 Julio, you brought up advantages and disadvantages. We have a few more minutes to wrap things up. We now have 3 new targeted drugs approved in relapsed large cell lymphoma for patients who are either not going to get CAR [chimeric antigen receptor] T-cell therapy or they’re post–CAR T. How do you select from these drugs? What are some of the advantages and disadvantages? What’s the algorithm? Julio, why don’t you start, but let’s have everybody weigh in on the future of treatment.

That’s a good question. We now have 3 new options other than CAR T: polatuzumab, tafasitamab, and selinexor. Depending on what the patient’s wishes are, 1 of the things I look at in cancer is: Is this an indefinite treatment, or is this a time-limited treatment? Polatuzumab plus bendamustine-rituximab offers a time-limited treatment of 6 cycles. Patients can achieve good PFS [progression-free survival] of almost a year. That’s attractive to patients. Many doctors are familiar with bendamustine-rituximab, so the treatment can be done in a community. That’s something I consider.

Many doctors are also familiar with tafasitamab-lenalidomide and know how to manage the adverse effects. Even though lenalidomide is not approved for DLBCL [diffuse large B-cell lymphoma] as a single agent, we are very familiar with it because we use it for other diseases like multiple myeloma, mantle cell lymphoma, and follicular lymphoma, and we frequently use tafasitamab-lenalidomide for DLBCL.

Tafasitamab is an Fc-engineered antibody. We have a few engineered antibodies approved, such as obinutuzumab. Doctors are familiar with monoclonal antibodies and how to use them. However, 1 of the disadvantages is that it’s an indefinite infusion, so treatment involves continuous infusions until disease progression. As we can see, the data look good, so many patients ended up with long-term treatment. I wish we could predict which patients will respond with limited therapy. Can we use tools like MRD [minimal residual disease] or PET [positron emission tomography] scans to determine for which patients we can stop treatment? That will be an important question.

For selinexor, we know the toxicity is novel. Selinexor is approved for multiple myeloma, so it has been around for some time. Some doctors should be familiar with the management of the adverse events like anorexia, fatigue, or nausea. The advantage is that it’s administered orally, so patients don’t have to have a line and it can be done with a local oncologist. We have to monitor closely, but it’s an indefinite therapy. We don’t know how long patients have to stay with this treatment, especially good responders. Also, we don’t know who the best responder will be—that’s something that we need to understand more from long-term data with more patients.

In relapsed/refractory DLBCL we are now moving toward what folks in myeloma have been dealing with for a long time. We have a number of agents, which are active. The question will be how to sequence, combine, and apply them to prolong patients’ lives with immunotoxicity.

Some of the unanswered questions we have are: How many patients of this particular therapy are resistant after progression, and how many of them will respond to subsequent treatment? You brought up a very good question: Are folks who are treated with tafasitamab-lenalidomide responding to CAR T therapy? Is the opposite true? We can acquire those answers from real-world data as we are using those combinations. Because, systematically, randomized studies are probably not going to be common in this space.

The other question is: If you use a certain treatment that results in toxicity, will this toxicity prevent patients from entering subsequent therapy? We know that some patients who relapse after CAR T-cell therapy are so beaten up with low counts, that they are unfortunately not candidates for clinical trials or any other therapies, which is a negative aspect of this treatment. The same could happen with some of the regimens using chemotherapy backbone. For example, bendamustine-Rituxan [rituximab] is myelotoxic and some of those patients can develop myelosuppression after the treatment, which may render them ineligible for other therapies.

We have to learn how to better sequence these drugs. A lot of the evidence regarding how to use them will be coming from real-world data. I hope as a community we can work together to generate these real-world data in order to learn the best sequence and get the most out of these therapies for our patients. Overall, this is a very welcome change. We now have more drugs than we had before that have manageable toxicity, and we’ll be able to apply them better and better over time.

I think that’s all well said. As I was pointing out with selinexor and with the tafasitamab-lenalidomide, there appears to be a small tail on these curves of patients that achieve durable remissions. That tells me 2 things. One is that unfortunately, even with these newer therapies, they are not curative. The median remission times for the majority of patients are often a year or less, so patients are still succumbing to this disease. There are some hints that there may be some populations that we can cure or even achieve durable remissions. I hope that as a field, we invest in trying to find out who those patients are, because then we can really change the course of the disease, not just get a 6-month PFS.

 How do you identify those folks or that tail? It’s tough.

 Relapsed large cell lymphoma has never been a chronic disease, unlike some of the other blood cancers we treat. It has a terrible prognosis and patients unfortunately can die quickly. There are occasional patients who are slow progressors and live a long time, but they are the minority.

You wonder with all these new targeted options, are we going to be able to string these together, 1 after the other? I don’t know. I mean, they are all now suddenly available at the same time, and there probably are not many people in the world who have been through 1 after the other, probably 0 or very few. If we string these together, will we be able to turn this into a more chronic disease than it’s been so far? It’ll be interesting to see. I would echo the thought that some real-world data might answer that question.

It’s good that we raise these questions. For a change in relapsed large cell lymphoma we have a lot of new options for our patients. It’s a great position to be in. We’re seeing more and more hope in a disease that has been tough to treat. When CAR T-cell therapy first became available, I said suddenly there’s hope where previously there was none. Now we’re seeing more of that with some of these targeted therapies in the relapsed setting.

Thank you all for this excellent discussion. We hope that you found the information to be valuable to your clinical practice. Thank you for watching the 

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Treatment of R/R DLBCL: Beyond CAR T Therapy

 Let’s transition to selinexor, which is the third of these new targeted drugs. Nathan, tell us about selinexor and how you see this drug being used in lymphoma.

This is a new class of drugs called SINE, a selective inhibitor of nuclear export, which essentially inhibits a shuttle protein called XPO1. This protein moves certain key pro-survival and tumor suppression proteins in and out of the nucleus. That is relevant to 

 and others because they contribute to cell survival and cancer. If you can inhibit those by keeping them from shuttling in and out of the nucleus, you could potentially design an anticancer drug.

Selinexor is an inhibitor of this XPO1 protein. It has been approved in multiple myeloma, and recently it received approval for large cell lymphoma based upon a large trial. Initially the trial was nearly 300 patients and centered on examining several different doses. Eventually, if you bore down on the FDA-approved dose, which was around 60 mg twice daily, they had around 120 to 130 patients. Here, those patients are all beat up. These are all relapsed large cell lymphoma patients. I believe nearly 75% of them had been refractory to their last therapy. With this oral drug they saw an overall response rate of possibly 28% or 29% with a CR [complete response] rate of around 12%, and there was a small population of patients who had durable benefit.

However, this isn’t going to replace CAR-T cells, but for a population of people who are failing other lines of therapy, the drug has a place. It is FDA approved for patients who have failed 2 prior lines of therapy with a diagnosis of large cell lymphoma. In practice, it will likely be used for that select group of patients who are either failing CAR [chimeric antigen receptor] T cells or ineligible for some other treatments. However, it does have benefits with an almost 30% response rate, particularly in a small population of patients who have good and long responses. I would like to see a biomarker to identify who those patients are because despite the small population, some of these patients do well.

Adverse effects of the drug, especially at the higher doses, were associated with anorexia and GI [gastrointestinal] adverse effects. My sense is with these lower doses, it is much more tolerable. I personally was involved with the phase 1 studies and in those studies, we were at high doses, and it was tough on patients. My sense is with more reasonable doses, most patients can tolerate the drug relatively well.

 The response rates were not as impressive as the tafasitamab-lenalidomide, but if you look at the details of the eligibility, the patients were a more heavily pretreated. There were more patients who had had prior transplant, and more patients who were refractory to their last line of therapy. I believe it was a different patient population making it tough to compare across trials to see which is the more effective treatment.

Looking at the study closely, there are some patients who are well over a year out and remain in remission. It has activity, but like many of these drugs, the future is defining who those good responders are.

I think some of the supportive care around use of selinexor has improved as well, which makes this therapy more tolerable to patients. Based on response rate, the drug has good potential for combination with other drugs, particularly novel agents. It’s a different mechanism of action from other drugs and possesses preclinical data, which could build interesting combinations to watch in the future.

The other advantage is it’s administered orally. Patients do not have to go to an infusion center or need to have a line. I agree with Dr Fowler, we need to identify which patients benefit and then as Dr Nowakowski said, open the options for combination that will likely improve the efficacy of this drug.

Phase 2B SADAL Trial in R/R DLBCL

 Greg, tell us about the RE-MIND study that you were involved in and how that contributed to the approval of tafasitamab and lenalidomide.

 Yes, John. The RE-MIND study was done to support approval of this doublet in the relapsed and refractory space because neither lenalidomide nor tafasitamab is approved as a single agent. As you can see, it’s a paradigm shift where the FDA recognized that the activity of the doublet is critical for the efficacy of this combination.

The study aimed to differentiate the impact of lenalidomide from tafasitamab in the combination. One of the obvious solutions would be to conduct a randomized study and randomize patients simply to lenalidomide or tafasitamab and lenalidomide. However, we all felt this type of study would not be feasible. We have studied lenalidomide now for a long time in relapsed/refractory diffuse large B-cell lymphoma and consistently across different studies, including with the addition of rituximab, the response rate was somewhere between 25% and 30% and the duration of response—even with rituximab—was limited, measured in about 3 to 4 months.

Because of that, clinically, to design a randomized study would be quite difficult. This is where the agency supported the innovative idea of using the real-world data to differentiate the impact of lenalidomide from the doublet in this combination. To do that, we identified the patients who met the same inclusion criteria. They were matched for 9 predefined covariates.

This was a large global study: 490 patients were treated with lenalidomide monotherapy at 25 mg daily from days 1 through 21. The standard dose was identified. Then patients were matched to baseline covariates. Because close matching was needed, at the end there were 76 patients, both in the L-MIND cohort and in the RE-MIND cohort, who were matching for those characteristics. The patients in both cohorts were then compared for their outcomes.

