Moffitt’s Dr Julio Chavez Discusses New Treatment, Sequencing Options in DLBCL

Julio Chavez, MD, MS, is associate member in the Lymphoma Section of the Department of Malignant Hematology at Moffitt Cancer Center. His research focuses on lymphoid malignancies, especially aggressive lymphomas, virally-related lymphoid malignancies and chronic lymphocytic leukemia. He is currently the principal investigator in clinical trials examining targeted agents and immunotherapy. Chavez spoke with The American Journal of Managed Care® (AJMC®) about how new approvals will alter decision making in the treatment of diffuse large B-cell lymphoma (DLBCL).

This interview is edited lightly for clarity.

AJMC®: What percentage of patients with diffuse large B-cell lymphoma, or DLBCL, are refractory to or relapse on frontline therapy?

Chavez: The standard therapy for diffuse large B cell lymphoma is a chemotherapy regimen that we call R-CHOP (rituximab with cyclophosphamide, doxorubicin hydrochloride, vincristine [Oncovin] and prednisone). The rate of relapsed and refractory DLBCL depends on many factors such as cancer stage, IPI score (International Prognostic Index), and some biological factors. But in general, we consider about 30% to 40% patients will relapse to frontline therapy.

AJMC®: What clinical or other features relate to prognosis at this stage of this disease? And what is the significance of things like high risk molecular features after a relapse?

Chavez: There are several factors that will affect the prognosis on patients who relapse to frontline therapy. In my practice, and in the data I see, the timing of relapse is an important factor. Either patients are refractory, meaning they had no response to frontline therapy, or they had an early relapse, which means they relapsed within 12 months of initial therapy. This is probably the strongest prognostic factor. However, there are others too, including genetic abnormalities, such as MYC and BCL2 and/or BCL6 rearrangement. Those patients actually do poorly even with tolerated chemotherapy—so much so that we question the value of autologous transplant in those patients.

The IPI score is another prognostic indicator; the higher the IPI score, the worse [patients will do] in the relapsed setting. Also, there is the tumor burden—higher tumor burden, [whether that is determined] by size or by metabolic tumor volume using PET scan imaging, also is associated with poor prognosis indicator factors.

AJMC®: What are some recommended options when we talk about second-line therapy? And what factors do you use to determine your choice of therapy in this setting?

Chavez: As you know, traditionally, the first thing that we ask ourselves is whether or not a patient is transplant eligible. A transplant eligible patient has the potential to have a curable disease through additional interventions, such as salvage chemotherapy followed by autologous transplant in chemosensitive patients. There are different regimens out there; I don't think there is one regimen that is better than the other. But I usually recommend that community doctors or my colleagues use the regimen that they're most familiar with—try not to do anything new. Then, [there is] referral to a transplant center, so the patient can be set up for autologous transplant.

For transplant ineligible patients, the situation is a little trickier; however, this doesn't mean there are no treatment options. We don't expect patients to be cured. But there are treatment options out there, even some mild chemotherapy. Some targeted therapies are currently approved in the second line, such as tafasitamab and lenalidomide. Polatuzumab-based therapies also are available.

And, now we have [chimeric antigen receptor] CAR T-cell therapy that has been recently approved as a second line. Whether CAR T cell therapy falls between transplant eligible or ineligible, I don't think we have that answer. Transplant ineligible doesn't mean the patient is CAR T ineligible. Other factors are associated with transplantation that would not necessarily make the patient ineligible for CAR T. So, CAR T cells should be considered even in a transplant ineligible patient, especially now that is approved in second line.

AJMC®: I appreciate you jumping into CAR T because that's what I'd like to ask you about next. Can you describe in more in detail your decision-making process around these CAR T cell therapies? When do you consider it? What patients do you think should receive CAR T versus other treatments that you might try? And what sort of factors do you consider when looking at CAR T cell therapy?

Chavez: It is an interesting question, because things are changing. A week ago, I had a different landscape. And now with approval [of axicabtagene ciloleucel in second-line treatment], things are going to change a bit more. So, CAR T cell therapy now is approved for second line use in patients with primary refractory or relapse within 12 months of therapy. I think we should stick with that patient population—those are the high-risk patients who had no response or had early relapse, who are less likely to respond to standard salvage chemotherapy. We should try to focus on those patients, whether they're transplant eligible or transplant ineligible—those criteria don’t really matter for CAR T. The vast majority of patients actually will fall into that category [of relapsed or refractory disease]. I would say in my practice is probably about 70% of patients who have this kind of early relapse or refractoriness.

However, we should consider other factors, such as how soon we can get patients to CAR T. Will the patient need some therapy in between the approval for an appointment in a CAR T center—for apheresis to make CAR T cells—and the manufacturing time? That time could easily be about almost 2 months, or even a month and a half to 2 months . That would leave a significant length of time in which patients will not receive therapy until they get into CAR T. My impression is that a proportion of patients will get some type of therapy; even though they progress to R-CHOP, they will get some type of salvage or some type of therapy to keep them stable until they get to CAR T.

