A discussion on updates presented at the ASH (American Society of Hematology) 2020 Annual Meeting on developments in the management of relapsed/refractory B-cell lymphomas.

Data from the following clinical trials are discussed:

Abstract 339: Efficacy and Safety of Zanubrutinib in Patients with Relapsed/Refractory Marginal Zone Lymphoma: Initial Results of the MAGNOLIA (BGB-3111-214) Trial

Abstract 403: Glofitamab Step-up Dosing Induces High Response Rates in Patients with Hard-to-Treat Refractory or Relapsed Non-Hodgkin Lymphoma

Abstract 2104: A Phase I Investigator Sponsored Trial of Selinexor (KPT-330) and Rituximab, Ifosfamide, Carboplatin and Etoposide in Patients with Relapsed or Refractory Aggressive B-Cell Lymphomas

Abstract 599: Polatuzumab Vedotin Plus Venetoclax with Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Primary Efficacy Analysis of a Phase Ib/II Study

Abstract 598: Phase 1b/2 Study of Vipor (Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide) in Relapsed/Refractory B-Cell Lymphoma: Safety, Efficacy and Molecular Analysis

Videos

ASH 2020 Updates in Relapsed/Refractory B-Cell Lymphomas

Key opinion leaders provide insight into data updates from the ASH (American Society of Hematology) 2020 Annual Meeting on developments in agents for the management of non-CLL (chronic lymphocytic leukemia) B-cell lymphomas.

Abstract 2109: Selinexor in Combination with R-CHOP for Front-Line Treatment of Non-Hodgkin Lymphoma: Results of a Phase 1b Study

Abstract 405: Interim Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) as First-Line Therapy in Patients (Pts) With High-Risk Large B Cell Lymphoma (LBCL)

ASH 2020 Updates in Non-CLL B-Cell Lymphomas

Experts in the management of hematologic malignancies discuss various abstracts and data updates presented at the ASH (American Society of Hematology) 2020 Annual Meeting on chronic lymphocytic leukemia (CLL).

Abstract 123: Ibrutinib (Ibr) Plus Venetoclax (Ven) First-Line Treatment of Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): 1-Year Disease Free Survival (DFS) Results From the MRD Cohort of the Phase 2 CAPTIVATE Study 

Abstract 1318: Zanubrutinib in Combination with Venetoclax for Patients with Treatment Naïve Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma and del(17p) Arm D of the SEQUOIA (BGB-3111-304) Trial

Abstract 125: Five-Year Analysis of Murano Study Demonstrates Enduring Undetectable Minimal Residual Disease (uMRD) in a Subset of Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Patients (Pts) Following Fixed-Duration Venetoclax-Rituximab (VenR) Therapy (Tx)

Woyach Abstract 1305: Three-Year Follow-Up from a Phase 2 Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Chronic Lymphocytic Leukemia

Abstract 2216: Updated Safety and Efficacy Results from a Phase 2 Study of Acalabrutinib, Venetoclax and Obinutuzumab (AVO) for Front-Line Treatment of Chronic Lymphocytic Leukemia (CLL)

Abstract 544: Transcend CLL 004: Phase 1 Cohort of Lisocabtagene Maraleucel (liso-cel) in Combination with Ibrutinib for Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Abstract 545: Safety and Efficacy of CD19-CAR T Cells in Richter’s Transformation after Targeted Therapy for Chronic Lymphocytic Leukemia

ASH 2020 Updates in CLL

 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.

Standard of Care for Relapsed/Refractory DLBCL

I want to thank all of you. It's been a really great and informative discussion. We've covered the waterfront of relapsed and refractory large cell lymphoma. Before we finish up, I want to give you each a chance to give us a quick take home message for practitioners taking care of patients with large cell lymphoma, and I'll start with Nathan, then Matt, and then Kami. Nathan?

