Dr Paolo Caimi Highlights the Need for Access and Better Treatments in DLBCL

There’s a need for access to treatment and a need for better drugs in diffuse large B-cell lymphoma (DLBCL), said Paolo Caimi, MD, staff physician in the Department of Hematology and Medical Oncology at the Cleveland Clinic and associate professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

In this interview with The American Journal of Managed Care^® (AJMC^®), Caimi reviewed studies into therapies for DLBCL, how social determinants of health impact treatment, and novel mechanisms being studieda.

AJMC^®: Can you discuss how social determinants of health may impact diagnosis and treatment of DLBCL and what is the Cleveland Clinic doing to address these health disparities?

Caimi: There are social determinants for diffuse large B-cell lymphoma and for other lymphomas, although it may be a little bit different than for other more common diffuse cells. Still, socioeconomic status affects your access to care and affects your capacity to undergo the treatments and to tolerate them. We know that people who have lower socioeconomic status tend to have worse outcomes in general for lymphoma. I think that the number one thing that we have to do better as a community is recognize that and provide—as we discuss with some of our colleagues and over a period of time for our system—more assistance to those people who need it and not to those who have access to it. We forget that those who have the least access to it are the ones who need it most.

Our approach to addressing the health disparities is based on a couple of things. There are a couple of pillars. Number one is access. Where the hospitals are located in Cleveland. They're located close to areas where there's higher need. So, it's primarily having a good community access, facilitating the entry points towards a system. Ideally, once the patients achieve access, provide support for them that has to be personalized or adjusted to the person's needs.

Also, understanding that a lot of people have trouble coping with chemotherapy in different ways than you would expect. People sometimes can't take off work. It's not just symptoms, it's the economic impact of chemotherapy or treatments. I mean if you think of it purely for diffuse large B-cell, chemotherapy or immunotherapy right now are the mainstay of treatment. Most of them require you to either take at least some off or may force you by the symptoms to take some time off, and that's not easy for everybody. I think it's primarily trying to provide support, education before and after diagnosis. We know that people who have advanced disease who need in-patient treatment for their disease, who can't wait for their tests have worse prognosis. Consequently, if you delay your access, you're going to need treatment quickly after you're diagnosed very late and that affects your outcome.

Facilitating the entry is probably number one. Facilitating tolerability of treatment is the next one when it comes to not only development of symptoms but all the other aspects.

AJMC^®: How does anti-CD19 CAR T-cell therapy work for DLBCL?

Caimi: CAR T cell is a relatively new type of therapeutic approach. It's modification of a T cell to target a specific antigen. It's primarily genetic modification of a cell. It's done with viruses or other methods that lead the T cell to have additional receptors—a kinetic receptor because this is part of the B-cell on the surface—to attack the malignant cell. The target is CD19, which is something that is present on the tumor cells as well as normal B cells. The idea is to redirect your T cells to attack the cancer. They do take out the normal B cells but, thankfully, we can live without normal B cells, or we can live with very small amounts of B cell.

It's a cellular immunotherapy. It really doesn't require anything but to have the cells. It's not like a vaccine that requires you to mount an immune response to what they're injecting. This comes pre-activated. The way it works is probably not just by direct action against the tumor but also by recruiting other members of your immune system at the same time and kind of carrying them over to attack. The exact way it works in people who respond and the exact way it doesn't work in people who don't respond is still not well understood. We still can't predict well who's going to do great with it. We do know that it causes an inflammatory response that is called cytokine release syndrome that's associated with it.

There are people who have a neurologic syndrome called ICANS, it’s immune effecter cell-associated neurotoxicity syndrome. For that we know that the cells recruit parts of the immune system like macrophages and other cells to mount an exaggerated immune response. I tend to call it an immuno-inflammatory adverse event. One of the cytokines that is involved in this that very important is interleukin [IL]-6 and several medications can block interleukin-6 or block interleukin-1, which is also important.

