 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.

Videos

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

 Thanks to all of you for this rich and informative discussion. Before we conclude, I’d like to get your final thoughts and ask what you’re most excited about in therapeutics for CLL [chronic lymphocytic leukemia]. We’ll start with Dr Burke to give Dr Allan a chance to catch his breath.

 A couple of things strike me as particularly exciting. One is the novel BTK [Bruton tyrosine kinase] inhibitors, the noncovalent BTK inhibitors that we just heard about from Dr Allan. Those offer a lot of promise. The biggest challenge right now in the field are the patients with hard-to-treat CLL who progressed through the BTK inhibitor and venetoclax and maybe a PI3K inhibitor, those desperate patients who need help. The noncovalent BTK inhibitors offer potential for those folks.

The other big, exciting development is the use of MRD [minimal residual disease] to adjust therapy, not just in CLL but in a lot of fields. Think about lymphomas where we have treatments that work for a good majority of patients, but then there are patients whose cancers become resistant and then they relapse and do poorly. If we can identify who those patients are by using MRD assays to see who has residual disease, then we can tailor therapies earlier and try to make an impact when we know we have the potential to help more. In CLL, tailoring therapy based on MRD assays and result is an exciting way forward for the field.

 Dr Allan, what are you most excited about?

 I’m excited about these combinations of therapies. We’re seeing great clinical synergy. We see the vast majority of patients—regardless of high-risk features—able to achieve MRD negativity, which we know translates to longer-term remission. I’m excited about that. I also echo Dr Burke a little in trying to get behind our thoughts of what is personalizing the treatments for our patients. But I really want to dive into the data and find cytogenetic abnormalities that may respond better to a certain approach.

We have a little evidence that that there may be something there with BTK inhibitors or 11q, and wecan start to tease out certain patient populations that might actually do better with a specific approach. It’s not going to be a discussion of only what the patient wants, which is what we do now, but rather we will tailor therapy to evidence-based practice guiding treatment, so we know this is going to be the best treatment for you. With maturation of all this data and larger numbers of patients being treated in uniform manners and similar populations, we’ll be able to start to tease that out and have meta-analyses type of studies. I’m excited to see research into those areas as well.

 In addition to what was just mentioned about combination therapy and using an MRD-guided approach, I’m excited that no matter how different high-risk disease, there are patients who are still in need of different types of treatment and novel treatment approaches. It’s good to see that immunotherapy specifically is still active for CLL. We definitely do have patients who need treatment beyond what we discussed today.

Maybe this is more hopeful than exciting, but with more treatment options, I certainly hope that translates to affordability and availability for patients around the world. Hopefully more treatment options will create some competition that eventually patients will benefit from. We shouldn’t forget that these drugs are not necessarily available for all CLL patients in different countries. With more agents, there will be a situation where we can help other patients have access too.

 Again, thank you all. To our viewing audience, we hope you found this 

® discussion to be useful and informative. Thank you.

Future Directions in CLL

 We have just a few more minutes. I think we will wrap things up with the new agents. I’m going to ask Dr Allan in a second about the reversible inhibitors of BTK [Bruton tyrosine kinase]. But John Burke, maybe you can comment on the cellular therapy and CAR T [chimeric antigen receptor T-cell therapy] and whether that represents promise for our patients with CLL [chronic lymphocytic leukemia].

 At the ASH [American Society of Hematology Annual Meeting], we saw data on the CD19-directed CAR T-cell product liso-cel, and they showed data on 23 patients, most of whom had failed ibrutinib and demonstrated an overall response rate of 81%, a complete response rate of 45%, and then an MRD [minimal residual disease] undetectable rate of 75% to 85%, depending on blood vs bone marrow. The toxicities were not trivial—74% of patients had some degree of cytokine release syndrome, although only 2 were rated as grade 3.

They saw tumor lysis syndrome in 17% of patients, suggesting clear activity. The data remain fairly early. That particular product would certainly appear active in this high-risk population, but it’s also pretty toxic. CAR T is not something I have referred many patients for, and right now I save it for last. We’ve also seen data that CAR T can be added to ibrutinib, but these data weren’t presented at the last ASH.

Patients who had been treated with ibrutinib for 6 months and failed to achieve a certain degree of remission, then had CAR T added. The CAR T helped clear the bone marrow, and patients achieved deeper remissions but at a fairly considerable toxicity cost and financial cost as well. I’m a little uncertain about where the final role of CAR T will be, but right now it remains a research tool.

 In terms of newer agents in development, there’s a lot of work going on with the next generation of BTK inhibitors, the reversible inhibitors. Dr Allan, I know you’ve done some work with the reversible inhibitors. Can you highlight some of the features of those new agents? How do they differ from what we have available with the irreversible inhibitors and what we’re seeing with the activity for those in compounds?

 Absolutely. It’s important to remember that the 3 big FDA-approved BTK inhibitors are all covalently bound to the protein BTK at the Cys481 amino acid, which is within the kinase pocket, prevents activation and phosphorylation, and inhibits and kills the enzyme irreversibly. Therefore, the only way for the cell to make more BTK is to transcribe it, translate it, and then repopulate the protein, which then is inhibited the next day when you take the new BTK inhibitor.