If you look at the L-MIND study, as we mentioned before, the response rate was 67%. If you look at the patients treated with lenalidomide monotherapy with the same clinical characteristics—same performance status and multiple covariates—the best overall response rate was 34%. The addition of tafasitamab doubled the response rate in those patients.

Similarly, if you look at the progression-free survival [PFS], there was a significant benefit in terms of the progression-free survival and overall survival for the doublet vs lenalidomide monotherapy. For example, median PFS for lenalidomide monotherapy, consistent with previous studies, was about 4 months. In the L-MIND cohort, the median PFS was 12 months. The median overall survival, somewhat consistent with the previous studies of lenalidomide alone, was about 9 months. For the doublet, the median overall survival was 20 months. Therefore, the outcomes improved significantly with the doublet, which provided the momentum for the clinical approval of the combination.

 Instead of doing a randomized phase 3 trial, they did a retrospective trial, and you get a good comparison of lenalidomide alone vs the lenalidomide-tafasitamab combination.

 Exactly. As I said, this will be a new paradigm, which we’ll likely see more and more because we have a lot of exciting agents in the pipeline in diffuse large B-cell lymphoma under study. Many of these agents will not be able to be tested in randomized studies for different reasons. If we can use some of the real-world data—the data we already have—to support development of those agents, particularly if they are used in combination, it will help accelerate development in the field, just as we have seen with L-MIND.

 Accelerate development of new drugs, and reduce the cost of development of new drugs. All that might translate to good things for all of us.

 Let’s take a couple of clinical scenarios. One is you have a patient in front of you who you’re thinking might get to CAR [chimeric antigen receptor] T-cell therapy. Of course, your CAR T-cell therapies are going to be targeting CD19. Should you use or not use monoclonal antibody tafasitamab in a patient where you’re going to have the same target? What do we know about tafasitamab and its effect on CD19 on the B cells? Similarly, if you have a patient who has relapsed after CAR T-cell therapy, do you think this is a treatment that should work or could be tried? Or should it be avoided if your patient has already been exposed to a CD19-targeting CAR T-cell therapy?

 This is a great question. It goes back to the mechanism of how those drugs work. Saad Kenderian from the Mayo Clinic in Rochester, Minnesota, recently presented his preclinical work, which showed that the epitopes recognized by CAR T cells are different from those recognized by tafasitamab. This gives you the idea that those treatments still could be effective, provided expression of CD19 is present.

There are unfortunately limited data on resistance to tafasitamab. In the setting of CLL [chronic lymphocytic leukemia], where the blood was collected again, there was no evidence of CD19 loss in patients who were treated with tafasitamab. It appears that a resistance to tafasitamab is not mediated through CD19 loss. It will be important in future studies to collect more biopsies from patients with diffuse large B-cell lymphoma at the time of relapse and see if this is the case in large cell lymphoma as well.

The other anecdotal evidence comes from the clinical studies, where there was a patient who was treated with tafasitamab-lenalidomide and, after progression, went to CAR T-cell therapy. This patient responded to CAR T-cell therapy with durable benefit. There is some anecdotal experience that CAR T cells are still effective after progression on tafasitamab-lenalidomide. We are using it more and more and will see more data regarding efficacy of CAR T cells after tafasitamab-lenalidomide.

What about the other way around? That’s an important question because there are some frontline trials done in this setting as well. Based on what we know about the CAR T-cell resistance, some of the patients may have CD19 loss. On the other hand, a significant proportion of the patients treated with CAR T cells did not have CD19 loss. This is either disappearance of the CAR T cell’s clone or some other mechanism of resistance we don’t fully understand yet. Those patients who have CD19 would definitely be candidates for tafasitamab and lenalidomide treatment. As we see more and more of those patients and use tafasitamab in practice, we will get more experience in how effective this treatment really is in patients who are progressing after CAR T-cell therapy.

Because there is promising and high response rate and activity in the relapsed/refractory setting, there is a plan to move this doublet to frontline therapy with the addition of R-CHOP [rituximab,cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine sulfate, prednisone]. As you know, lenalidomide had been studied with R-CHOP [rituximab,cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine sulfate, prednisone] therapy in patients with newly diagnosed diffuse large B-cell lymphoma, called R2-CHOP [lenalidomide, rituximab,cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine sulfate, prednisone]. Unfortunately, R2-CHOP [lenalidomide, rituximab,cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine sulfate, prednisone] did not improve the outcomes of patients with newly diagnosed diffuse large B-cell lymphoma. The study was a randomized phase 3 study called ROBUST.

There was another study called E1412 that showed some signal of activity toward lenalidomide, but this was a much smaller study. Because there is such a synergy between tafasitamab and lenalidomide, there is now interest in moving this to the frontline setting. The phase 1b study, which was recently completed, is looking into the feasibility of adding tafasitamab to R2-CHOP [lenalidomide, rituximab,cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine sulfate, prednisone] backbone and moving it forward to the future randomized trials.

RE-MIND Study in R/R DLBCL

 Let’s transition. In the last year we’ve seen a lot of novel therapies approved in large cell lymphoma, more than anytime that I can remember in my 17, 18 years of practice. To my recollection, we’ve seen approvals of polatuzumab vedotin. In the last month or 2 we’ve seen approvals of selinexor and then the combination tafasitamab-lenalidomide. These are new treatments for all of us and for practitioners around the world. Let’s talk about these treatments. Nathan, I’ll pick on you first to tell us your experience with polatuzumab. That was the therapy approved a year or so ago, along with bendamustine-rituximab. What’s your experience with that? Tell us about the drug and how you use it in your practice.

 Polatuzumab is a conjugated antibody with MMAE [monomethyl auristatin E] conjugated to an antibody against CD79b. This CD79 is part of the B-cell receptor, so the good news is that target is on all lymphoma cells. The purpose of this study was to combine the novel conjugated antibody with bendamustine-Rituxan [rituximab]. In practice, when we’re treating patients who are either failing chemotherapy or are ineligible for transplant, bendamustine-rituximab is a standard go-to treatment option.

The study that led to the approval of this drug was published by Laurie Sehn and her colleagues, and it’s a pretty simple design. They randomized people, 40 patients in each arm, to either receive BR [bendamustine-rituximab] or bendamustine-rituximab plus pola [polatuzumab vedotin]. It showed me that BR [bendamustine-rituximab], unfortunately, is not a great drug for a lot of these patients. The median overall survival with BR [bendamustine-rituximab] was only about 5 months. When you added polatuzumab, the median overall survival almost tripled to over a year. Complete response [CR] rates were a lot higher, about 17% vs 40%. PFS [progression-free survival]—not surprising with overall survival being longer—was also longer when you added polatuzumab to BR [bendamustine-rituximab]. That was pretty surprising. If you look at the history of these conjugated antibodies like CD22, they have not made that big of an impact in large cell lymphoma. Whether it’s a target or the warhead, it appears that pola [polatuzumab vedotin] had efficacy. What I often wonder is: How would that group have done without BR [bendamustine-rituximab]? Because it looks like BR [bendamustine-rituximab] did not add a whole lot in the refractory population.

The drug is easy to give. It’s an infusion associated with some thrombocytopenia, neutropenia, which was higher in the BR [bendamustine-rituximab]–polatuzumab arm. They also saw some peripheral neuropathy. Overall, the drug is well tolerated. We’re now using it in combination with BR [bendamustine-rituximab] for patients who are transplant ineligible and even in some patients whom we’re trying to get to transplant or who fail other chemotherapies. 

 Great. I found that to be useful combination in my practice. For some folks who may have been exposed to BR [bendamustine-rituximab] or have trouble with counts, I can dial down on the bendamustine component, keep the pola [polatuzumab vedotin] dose reasonable, and still get some good results. We know that pola [polatuzumab vedotin], along with rituximab alone, can work well too. That would be my tip for those who are new to that combination therapy

Great. Why don’t you tell us about tafasitamab? I know you have a lot of experience with that drug and some of the trials. You can tell us about the data supporting the recent FDA approval of taf [tafasitamab] and len [lenalidomide].

 Tafasitamab was approved in combination with lenalidomide in relapsed/refractory diffuse large B-cell lymphoma [DLBCL]. The FDA deserves credit for recognizing that sometimes for the treatment of this aggressive disease you need doublets. None of the drugs is approved as a single agent. The FDA changed the paradigm and approved the doublet because of high efficacy seen clinically for this combination of patients with relapsed and refractory diffuse large B-cell lymphoma.

If you look at the drug label and that population, tafasitamab-lenalidomide is approved for patients who are not eligible for transplant. Therefore, they are either relapsing after initial induction therapy and are not transplant candidates because of comorbidities—such as performance status, age, or other issues—or they are patients who are not responding to salvage therapy and cannot proceed to transplant or are relapsing after a transplant. It is a broad approval in this regard. Tafasitamab-lenalidomide is also approved for patients with transformed lymphoma, de novo DLBCL, but also patients with relapsed transformed diffuse large B-cell lymphoma are eligible for this combination.

As you mentioned, the approval is based on the L-MIND study, which enrolled patients with relapsed/refractory large cell lymphoma, who have had 1 but no more than 3 lines of therapy and are not eligible for high-dose chemotherapy with autologous stem cell transplantation. Those patients were treated with tafasitamab-lenalidomide. Lenalidomide used here with tafasitamab is actually at the standard dosage, 25 mg daily from day 1 through 21 of a 28-day cycle—the myeloma dosage, if you would, which we are familiar from myeloma studies—but higher than what’s used typically in combination with rituximab, which is 20 mg when used in this setting.

Tafasitamab is initially given weekly for cycles 1 through 3. During the first cycle it’s also given on day 4. Later on, it’s given only on days 1 and 15 as infusion.

In the L-MIND study, the total duration of therapy was 12 cycles. In patients who are responding and having clinical benefit, investigators could continue tafasitamab as a single agent indefinitely because of the limited treatment options otherwise available for those patients. We have a feeling it will be hard to stop giving tafasitamab as a single agent in folks who are potentially benefiting from it.