 In the past 5 years, we've seen a huge change in the outcome of patients who are failing auto transplant. To me, that's the biggest take home message of what’s happened in the last several years; patients who fail transplant—in the past, I was trying to do everything I could to find something just to prolong outcomes— now have curative regimens that are curing a significant portion of them and there are even better versions of those coming out in the next couple of years.

It's a great time to refer patients to clinical trials because some of the cellular therapies look very active and so it's a wonderful time for patients. Not that it's ever good time to have relapsed large cell lymphoma, but the outcomes and the available options are like nothing we've seen in generations.

 I don't want the perception to be that cellular therapy for is all, rather a discussion on cellular therapy for all is reasonable. Many patients may not go on to get cellular therapy and, as we pointed out in this discussion, there are a lot of new compounds being studied and some that will make it into the commercial use. But at the end, thinking about large cell lymphoma even from a diagnosis, it’s important to determine what your strategy is going to be and you hope that you're in that bucket of 75% that may be long-term survivors. You know that you have to prepare for the quarter that are not. That's where the game really gets tough and you need a strategy. You need a team to have the strategy in relapsed/refractory large cell lymphoma and a lot of times, it helps to have a cellular therapy institution in your corner.

I agree with Nathan that it's an exciting time in relapsed/refractory large cell lymphoma with the approval of agents such as CAR T [chimeric antigen receptor T-cell] therapies, polatuzumab, the excitement of potentially tafasitamab and lenalidomide. These are providing options to patients who previously didn't have options. We are curing more patients with CAR T therapy and hopefully we just get better as far as outcomes from those therapies as we improve the constructs and decrease toxicity.

I think that, moving forward, places that we can continue to do better are increasing the rate of cure in those patients with high risk disease from the beginning. In patients who are not candidates or who progress after both auto [autologous stem cell transplant] and CAR T, we can work towards having more effective options, possibly in some of the immunotherapies like bispecifics.

 I think large cell lymphoma is getting more complicated despite our profiling data has not translated into improved outcomes. People are used to kind of giving everybody R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxy daunomycin), vincristine sulfate (Oncovin) prednisone] upfront and crossing their fingers but I think the relapse setting is becoming more and more complex. Probably, before long, we’ll need more sophistication in how we approach these patients. Hopefully, that means we're using them more effectively and have more tools at our disposable.

Thank you all again. I want to thank our audience for joining us today as well. We hope you found this 

 discussion to be useful and informative. Thank you.

Closing Thoughts on Treatment of R/R DLBCL

Nathan, 1 of the things I'm struck by is how all of these things going to improve outcomes for patients. One of the things that is pretty clear to me from our discussion is that we really don't have any molecular predictors of who should get what for any of these therapies. It's really a clinical decision: you have refractory large cell lymphoma, you can get a CAR T [chimeric antigen receptor T cell], you get it. You want an oral therapy? Okay, maybe you'll get selinexor. You want a chronic therapy that's well-tolerated? Okay, maybe you'll get tafasitamab /lenalidomide. Or maybe you're not a stem cell or an aggressive chemo candidate, maybe you'll get polatuzumab. It doesn't address relapse setting. I guess we would argue we have the most data, though limited with CAR T-cells.

Beyond that, we have no molecular predictor, biomarker, profiling, any of these things that tells us what to do, other than what we've talked about today, which is your impression of the drug, your impression of your patient, and what seems to fit what they want to do. Whether or not it's let's go for the long-term remission and cure with 1 set of agents or palliation with another set of agents, how do you think we can move this forward in a reasonable way?

 This is something we see across the cancer space, especially in lymphoma, and something that we have been talking about for more than 20 years in large cell lymphoma. It started off with ABC [activated B-cell] vs germinal center B-cell subtype, and there are more refined systems to cluster patients into different groups that came out from Margaret Shipp, MD, and Louis Staudt, MD, PhD. I think there was a recent paper in 

 looking at trying to cluster patients into different groups based upon their genomics.