We know that the resistance mechanism is a mutation developed in BTK at that Cys481 residue, which is then turned from a cysteine to a serine, disrupting the irreversible binding and covalently binding to the protein. Therefore, the molecule gets kicked out. That’s the major mechanism of resistance we recognized in the vast majority of patients who progress that have been reported, a BTK mutation is typically present. These covalently bound molecules have short half-lives.

Therefore, the drug is in and out of the kinase pocket, gets washed out of the system based on its pharmacokinetics [PK], and the enzyme is then able to fire again, allowing the CLL to signal through the B-cell receptor. One way that has been devised to overcome that is to use what’s called a reversible BTK inhibitor, where the drug no longer binds into the pocket irreversibly but instead goes in, interacts with the pocket, inhibits activation, and throughout the day goes in and out of the pocket within that cell.

The PK is a little better on these reversible BTK inhibitors. These molecules have longer PKs. They’re hanging around the body. Therefore, they’re staying in the cell longer. They’re not getting broken down. By having a reversible inhibitor, you can have relatively prolonged inhibition of the protein and have high occupancy rate, even though the drug is not covalently bound. There are 3 reversible BTK inhibitors currently advancing in clinical stage and at least 1 or several others that are coming on board and trying to get into the clinic now.

The current studies are entering phase 2 populations and are emerging from their phase 1 data. Limited data have been demonstrated. These patients that are recommended for these studies are very high risk. They have BTK mutations. Most are 17p deletion, so it’s a really difficult patient population to treat. It’s hard to glean efficacy from this specific population.

We found that these inhibitors do have activity and different selectivity for their kinome. Some are rather specific, much like acalabrutinib and zanubrutinib, and don’t have a lot of other off-target inhibition. Others have similar kinase inhibition, like ibrutinib. Then there are other molecules that have a broader inhibition of other molecules. What we’re starting to tease out is if it all depends on BTK inhibition, or is it some other off-target effect based on these different molecules?

We’re starting to learn and see activity. As we start to expand in these phase 2 populations, that’s where we’re going to glean from our efficacy. We’re going to get less patients who have been pretreated. It remains unclear to me if these drugs will be in a niche in which we’re only going to be using them for patients who progress with BTK inhibitors and patients who have BTK mutations. Or will the reversible BTK inhibitors be able to potentially unseat covalently bound BTK inhibitors?

It is possible that you may be able to prevent the mutation by using reversible BTK inhibitors because that evolutionary pressure is not there, but that remains to be seen. What has been reported is that these drugs do appear safe. They don’t appear to have huge rates of atrial fibrillation. They don’t have huge rates of other toxicities that we sometimes attributed to our covalently bound BTK inhibitors, such as arthralgias and diarrhea. We’re learning here and we’re starting to target our resistant mechanism, and that’s where we are in the current state.

We’ll see at ASH, I think, the big 3 companies that have a molecule in advanced stages showing more results with larger patient populations, and we’ll start to glean if there are differences among the molecules. We don’t quite understand that yet. We don’t know if there’s a winner of the 3 that are currently far ahead, but we’ll start to understand that and the toxicities and to make sure that these patient populations are similar so we can understand why 1 is better. Is it a potency issue?

Is it a patient population issue? What patient factor might predict response? Or is it some other off-target effect that, as the science catches up, we would start to learn? We’re using these drugs. They’re coming down the pike, and I do think there will be some value in them, especially in this special resistance niche of patients. It remains to be seen if reversible BTK inhibitors can cross the threshold to be adopted broader.

Novel Therapies for CLL

 You mentioned PI3K inhibitors. Let’s touch briefly on PI3K inhibitors and their utility. Dr Shadman, what are your thoughts on PI3K inhibitors, and what has your experience been with them? How do they fit into what we’re doing today with therapeutic strategies in CLL [chronic lymphocytic leukemia]?

When we think about the novel agents that we have for CLL, the 3 big groups are basically BTK [Bruton tyrosine kinase] inhibitors—including the next generation, second generation, and now third generation—BCL2 inhibitors, and PI3K inhibitors. PI3K inhibitors are in the 2 large studies for CLL therapy. As John Allan just mentioned, they’re usually not the first or second choice most of the time.

Based on the initial experience, using these agents in the frontline setting usually comes with more toxicity. These are treatments we think about using in the relapse setting. You have 2 approved drugs for CLL, of course: idelalisib and duvelisib. Idelalisib was the first drug approved, and it’s a PI3K-delta inhibitor. A randomized study combined idelalisib with rituximab and the control arm was placebo and rituximab.

The study showed PFS [progression-free survival] and OS [overall survival] benefit based on a relatively short follow-up. I believe the PFS was 5 to 6 months for the control arm and not reached for idelalisib-rituximab. There was an OS benefit. The study population included patients with normal kidney function, significant myelosuppression, and patients with coexisting issues. Recently last year the long-term follow-up was published in the 

 It sounds as if they looked overall for patients who received the combination therapy idelalisib-rituximab.