If you look at the study overall, 81 patients who were treated in the study showed high response rates and longer duration of response. Also, if you look at the characteristics of those patients, as you would expect in this population, many were older. All of them had previous rituximab therapy, of which a high number were either Rituxan [rituximab]–refractory or refractory to most recent therapy.

The primary-refractory patients were excluded from the study; however, the definition of the study changed in its duration. Some of the primary-refractory patients were included in the study, and a subset analysis of those patients didn’t show different results later on than in patients who were not primary refractory.

If we look at the primary end point of the study, the overall response rate was over 60%. It’s a very high response rate. If you look at the CR [complete response] rate, it was about 43%. These are high rates of deep responses. There are 2 important points to note. One is the CR rate or overall response rate because if patients are not responding, they would be lucky to progress. This progression may render patients ineligible for other therapies because of changes in the performance status or other factors. Second, the initial response rate is important because it identifies those patients who benefit. Even if they relapse, they’re positioning into other therapies later on.

Also, the duration of response was quite remarkable. If you look at the initial publication, 72% of the patients had a duration of response of at least 12 months at the cutoff. We’ve recently seen the update in EHA [European Hematology Association Guidelines] with a longer duration of response, now approaching 13 months. Those are durable responses seen with this combination.

What about toxicity? Well, it’s primarily hematological. We see neutropenia. We see thrombocytopenia. Just as you would expect with the combination of IMiD [lenalidomide] and the antibody, the growth factor support was allowed on the study. In practice it will be used to maintain the dosing intensity, which helps with neutropenia and reducing the incidence of neutropenic fever. Thrombocytopenia was seen but wasn’t severe in association with bleeding. The nonhematological toxicity was not common. Infusion reactions were quite rare, which was good to see, because this allowed the infusion to be relatively rapid.

With this combination, we see exciting results with high response rate, durability of response, and the combination can be given to patients with borderline performance status or hematological intensive therapies. You can watch closely for toxicity, adjust the dose of lenalidomide if needed, and use growth factor support if needed to get those patients through therapy.

L-MIND Study in R/R DLBCL

 You bring up CAR [chimeric antigen receptor] T-cell therapy. Let’s talk about that. We’ve now had CAR T cells available for a couple of years. Dr Chavez, let’s start with you. What is your approach? How do you select patients for CAR T-cell therapy? How do you select patients who are not candidates for CAR T-cell therapy? What advice would you give to community doctors like me, where you look at a patient and say, “This is not a candidate for CAR T-cell therapy?” Are there such patients? How do you approach the choice between the different agents that are available? Last, a nice topic Greg brought up would be minimizing toxicities in the modern era with CAR T-cell therapy. It’s a meaty discussion about CAR T-cell therapy. Let’s get into that.

 Those are good questions. Chimeric antigen receptor therapy is approved for diffuse large cell lymphoma refractory after 2 lines of therapy. The question of who is eligible for CAR T therapy is the million-dollar question because there is no guidance. If you read the label of the FDA, it just says patients had to have DLBCL-NOS [diffuse large B-cell lymphoma, not otherwise specified], primary mediastinal B-cell lymphoma, transformed follicular lymphoma, or high-grade B-cell lymphoma, and the patients had to have 2 lines of therapy. It doesn’t even mention what lines of therapy. You can have R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. You can have antibody. Then you mentioned CAR T, but there is no guidance of who will be the best patient to retrieve it.

We’re trying to use eligibility criteria of clinical trials—for instance, ZUMA-1, which led to the approval of axicabtagene ciloleucel. However, as we know, trials exclude patients who otherwise would be eligible, so patients who had CNS [central nervous system] involvement, a stroke, or a prior thrombosis. Those are the things that we see commonly that we feel that the patients can be treated with CAR T, but they were excluded from trials.

We did multicenter analysis with Mayo Clinic and The University of Texas MD Anderson Cancer Center, like a retrospective review of cases of CAR T-cell patients treated with diffuse large B-cell lymphoma. We looked at variables outside the clinical trials—patients who had comorbidities such as chronic kidney disease, thrombosis, and active thrombosis. It didn’t actually affect the efficacy and the toxicity. The most important factor was performance status, actually. Performance status was the strongest predictor of poor survival and toxicity. My recommendation, because we don’t have clear rules for which patients are eligible, it’s not age and not really comorbidities. It’s mostly performance status, so we recommend doctors identify the high-risk patients—as Dr Fowler mentioned, primary refractory patients or those with lymphoma—who don’t respond to therapy and refer them early.

Community doctors know when CAR T is indicated. But sometimes when you see a patient who you know will not respond to standard salvage chemotherapy, I would refer for CAR T evaluation—especially a primary refractory double-hit lymphoma that relapsed.

In our clinic in CAR T, we assess the patient. We look at their labs. We do a physical examination. We look at the prior history. Essentially, it’s performance status of how well the patient feels, how well the patient is at the time you see it, so you can actually predict how well they’re going to perform in the future. This is because, unfortunately, the CAR T-cell therapy is not available right away. There is a process. It has to be approved by the insurance. They have to schedule apheresis, and then you have to wait for manufacturing time. The fastest CAR T is axicabtagene ciloleucel, and it takes about 17 days.

Let’s say I see a patient today. I tell him or her, “You will be dealing with CAR T if everything goes smoothly within a month.” That month is critical how to keep the patient stable. My recommendation is to refer patients with high-risk diffuse large cell lymphoma to a CAR T-cell evaluation.

In regard to the available options for CAR T-cell therapy, we have 2 options approved so far. We have axi-cel—axicabtagene ciloleucel—and tisagenlecleucel. There are differences in the structure of the CAR T-cell. One, the difference is a costimulatory. The costimulatory is CD28 in axi-cel [axicabtagene ciloleucel] 4-1BB. In tisagenlecleucel, we cannot say that more than 1 is better than another because they weren’t compared head-to-head. However, in my experience, I feel the tisagenlecleucel is less toxic, so I tend to use tisagenlecleucel in older patients or patients who have more comorbidities because the neurotoxicity, the CRS [cytokine release syndrome], is less.

With tisagenlecleucel, in patients who have high tumor burden disease, you don’t tend to see a very good response, so that’s why for patients who have high tumor burden—we can see it in about half the patients—we tend to use more axicabtagene ciloleucel, because the CD28 works a little faster. However, that is my own experience. I don’t know if others have a different experience. There were not comparator head-to-heads, but that’s the way I assess how to choose which product. If a patient has an aggressive disease, you know that with axicabtagene ciloleucel you’re going to have in a shorter period of time than tisagenlecleucel. That takes around 23, 24 days. As opposed to tisagenlecleucel, that is almost a week earlier, so that’s also something to keep in consideration.

In terms of lisocabtagene maraleucel, it’s another 4-1BB, a CAR T cell. The way it’s made is that it has a 1:1 CD4/CD8 T cells that improve the chance to have a better memory of naïve T cells that have better expansion, especially more persistence. That’s the rationale of using this type of technology. It’s not approved, but we expect it to be approved with the same label. The question is if you are adding another product, then how are you going to choose? It’s going to be based on the safety profile basically and the familiarity of the doctor. We want to treat patients with the safest product. So far, the toxicity profile looks manageable, a little similar to other CAR Ts, so we just have to be more aware of how to use this product, to use it in real life.

 I have an open question for anybody who would like to answer. Is there a difference between the effectiveness of these products, and is there a difference between the toxicity profiles? Did we just get better over time at managing the toxicities? Can you guys comment on how we are managing those toxicities differently maybe now than in the early days of CAR T-cell therapy?

 I think we are getting better at managing them. Very early on we didn’t recognize what a lot of the toxicities were, so there was a delayed response. For example, many of these patients now, when they develop certain levels of neurotoxicity or cytokine release, we move them directly to the ICU [intensive care unit] for very close observation. Before, unfortunately, many of these patients really decompensated before we got aggressive. Many times, that monitoring includes MRIs, neurological consults, lumbar punctures, and aggressive uses of steroids and anti–IL-6 when patients start to show signs of decompensation.

From my impression, even moving that early intervention ahead 1 or 2 days often changes the outcome. We were using steroids and anticytokine drugs before, but we intervene with them a little earlier and we monitor patients closely. I think the outcomes are better because we’re better at recognizing the adverse events.

 I would agree here completely with Nathan. We definitely are better at recognizing the toxicity. Also, what has changed is that people now have more experience in many centers that treat a volume of CAR T-cell patients and a specialized team that focuses on care of those patients. They’re very good and skilled now at recognizing those toxicities earlier.

I would bring another issue too for a lot of patients. Particularly for the older patients or patients willing to travel for different reasons, sometimes social reasons, this really gets to be an access problem. This is because we have those centers, which do perform CAR T-cell therapy and have a relatively high volume of patients. On the other hand, in a lot of smaller community types, this therapy is not available. For many patients, that’s a significant barrier. We’re trying to overcome those barriers and provide the social support and financial support and as much medical support as we can. But a lot of those older patients will not be able to consider actual therapy, which requires significant travel or hospitalization. That’s another thing to change, even as we are getting better in recognizing toxicity.

CAR T in Transplant-Eligible and Transplant-Ineligible DLBCL

® presentation broadcasting from across the country. Today’s discussion will be focused on systemic therapy for relapsed and refractory diffuse large B-cell lymphoma.

I am Dr John Burke from Rocky Mountain Cancer Centers in Aurora, Colorado. Joining me today in this discussion are my colleagues Dr Julio Chavez from Moffitt Cancer Center in Tampa, Florida; Dr Nathan Fowler from The University of Texas MD Anderson Cancer Center in Houston, Texas; and Dr Greg Nowakowski from the Mayo Clinic in Rochester, Minnesota.

During the next 45 minutes, we are going to discuss emerging treatment options for diffuse large B-cell lymphoma after disease progression and the questions surrounding how to use these novel approaches in clinical practice. Without further ado, we’ll go ahead and get started.