To date, I have not seen any of these systems used to select treatment. That's the next step—to identify these biologic subsets of large cell lymphoma and treat them differently based upon some hypothesis that that biology can be treated by some targeted agent or some immunotherapy. These things are desperately needed. There are multiple groups that are performing these analyses, dividing groups of patients by their biological characteristics either using some marker or multiplex imaging or genomics. We really need to define the biology by some assay and then using that as a way to put patients into different treatment groups. That’s the holy grail because the one-size-fits-all approach can only move the bar so much in large cell lymphoma. CAR T-cells, which are incredibly exciting, still only have 30% or 35% of patients with long-term benefit. We don't know why that is, so we treat 100% of patients to get that 30% outcome. That's a long answer to your short question but biologic predictors are what we desperately need for this disease.

Before we wrap up, I just want to ask, Matt and Kami, your thoughts about cost and how that affects your patients. We've alluded to it a little bit but, Matt, are you having trouble with getting approvals for the drugs you want to treat your patients with? Are they coming back and saying their co-pay is too high? How often does that come up?

 It comes up more than it used to. I'm doing many more peer to peer discussions explaining why I'm going down a course that I am. If you think about our highest cost therapeutics right now, it probably is CAR T, unless you are on an oral therapy that is a continuous therapy that's priced out month per month. Then if you're getting to 2 years on some of those drugs, they can be expensive. That's great if you're on an oral therapy for 2 years from a relapse/refractory large cell standpoint.

One of the ways to drive down cost that isn't the cost of the product from a cellular therapy is if they're not in the hospital. If you can decrease the in-hospital cost—I guess in MD Anderson [Cancer Center],no patient was to be sitting in the hospital unnecessarily—I think that that would be one of the avenues to do some cost savings as a total bundled price. There was a lot of cost CAR T-cell data at EHA [European Hematology Association Annual Congress] just released, trying to look at modeling around this.

Different countries have different cost structures; I saw a French and a Canadian. I know that were trying to do our own certain analyses here, but I think it will factor into it. I don't know where things will be priced out in these newer IV [intravenous]and oral drugs, but I can imagine is going to be part of the discussion also.

Cost is becoming something that I have to talk about frequently and it can be very frustrating and uncomfortable. We have all these oral therapies, while they are available, can be very expensive. There are patients that may have a co-pay of nothing where there's patients that have a co-pay of a couple thousand dollars a month or a 1-time co-pay of $5000 and that they get it for the rest of the year free. Those are significant costs to patients and it's frustrating to have to tell somebody we have this therapy that can help them but it's just not affordable for them or its it's going to make them go broke. To Matt's point, with cellular therapy, you can get it approved by your insurance company for the therapy, but then you have to still negotiate the cost of the hospitalization and the supportive care, like tocilizumab and those things. It can become prohibitive even if you get coverage for the product. We need to find ways to make these more cost-effective. We have to do better for people in that respect.

Improving Outcomes in Patients With R/R DLBCL

I want to move towards, in our last few minutes, talking about other agents. We've talked about a couple that are either approved or farther along in the regulatory review process. I remain struck by the number of agents that continue to be studied. You might think that we've reached our limit, so to speak, in immunotherapies and antibody-based therapies, but there a number of bispecific antibodies and there are versions of bispecific antibodies where different companies have engineered their own version of a bispecific or a new type of antibody. We have antibody drug conjugates. We have the bispecific T-cell engager [BiTE], blinatumomab, approved in certain settings. What do you think about—before we get to other categories of drugs that you're excited about—these novel immunotherapies, for lack of a better term?

I'll ask Matt to go first, and then Kami and Nathan, and share your thoughts on where these fit. Some of them have data, both the antibody-drug conjugates and the bispecifics, that are approaching or even better than some of the things we talked about today. So Matt, your thoughts.