The median PFS was around 20 months. The take-home point from this paper is the toxicity data. One of the factors we consider when deciding whether to use PI3K inhibitors is the toxicity—namely, colitis, pneumonitis, and transaminitis. As I mentioned, these toxicities seem more common in patients who were previously untreated, maybe because their immune system is more intact.

When we looked at the long-term follow-up data, the longer exposure to idelalisib, the adverse effects like diarrhea, colitis, and pneumonitis become more common and more prevalent. For example, diarrhea grade 3 or more is in the range of 16% when you continue to take idelalisib, and grade 2 diarrhea is in the range of 17%. When you think about grade 2 diarrhea as having 4 to 6 stools per day, that is significant.

The same is true with colitis. For those of us who deal with colitis as a result of taking idelalisib, in my experience the patients who I treated early on treat graft-vs-host disease with the same type of approach: high-dose steroids and tapering. Some patients had to go back on the drug because at the time, there were not many other options. The drug had significant toxicities: pneumonitis, at 6% of grade 3 or more with longer use. We usually see hepatitis early on after starting therapy.

Usually hepatitis doesn’t come back, and the longer follow-up confirms that. Duvelisib is the other drug. It’s a PI3K-delta and PI3K-gamma inhibitor. Duvelisib is also approved as monotherapy for CLL based on the head-to-head randomized trial comparing duvelisib with ofatumumab. The median PFS was 13 months, 13.3 months vs 10 months in favor of duvelisib led to its approval.

I’m not sure how much duvelisib is used. To know more about the true rate of toxicity, we need to use the drug beyond the initial clinical trial. We need to get more real-world data, but it sounds like diarrhea and colitis are the common toxicities. These are recorded separately in the paper, so it’s hard to know the true rate. But to me, the drug seems to have the same toxicity profile with hepatitis occurring a little less. It’s not recorded.

The incidence of hepatitis was less than 10%. But again, we need to use duvelisib more, and the drug has more indications as being used in T-cell lymphomas, for example, more recently. We may get more toxicity information from different histologies. PI3K inhibitors as a group are extremely effective, but if we have to use them, we need to be mindful of the toxicity, mainly infections and autoimmune adverse effects, and prepare prophylaxis that needs to be used. There are strategies to make PI3K inhibitors better tolerated.

At ASCO [American Society of Clinical Oncology Annual Meeting], we have some strategies—maybe we should call them next-generation PI3K inhibitors—in terms of scheduling. We give PI3K inhibitors less frequently after an initial phase. In that approach we may have a PI3K inhibitor that has a different toxicity profile that may be available for CLL and other lymphomas. For umbralisib there are many studies in combination with a CD20 monoclonal antibody and other combinations. We have some work to do from a toxicity standpoint, but in patients who I had on these drugs, and even patients who are high risk, it is extremely effective medication as long as you control the adverse effects.

I see PI3K inhibitors as a third-line treatment in patients who either progress on both BTK inhibitors and venetoclax, or for some reason they can’t tolerate BTK inhibitors. There may be a future in combining PI3K inhibitors with other drugs. It sounds as if the future involves a venetoclax-based therapy. If a BTK inhibitor for any reason is not a good partner, maybe a safe PI3K inhibitor could be used.

Drug-drug interactions are significant with PI3K inhibitors and venetoclax. But there are studies that have shown safety for duvelisib and the newer generations of PI3K inhibitors.

PI3 Kinase Inhibitors in CLL

 We talked about first-line therapy and what drives selection of first-line therapy. Patients do well for many years, but some of them do relapse or progress on treatment. Therefore, therapeutic sequencing is an important concept. There are not a lot of data around therapeutic sequencing. I wonder, Dr Allan, if I could ask you to give us your thoughts on the major concepts regarding therapeutic sequencing. For example, if we start with a BTK [Bruton tyrosine kinase] inhibitor, what do we do next if a patient progresses, and where are we trying to get that patient for long-term disease control? If we start with a BCL2 small-molecule inhibitor, what is the sequencing strategy in that case?

 That’s a great topic and a hot topic, but we don’t quite know the answer to whether there is a best sequence for our patients. The only way to find the answer is to start patients on 1 therapy and have a long-term study that then follows patients switching to another therapy upon progression. Because these patients do so well and following that PFS [progression-free survival] too, depending on your sequence, a study with a long-term follow-up would be the only way to truly identify the best sequence. That’s never going to happen because it requires a large number of patients and long-term follow-up. Therefore, we’re left looking at studies that have been performed, where 1 of the inclusion criteria is exposure as a prior therapy to say a BTK inhibitor or a BCL2 inhibitor.

The only prospective clinical trial that’s been designed and reported and published in that manner is looking at true ibrutinib progressors in patients with a BTK inhibitor intolerance and salvaging them with venetoclax. This was a smaller phase 2 study that enrolled patients with true progression and/or intolerance. This study had close to 100 or so patients, of which the vast majority—close to 60%—had progression on BTK inhibitors.