Dr Nowakowski, I’m going to have you get us started. Tell us about the prognosis of patients with relapsed large cell lymphoma. What factors do you look at? How do you counsel your patients? How do you, in your institution, approach chemotherapy choices for patients with relapsed disease who are both transplant eligible and transplant ineligible?

Thanks, John. With frontline therapy with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], we cure about 60% of patients. Unfortunately, about 40% of the patients would relapse, and typically they relapse within the first year or 2, so that’s relatively quickly. We know the outcomes of those patients unfortunately remain very poor. The analysis from SCHOLAR-1 study showed that the median survival was approximately 7 months for patients with refractory disease, and only about a quarter of the patients were alive about 2 years postrelapse. This is also true if you look at a lot of other databases and retrospective analyses in this patient population, so we clearly need better therapies for those patients.

In general, the approach of those patients followed the pattern of being eligible for high-dose intensive chemotherapy. If the patients are eligible for intensive salvage chemotherapy, followed by high-dose chemotherapy in transplant, that’s still standard of care in this setting.

There are other factors that play a role in patients eligible for this therapy. This is primarily age, comorbidities, organ function, and performance status. There could be some other factors, including patient preference, in terms of the selection for the transplant.

In the long term, the outcome of those patients is still not as good as we hope for. Only about 50% to 60% of the patients will have good enough response to intensive salvage chemotherapy, to later proceed to transplant, and still even after transplant, approximately 40% will relapse. At the end, relatively few people will benefit from this approach, but we have now a lot of historical data. That is basically the curative approach in this setting and still remains the standard of care. This standard-of-care approach has recently been challenged by CAR [chimeric antigen receptor] T cells and some novel approaches that we will discuss later. However, that’s still standard of care for patients who are transplant candidates.

If you look at the patients who are not transplant candidates, those patients are typically candidates for palliative chemotherapy or targeted therapies. With new approvals in this space, we consider those therapies to be largely still not curative. The goals of those therapies are mainly palliative.

The CAR T cells are being more recognized as a potential new modality in this patient group as well. This is moving forward because we have better ways of dealing with CAR T-cell toxicity. Perhaps over time we’ll see that more of those patients might be candidates for CAR T-cell approaches.

However, there is a still a very large group of patients who would be eligible for CAR T cells, not eligible for transplant, and the options here are quite limited. It’s clearly an unmet need in diffuse large B-cell lymphoma at this point. Fortunately, and we’ll discuss it later as well, another new therapy is coming in this space.

You also asked about biological factors that predict outcomes of patients in relapsed/refractory diffuse large B-cell lymphoma. This is actually interesting because in the frontline setting, cell of origin, the ABC vs GCB subtype, double-hit status—so presence of 

 translocation or even triple hit—they are prognostic. Those patients don’t do as well with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] chemotherapy, and they have a higher relapse rate.

However, the relapse itself is a bad event that seems to be almost an equalizer for biological prognostic factors. If you look at cell of origin or some other predictors, they don’t necessarily predict poor prognosis in those patients because unfortunately the majority of the patients who have relapsed and refractory diffuse large B-cell lymphoma will not do well.

 Dr Chavez, at your institution, what is your approach to transplant-eligible patients? Do you have a standard chemotherapy salvage regimen that you use there?

 We have a few regimens out there that are being used for salvage chemotherapy, like ICE [ifosfamide, carboplatin, etoposide] or rituximab, ESHAP [etoposide, methylprednisolone, cytarabine, cisplatin] or DHAP [dexamethasone, cytarabine, cisplatin]. We use GDP with consistent gemcitabine, cisplatin, and dexamethasone in combination with rituximab. I found this a little more tolerable. There is actually a trial showing that the quality of life and the recovery time for patients is better, and the efficacy is not less than the standard like ICE [ifosfamide, carboplatin, etoposide] or ESHAP [etoposide, methylprednisolone, cytarabine, cisplatin]. It’s easy to give to because day 1, day 8, the patient doesn’t have to be admitted. They don’t have to come every day to do chemotherapy. There are some considerations to keep in mind, like we see more hematology toxicity, especially thrombocytopenia, as well as electrolyte abnormalities like hypomagnesaemia and hypokalemia with cisplatin. I would caution for older patients, especially over age 70, because they may have more renal toxicity. Very rarely you see ototoxicity now in head and neck cancers, but this is something to consider too.

 When thinking about what to use as salvage for these patients, I look at 3 main things. One is, as Julio mentioned, is the performance status of the patients to see if they’re eligible. The other things would be looking at what their first-line regimen was and how long that first-line regimen lasted.

I generally think of patients that are primary refractory to induction therapy as unfortunately having a pretty low likelihood of responding to salvage chemotherapy. I still use R-ICE [rituximab, ifosfamide, carboplatin, etoposide] or R-DHAP [rituximab, dexamethasone, cytarabine, cisplatin] in those patients. Very quickly, in fact even as I’m screening them, giving them ICE [ifosfamide, carboplatin, etoposide] or DHAP [dexamethasone, cytarabine, cisplatin], I’m thinking about CAR T-cell therapy. This is because those are the patients who unfortunately usually don’t do that well, even with salvage standard chemotherapy.

Standard of Care for Relapsed/Refractory DLBCL

 R2-GDP-GOTEL is a phase 2 clinical trial that combined lenalidomide with a very well-known regimen for salvage chemotherapy, R-GDP, which consists of rituximab, cisplatin, dexamethasone, and gemcitabine. The patients were to receive lenalidomide from day 1 to day 14, in addition to the standard dose of R-GDP [rituximab, cisplatin, dexamethasone, and gemcitabine], up to 6 cycles. Patients who completed the regimen and had at least a PR [partial response] or complete remission [CR], they went on to receive lenalidomide as maintenance. They enrolled 79 patients, 78 patients were evaluated for efficacy and toxicity. The overall response rate was 59%, with a CR rate of 32%. The adverse events were mainly related to the chemotherapy, like thrombocytopenia and neutropenia, patients had rashes, also febrile neutropenia of course, reported in about 14% of patients. Further biomarker analysis showed that there was no difference in responses according to the cell of origin, and also the regimen was active in primary refractory lymphoma. Unfortunately, there were 4 toxic deaths in the study. That’s important to know when we add a new agent into our salvage regimen.

The conclusion is that this is an active regimen, it’s a phase 2. The question is whether this is better than the standard GDP [gemcitabine, dexamethasone, cisplatin]. The reported efficacy of gemcitabine, dexamethasone, cisplatin, the overall response rate is about 45%, with CR rates in the range of 13% to 15%. Keep in mind that the earlier studies didn’t include a PET [positron emission tomography] scan as mandatory to assess for CR rates, so we don’t really know the true CR rates in the earlier studies. That’s just to keep in consideration. Also, I would say that long-term follow-up is needed to see whether that matches the long-term efficacy of this regimen in these patients. Until we know whether we need to add lenalidomide to the gemcitabine, dexamethasone, cisplatin regimen in real life, I think it’s early to say. There were some toxicities and 4 deaths in a relatively small study. I think we should be careful. Whether we need to add it, I think the decision has to be made based on a larger study, or a phase 3 randomized study.

The Smart Start study is a single-center, phase 2 clinical trial that was presented by Jason Westin, MD, and colleagues from The University of Texas MD Anderson Cancer Center. It’s a trial that consisted of 2 phases. There was a lead-in phase of rituximab, lenalidomide, and ibrutinib for 2 cycles, followed by the combination plus chemotherapy. Whether it was R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] or EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin], it was physician discretion to decide which regimen the patient would go on. The overall response rate was 86%, with a CR rate of 36%, which is expected for lenalidomide and ibrutinib. There is not a high CR rate. But once the patients completed the chemotherapy part, up to 6 cycles, the overall response rate was 100%, with a CR rate of 95%. The 1-year PFS [progression-free survival]—the study has a short follow-up—was 95%.

The adverse events were expected as related to the chemotherapy agents used. There were some toxicities that we typically don’t see in patients who receive chemotherapy, like Aspergillosis. There was a patient who had CNS [central nervous system] Aspergillosis, and 1 patient who died of Aspergillosis, probably systemic Aspergillosis. That underscores the fact that adding another agent into a chemotherapy regimen could be complicated. There are descriptions of fungal infections with ibrutinib, especially in combination with steroids and cytotoxic agents, so that’s something physicians have to keep in mind.

The other interesting thing about this study is the time to initial treatment, that was about 24 days. The reason I’m pointing this out is it’s a little unusual for patients to wait 3 weeks or almost 4 weeks to start therapy, especially with an aggressive lymphoma. That tells us about a possible selection bias. You’re probably selecting the best patients, the more stable patients to do these therapies, whereas the sickest patients, the patient who was in the hospital with aggressive disease, probably is not eligible for this trial.

Overall, I think the combination showed activity in DLBCL [diffuse large B-cell lymphoma], it’s promising activity. Whether that will implicate a change in the standard of care, I think it’s early. We need to sort out this question in a randomized clinical trial, phase 3. Finally, we have to consider the cost, because you’re adding lenalidomide and ibrutinib, and that can easily be a costly therapy over 6 months. I think it’s a study that showed very interesting activity. Tolerability was acceptable. Some of the infections that we typically don’t see with the standard chemotherapy, such as Aspergillosis or fungal infections, were shown in this study, so that’s something we have to keep in mind when we decide whether to do this treatment. I wonder whether patients need to complete 6 cycles of chemotherapy. That’s something that needs to be studied. Probably fewer cycles of chemotherapy would be more convenient and may not impact efficacy. I believe there will be a follow-up study with fewer cycles of therapy to see whether that will be feasible.

Novel Therapies: R2-GDP-GOTEL and Smart Start 

The POLARGO study, as it’s called, is a large, global phase 3 trial that compares a standard chemotherapy regimen, R-GemOx, which is rituximab, gemcitabine, oxaliplatin. And the comparator arm is rituximab, gemcitabine, oxaliplatin with polatuzumab vedotin, which is an antibody-drug conjugate now approved for diffuse large B-cell lymphoma.