 Some of the bispecifics, like glofitamab, which has 2 different binding domains; CD20 that then engage CD3. You have—it's always fun trying to learn the new names—epcoritamab, which is a subcutaneous injection going after the same space. It's going to be generating data but not a lot of the data will follow CAR T. We’re going to get response rates and PFS, but they aren't going to be in the population where you enter the playing field.

It's great to have the data because if you don't have data there, you're not going to want to go into those populations. I'm excited about seeing those drugs get a longer follow-up. We've got the overall response rates and CR rates, but we need durability.

There's still some good data out there. There are 3 CD19 ADCs that have been developed, all showing pretty similar responses, however 2 are not going to be further developed due to toxicity. The third one had good responses that don't last long and is probably going to have to be in combination—kind of like some of the other agents we talked about today—to really get good remissions. I think the bispecifics are interesting. A few of those have been looked at in the post-CAR T setting and have activity there, which is probably one of the highest unmet needs of those patients who are post CAR T.

 Mosunetuzumab had a couple of post-CAR T patients on it, if I remember the data correctly.

Yes, that one and then the Regeneron Pharmaceuticals one just recently put out data with some responses post CAR T. We have potential therapies, like selinexor, to offer those patients.

 At least it shows that they're listening to us because a lot of trials have been trying to write off patients by not allowing prior exposure to CD19 CARs. Why are you doing that? That's exactly who we should be studying. Yes, create an expansion cohort for all you want and analyze the data differently, but we need to understand that population.

Nathan, your thoughts on some of these new drugs?

 I will echo what everyone said already. When we were looking at the BiTE molecules a couple of years ago, there was some sense that they would maybe displace CAR Ts. But a lot of the data that were seeing now is immature. I don't think that the durable CR rate appears to be at the same level that we're seeing with CAR T-cells, at least in large cell lymphoma. So I don't see these replacing CAR Ts, but I agree with Kami and Matt that they will probably follow CAR T as a salvage for these patients.

The other thing I thought at this most recent ASCO, there was a nice abstract on AlloCAR T and it would be very interesting to develop an off-the-shelf strategy for CAR T where we you would have something that's sitting in your blood bank and able to be given to patients when they relapse. Those studies are still very small, but that would be something we should consider more.

Matt, you've talked about the access and applicability of CAR T. It strikes me that there's a large percentage of people who could benefit from CAR T that are not getting them. It also strikes me that having new agents around is going to make that number of patients getting CAR T even smaller because there will be alternatives. Whether or not they're appropriate, it's good for patients to have alternatives.

The fact is people will be more inclined to say “You got to go get CAR T.” And now the discussion will be, “You should get CAR T but you could get this or that.” How do you think that's going to change the big picture?

 I still have a lot of hair to pull out in my career, but I think it just comes back to being a resource to have those discussions about who in this population is appropriate to go to CAR T cell and who isn't. It's great that we're getting all of these new classes, more drugs to have the discussions about. It's a chess match against large cell lymphoma and knowing what piece to play next; You may be moving 1 piece to make a move 3 times down the road and that may be CAR-T-cell because that's what the data shows. 

We have to continue to encourage that if you're doing a CAR T-cell study, you should be able to get a CD19 BiTE or you should be able to get a CD19 antibody for the CAR T cell so that we know and can inform the patients about this. We want to not exclude the patients from the studies so that they can't get a CAR T-cell or the next generation CAR T-cell because that may be the patient population that does derive benefit.

So Kami, you at Ohio State University Medical Center clearly have lots of access to CAR T, yet you’ve been participating in a variety of different trials, including some of the agents we've talked about today, which in some ways tells me that you see excitement and promise in some of the things that are not CAR Ts that we've talked about, that they're fulfilling or potentially filling a need for your patience. Why do you think that is, from the standpoint of just ease and toxicity?

I’m putting you on the spot here but I just want to see how people in practice should think about this. Clearly, going on a trial with tafasitamab offered something to those patients that was attractive. So how do you think about it because I think it's the same way people are going to have to think about it in practice.