Mind you, patients in this study are heavily pretreated with relapsed/refractory CLL [chronic lymphocytic leukemia] from the era of the earlier BTK use, which is where we’re hopefully emerging from, so we won’t be treating these types of patients anymore. But we found that venetoclax has great salvage abilities, and response rates were close to 70%. CR [complete response] rates were relatively high in the patient population with refractory CLL. Peripheral blood MRD [minimal residual disease] rates were in the 40% range, which didn’t necessarily translate to deep bone marrow disease negativity. Not a lot of patients had deep bone marrow disease negativity, so that’s a little unknown.

We found and have shown that if you can get patients in an MRD-negative state, those patients had a PFS that wasn’t met at the time—they had reported it and never had another follow-up. But overall, patients had a PFS of about 2 years when they get venetoclax-based salvage therapy. In this case, again, patients were highly refractory and had previous progression on BTK inhibitors, so that is typically the classic standard of care.

If you start a BTK inhibitor, we then flip to a venetoclax or a BCL2 inhibitor–based treatment. Whether you add an anti-CD20 monoclonal antibody or you do fixed-duration therapy is based on MURANO data. Though it is important to remember that in the MURANO study, only a small number of patients of the total patient population had prior BTK inhibitor exposure. Therefore, we didn’t get our answer from that study. Ultimately, though, you typically do some venetoclax-based treatment.

Based on some real-world evidence, personal experience, and cross-study comparisons, we know that switching to another B-cell receptor antagonist like a PI3K inhibitor after a BTK inhibitor, progression is probably not going to MRD negativity. If you come off a BTK inhibitor for intolerance, PI3K inhibitors can have some activity and get you to MRD negativity, but they have their own issues with intolerance and toxicities. As we said, venetoclax is a very well-tolerated drug. Patients do well on venetoclax. We can salvage these patients who are tough to treat because we know that if they’re progressing on a BTK inhibitor, disease biology is saying something.

That typically indicates 17p deletion. There is a small subset of patients who don’t have a 

 mutation, but they are common among patients who truly progress. They need a switch out of the treatment pathway, so to speak, and fortunately, we have venetoclax to do that. The flip side of this is now that the CLL14 study is around, and many people are adopting and are attracted to this fixed-duration therapy, we’re getting a new wave of patients who’ve been BTK inhibitor naïve. We don’t have current prospective clinical data of true patients being salvaged with BTK inhibitors post-venetoclax progression or relapse.

Fortunately with time, we’ve gotten some real-world data from collaborating groups around the world to be able to put enough patients in relapsed/refractory settings who had been BTK inhibitor naïve. We now have relatively significant numbers in real-world settings to where we can see response rates resemble what we see when you use a BTK inhibitor in a patient who is BTK inhibitor naïve even though they progress and relapse on venetoclax.

That data provide some encouragement from the community and from providers. It allows us to at least educate our patients that it doesn’t matter so much which drug you use first. You will be salvaged regardless of which drug you use, and it makes sense. These are completely different mechanisms of action. They don’t have cross-talk too much and the mechanisms of resistance with a venetoclax or BCL2 inhibitor are very different from the mechanisms of resistance we see with a BTK inhibitor–based treatment.

Fortunately, we know that the sequence doesn’t seem to matter too much. You can tailor therapy a little, but classically, you’re staying in a BTK pathway then a BCL2 pathway or the opposite. You’re not typically doing a B-cell receptor or a BTK inhibitor staying within the B-cell receptor antagonism and going to a PI3K and then to a venetoclax, because it is probably not going to get you to MRD negativity. That’s typically my practice. Depending on which class of drugs you use first, you use the other class second.

We don’t know if there is a frontline impact on long-term survival, so we don’t know if there is a best first-line treatment. Those head-to-head studies haven’t been done. We’re getting that, but the studies have all been combinations vs monotherapies. It is an exciting time, but using 1 pathway and then the other has typically been my practice. When talking to my colleagues and other people in the community, that’s the train of thought currently in therapeutic sequencing.

Therapeutic Sequencing in CLL

 Dr Burke, in terms of BTK [Bruton tyrosine kinase] inhibitor–based therapy, what can we expect in the relapsed setting in general? We talked about first-generation versus second-generation compounds. What can we expect if we put a patient who’s been previously treated, maybe with BR [bendamustine, rituximab], on a BTK inhibitor–based therapy? Most trials that have been done in the relapsed setting enrolled patients who’d had prior chemoimmunotherapy. In that setting, what can we expect with a BTK inhibitor–based therapy as relapsed treatment?

: If you look to the data, the original study that we have the longest follow-up with is RESONATE, which compared ibrutinib with ofatumumab in patients previously treated with chemoimmunotherapy. The long-term follow-up was published last year, and they reported a median PFS [progression-free survival] with ibrutinib of 44 months, just under 4 years. The median overall survival was a little over 5 years. I think the RESONATE study is the best long-term follow-up data we have with ibrutinib.