The purpose of this study is to demonstrate or test whether the introduction of this antibody-drug conjugate improves the outcome of patients with diffuse large B-cell lymphoma treated with rituximab, gemcitabine, oxaliplatin in the relapsed/refractory setting. This trial is ongoing, but I think there’s a fair amount of optimism that we may see a positive result here, which would improve or expand the number of treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma.

I think you’re referring to the LYSA trial presented at ASCO [the American Society of Clinical Oncology annual meeting], which was atezolizumab, a checkpoint inhibitor, with obinutuzumab and venetoclax in relapsed/refractory large cell lymphoma. This was a small number of patients.

I think 80%-plus of patients had at least 2 lines of therapy, and two-thirds of them were refractory to the last regimen. I don’t remember the exact number of patients, but the trial was reported with an overall metabolic response at the end of treatment of 24%, and an 18% complete metabolic response. It’s early for the follow-up, but this is again one of these combinations, a biological agent plus immunotherapy. That might bring an opportunity to the unmet need of patients who are not eligible for high-dose therapy, transplant, or potentially CAR [chimeric antigen receptor] T-cell therapy. It’s another example of the impact of immunotherapy as well.

I would like to summarize and say that this is a very exciting time in the field of medicine, particularly in lymphoma where we have been, for decades, doing R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], which remained as the standard of care default. But we definitely should be aware that this is not sufficient in a high-risk IPI [International Prognostic Index] patient, double hit, double expresser, and non-GC [germinal center] subtype, and other high-grade lymphoma that I alluded to previously. And I think that these patients should be recommended for clinical trials and probably more intensive therapy and maybe cell therapy consolidation, like the ZUMA-6 trial looking at CAR [chimeric antigen receptor] T-cell therapy as consolidation in patients who have double-hit lymphoma, high-grade lymphomas.

It is really not altered, but probably underestimated. But the future is the biological classification of lymphoma and trying to improve this curve that we see, to identify truly the high grade. And to do this, we need to have a baseline signature that is usable in routine and actionable. I think cell-free DNA, or circulating tumor DNA, is likely to be more usable and used in the future. As I mentioned, immunotherapy is more and more part of the induction or pre-phase consolidation. And again, given all the opportunities that I just mentioned tonight, it reflects on the fact that it is really important to encourage physicians to go to clinical trials, to participate. The reason being is that when you look, the impression is that large cell lymphoma now is a clinical result, the outcome is so great. But when you look at real-world data in high-risk patients, the outcome particularly in a high-risk patient is still very poor. So I would encourage physicians to look at clinical trials in this population as well. Thank you.

Novel Treatment Combinations for R/R DLBCL

We still have unmet needs for patients with diffuse large B-cell lymphoma. As I mentioned, for older patients in their 80s and above, even standard therapy with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] is very difficult to receive. And in those cases after failure of less intense regimens, such as mini R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], or bendamustine, or others, there is a significant unmet need for patients to be treated with targeted agents. Tafasitamab with lenalidomide is likely to be an option for those patients in the future, as well as selinexor, and polatuzumab vedotin, which is approved in combination with bendamustine/rituximab.

 I think overall in cancer, immunotherapy will continue to expand dramatically. I think more and more we’re going to try to combine small molecules, biological agents as sort of an induction with or without immunotherapy, and immunotherapy afterward as a consolidation. That’s 1 model. But there’s also lymphoma—more and more we see that we can, as I mentioned for example, the R-squared, ibrutinib window-type trials in the patients who are particularly non-GC [germinal center] subtype and frail patients can respond really well to this and have a shortened version of chemotherapy. And then there are ongoing trials looking at checkpoint inhibitors in combination with chemotherapy. BiTE [bispecific T-cell engager], as I mentioned, combination with trastuzumab, in combination with chemotherapy. More and more we’re going to integrate that.

And the third piece that is important is the role of immunotherapy as an immuno-consolidation post-induction. We know that cell-free DNA might help us with the depth of response in those patients. But we know that the patient’s immune status post-chemotherapy—although we don’t have a great way to quantify it, but based on the ratio data from the Mayo Clinic, for example, the ratio of lymphocytes to monocytes, across the board in a number of diseases and many subtypes of lymphoma—shows that it has a dramatic impact on the outcome. We don’t exactly know yet how to tackle this, but that’s an opportunity as a consolidation eventually. Definitely the question is more novel therapy, more immunotherapy, either in addition or to replace chemotherapy.

 With the new therapies coming to the clinic, how does cost affect your patients’ access to treatment? I’m sure that cost and access impact a patient’s and oncologist’s decision and, hence, care for therapies, especially for an aggressive disease like diffuse large B-cell lymphoma. Not only the cost of the drug itself, but also the cost of the logistics, such as in CAR [chimeric antigen receptor] T-cell therapy. There is a lot of cost implicated in treating the adverse effects, admission to the hospital, admission to the ICU [intensive care unit], the use of a caregiver, the caregiver has to be off work, the patients cannot drive for 2 months. There is cost in relation to that.

When you talk about the combination of tafasitamab and lenalidomide, I would think that it will be a top price for tafasitamab. But then you have to add the cost of lenalidomide, and whether insurance can cover part of the cost of lenalidomide, there may be a copay for patients. That should be considered in terms of the cost. Tafasitamab is a treatment that is given indefinitely. Patients get treatment for as long as they respond or for as long as they tolerate the medication. So that’s a cost because patients have to keep coming to an infusion center, they have to maintain a line. If they have complications related to the line, like infections or thrombosis, that adds to the cost because we have to treat those conditions. It’s important to consider those.

In the case of selinexor, which is a single oral agent, it will have definitely a top price. It doesn’t have the cost of hospitalization, it doesn’t have the cost of having an IV [intravenous] line. It’s an indefinite treatment, so if there is a patient who had a response, those patients have to remain on the drug for a long time. As far as I remember, in the trial some patients went on treatment for up to 3 years. That should be a consideration in regard to the cost. However, there are other costs that should be considered for selinexor. It’s a novel agent, has specific adverse effects that need to be taken care of, such as diarrhea, nausea, adding the medications to treat the nausea, adding the medications to treat the diarrhea. There are issues with cytopenias as well as thrombocytopenia. There are recommendations in the trial about using growth factors, they also have costs. So it is important to keep in mind when we use the novel therapies available, the other costs that are outside of the specific medications.

Relapsed/Refractory DLBCL: Unmet Needs

There is a potential for tafasitamab in combination with lenalidomide to significantly impact the treatment landscape for diffuse large B-cell lymphoma [DLBCL] in the relapsed/refractory setting.

As I mentioned, the standard approach really should still be CAR [chimeric antigen receptor] T-cell therapy for patients who are young and fit enough to receive this therapy. But for patients who relapse after CAR T cell, or who are unable to make it to an authorized treatment center for CAR T, or are of significantly advanced age or with poor performance status, in those cases more traditional pharmacologic therapies are likely to be needed. And they will probably cycle through on an ongoing basis as the patients will likely eventually lose their response to these agents.

In the case of tafasitamab, this is an anti-CD19 monoclonal antibody, which was studied in a phase 2 trial in combination with lenalidomide for patients with relapsed/refractory diffuse large B-cell lymphoma. And what was reported and recently published was that a high proportion of patients, somewhere in the 40% to 50% range, achieved reasonably long-term remission with an impressive overall response rate of this combination.

With the anticipated approval of tafasitamab, in combination with lenalidomide for diffuse large B-cell lymphoma, I think we’re going to have more in our armamentarium and more options for patients with this disease.

The Re-MIND study was presented at the ASCO [American Society of Clinical Oncology] annual meeting. It’s an interesting study looking at lenalidomide as a single agent in the relapsed large cell lymphoma and to use it as real-world evidence to compare with the L-MIND trial, which was tafasitamab plus lenalidomide, where I mentioned the results were very impressive. This was to try to compare the outcome of this population with a combination versus a single agent. I think this was an important work because the awareness of the importance of real-world data is increasing rapidly. And these real-world data can confirm the clinical benefits of a new trial but also give you, if we can see a control group, although this was not completely matched as a control group, to suggest that the combination was really beneficial, with the anti-CD19 in addition to lenalidomide.

Emerging Treatments for Relapsed/Refractory DLBCL

The FDA approval for selinexor is anticipated this summer, and it is likely to be approved for relapsed or refractory diffuse large B-cell lymphoma [DLBCL].

The treatment landscape for diffuse large B-cell lymphoma is changing now that we have CAR [chimeric antigen receptor] T-cell therapy. It’s important to know that although a proportion of patients with CAR T cells may be cured, as I mentioned previously, with this therapy, 60% or more of the patients will not enter durable remission and will relapse.

For those patients, there are limited treatment options. Polatuzumab vedotin is a treatment option for those patients in combination with bendamustine and rituximab, which is approved in this setting. It’s anticipated that selinexor will also be approved in this setting.

This is an oral agent that can be used as a single agent in third-line therapy, as I mentioned, it was just approved. But I think the real benefit will be when we start to combine this with other agents, and hopefully have better disease control.

In my opinion, what I look at more is efficacy, how efficacious is a drug or a regimen. For patients with DLBCL, what I typically do is ask them what are their goals, if their goals are to cure the disease, or to maintain the disease in some type of remission, but no cure. If they want to achieve a cure and they’re healthy enough to do it and they don’t have a lot of significant comorbidities, I offer what is the standard of care, which is CAR T-cell therapy. That’s the main thing. I would say with all the CAR T-cell drugs available, essentially, the majority of patients could get CAR T-cell therapy. Age is not a limitation. Our oldest patient was 84 years old, he was in good shape, he was able to get treatment and he’s in remission. I think that’s a reason we have to offer what is the best care and best option, which is a curative option.