When looking at your patient, you need to know what are they able to tolerate if something is very well-tolerated and they can get a good response from it. Regarding access, they have to come to us for the trial, but just in general, Ohio serves a big population. There's a lot of land here for a small amount of people so we serve a number of states. When you're looking at making recommendations for therapy, not everybody can have access to the big center; not everybody can wait to have their CAR T sent off, manufactured, and returned and not get therapy in between that time. Sometimes it's still an insurance issue or a financial issue; you have to have the coverage and pay what isn’t covered. You have to stay within a certain closeness to Ohio State for a certain amount of time after you leave the hospital. All those represent challenges for our population in this area.

Emerging Therapies for R/R DLBCL

I want to move to another drug that is undergoing regulatory review for relapsed and refractory diffuse large B-cell lymphoma and that is selinexor. This is an agent that has a somewhat different mechanism of action and is already approved in some myeloma subsets so the audience may be familiar with it. Nathan, tell us why selinexor might be a reasonable agent for this patient population and the data supporting its potential use.

This is a new class of drugs and it's not anything that we have for large cell lymphoma or any other cancers. It's called a SINE [selective inhibitor of nuclear export] and it targets certain proteins that are exported out of the nucleus that gives cells a pro-survival advantage. It is not necessarily specific to large cell lymphoma, but it targets the mechanism that large cell lymphoma probably uses to keep itself alive and potentially resistant.

The drug is oral. It's a single agent. It's associated with some unique effects– a lot of which are GI and we've seen now some fairly decent size phase 2 trials targeting patients that have large cell lymphoma. In this trial [phase 2b SADAL trial] looked at a fairly difficult population. Most of these patients had at least 2 prior lines of therapy, some patients were failing transplant, and some patients were double-hit patients. In that study, they saw almost 30% overall response rate with a complete remission rate of around 10%. If you think about CAR T-cell data and others, it's not quite as good. It's a single drug so it’s fairly easy to give. It is effective in a subset of patients that have pretty difficult-to-treat large cell lymphoma, including patients that have double-hit lymphoma.

One thing I really thought was interesting with the drug is that in the responders, we saw pretty good long-term responses. In fact, if you look at patients that have PR or better, the duration of response is over 2 years. There is a select group of patients that do achieve durable benefit with the drug.

I want to ask Matt and then Kami your experiences with the drug if you've used it, and/or your take on reading the literature about it from the standpoint of efficacy as well as the safety profile. So Matt, your thoughts.

 I have not used the drug in lymphoma. We do have it available in myeloma, as you pointed out, and use it in a clinical and a research setting. My read of the initial paper that was published is it went on an adventure of dose-escalation, dose-finding, and schedule-finding driven mostly by GI toxicity, as was pointed out. How could you get enough drug in the subjects that allow them to respond and want to stay on it? Over time, if it takes a while, where's the enthusiasm for continued use?

If this drug is going to continue to be used, it may have to be with other drugs, if it can be playing in the sandbox together. We have these other novel agents, like tafasitamab and some other oral lenalidomides, where you're seeing longevity in this population. We also should be studying patients are who are responding, even if it’s a small piece of the pie, so we can know who it's worth potentially having those toxicities. Those toxicities can be manageable over time, per the paper. We really need to identify those patients.

I've had experience with the drug in a few different ways. We were involved in the phase 1 study, and as mentioned, there was this toxicity, weight loss, and fatigue, and those seem to be problematic. However, once they were able to address these effects by looking at appetite stimulants and scheduled antiemetics, we have a phase 2 study in combination with ibrutinib and it seems to be much better tolerated with the use of these agents now that it's recognized that there are side effects.

It's an oral therapy that can be given to high risk patients so it does provide an option for those patients. When you look at the overall responses, I think that Matt and Nathan are right, that it's probably best used in combination with another therapy to get the best bang for your buck.