With acalabrutinib, we have the ASCEND trial that compared acalabrutinib with the control arm, which was a mix of either bendamustine-rituximab or idelalisib-rituximab. We saw improved PFS with acalabrutinib in that trial. For patients who have been treated previously with chemotherapy, a BTK inhibitor or the venetoclax-rituximab combination therapy is the way to go over salvage chemotherapy. I saw a patient not that long ago who had previously been treated with fludarabine-based chemotherapy and then relapsed and saw a doctor who recommended BR.

I cringed because we now have data that suggest that patient would be better served by either a BTK inhibitor or venetoclax-rituximab. That’s the key point practitioners need to know—those are the standard approaches now for second-line therapy after previous chemoimmunotherapy. Median PFSs are in the range of 4 years.

 In the relapse setting, what population of patients worry you? Are you still worried about 17p deletion, even though we know that the targeted therapies have activity in patients who are 17p deletion mutated?

 aberrancies still fare less well than those who do not have those in the relapsed setting. Most of the other gene mutations seem to have less prognostic importance, which is true in the untreated setting as well. In the previously untreated setting, there was a publication in 

 just 2 months ago based on the CLL14 study showing that venetoclax seems to overcome some of the adverse prognostic implications of, say, deletion 11q. The only FISH [fluorescence in situ hybridization] abnormality that conferred a less favorable prognosis with up-front therapy with venetoclax-bendamustine was 17p or 

It’s true that these targeted agents are overcoming a lot of the other adverse prognostic and genetic factors but not 100% overcoming the 17p problem.

BTK Inhibitors in Relapsed/Refractory CLL

 Dr Shadman, let’s switch gears now and move to relapsed disease. You spoke a lot about the CLL14 study, which analyzed venetoclax in the frontline setting. Let’s transition to the relapsed setting and the application of venetoclax in the relapsed setting. The MURANO trial led to approval for venetoclax-rituximab in the relapsed setting and has been updated recently. Can you highlight the information from that update?

 MURANO was the study that brought venetoclax-based therapy in combination with rituximab to the relapsed setting for CLL [chronic lymphocytic leukemia]. Patients were given a chemotherapy-free regimen that was time limited—in this case, 2 years. Patients were randomized in a 2-arm study to either venetoclax-rituximab—here venetoclax started first, and a patient received that treatment for 2 years—or bendamustine-rituximab. It was not an MRD-guided study. All participants stopped at 2 years if they could tolerate and if they were responsive to treatment.

The standard arm of the study was bendamustine-rituximab, a commonly used regimen. Around 40% of patients, distributed between the 2 arms, had an abnormal 

 deletion or mutation. The study showed both PFS [progression-free survival] and an overall survival advantage for venetoclax and rituximab, and I believe a PFS of around 86% vs 35% in the initial report. This is another situation in which achieving an MRD-negative state at the end of treatment is important for prognostic information and because that translates to a longer PFS.

At the last ASH [American Society of Hematology Annual Meeting] in 2019, Dr John Seymour presented the 4-year follow-up of the MURANO study, in which we continued to see improved PFS in the venetoclax-rituximab arm—57% vs 5%. The most important piece of that presentation, looking specifically at MURANO, was that we have clear numbers of PFS in patients who have an undetectable MRD, and that is uMRD4, with a median of 22 months being off therapy.

Eighty-six percent of patients who have uMRD at the end of treatment are PFS vs 60% in patients who are considered low MRD, which is 10-2 to 10-4 vs about 7% in patients who have more disease burden, defined as more than 10-2. The MRD achieved at the end of treatment gives valuable information on what to expect in terms of clinical progression.

The important data that came out of this long-term follow-up help us answer the question Dr Burke asked earlier, which is do we use MRD in clinical practice? In my case, my official answer would be no. I try to go with 1 or 2 years of therapy, but I have been looking at MRD because the MURANO long-term follow-up shows that the kinetic of the MRD matters. When they looked at the patients who had detectable MRD at the end of treatment, the patients had a rising MRD level before the end of therapy.

In a way, we can use MRD to predict if a patient will have relapsed CLL. If you start checking a little earlier and see the rate of the level of detectable CLL rising, you know that your patient won’t achieve an undetectable state at the end of 2 years and probably won’t achieve an undetectable state if you continue the current course of treatment. Not only will you not see improvement, but you will see more disease. Do I use that? I have. For a number of patients I started looking at their MRD a little before the end of therapy. If I see that their levels are going down, and if I can treat them for 26 months instead of 24 months and then stop and they achieved detectable MRD state, I do it. This is not based on any data, but I think most of us try to create some data for ourselves.

That’s my small project. But really, this is another discussion that I have with patients. I tell them that the whole idea of going on this therapy is to have a fixed-duration therapy. If I want to continue to chase an MRD, that may not be the smartest idea. But if I see that trend and if I feel that by treating 2 more months we can get an undetectable state, then I will. Some patients feel much more comfortable stopping treatment if they know they don’t have any detectable disease, using what we have in terms of the MRD assessment tools.