If the patient prefers not to undergo CAR T-cell therapy, not only because of the adverse effects, but also because of the logistics—traveling, leaving home, staying in a different place—that’s definitely a factor in deciding whether to pursue CAR T-cell therapy. In those cases in which CAR T cell is not possible for all those reasons, the patient is too weak, too sick, or logistic reasons, then oral agents such as selinexor play a role. Also other agents can be given closer to home, like monoclonal antibodies such as tafasitamab or polatuzumab. Those are viable options in the community.

When you have all these options, you have to choose the option that is more efficacious, but at the same time, less toxic. As I mentioned before, the monoclonal antibodies are used commonly by community oncologists, so they’re familiar with it. I wouldn’t see a problem in using tafasitamab orpolatuzumab. So there are options for those patients and they know how to use them. Selinexor is a novel agent, so you have to try to learn how to manage the adverse effects. Also the activity is modest. I don’t deny there is activity, but it’s not probably the greatest clinical activity, if you compare it to tafasitamab with lenalidomide, or polatuzumab/bendamustine/rituximab.

Finally, the other aspect is the maintenance of an IV [intravenous] line. So far, selinexor is the only oral agent approved for diffuse large B-cell lymphoma in the relapsed/refractory setting as a single agent. That’s definitely convenient because patients just take 1 pill. But again, it’s probably the less important factor in my opinion.

One of the things that has come up recently, one of the concerns, is that we’re experiencing the global pandemic of COVID-19 [coronavirus disease 2019]. This has led to some concern about intensive treatment regimens that are highly immunosuppressive, including autologous stem-cell transplantation, and potentially CAR T-cell therapy.

In my mind, the risks and benefits of using immunosuppressive therapy have to be weighed against the risk of infections, including COVID-19. But for a treatment for a disease such as relapsed diffuse large B-cell lymphoma, I think the benefits of the therapies that we discussed, including transplant and CAR T, still outweigh those risks.

There may be patients who are presented with the option of continuing to receive IV therapy as opposed to an oral agent like selinexor that can be taken at home. And it’s possible that an oral agent may be safer because of less exposure to the patient, but it also has to be taken into account that some of these agents can cause neutropenia and even if they’re oral, and that can predispose patients to infection.

SADAL Trial Regimen FDA Approval

The mechanism of action for selinexor, which is a novel targeted agent, is that the medication works as a selective inhibitor of nuclear export. Nuclear exporters are proteins that cycle transcription factors and other regulatory proteins between the nucleus and the cytoplasm of the cell.

By inhibiting this nuclear export protein, selinexor leads to accumulation of various protein regulators that leads to reduction, cell proliferation, and apoptosis of the target cell. We know that certain malignant cells, including diffuse large B-cell lymphoma [DLBCL], are sensitive to this agent, and recent data have shown that it’s clinically active in this disease.

Selinexor is an exportin XPO1 that is an inhibitor. XPO1 is overexpressed in lymphoma and correlates with a poor outcome. This oral selective nuclear transport inhibitor has shown activity in a preclinical setting and was tested in aggressive lymphoma, in large cell lymphoma, in the third-line setting. It was testing a number of lymphomas in the SADAL study, including large B-cell lymphoma. These patients have really no options. This was a heavily pretreated population of 120-plus patients. And the response rate was 36% and 15% CR [complete response]. This was something that was very interesting because we had some patients who were not very high-risk large cell lymphoma but multiple failures and who had very durable response.

It was a single agent. This is really interesting, and it was approved last month in June. Based on that, the next step is to try to build up this activity and the mechanism that would make a lot of sense combined with other agents. It is being looked at in a very interesting trial that is looking at the number of different arms, combining selinexor with chemotherapy, biological agents, and checkpoint inhibitors to see how we can build a new regimen for patients who are not eligible for CAR T [chimeric antigen receptor T-cell therapy] or transplant or fail after CAR T cells.

Selinexor is a novel agent that has been recently approved for relapsed/refractory diffuse large B-cell lymphoma, after at least 2 lines of therapy. In the trial, about 17% of patients discontinued the drug because of side effects, mainly related to GI [gastrointestinal] toxicity, nausea and diarrhea, and also hematology toxicity, specifically neutropenia and thrombocytopenia. This trial, when it was studied in non-Hodgkin lymphoma, actually utilized a higher dose of selinexor. In the SADAL study, they actually used a lower dose of selinexor but also showed the adverse effects I just mentioned. Part of it included the use of olanzapine during the treatment, especially given the day before, following 5 days after the treatment. Also, they include the use of appetite stimulants and growth factor support to prevent the hematology toxicity. They reported that the adverse effects were manageable in those patients, but they still show a significant rate of GI toxicity specifically.

As I mentioned, in the SADAL study, selinexor in relapsed/refractory DLBCL, they administered the drug at 60 mg on days 1 and 3 every week until disease progression or development of intolerance. All patients were required to receive ondansetron, which is a common antiemetic medication for cancer patients. After patient discussion, they also received olanzapine to prevent nausea. In the non-Hodgkin lymphoma study, which was probably 3 years ago, they included all histologies, including DLBCL. They tested the selinexor at 3 mg/m2, all the way to 80 mg/m2, which was the highest dose. They actually break down in those levels, and essentially there was no significant difference in response rates, even with the lowest dose. They showed an overall response rate of 31%, but that was across all histologies. Based on that data, I don’t think those modifications could have affected the efficacy of the drug. I believe that actually was a good move from the investigators—to use a lower dose, a less toxic drug—because it seems that the toxicity was dose related.

Selinexor has an advantage. The main advantage is it’s a single agent and an oral agent. These 2 factors actually help physicians treat patients. Because they don’t need an IV [intravenous] line, the patients don’t have to come every time to get the therapy. So it’s convenient. The schedule could be a challenge. Patients get selinexor on days 1 and 3 every week, so I’m not sure whether patients will be able to remember. It’s easy when you take a drug every day or once a week, but if it’s twice a week, you may forget. It’s important for the clinicians or the nurses to follow up with the patients when they receive this therapy.

Also, it’s important to know that this is a novel agent with a novel mechanism of action, so the toxicity profile is also novel. Physicians are familiar to use monoclonal antibodies like tafasitamab, so there may be more appeal to use that drug as opposed to selinexor because it’s still unknown, it’s new, and no one has used it, unless they did it for myeloma patients with selinexor.

There are other drugs that are not approved for DLBCL but that doctors are familiar with, like lenalidomide. Lenalidomide has activity in relapsed/refractory DLBCL. Physicians know how to use it because it has been in the market for a while for other conditions such as MDS, myelodysplastic syndrome; mantle cell lymphoma; or even multiple myeloma. Physicians are very familiar with it, and even if it’s not approved, I don’t see any issues with insurance approval or around the co-pays that we sometimes see with this drug.

When using selinexor, physicians have to make sure they know the efficacy and toxicity, so that patients are not surprised and they’re managed appropriately.

SADAL Trial Overview 

 The long-term treatment outcomes for patients treated with CAR T [chimeric antigen-receptor T-cell] therapy are very impressive in the sense that historically we knew that these patients really had very limited overall survival. What we can see in some of the long-term studies is that there are about 30% or 40% of patients who achieve durable remission after treatment with CAR T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma.

This really represents a paradigm shift where previously most of the treatments would have been palliative or clinical trials of new drugs. This really has become the standard of care, and it suggests that patients can be cured with this approach.

Given the known adverse effects of CAR T-cell therapy, especially CRS [cytokine response syndrome] and neurotoxicity, there is always a concern of how our older-patient population will tolerate these therapies. The way I see it, it’s more than age. It’s a functional age that is driven by other factors, like physical health or impact of comorbidities.

This interesting study is based on the retrospective study of 77 patients. They include patients over the age of 70 years old, and what they did is they divided patients from 70 to 74 and 75 years and older. Patients received a standard of care CAR T-cell therapy, either tisagenlecleucel or axi-cel. One, the PFS [progression-free survival] was no different, the overall survival was worse in patients older than 75 years old, and more interestingly, it was what they analyzed actually. They did a multivariate analysis that showed the use of axi-cel and risk score, hematopoietic cell therapy comorbidity score that is used commonly in transplant patients. When the score was more than 2, it was associated with a worse PFS. In terms of toxicity, they found out that patients who developed grade 3/4 cytokine release syndrome was associated with higher CIRS [cumulative illness rating scale] score, which is a comorbidity-illness score that measures the comorbidity and the impact on the patients, and also the use of axi-cel was associated with CRS. In addition, the CRES, which is CAR T-cell-related encephalopathy syndrome, was also associated with older age and CRES score of more than 6.

What this tells us is this is a valuable study that is evaluating patients older than 75 years old and the toxicity associated with CAR T-cell therapy. In real life, we do see those adverse effects. We prefer to use the less toxic product that’s proven by this study. We feel the axi-cel, while it’s very effective treating lymphomas, is essentially more toxic than tisagenlecleucel or other similar CAR T cells. However, age by itself is not the only factor that we keep in account. We also take into account other factors, specifically comorbidities, that we call functional age.

CAR T-Cell Therapy Clinical Trials 

 I alluded to the limits and practical issues to get access to the CAR [chimeric antigen-receptor T] T-cell therapy. But what do we do to try to make it better? With this ASCO [American Society of Clinical Oncology] 2020 Annual Meeting data, there was a small experience on re-treatment. Can you re-treat those patients with CAR T? And the reasoning behind this is that there is some evidence that these T cells will not stick around long enough. There was some discussion that on the need or not to have precise CAR T-cells. We had about one-third of the long responders in the ZUMA-1 trial who did not have resistant, long-term precision CAR T cell.

With the recovery of the B cells and even immunoglobulin, after a year we can see the CAR T cells disappear. But there’s also the idea that we can re-treat those patients who relapse. This was a small number of patients who were from the axi-cel setting, and over half the patients achieved a response: 4 CR [complete response], 3 PR [partial response]. What was interesting is that some of these responses can be durable: close to 3 months, up to 225 days for the longest. There was a rate of CRS [cytokine release syndrome] at re-treatment, but it seems there was less neurotoxicity and maybe also less CAR T expansion. We don’t know exactly how to read this, but it’s feasible.