We participated in some trials and now that the dose level is better settled as you cited, it does seem to be better tolerated. It's going to be important for people—when they have access to it and are considering using it—to really think about the toxicity in the context of the dose they're using rather than the up-and-down doses that were studied.

We have also had a study looking at it in combination with RICE [rituximab, ifosfamide, carboplatin, etoposide] chemotherapy in relapsed large cell lymphoma. Interestingly, it may be tolerable and can be given with chemotherapy, with support from a randomized trial, and that’s what you're seeing with your ibrutinib study.

Nathan, as you look at this, if you have this available as a single agent and you had a patient with large cell lymphoma, where do you see this used relative to CAR T-cells, tafasitamab, and other kind of standard chemotherapy drugs? The nice thing about it is it's an oral regimen that is relatively easy from the perspective of administration for patients to take. Who do you think would be the patient getting single agent, assuming you have access to it and had a patient population?

When I think about patients that are failing CAR T, and that's going to be at least half, maybe more of those patients, I don't have good options for those patients. Generally, I'm thinking about clinical trials. We talked about a Revlimid-containing regimen, but we’re still grasping those patients. We often do things like radiation to limited sites, but they don't have a lot of great options that could give them a durable remission.

What I really liked about this is that in those patients who responded, they've got over 2-year PFS. So that suggests that it's an active drug. I don't think this is going to replace auto [autologous stem cell transplantation] or CAR T. In patients that are failing those kind of approaches, we don't have a lot and we can do Revlimid and Revlimid plus a CD19. Post-CAR T-cell failure patients or patients that would not qualify, and are not near a center are the obvious population.

Kami and Matt, your thoughts, anything different?

Safety and Efficacy of Oral Agents in R/R DLBCL

So Kami, in a world where you have a relapsed large cell lymphoma patient who has not had a good response to second line chemotherapy and is not a great candidate for it, you now might have tafasitamab and lenalidomide as an option and you have CAR T-cells as an option. In the assumption that both are available in a clinical setting, how would you think about approaching those? Clearly and outpatient regimen that's easy to give relatively speaking versus CAR T-cells that are more complex but also for the effective in refractory patients, how do you think about that decision as you would move forward?

As I mentioned regarding the population of patients treated on that trial and as Matt also mentioned that with some other differences, the one downside to the population of patients is they weren’t heavily pretreated. They weren't primary refractory and they weren't double hit patients. We know that those patients do better with CAR T and I would be hesitant to use this combination in somebody who had access to a CAR T center and was in that population of patients that hadn't been studied in this study.

For patients who fit these criteria and both are available, they both have similar responses, similar CR [complete response] and durability is very good with tafa [tafasitamab] len [lenalidomide] also. It's much less toxic, it's much easier to access and it could be given at any center across the country as opposed to sending a patient to a CAR T center. If a patient was not a candidate for CAR T, I would definitely offer the tafa len.I think if it's a patient who had a good response to chemo and is on the board for something, that's a patient I would offer tafa len to if they couldn't get access to a CAR T center. For some of the higher-risk patients, I think we need more information on tafa len and if that really works in those patients like CAR T does.

Matt, you alluded to some of these key questions but if tomorrow you had access to one and you have a patient who says they could do either one of these things and would like to try the tafa first, because it's less involved and outpatient and everything else, and do the CAR T if that doesn't work or they relapse. Speaking to the CD19-directed approach, how would you answer that and what would you advise that patient as to the best strategy?

 We have an access issue in relapsed refractory large cell lymphoma anyway. I would be thrilled to be part of the discussion about when to use tafa len versus CAR T cell. If it has to be in the Covid-19 era over telehealth, I think that is still worth the time to have laid the roadmap from that because the data is showing us tafasitamab lenalidomide, in the appropriate patient population. It wasn't just a flash one abstract wonder, it's held over time in that patient population. If you’re going to use it first before CAR T cell, there has to be a strategy and you have to be looking to make sure that, just like large cell lymphoma, they are not progressing fast enough. You can't caught on your heels not thinking about CAR T-cell­ therapy right after that. What are you using otherwise, pola-BR [polatuzumab vedotin plus bendamustine/rituximab]? Polatuzumab single-agent or lenalidomide already, ibrutinib maybe?