The longer follow-up of the MURANO study shows that a time-limited chemotherapy-free treatment using only 1 of the novel agents in the relapsed space is effective. We talked a lot about combinations, and it’s great to use our best drug up front and hopefully cure patients, but I also think about the situation in which a patient stops responding to both. Having a combination of venetoclax with a non–BTK [Bruton tyrosine kinase] therapy is reassuring because you know you have a very reliable drug as a backup plan. This was the MURANO summary and follow-up.

MURANO Trial Update in R/R CLL

 Before we move on to relapsed disease and management for relapsed disease, I want to touch on MRD [minimal residual disease] briefly because it’s been mentioned many times. I agree with you, Dr Allan. We are very focused on MRD in our clinical trial and our clinical trial design—MRD as an end point, MRD as a surrogate marker for depth of response, and prolonged progression-free survival [PFS] for patients with MRD negativity.

Dr Burke, what is the utility of MRD testing in the standard management of patients with CLL [chronic lymphocytic leukemia] in the community? Is MRD useful, or do we stick with fixed-duration and stopping treatment at fixed duration? For example, with venetoclax-based therapy at 1 year for frontline and 2 years in the relapsed setting.

 I’m somewhere in between. Bill, you and other experts who have been doing this for years have probably been doing MRD on your clinical trials for a long time. Right now, the average community practitioner is not doing MRD at all. I am in a phase where I have increased my use of MRD, even off study. That could be debated whether one should even do that. For me, MRD is a prognostic tool when a patient finishes venetoclax therapy.

MRD helps the patient and the physician understand the patient’s likelihood of relapsing within the next few years. As has been discussed, you have patients with MRD negativity who have a relatively favorable PFS and a low likelihood of relapsing, whereas patients with MRD positivity are much more likely to relapse quicker. MRD is a prognostic tool, but it doesn’t tell you what to do with the information. If a patient is MRD positive, should the patient continue the current course of therapy?

Should the patient go ahead and stop therapy at 1 or 2 years or whatever the defined plan was? Should the patient switch therapy or add a therapy? These are all options, and we don’t know the answer to that question. A trial like CAPTIVATE is going to start getting an answer to that, but these are unknowns. You’ll hear opinions, but you won’t really hear data-driven answers as to what is best for that patient. Likewise, I don’t think we know the best duration of therapy for patients who are MRD negative.

Right now, we have this defined period and we can reassure patients that they’re likely to do relatively well when they stop therapy if they are MRD negative. But would they be better off continuing therapy for a longer period of time with venetoclax, as you do with a BTK [Bruton tyrosine kinase] inhibitor? I don’t think we know the answer to that question. These are a lot of unknowns that we are facing in the field. Should a community practice center check MRD at the end of a venetoclax regimen—1 year, 2 years? I offer that as an option to my patients if they want to know the prognostic information.

If they want to know their likelihood of recurrence within the next couple of years, then we can do that test. If they’re not that interested and they’re worried about cost, MRD is certainly optional and can be omitted for routine clinical practice. There’s my perspective.

Utility of MRD Testing in CLL Management

I’m going to ask Dr Allan in a second about the new and novel combinations of targeted therapies, but maybe Dr Burke can give us an idea of his experience with venetoclax tolerability and safety. What are the things you’re thinking about when you’re planning patients on venetoclax? What’s been your experience with tolerability and safety?

 I would add a few comments. As an oncologist, I think it’s amazing when patients come in and tell me they have no adverse effects and I hear that a lot with venetoclax. I use it quite a bit. I don’t mean to say that it has no adverse effects, but patients come in after 6, 9, 12 months of therapy and they say they feel fine. That’s not everyone, but it’s a lot of patients. I find venetoclax to be a well-tolerated drug. One issue I’ve had with patients’ tolerance of venetoclax is neutropenia. In order to try to maintain them on a full dose, I give a fair amount of growth factor, particularly during the first 6 months when they’re on obinutuzumab.

I’ve had 1 patient for whom I had to stop therapy because of thrombocytopenia. He went into the teens and didn’t come out of it, but I think his underlying liver disease was the cause. Rarely have I had to stop therapy, and so in general I think venetoclax is a well-tolerated drug. I found that giving GCSF helps me maintain dose intensity without having too many pauses. I’ve had to admit 1 patient with a neutropenic fever, but that is rare.

In the frontline setting, as we heard from Dr Shadman, you can debulk patients with obinutuzumab and reduce their tumor burden. I have never had to admit a patient for tumor lysis syndrome [TLS] prevention in the frontline setting because I’m in no rush to start venetoclax. I don’t feel the need to follow the label to start venetoclax on day 22 of cycle 1 all the time. You can give patients a couple of extra doses of obinutuzumab if you need and debulk them further before starting venetoclax to make sure it’s safe.

I’ll repeat a CT scan. With this method, I’ve been able to keep every patient as an outpatient. By doing that, following the label, and checking the TLS labs on schedule on day 2 and on day 3, it’s been very safe. I had really no problems with venetoclax.