And here, it is important to have close communication between the referring doctor and the CAR T cell doctor to discuss bridging options. I just had a conversation early this morning on what is bridging. The traditional definition of bridging was between apheresis and the actual CAR T cell treatment (infusion). But now we're talking about different bridging—this is bridging from the time the patient progresses to R-CHOP or a frontline therapy to the time that they do the apheresis for the CAR T cell treatment, so that may indicate a couple of cycles of chemotherapy or other novel agents as well. The good news is that we have options. We have a treatment available that we can use for patients that are not too toxic, and that will probably keep patients stable enough to do CAR T. A discussion with the CAR T cell doctor and referring doctor will be important, just to kind of determine the best strategy to get patients to CAR T.

AJMC®: Of course, there's a significant economic burden around CAR T therapy, and you alluded to the extended process associated with this therapy. Does that impact your decision making? Are you more willing to try something in that sort of bridging phase that you discussed? A novel agent, something new to market, in order to see maybe can we stave off CAR T therapy for that much longer, or even perhaps indefinitely, depending on where the where the patient is in their disease?

Chavez: So, good question. I think, unfortunately, I would say no. I think what is important is to save lives because patients with primary refractory disease and early relapse, they have high rates of death. And I'd say autologous transplant and salvage chemotherapy or CAR T-cell therapy are the only curative options. I'm sensitive to the economic burden that will be involved. However, we had to weigh the benefits of saving lives and saving money. I think if CAR T delivers what it promises, I would think that will [help patients] avoid other problems later on like more therapy, allogenic transplant, more autologous transplant. In the end, curing more patients may actually mean saving money, by [avoiding] future treatments that the patient will get. So, it is important to consider the economic burden. But if it's a therapy that can potentially cure patients, it's hard to justify something against it.

AJMC®: That is a great point. So, what do you think is needed next to improve outcomes in patients with relapsed/refractory DLBCL? Do you think CAR T cell therapy will eventually replace transplantation, for example?

Chavez: In some, perhaps the majority of cases, it will. This is especially true for those patients who had like early relapses, and definitely in those cases, it will. The question is not whether it will replace it or whether autologous transplant will go away. The question mainly will be the sequence. Can we do autologous transplant after cardiac failure? Patients do relapse after CAR T, and the [data] show that about 50% of patients will relapse after CAR T. Can we still do autologous transplant after CAR T? We don't know the answer. So, I think that needs to be explored.

I would say it's a little bit early to say that autologous transplant will go away. I think it will remain for a good proportion of patients, especially the patients who have had late relapse, those who don't respond to CAR T, and if they have chemosensitive disease. I think we could plan a sequencing of treatment, not only including transplantation, but other agents too, such as bispecific antibodies, once they receive approval. Some of the agents that we have available will serve as a bridge to something more definitive.

Given the availability of CAT T cell in second line, the number of autologous transplants will decrease, but they won't go away. Doctors will have to use good judgment to decide how to best use these therapies for patients.

AJMC®: Would you ever envision a time, in 5 to 10 years, where we might move away from using R-CHOP frontline and might move to these highly effective, sometimes curative therapies, such as CAR T or some other novel agent?

Chavez: I think it's possible. I think it depends mostly on the mindset. R-CHOP has been the standard regimen for lymphoma, for DLBCL, for over 3 decades. It’s hard to take away that mindset, and you can see how the trials are being designed—[with] combinations, everything has the backbone of R-CHOP. One idea that challenges this is whether can we cure DLBCL in the frontline setting without R-CHOP or less R-CHOP, at least. Instead of giving 6 cycles, can we do just 1 or 2, and then do some type of maintenance—so CAR T, 1 or 2 cycles of R-CHOP or bispecific antibodies. I think we can get to that point.

One of the studies showed this as a proof of concept. Patients have 2 cycles of chemotherapy [and] have residual disease. They went on to receive CAR T cell therapy. These were high risk patients, with high IPI scores and also a double hit lymphoma. One [element] of the trials is whether the patients have high risk factors. It is feasible—we saw a high response rate, and after several years we still have patients in remission. So it's a proof of concept that we don't have to do a full R-CHOP regimen. I think we can get to that point—we just need to do more confirmatory studies. You have investigators willing to participate in these studies to potentially replace chemotherapy. But it will take some time; I don't think it will go away completely. Remember, chemotherapy cures the majority of the patients, even for those with stage IV disease. So, we have to be very careful to say, “this is the end of chemotherapy.” I think is going to take a while. It will still have a role for some patients, even as a bridge therapy. The most important thing is to do is to develop the studies to answer those questions.

AJMC®: Are there any considerations when it comes to disease management in DLBCL that you'd like to share? Any closing thoughts in this area?

Chavez: I think we are living in an exciting moment. You know, I started my career in pharma right at the time when these therapies came through—so, I think we have exciting options. CAR T therapy is becoming the centerpiece of the treatment in DLBCL. I do know that not all patients can be cured with CAR T, so we have other options—such as targeted agents or bispecific antibodies. Clinical trial participation is important—that’s probably my first thought. The second thought will be for CAR T cell therapy to be successful, the earlier we see the patient, the better the outcome. The more we wait, the sicker patients become, which makes it harder to seek a curative option.

So, outside a standard form of chemotherapy and autologous transplant, CAR T is the only available curative option for patients. If it's proven that to be better than autologous transplant and well tolerated, it's important for community doctors to start thinking about referring patients early, especially those patients that we know will relapse—including those with high tumor burden, high IPI score, or double hit lymphoma. Early referral is important so we can assess the patient, and then offer treatment or take the next steps to cure the disease.