There is a period of time where you're seeing that you want to go to CAR T-cell [therapy] and you can't or it's going to take long because of logistic reasons. I’ve spoken to this whole mysterious time when you want to do CAR T cell and it's just taking forever to get to apheresis for numerous reasons, tafa len seems to be reasonable, as Dr. Maddocks pointed out, because of the toxicity profile. I'd like to get experience with the drug but to take those patients out of the running for CAR T-cell. If it takes a couple of weeks to get them to their apheresis and then another 3 weeks to get them there, maybe tafa is the best option because it's 8 weekly doses early on. You're getting drug exposure and then you give them the intent to go to CAR or they could say no, and you haven't lost anything if they're responding.

The one concern people have is just sequencing the CD19 therapy, like Matt touched on a little bit ago, and really does that, using that tafa len as a bridging therapy to CAR T, make the CAR T less effective? We just don't have enough information to say that. There was one patient that's been reported on the L-MIND study that responded to tafa len, progressed after, went on to CAR T and has over a year remission.

But that is an N of one and you can't base anything on one patient. As Matt said, there is preclinical data on treating cells with both the CD19 and that doesn't affect the CAR T effector function. As this becomes available to people, we'll hopefully know more about if there is an effect on the CAR T efficacy.

 I think it's important, as we've looked both in the polatuzumab BR coming out and the tafasitamab lenalidomide coming out, that each dose of tafa that's delivered is likely a CAR T-cell patient somewhere in your region. Are you able to and are you having those conversations? Do you have a network established that can say let's work together to decide what the next steps are. And if that next step is tafa len or pola-BR or some other combination therapy that that doesn't include CAR T-cells, so be it. Then we've at least checked that box on the discussion in large cell lymphoma that we should be having with patients out there in this disease state.

I just want to ask if there's any data on collecting CAR Ts, having had a patient of mine with mantle cell who recently couldn't get CAR Ts collected because they weren't enough T cells. I know that doesn't come out very often but it’s certainly a consideration. Do we have any data of collecting T cells after lenalidomide? And that might be a good thing. It might be a bad thing. I don't know. Any data on that? Is that an issue?

 I have not seen any but I bet you there will be data coming out because of the R2 [lenalidomide (Revlimid) and rituximab] CHOP [cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone] versus CHOP studies that were done. There were patients that were refractory they are. If I had to go back and look at that question, I would key in on that population and see what their outcomes were to second line and how many of them got CAR T-cells. The problem is that they're all going to have gotten another light of therapy that kind of tackles those T cells. It's going to be hard to interpret, unless you're coming off of some of the lenalidomide. There was the Spanish data looking at len plus R-GDP [rituximab plus gemcitabine, dexamethasone, and cisplatin] but that was a transplant ineligible population. The data is out there but it's just kind of just made somebody's ASCO abstract for 2021.

There you go. It's out there for whoever wants to tackle that one. There's a study looking at tafasitamab up front. I don't know, Kami, if you’ve been involved in that study or have any insights into that. I don't know if it's open and accruing yet.

There is a phase 1 study open at a small number of centers. We're not involved but it's actually looking at R-CHOP plus tafa and then R-CHOP plus tafa and len. That's ongoing with a planned phase 3 study with R-CHOP and then R-CHOP plus len plus tafa.

 I think it's going to be interesting because I've looked at eligibility for that. It does exclude double hits. It does allow I think it's IPI 2 to 5. There are competing randomized trials in the higher risk groups so maybe it's a good thing to have multiple upfront trials going after what cell lymphoma in different groups. Maybe if we do different things, then there will be a positive trial against R-CHOP instead of all negative trials.