From the start, tocilizumab has been shown to work for cytokine release syndrome as a treatment. There's one study that used prophylactic tocilizumab early on and it didn't really show significant improvement in outcomes for decreasing the risk of neurologic toxicity. Subsequently, we tried to do it for patients who received CAR T-cell therapy when I was at University Hospitals [Cleveland Medical Center], and we really did see that if we gave it immediately before for everybody, we saw low rates of cytokine release syndrome and we really didn't see an increase in neurotoxicity. What happens is when you give tocilizumab, you block the receptors so you're not increasing the clearance, you're actually decreasing the clearance interleukin-6 so you could have a rebound increase. That was one of the concerns early on of giving prophylaxis is that maybe we're just shifting everything to have a very high increase in interleukin-6. What we saw is that we have no increase in cytokine release syndrome. We saw actually less. We didn't see a grade 3 event after we started it, and we really didn't see an increase in neurotoxicity probably because we're blocking the self-perpetuating event that increases IL-6 and increases other cytokines by giving it before it could happen and the efficacy was the same.

But we didn't do a prospective study. The use of prophylactic tocilizumab is not yet validated prospectively. It's certainly safe—whether it provides sufficient benefit. it's unclear. I think for high-risk patients, it should be considered. There is early phase 2 data for the cohort 6 of ZUMA-1 that gave prophylactic corticosteroids and then early treatment with tocilizumab and that study showed that the outcomes were similar in terms of response with low rates of toxicity. I think in general the whole community has gone to the moment the patient looks like they have CRS, treat it. Meaning that you don't wait for progression of the storm: nip it in the bud, control it quickly, and I think that's where you probably will see progressively as we do more and more CAR-Ts is that the incidence of severe cytokine release is starting to go down, because we're catching it really early. So, the moment a patient has fever, we get the tocilizumab ready.

AJMC^®: What insights can you share from the SADAL study investigating single agent Selinexor for relapsing remitting DLBCL, and which patients would you consider to be candidates for this treatment option?

Caimi: Selinexor is an inhibitor of nuclear export. It's an oral medication. It was studied in a couple of doses in the SADAL study for a very specific subgroup of patients, who have relapse disease but a slow relapse. There were some responses in those patients to gain it approval. It's a drug that has certain benefits. One of them is that it's oral. The other one is that its side effects can probably be managed at the currently approved dose and that the side effect profile is more of a GI [gastrointestinal] toxicity with some hematologic toxicity rather than neurologic toxicity.

In general, I think it's a drug that is to be considered on somebody who is not a good candidate for the other treatments that are available. It seems to be at least more efficacious as a single agent or than the combinations that are currently available like tafasitamab-lenalidomide or polatuzumab vedotin-bendamustine-rituximab. Patients who are not candidates for those drugs and potentially people who have had a slow evolving relapse would be considered. Those patients may benefit and may actually be able to kind of sustain a response for quite a while.

AJMC^®: You were the primary investigator on the LOTIS-2 trial investigating loncastuximab tesirine in relapsing remitting DLBCL. What is the proposed mechanism of this medication in relapsing remitting DLBCL, what are your key clinical takeaways from the study, and where do you think this agent might fit into the current treatment landscape?

Caimi: Loncastuximab is yet another agent that targets CD19, which is a surface molecule that that is present on B-cells and malignant B-cells. It's an antibody drug conjugate [ADC], so it's an antibody that carries a payload of chemotherapy. It is really the first approved antibody drug conjugate that targets CD19, but also it is the first one with a specific type of payload, which is tesirine, which is a little bit different than the other ADCs that are approved that target a microtubule pathway in the cell. This one targets the DNA…and causes double strand damage. The toxicities are somewhat different. It really doesn't cause neuropathy. It can cause changes in liver enzymes, which are relatively mild, and we don't really know the clinical significance yet. It really doesn't cause any liver damage. It causes some low blood counts, and it causes sun sensitivity, meaning the people need to avoid being in the sun, and rash. The mechanism of action is primarily targeted-delivery chemotherapy. It's not really an immunotherapy.