 Dr Allan, tell us about the combinations BTK [Bruton tyrosine kinase] inhibitor plus BCL2 inhibitor, the interest in the combinations, and the results.

 I should give credit to The University of Texas MD Anderson Cancer Center for publishing data that show for the first time the preclinical synergy between BTK inhibitors and BCL2 inhibitors. We are seeing this now translate to clinical efficacy as well, not just additive properties between these drugs. We can utilize the modulation of different pathways and then hit them hard with both of these drugs. A lot of work has been done.

There have now been a few clinical trials. Nitin Jain from MD Anderson has published some of the first frontline data with combination BCL2 inhibitors, venetoclax, and ibrutinib and showed MRD [minimal residual disease] rates that rival or were better than what we used to see with chemoimmunotherapy, especially in high-risk patients. We are seeing that clinically. There has now been transition where the industry has started to turn out larger-phase studies with more patients.

We’re starting to introduce MRD-based thoughts and response adaptive therapies vs fixed duration. One of the major studies we will watch for updates is the CAPTIVATE study, which is a study by Pharmacyclics looking at a combination of ibrutinib-venetoclax in treatment-naïve frontline patient all comers. This study is special in that it has 2 cohorts.

The first cohort is an MRD-response adapted cohort, where the patients are debulked with ibrutinib for 3 months and then treated with an additional 12 months of venetoclax plus ibrutinib, so 12 months of combination but 15 months of total treatment. At the end of that time in the first cohort, MRD assessments are made in the bone marrow. At previous congresses, the groups have published MRD rates in the bone marrow showing up to 72% of patients are MRD negative in the bone marrow with the combination of ibrutinib and venetoclax.

Let me remind you, there are no anti-CD20 monoclonal antibodies in this treatment regimen. This is all completely oral, which makes the study unique and special, and we’re seeing impressive results. The CAPTIVATE study is randomizing the MRD-negative patients. Remember, 72% of over 160, 170 patients were MRD negative. They were randomized in a placebo double-blind fashion to placebo or continual maintenance ibrutinib. For the first time, we’re going to see if we need maintenance.

We will find out if a patient population seems to benefit from maintenance. We are putting MRD into a response-adapted thought where we’re not measuring MRD, not knowing what to do with it. We’re going to start to learn what to do with it. The 25% of patients who don’t achieve MRD are randomized to monotherapy ibrutinib vs continuing the doublet venetoclax-ibrutinib and then a period of continual ibrutinib after that. That will be an interesting group to see who is not reaching MRD and then how well they do.

In that group, we’ll be also able to see if their MRD is deepening over time, because that is the big question. Right now, a lot of the data show that patients either reach MRD negativity or don’t within the first year or 2. After the second year, MRD doesn’t seem to deepen. There is something about the biology of CLL [chronic lymphocytic leukemia] that keeps MRD from deepening. The study also has a fixed-duration cohort where they enrolled another several hundred—150, 160, 170—patients who are receiving the same regimen and stopping regardless of their MRD status.

Because of the power of these 2 cohorts, they will be able to do a cross-study comparison to understand the value of stopping and the value of continual maintenance therapy in the patients who do achieve MRD. There’s a lot of power in the study. Now there are many other studies that are looking at combinations of triplet and stopping therapies, and we can go through a whole list of them. A few studies were conducted by cooperative groups.

Alliance has a study, A041702, in older patients with a triplet obinutuzumab-ibrutinib-venetoclax vs ibrutinib-obinutuzumab, where those patients are going to have a response-adapted therapy and at the end of that a combination therapy. There is an ECOG study as well, EA9161, which is for patients younger than 70 years old, where patients have a fixed-duration for the triplet regimen vs continual therapy of ibrutinib-obinutuzumab. A limitation of the study is that there isn’t a monotherapy ibrutinib arm or a fourth arm without anti-CD20 monoclonal antibodies plus the combination therapy.

We are limited in terms of understanding the benefit of that anti-CD20, whether it is going to help or not. We’ll start to see MRD rates, and these are all very similar patient populations, so we will be able to make comparisons across studies to see if these MRD rates are any different or can have an additive effect. Can we push people into the 80% bone marrow disease negative state with anti-CD20 plus the doublet?

These are exciting times, and over the next 2 or 3 years we’re going to start to see answers to those questions as the data continue to mature. These studies have an ability to impact how we might treat patients in the future. Right now, we use monotherapy sequencing treatments.

In the future, we will likely—as we did with fludarabine in adding cyclophosphamide and then rituximab—start to add all our treatments, putting our best foot forward, getting the vast majority of people to MRD-negative states. We’ll pick and choose the high-risk patient who we’ll be able to leave on a continual maintenance therapy vs the low-risk patient who might be able to receive 15-month stop and then maybe go 6, 7, 8 years and then receive the regimen again as a second treatment for a fixed-duration. Over the course of 15 years, they may have 2 or 3 years of total treatment.

