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Expert hematologist-oncologist Grzegorz Nowakowski, MD, reviews data from the 5-year analysis of the L-MIND study combining tafasitamab with lenalidomide in relapsed/refractory diffuse large B-cell lymphoma.

Five-year Efficacy and Safety of Tafasitamab in Patients With Relapsed or Refractory DLBCL: Final Results From the Phase II L-MIND Study

 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 

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.

Grzegorz S. Nowakowski, MD, Mayo Clinic

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