There is an interesting question being explored at some other trials: Can we do repeat infusion of CAR T? That’s 1 strategy. The other 1 is that can we improve by bringing the CAR T earlier. That’s the question about the timing of the CAR T if we do it earlier in the second line. There’s the ZUMA-7 trial that has completed, but the results are pending. This other study is with liso-cel and tisa-cel also at a second line with a crossover, so in second-line therapy, randomizing against salvation transplant.

There was an interesting study looking at liso-cel in patients who are not transplant eligible. It is an interesting study because liso-cel potentially has an initial toxicity profile, so it might be easier to do. It’s a slightly different product when the CD4 and CD8 subtype of T cells are prepared separately and infused separately. They get the same for the patient. What was impressive in that study was not a huge number of patients but that the overall response rate was 89% and the CR rate was 56% with very low toxicity, and 12 of 29 patients we have done as an outpatient. This is really important because that offer is potentially an option for these nontransplant-eligible patients. It’s for durability, but this is something to take into account.

As for the results and data on the dual CAR T anti-CD19 and -CD22 in combination with pembrolizumab, there’s a very interesting study called the ALEXANDER study. The rationale for this is there is a subset of patients in large cell lymphoma that become resistant to CAR T because they lose CD19 expression. It’s something we see more frequently in ALL [acute lymphoblastic leukemia] as a mechanism of resistance than in large cell lymphoma, but it still happens. And so we try the dual CAR T CD19,-CD22 with PEMBRO [pembrolizumab] to try to see if we can improve. Knowing that a checkpoint blockade is also 1 of the mechanisms of resistance, can we improve the responses seen? This is dose escalation, not a large number of patients. But the response rate was very high: 10 of the 11 CRs. A small number are ongoing. There was no grade 3 CRS and 1 grade 3 neurotoxicity. The recommended phase 2 is 150 to 450 million, and we did want PEMBRO [pembrolizumab] selected.

The last study at ASCO that is worth mentioning was the ALLO CAR T-cell off the shelf. That is a product called ALLO-501, a gene-editing-based technology to remove the T-cell receptor and CD52. This is also used as a dose escalation, presented by Dr Sattva Neelapu. It shows a response rate of 63% with half these patients in complete remission, and 75% of the patients who responded were still in response at the time of cutoff.

That’s also interesting because there was no GvHD [graft-vs-host disease], and there was allogeneic healthy T cell. There was no dose-limiting toxicity, 1 grade 3 CRS, and no neurotoxicity. That’s very appealing because it would be off-the-shelf, ready-to-go T-cells. Potentially that’s very important because 1 of the factors of failure of CAR T is the T-cell fitness. Patients who are heavily pretreated have a lot of immunosuppressive adverse effects with the active disease of ongoing lymphoma. These patients don’t have the best activity. If we have normal allogeneic normal T cells, that might address the problem.

The last aspect that is also important was from ASH [American Society of Hematology Annual Meeting], and this is the BiTE [bispecific T-cell engager] antibody because we know that patients still can fail quite a bit of CAR T cells, and it was an anti-CD20 bispecific antibody, a BiTE antibody, presented in a plenary session at ASH. It was very impressive because this was a response rate of 39%, 22% CR. But there were some responses, durable and a CR durable in continued remission, even in patients who had stopped therapy after 16 months of treatment. This is also being explored in the frontline setting in combination with chemotherapy, CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]–POLA [polatuzumab] versus R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. A number of initiatives are trying to address the new unmet need that we have in CAR T cells. Now we know how to manage more toxicity. Can we improve on efficacy and look at easier ways to use those CAR T cells?

CAR T-Cell Therapy Response Rates

 Chimeric androgen receptor T cells, or CAR T cells, are autologous T cells, T lymphocytes, that are derived from the patient. They have to be collected through a standard leukapheresis procedure at an authorized treatment center. Then the cell product in a self-contained isolated sterile container is shipped to a manufacturing center. Right now, in 2020, there are 2 FDA-approved therapies, axi-cel and tisa-cel. The 2 FDA-approved therapies are both directed against anti-CD19 on the target of B cells. And the chimeric antigen receptor is introduced into the patient’s own T cells through a viral transduction method, which is done, again, in an authorized treatment center in a manufacturing facility that works with an authorized treatment center. That viral transduction process takes a couple of weeks to take place, then those cells expand to sufficient numbers that can then be used to be delivered to the patient for therapeutic benefit.

In our center we have been involved quite a bit in CAR T cells with the NCI [National Cancer Institute] for 7, 8, 9 years ago now. When the patients who are candidates for this with the approved CAR T cells are in third-line setting, there are a number of ongoing trials that they are trying to look at if we can take advantage of this approach early on in the disease.

But what’s really important to summarize is that there are 3 different products among the most advanced axi-cel therapies from the ZUMA-1 data. Now that we have follow-up with this, the tisa-cel from JULIET and liso-cel from the JCAR017 trial TRANSCENDWORLD, they’re slightly different in terms of the signal CD28 for axi-cel and 4-1BB for tisa-cel and liso-cel. There’s a slight difference in the population of relapsed/refractory, the dosing process, the bridging therapy allowed on that. What is interesting is that the response rates went from 52% to 83% and the CR [complete response] rate from 40% to 58%. In a population that really has no option, this is quite considerable. And what is interesting in that setting is that there is some late delayed response. Up to 20%, 30% of patients can have a late response. Sometimes it can take up to a year, and that’s really important. Typically patients respond very rapidly, but it can take a while because it’s a live therapy. This is very important.

With our long-term follow-up, what is interesting also is that particularly in the ZUMA-1, where we have the longest follow-up, we’re at 27 months and close to 40% of the patients are doing really well and half the patients are alive. This is very impressive, and potentially a good fraction of these patients can be cured. One issue is the durability of the remission in this population, because the relapse is still definitely an issue, and the salvage after CAR T is very difficult. The patient who has CNS [central nervous system] involvement, for example, is also a significant issue.

There are some data—not a lot of data, particularly on tisa-cel—looking at patients who had known CNS disease, including disease with some durable responses. But overall, there’s not a lot of experience, and it could be a challenge, particularly toxicity from T cells. Toxicity from the CRS [cytokine release syndrome] and the neurotoxicity are very well known now. But we can manage this toxicity much better preemptively with tocilizumab and then with steroids. One of the questions that comes up is, what’s the best timing and the best combination that you can build on CAR T cell and how we overcome the resistance to CAR T? Those are the issues that I can see in CAR T.

How does CAR T-cell therapy affect patient outcomes and costs? We currently have 2 CAR T-cell products approved for relapsed/refractory diffuse large B-cell lymphoma, tisagenlecleucel and axicabtagene ciloleucel, but there has not been a comparison head-to-head. In clinical practice, there are some differences in terms of toxicity and efficacy. They both have the inherent risk of CRS and neurological events. There is probably more toxicity with axi-cel than tisagenlecleucel. But in general, both carry the same risk, so the patient has to be monitored closely in CAR T-cell therapy centers.

One of the challenges is some patients live far away from the centers, so they have to relocate into the cancer center, and that adds cost. They need a caregiver to stay off work for 1 or 2 months, and that’s another type of cost that families endure with the CAR T-cell therapy. I’m not talking about the cost of the treatment. CAR T-cell therapy is a very expensive treatment. There are also the management of the adverse effects, the use of tocilizumab on admission to the hospital, the use of an intensive care unit bed. Those factors increase the cost. For these reasons, cost and logistics, some patients may decide not to do CAR T-cell therapy, even though it’s a curative option.

CAR T Cell Therapy in Relapsed/Refractory DLBCL

 For patients who have relapsed or refractory diffuse large B-cell lymphoma [DLBCL], the standard of care remains second line, sometimes called salvage chemotherapy, usually with a platinum-based regimen such as R-ICE [rituximab, ifosfamide, carboplatin, etoposide] or R-DHAP [rituximab, dexamethasone, cytarabine, cisplatin].

About half of patients who have relapsed or refractory DLBCL, who receive salvage or second-line platinum-based chemotherapy, will achieve a remission. Those patients are most appropriate to be referred on to consolidation, high-dose chemotherapy with autologous stem-cell transplant.

Of the patients who then go on to transplant, probably about 40% or in some series about half, will have a durable remission. But remember, only about half of the relapsed patients make it to transplant. So we’re talking about less than 1 of 4 patients with relapsed disease actually being cured with a standard salvage approach.

Second, for patients who receive second-line chemotherapy and fail to have an adequate response to let’s say a platinum-based regimen—such as R-ICE [rituximab, ifosfamide, carboplatin, etoposide], R-DHAP [rituximab, dexamethasone, cytarabine, cisplatin], or maybe rituximab with gemcitabine and oxaliplatin—it’s another regimen.

For those patients, the outcome has historically been extremely poor with very short overall survival measured in months. Over the past couple of years, since 2018, we’ve had FDA approval of anti-CD19 CAR [chimeric antigen receptor] T-cell therapy, which is the most appropriate treatment for patients who do not respond to second-line chemotherapy.

 Yes. Polatuzumab vedotin is an antibody-drug conjugate, humanized anti-CD79B monoclonal antibody, conjugated into MMAE(?). CD79B is a B-cell specific marker expressed on the surface of a number of lymphomas but particularly diffuse large cell lymphoma. As I mentioned, this was a treatment that was done in patients with relapsed/refractory, not candidates for transplant. In 40 patients per arm, the CR [complete response] rate was 40% versus 50%. It was a clear advantage in the duration of response, PFS [progression-free survival], and overall survival. This was relatively easy to tolerate. This is a population that is sometimes difficult because they have received several lines of therapy. But there is an ongoing phase 3 POLARIX trial that is trying to integrate this in a complex frontline setting to compare with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. This is really going to be an important aspect, particularly because these patients might not be candidates for doxorubicin. Who knows, in the future that might be an option for these patients.