Treatment of R/R DLBCL: CD19-Directed Therapy vs CAR T

As we move toward other emerging options for relapsed and refractory diffuse large B-cell lymphoma, we have a number of new potential agents that are out there.

One that is undergoing regulatory review right now is the anti-CD19 antibody tafasitamab [tafa]. It's been studied primarily in combination with other agents, including lenalidomide [len]. I know, Kami, you have led some of the trials around tafasitamab. Can you tell us a little bit about what it is first from the audience that may be unfamiliar and some of the initial studies that have been on primarily in relapsed and refractory large cell lymphoma with this agent in combination, particularly lenalidomide?

Tafasitamab is actually a CD19 monoclonal antibody. The Fc portion has been enhanced to increase ADCC [antibody-dependent cell-mediated cytotoxicity] and ADCP [antibody-dependent cellular phagocytosis]. There was a single arm study that looked at the monoclonal antibody tafasitamab alone in relapsed refractory non-Hodgkin lymphoma and they saw some responses in diffuse large B-cell lymphoma but notably there was a handful of patients who achieved a complete remission. The median duration of response in those patients was over 20 months, signaling that there might be some activity in this agent with large cell lymphoma.

The combination of tafasitamab and lenalidomide was evaluated in a phase 2 study that combined the 2 drugs for 12 months. The antibody is given once a week for the first 3 months and then every other week for months 4 through 12. Lenalidomide was given at a dose of 25 mg. After a year of therapy, patients were allowed to continue on tafasitamab maintenance. The further rationale of this trial is that the lenalidomide activates NK [natural killer] cells and that brings more cells for tafasitamab to act on.

The phase 2 trial of the combination showed pretty high response rates. It showed a 60% overall response with a little over 40% of those patients achieving a complete remission. The patient population in the study was allowed to go on trial with relapsed/refractory disease with a median prior therapy of 1 to 3; the population had median prior therapy of 2. These weren't extensively or very heavily pretreated patients.

It was really targeted at those patients who relapsed after their initial therapy or maybe received a first salvage and then are not candidates for autologous stem cell transplant. The therapy was pretty well-tolerated with toxicity mainly being hematologic, fatigue and diarrhea. Really when you look at the toxicities after the first year of treatment, the majority of them resolved, really suggesting that the toxicities that were seen with the combination were primarily what you see with lenalidomide alone. There were very few infusion related reactions. About three quarters of the patients were able to stay on a lenalidomide dose of 20 mg or higher.

Matt, I want to ask you your take on this agent. We just talked about CAR [chimeric antigen receptor] T cell data with and we’ll come back to whatever comparisons we can draw. How does this compare with either lenalidomide alone or anti-CD20 alone? Are these patients characteristic of this population? Are they the same people were seeing with CAR T cells? I know that the RE-MIND study tried to make some comparisons, obviously with different cohorts. How do you interpret this phase 2 data regarding this combination in light of the patient population that we may want to apply this combination to in the future?

 Dr. Maddocks, correct me if I'm wrong here, but I was just waiting and waiting and waiting for the publication and I think it came out recently in 

 because some of the methodology of the study, too, is that the patients couldn't have double-hit or triple-hit biology. My understanding is that you couldn't have been primary refractory to your first line of therapy. If you were refractory to R-CHOP [rituximab cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone]—or any CD20-targeted monoclonal antibody—or dose-adjusted EPOCH [etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone], you couldn't be in the study also.

There are some differences there because we've seen on CAR T-cell therapy those patients, double-hit, CAR T-cell appears to be as agnostic. It doesn't care that you're a double-hit. You can still respond and have durability. The same thing is that if you're primary refractory, you're still going to CAR T-cell likely double refractory with a lot of disease and those people have gone chemotherapy jumping from one to the next.

Nathan H. Fowler, MD, MD Anderson Cancer Center

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