotherapy represented a major advance in the frontline treatment of patients with DLBCL. Since then, we hadn’t made many major advances until more recently; these advances have really moved the needle for how we manage patients, primarily in the relapsed setting.

We also know that’s not the end of the story. Now, molecular studies are looking at large cell lymphomas that really break them down into multiple different groups, perhaps 5 different types of large cell lymphoma, based on their genetic signature. That might further lead us to advances in therapies for specific subsets of patients, but we’re not quite there yet.

We have looked at a variety of other up-front regimens. Most recently, dose-adjusted rituximab with EPOCH (R-EPOCH) chemoimmunotherapy. While we believe there’s significant role for that [regimen], primarily in primary mediastinal DLBCL, the standard of care for the vast majority of patients continues to be R-CHOP in the frontline setting.

We also recognize that some patients do extremely poorly because of genetic risk, particularly those who have double-hit or triple-hit lymphoma. Always screen for [double-hit or triple-hit lymphoma] with a fluorescence in situ hybridization test that looks for gene rearrangements between the MYC gene, BCL-2, or BCL-6. If we see those, [we know] that this is usually a very aggressive large cell lymphoma. Those patients might be even more appropriate for a regimen of dose-adjusted R-EPOCH. Someone who has double-hit or triple-hit lymphoma without those gene rearrangements but has overexpression of those genes, which can be seen by immunohistochemistry and cytochemistry, have more of an intermediate risk and often are treated with R-CHOP, as well.

What is the biggest challenge in the space?

Approximately 40% or so of patients will relapse; that’s a big problem for us. We need to try to work to cure those patients. The standard of care has been to try to get patients to an autologous stem cell transplant, if they’ve relapsed. The thinking is that they need higher doses of treatment. When you deliver very high doses of treatment to kill all the remaining lymphoma, you’ll kill the normal blood-forming cells. That has to be done safely by stem cell rescue, and in particular, we use autologous stem cells for the transplant procedure. While we still do transplants, we understand it’s not a viable alternative in the vast majority of patients who relapse.

If you take 100 patients, and you cure 60 of them, that means 40 patients will relapse. Of those 40, only about half of them end up getting a transplant. Why? It’s because they’re not sensitive to chemotherapy, and if they’re not sensitive to chemotherapy, there’s really no reason to be moving to a transplant. Or, they may have comorbidities or other issues that don’t allow them to get a transplant.

Of those 100 patients, 60 are cured up front, and maybe 10 are cured with the transplant. That leaves 30 who still need effective treatment. We have some newer agents that are very important for patients with relapsed disease. The biggest one to know about is CAR T-cell therapy which is important in that it provides an opportunity for cure for patients who failed a transplant or perhaps were never able to get to transplant. CAR T-cell treatments are very important for those types of patients. It appears that CAR T cells can provide long-term survival for about half of those patients. Still, many will relapse or fail CAR T-cell therapy.

What are some of the agents that are generating excitement in the relapsed/refractory setting?

Now, we have a variety of other agents that have been recently approved which we’re excited about. Right now, we’re particularly excited about an anti-CD19 agent called tafasitamab which was evaluated in combination with lenalidomide in the phase 2 L-MIND trial. The data are extremely encouraging. The combination recently gained accelerated approval based on data from L-MIND in the relapsed setting.

Another agent that has recently been approved is selinexor. Selinexor is an advance in that it’s a new class of drugs. It’s what we call a nuclear transport inhibitor. The agent is approved for use a little further down the line but is an option for patients. We have to still figure out the best way to use it. Some toxicity is associated with the agent.

We also have polatuzumab vedotin which was approved in relapsed large cell lymphoma for use in combination with bendamustine and rituximab; it’s another important agent that is valuable for patients in the relapsed setting. Polatuzumab vedotin is an antibody-drug conjugate (ADC) that is kind of like brentuximab vedotin (Adcetris), which is approved in Hodgkin lymphoma. [The former] ADC targets CD-79b on the surface of B lymphocytes and the data suggest that it’s very efficacious. The ADC gets internalized and then the cytotoxic chemotherapeutic agent, the monomethyl auristatin E, is cleaved from the antibody, and the microtubular inhibitor causes mitotic arrests and cell death.

We’re also excited about therapies that are still in development, particularly bispecific antibodies, which have tremendous excitement and promise. A lot of recent data have looked at bispecific antibodies. The advantage there is that they’re off the shelf. We can deliver [these agents] quickly and repeatedly to patients because they’re adaptable and can be tailored to the specific clinical situation. These drugs have a lot of activity in targeting the malignant B lymphocyte and bringing in the second target, which is the T cell, to hopefully kill the lymphoma cell and produce some benefit. We’re still waiting for further data, but it’s exciting to see where we’re at and where we’re headed with bispecific antibodies.

A variety of other approaches are also gaining traction. Some of them are in the cellular therapy space. We are excited about allogeneic CAR T-cell approaches and natural killer T cells, which are off the shelf; [these approaches] are gaining enthusiasm. A variety of other exciting agents [have emerged], as well, including novel BCL-2 inhibitors, BCL-XL inhibitors, and several others that we’ll learn more about in the near future.

One of the biggest problems that we have with CAR T-cell therapies, or any of these other novel agents, is getting patients to the therapy. If the disease is refractory and growing fast, and if we’ve delayed any significant amount of time, it can be extremely difficult for these patients to get the treatment they need.

References

1. FDA approves Monjuvi (tafasitamab-cxix) in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). News release. MorphoSys AG. July 31, 2020. Accessed August 10, 2020. https://bwnews.pr/3jZhE5g.
2. FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. News release. FDA. June 22, 2020. Accessed August 10, 2020. bit.ly/37VnEXd.