As we mentioned before, there will be a significant percentage of patients who will not respond to standard chemotherapy such as R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], and the standard of care for those patients is to receive chemotherapy followed by autologous transplant. However, this standard of care may not be applicable for all patients for many reasons, such as comorbidities, old age, access, or patients cannot get into a transplant center, for instance. The same applies for other regimens that are currently approved, like the CAR T-cell therapy, in which again the logistics, the cost, and the access will be a challenge for them.

In that regard, treatment options for ineligible patients for CAR T-cell therapy or transplant are needed. One of the agents that are approved, polatuzumab in combination with bendamustine and rituximab, is an interesting option for patients because it can be done in the community. Community doctors are familiar with the administration of BR [bendamustine, rituximab], and polatuzumab is a monoclonal antibody that has been approved for over 6 months already, and oncologists are familiar. It’s a time-limited therapy option, so patients don’t have to be on indefinite therapy, which is a convenience. But it’s not a curative option. That should be considered.

Other agents that are in the pipeline, like tafasitamab, is also an outpatient option. One of the disadvantages is that while it has good overall response rates, patients have to remain on treatment. So in theory, we cannot talk about cures with this regimen. Finally, selinexor, which is a recently approved regimen, is oral. The advantage is it’s not an IV [intravenous], you don’t need a line; however, some of the toxicity profile remains challenging because it’s a new agent and the doctor has to be familiarized with the agent. Also, its efficacy—in my opinion, it’s a modest efficacy, about 31% response rate, a little over 10% to 15% CR rates. That is the information that physicians need to know, that they can transmit to their patients in order to make a decision.

Relapsed/Refractory DLBCL Treatment Landscape

The question often comes up: What percentage of patients are refractory or relapse after standard frontline therapy? Depending on the risk category, this could be as high as 30% or 35% of patients who initially respond to R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and then relapse, or a primary refractory. Primary refractory disease is fairly rare, probably less than 5% of patients. But it does occur, and it typically results, or is manifest by, a positive PET [positron emission tomography] scan or a progressive disease during primary care for your R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. The more common scenario, which is going to occur in about up to a third of cases, is relapse after achieving a remission. Usually those relapses occur in the first year or 2 after completion of primary therapy.

For the patient with refractory/relapsed lymphoma, these patients can receive salvage chemotherapy and then high-dose therapy and transplant. The question is, is that who can qualify for this? Well, for the patients who are in first relapse and have chemotherapy-sensitive disease—the more chemotherapy sensitive, the better—reaching a PET-negative prior to high-dose therapy and transplant clearly has an impact. The issue here is that some of these patients are not great candidates for transplant high-dose therapy, but also some of these patients do not respond well to the second line. The primary refractory patients and the early relapse do very poorly in that setting. So this is not something that we actually recommend necessarily.

When you look at the overall in a patient in the R-chemotherapy [rituximab chemotherapy] era, the outcome of patient after high-dose therapy and autologous stem cell transplantation is still in the range of only 10% to 15% of the patients that you save. This is not the perfect option at this point, but thankfully we have other options we’ll talk about, including cell therapy.

The patients who are eligible for transplantation are really an unmet need. Similarly, so are the patients who fail after transplantation. There is some option now, so we’ll talk about CAR T [chimeric antigen receptor T cell] and cell therapy in a minute. But it may be easier to use. The polatuzumab data refer to BR [bendamustine, rituximab], which was very impressive and is approved. It was 40 patients per arm, but the CR [complete response], which was the primary end point, was 40% versus 15% and with a very significant difference in duration of response and survival. This is interesting. The R2 [lenalidomide, rituximab]–ibrutinib is something that we presented updated at ASH [American Society of Hematology Annual Meeting] in a non–GC [germinal center] subtype. It’s important because we go with age: Up to two-thirds of elderly patients, over 70 and above, can be ABC [activated B-cell] or non-GC subtype, so this is really 1 of the unmet needs we alluded to before.

For these patients, R2 [lenalidomide, rituximab]–ibrutinib, during the chemotherapy-free part, we had a response rate of 60% and some very durable response. Patients were well over 3 years with the disease control with R2 [lenalidomide, rituximab]–ibrutinib, particularly in a non-GC diffuse large cell lymphoma. This is something to keep in mind. Finally, there are the L-MIND data, which is lenalidomide plus anti-CD19, tafasitamab, and the response rate in this situation was also very impressive and very durable. This is really potentially an option and that has been combined in a frontline setting in the context of BR/POLA [polatuzumab], or bendamustine-rituximab and POLA [polatuzumab], so we’re trying to integrate this novel therapy in the frontline setting.

In patients who are not candidates for transplant, this is really again an unmet need. Those are perfect candidates for clinical trials, and we’ll talk a little more about cell therapy in that setting. But in reality, the patients who are truly not eligible for autologous stem cell transplant because of frailty or comorbidities are not going to be necessarily great candidates for CAR T cell, at least at this point.

What’s a typical response and duration of response after R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]? This is a challenging question, and it all depends on where you get the data. If we talk about outcomes in real life, the R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] outcomes are worse, as opposed to clinical trials in which there is an inherent selection bias. We tend to select the healthier and less sick patients in trials, so they will probably tolerate better the treatment and they will complete the treatment, and also patients will have less aggressive disease.

In general, what I see in my general practice is about 60% to 70% of patients are cured with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]; the rest, 30% to 40% of patients will either relapse or remain refractory. In terms of long-term remission, probably the most important data that we have is on the GELA [Groupe d’Etude des Lymphomes de l’Adulte] study, the French study that compared R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] versus CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], that showed that about 50% of patients were still alive at 10 years’ follow-up.

R/R DLBCL: Transplant Eligibility and R-CHOP

The treatment factors that affect newly diagnosed patients with newly diagnosed diffuse large B-cell lymphoma [DLBCL] include pretty standard clinical features, including age, functional status, and comorbidities. From the perspective of the disease, if the patient has double-hit lymphoma, that can also impact treatment selection.

For the majority of patients who have reasonable performance status, if they’re in their 60s or 70s and don’t have significant comorbidities, R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] is still going to remain the standard in the current era outside clinical trials. If they have significant advanced age in their 80s or late 70s, comorbidities, or really poor performance status starting with less inventive regimens such as mini-R-CHOP [reduced-dose regimen of rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or just palliative treatment with steroids, Rituxan, and cyclophosphamide, or vincristine, like R-CVP [rituximab, cyclophosphamide, vincristine, prednisone] is often used in that setting, that’s appropriate.

Again, for most fit patients who can receive R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], that’s still the standard outside double-hit lymphoma. As we discussed, if a fit patient has double-hit lymphoma, that’s when a more intensive regimen is usually offered.

The stage of diffuse large B-cell lymphoma can impact treatment to a certain extent. Most patients are going to be advanced stage, with stage III or IV, depending on the extent or absence of extranodal disease. Again, for those patients, 6 cycles of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] is still standard therapy.

In the case of limited stage—so a true stage I—there are data from recent trials that show for low-risk early stage patients, it’s appropriate to offer either 3 or 4 cycles of systemic therapy with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], sometimes followed by radiation. Increasingly we’re seeing data that suggest that if you achieve a complete metabolic response, for instance, after 3 cycles of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], completing systemic therapy with 4 cycles and omitting radiation is still reasonable and achieves very good outcomes for early stage, stage I or II, DLBCL.

For germinal center or nongerminal center, which is said to be activated B-cell subtype, there have been a number of trials over the past decade that have attempted to improve the outcome of patients with higher-risk, nongerminal center, DLBCL, which usually has an activated B-cell phenotype. Investigators have attempted to introduce proteasome inhibitor bortezomib, lenalidomide, BTK [Bruton tyrosine kinase] inhibitors such as ibrutinib. To make a long story short, all these trials have not been positive.

Despite the significant biological rationale for introducing targeted agents for these subtypes of patients, particularly the ABC [activated B-cell] subtype, none of the studies has panned out. Some of this may be related to patient selection in terms of not getting the higher-risk patients on the studies. Another part of this is likely that the method of assigning subtypes has been too crude, and we really need to move to a more advanced molecular testing method to discriminate the subtypes and then assign targeted agent pathway inhibitors, targeted agents in those specific pathways for those specific subtype.

This is an important aspect. When you see patients having comorbidities and cardiac issues, neurological issues, etc, we know that this is a difficult situation. The definition is the geriatric assessment, but basically if it’s an older patient, more than 80 years old and with some comorbidities, you can use an attenuated form of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], which is the mini-CHOP [reduced-dose regimen of cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. That could be very helpful. If the patients have cardiac dysfunction, we can replace the doxorubicin with etoposide or gemcitabine, or liposomal doxorubicin. Sometimes bendamustine–Rituxan [rituximab] will be used, sometimes combinations with antibody-drug conjugates that are being looked at in the frontline setting. Hopefully other combinations will emerge as a possibility.

In patients who are older, it’s important to mention here—the patients that are older, frailer, a bit but not necessarily cardiac dysfunction—1 thing that works really well is to give them somewhat of a prephase with vincristine, rituximab, and steroids for 5 days. Then they come back a week later and then we can get them started on R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. These patients do really well.

There’s finally novel therapy, as I mentioned, that might offer an opportunity to replace chemotherapy in that setting. There are the R2 [lenalidomide, rituximab]–ibrutinib data from The University of Texas MD Anderson Cancer Center, from the SMART START trial from Jason Westin. That has shown very high response rates and CR [complete response] rates after an induction that is basically nonchemotherapy option: response rate of 80% and CR over 36%. These patients can receive an abbreviated course potentially of R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] if they’re elderly. As I alluded to the polatuzumab, POLA, is used in the relapsed/refractory setting. We’ll talk a little later about this, but it is going to be integrated as well as bevacizumab is integrated in a frontline setting. We are building up by adding these types of therapy that might allow us to treat, even better, these patients who have comorbidities and issues that prevent them from using anthracycline.

Julio Chavez, MD, Moffitt Cancer Center

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