That’s where it’s moving. A lot of these questions that are up in the air may be moot and obsolete in a few years as we transition to combination therapy. I’m not saying combination therapy is going to be right for every patient. There might be a patient who is older and frail and may not be right for combination therapy. We have found from these studies that there do seem to be increased toxicities. Nothing new, but things like diarrhea might be a little more severe with a combination therapy.

There are also some cytopenia issues that we start to see with combination therapy. Therefore, some of our frailer patients who are older and have low-risk disease, they’re in their late 70s or early 80s and might do beautifully with a BTK inhibitor and never need another treatment in their lifetime. Treatment is not going to be 1 size fits all. For our younger patients who are more fit or older patients, combination therapy is an exciting opportunity for them to achieve the MRD-negative state, which we do believe is important, especially if we’re going to try to stop therapy.

That’s where some of the combination data are initially starting to come out. Some studies are being done with acalabrutinib. They’re being done with PI3K inhibitors in combination with venetoclax. As long as it’s a B-cell receptor antagonist PI3K or BTK, this synergy that you get with the BCL2 in modulation of that BCL2-protein population, you definitely see this synergy along with B-cell receptor antagonists.

We’re going to have a lot of options for patients. We are going to be able to tailor treatment, and we should keep an eye out for how these studies mature and when they start to report out, definitely with PFS [progression-free survival] rate as we start to get 3, 4 years out on some of these studies.

Venetoclax Combinations, Safety and Efficacy

 I’m struck when I sit with a patient and I talk about them going on a BTK [Bruton tyrosine kinase] inhibitor–based therapy as their frontline therapy. They’ll ask me how long this is going to work. In the frontline setting, I have to answer that I don’t know because even the long-term data we have, we don’t know what the median is in terms of progression-free survival [PFS]. We’ve never been in that situation before. But let’s switch gears and talk about a BCL2 inhibitor–based therapy, venetoclax.

Venetoclax is approved in the frontline setting, and that was based on the CLL14 trial. We have seen some recent updates regarding CLL14. Maybe Dr Shadman can summarize what we know in the frontline long-term follow-up from CLL14, the trial design, and what it showed.

 The CLL14 study, in my opinion, is 1 of the most important studies for CLL [chronic lymphocytic leukemia]. It brought time limits and nonchemotherapy, or chemotherapy-free treatment, into the first-line setting. That’s very important for our patients. The study was done by the German CLL Study Group. Patients with comorbidities, defined as CIRS [cumulative illness rating scale] score of more than 6 or kidney function with the creatinine clearance of less than 70 mL/min, were randomized to receive either venetoclax and obinutuzumab as a combination therapy for a fixed 1-year duration without any role from MRD [minimal residual disease] in terms of stopping the treatment.

Every participant received 1 year of treatment, starting with obinutuzumab, and then venetoclax was added. The control arm was chlorambucil and obinutuzumab. The primary end point of the study was progression-free survival with MRD, overall survival, and response rates as other end points. It’s important to mention that roughly 12% of patients had abnormal 

, either mutation or deletion, and 60% of patients overall had an unmutated 

 gene without much difference between the 2 arms.

The initial report we had from this study showed that the study met the primary end point with a 3-year PFS of greater than 80%: 82% in the VenG [venetoclax-obinutuzumab] arm and 50% in the chlorambucil-obinutuzumab arm. The benefit was seeing all the known risk groups for CLL, including 

 gene. Because we are talking about the fixed-duration therapy, the depth of response becomes very important. Therefore, the rate of MRD eliminations is a particularly important end point.

So in peripheral blood, the percentage of patients who received VenG [venetoclax-obinutuzumab] had 76% undetectable MRD with the sensitivity of 10-4, and then the percentage of patients with MRD negativity in bone marrow was 57%. This is very impressive because what we know from venetoclax-based therapies and from this study is that the duration of response and PFS is directly correlated with the depth of response, meaning that if you achieve that undetectable MRD, the PFS would be longer. In the recent ASCO [American Society of Clinical Oncology] Annual Meeting, we saw that 18 months after finishing therapy, 47% of patients on the VenG [venetoclax-obinutuzumab] arm were still in the undetectable MRD status, which is very impressive.

For the CLL14 study, we don’t have the actual estimates as we do for MURANO, such as the exact PFS for each category of undetectable or low MRD or high MRD, but we know that they are significantly different. Unlike the discussion we had about BTK inhibitors, achieving an MRD or adding a second agent really doesn’t help the overall benefit. I agree that the benefit is not necessarily PFS. Here with a venetoclax-based therapy, we are in a very different situation because the goal is to give a fixed-duration therapy and stop.

Therefore, it does matter how good that response is. The most recent follow-up at ASCO showed that undetectable status could be durable. We’re still not seeing any new safety signals with the current follow-up, which is important. There was some report of secondary malignancies, which the numbers I believe are in the 17% range for the treatment arm versus 10%, but they are mainly skin cancers. I don’t believe there were any concerns, from what I reviewed, that there is a specific type of secondary malignancy that is more prevalent in the treatment arm.

John M. Burke, MD, Rocky Mountain Cancer Centers

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