The LOTIS-2 study is a phase 2 study that was a registration study. It showed that as a single agent, loncastuximab is an active drug. The characteristics of the study are somewhat special. We talked about the selinexor study, where people were slow rolling and this study was kind of more an all-comer study: double-hits, people who failed CAR Ts, transformed lymphoma. It excluded people with bulky disease, because the antibody can’t penetrate and it didn't work in the phase 1 trial, but in general it was able to achieve responses f throughout the groups including older and younger patients. As a single agent about 24% complete response and 48% overall response. So, it's robust but modest, and it's a relatively combinable agent.

It's an agent that because of its toxicity profile it's good for patients who have been previously treated with drugs that damaged nerves, like everything they need for diffused large B. It may actually be able to be used after CAR T-cell therapy. A few patients were able to respond to this after CAR T. It may be able to be used before CAR T. It fits in the armamentarium of drugs that can be used in the second or third line. It could be potentially combinable with chemotherapy—we have to learn that. We need to learn how we can sequence CD19-targeting drugs, because there are now several CAR Ts. There's an antibody like tafasitamab and there's an antibody-drug conjugate, and we probably soon will see other cell products that target CD19. The question is can you keep on doing it like we do with rituximab or is it not really a worthwhile endeavor? Can you use it only once? The preliminary data suggests that in most patients as long as they keep expressing CD19, you can continue to use it. I think it fits; right now, it's in the third line. I think the question will be before or after CAR T? It's well tolerated in older patients so I think it's something that can be used outpatient, too.

AJMC^®: What are some novel mechanisms currently being studied for relapsing remitting DLBCL, and how would these novel agents potentially impact current treatment guidelines?

Caimi: It's a burgeoning, still growing field. I would say there's probably 2 large groups of mechanisms and a lot of immunotherapy. The immunotherapy that's coming is adoptive immunotherapy—there's CAR Ts and NK [natural killer] cells galore, and you'll see a lot of different cellular products. You'll see NK cells that target CD19, CAR Ts target CD20, and then you'll see new allogeneic cells—cells that are off the shelf—as well as cell line–derived cells. A lot of cellular therapy. Then there's a lot of immunotherapy that is looking at other checkpoint inhibitors…[including] CD47, which it needs to be clarified how well it works on its own, whether it needs to be combined. I think the SIRP alpha pathway is also something that's very interesting. A lot of surface molecules that allow escape to the tumor to some mechanism of persistence that if you block it, you facilitate an immune response toward the cancer.

Then there's intracellular pathways that can be blocked [including] MALT1 and CARD11 inhibitors. There's certainly BTK [Bruton tyrosine kinase] inhibition that is coming in second line or third line. The question is where that fits; there are some studies that are actually in phase 3 that are being studied right now. There's a lot of intracellular signals that can be exploited.

Something that's very dear to our institution right because Dr [Brian T. Hill] is leading an effort and doing studies on how can you target subtypes of diffuse large B with different drugs. I think selecting the right agent, but also how can you use all these different drugs because not all diffuse large Bs are kind of created the same. Some drugs can be used to target certain subtypes. I think that's probably where the field is going to go in 5 or 10 years—new drugs for very specific subtypes.

AJMC^®: Can you please provide any closing thoughts on disease management considerations for DLBCL that you find noteworthy to share with colleagues?

Caimi: I think one of the questions that comes up is: where do we see the unmet need in diffuse lymphoma and aggressive lymphoma? The answer is everywhere. Everybody will tell you, “it's in the people who failed CAR T” or “people with 6 lines [of therapy].” The truth is that it really took 30 years to prove that we can add something to R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone]. We're still using anthracyclines, which are great drugs, but they cause some toxicity. They still don't work at 100%, and there's still a group of patients who can't take this.

There's a need for access. There's a need for better drugs. There's a need for second-line regimens that are better. There's a need to identify who will benefit from CAR T so we don't spend a half a million dollars on a product when we could spend it on another product that may be better. I think that we have needs in first-, second-, third-line [disease] and maybe before you even treat the patient. I think that's the big question that we tend to lose sight of, and we just want the last new drug tested.