 Dr Wang, what are your thoughts on the mechanism of action of tafasitamab? Why are they dating or potentially engaged and on their way to get married?

 Great question. Tafasitamab is a CD19 monoclonal antibody that’s humanized and has some engineered FC portion, so it binds the CD19 on the cells and the mechanism of cell killing is mainly by antibody-dependent, cellular, subtle toxicity and antibody-dependent cellular phagocytosis, but then you do see a little bit of direct cell killing by apoptosis mechanisms. This works mainly by the immune system. Lenalidomide is a drug that is interesting and has a lot of immune modulatory effect. Maybe when you give the drugs together, lenalidomide can enhance the immune system [so that it] can target the cells that are flagged by the tafasitamab, if you will. In other words, they are synergistic when you give them together.

 When you give tafa-len [tafasitamab-lenalidomide] in the relapse/refractory setting—and I think we have some early [clinical trial] data with that first year with tafasitamab and lenalidomide—there can be patients who respond and there can be CR [complete response] achieved and there can be durability. Can you comment about the longer-term follow-up from the clinical trial data with tafasitamab-lenalidomide?

 Sure. The trial was initially reported a while ago, and then they had a 3-year update and most recently they had a 5-year follow-up data. The response rate is about the same. You see anywhere from a 40% CR rate and probably a total 60% response rate, with a longer-term follow-up. The exciting thing is you see the durability of the response holds very well. The 5-year data shows the duration of response to the median has now been reached, and overall, the progression-free survival in the entire population is about 1 year. For those who had only 1 prime line of therapy, the median progression-free survival reaches 2 years with the follow-up. The median overall survival, again, is just shy of 3 years for the entire population. For those who only had 1 line of therapy previously, they enjoy overall survival that’s very long at this point and has now been reached by 5 years of follow-up.

 It’s great to see those curves people 5 years out continuing to derive benefit and only being on a single-agent antibody every other week. I think that we continue to ask the questions of what those patients who came off or chose to come off the tafasitamab, how those patients are doing. One of the other things that has come out with the tafasitamab-lenalidomide data was the RE-MIND2 [clinical trial] data [NCT04697160]. It’s worth spending some time and talking about how that dataset came about. Can you talk through the several different cohorts from RE-MIND2?

 We know L-MIND [NCT02399085] is treating a trial population with tafasitamab plus lenalidomide, and it’s not a randomized control trial. The first-real world study was called RE-MIND, comparing tafa-len in the trial population versus lenalidomide single agent in a real-world population. Of course, you try to match the patient’s disease characteristics that showed a significant improvement compared with lenalidomide single agent; that’s the RE-MIND study [NCT04150328]. Then came along RE-MIND2, which is a larger registry study looking at the relapsed blood cell outcomes in the real-world again. They compared tafa-len outcomes again from the trial to the real-world population. Again, you try to match their disease and patient characteristics as closely as possible. RE-MIND2 enrolled over 3000 patients, a large pool to select the best match to the trial population. The first report of RE-MIND2 showed that the L-MIND regimen compared with the overall dealer’s choice regimen improved overall survival. That has a [hazard] ratio of probably 0.5, meaning a 1 full reduction in risk of dying from the disease. Then if you look at any regimen in the real-world setting, RE-MIND2 compared tafa-len initially with BR [bendamustine plus rituximab] and also with R-GemOx [gemcitabine-oxaliplatin plus rituximab, the older regimens, the hazard ratio is again 0.4 to 0.5. Most recently they also reported some other more modern regimen. They compared tafa-len with polatuzumab-BR. It’s being used recently, so the registry did not have a lot of patients who could match the L-MIND trial, but they have 20 to 30 patients for the pola-BR. And 20 to 30 patients for the R-squared [rituximab-lenalidomide] older regimen. Again, the regimen comparison favored L-MIND. Finally, they compared tafa-len with CAR [chimeric antigen receptor] T-cell therapy, close to 40 patients. They showed that overall survival is comparable in this comparison. We must recognize the limitations of such real-world comparisons, and although you try to match as closely as possible, those are probably unmatched imbalances that we need to consider. Basically, tafa-len works well in the trial population and compared fairly well with historical standard care. We look forward to seeing more, maybe real-world tafa-len data, to see whether that holds against the real world, other practices.

 Dr Flinn, you’re in the hot seat here. Dr Wang just gave a nice summary of not only L-MIND but the RE-MIND and the RE-MIND2 [trials] and how that population of patients was compared with the clinical trial population. Tafa-len has been out there. It’s been used in relapse/refractory large-cell lymphoma. How are you using it in your practice, and what’s your overall impression?

 So there’s another data set that looks at patients in the real-world experience, and the data is not quite as good as it was in the trial. Some people look at that as the cup is half empty, but I think it helps us tailor the way we use the drug. That’s an unfair comparison. The patients were treated with multiple [additional] regimens than were treated in the original clinical trial. There were primary refractory patients that were part of that experience. That to me explains the decrease in the response rates in progression-free survival. It also helps us know when we should be using this. So using it more that was in L-MIND, those patients who weren’t heavily pretreated, they weren’t primary refractory. To me, that’s the ideal setting. If you ask, who is that? To me it’s the person who I’m probably not going to [recommend] the CAR T-cell [therapy]. These are patients who are older patients who perhaps have had 1 prior therapy, maybe 2, [for whom] you can’t use the aggressive regimens. The exciting thing here is that in that patient population, we can probably still duplicate the results that we’re seeing in the clinical trial.

 Walk me through your lenalidomide approach. I think the tafasitamab, we’ve seen the [adverse effects] profile in the L-MIND dataset, and kind of in that first year of lenalidomide, you see the lenalidomide effects and you the lenalidomide effects drop off after 12 months. How do you finesse? Lenalidomide to me is a finesser, it’s a nuance, 25 [mg] might not be the right dose for everybody, but there is a right dose of lenalidomide for most patients. How do you get that sense in your practice?

 That’s right. There’s a little bit of experience in who you’re looking at, who the patient is, walking through what their renal function is, how old they are. Maybe [for] that 83-year-old patient I may not be coming in with full dose right [away], so maybe reducing [it] a little bit, and then going from there and [adjusting the dose] after the first cycle. If the patient unexpectedly did well, then maybe I do go up to [the] full dose. On the other hand, I might be having to [reduce the dose] further based on what their first cycle is.

 Are you talking about that initially up front, that…we can modulate the dose of the lenalidomide along the way?

 Absolutely. I had the same sort of thing when I talk to CLL [chronic lymphocytic leukemia] patients with venetoclax. [The] 400 [mg may not be] the exact right dose ,and we’re going to titrate. You have the same thing here with lenalidomide.

Videos

Panelists review data behind the combination of tafasitamab and lenalidomide in relapsed/refractory diffuse large B-cell lymphoma.

Tafasitamab + Lenalidomide Therapy in Relapsed/Refractory DLBCL

 Dr Westin, I talked to Dr Rhodes about writing down her IPI [International Prognostic Index] scores on her [patients with] newly diagnosed DLBCL [diffuse large B-cell lymphoma]. Are you starting to write down when the primary induction therapy ends, when that last cycle was? Is that now a start [of] the interval or the stopwatch, if you will, for that patient, and how has that changed in your practice?

 It’s important to look at how long [it] has been from first-line therapy to that relapse occurring, and we heard about relapsed/refractory disease, but what does that relapse mean in terms of time? Refractory is obvious, patients never get a good response, they don’t achieve a CR [complete response]. But [with] relapse, time matters. Patients who relapse early on often have much more difficult to treat disease and may need different therapies. For example, in the second line, we recently saw the readout of several randomized phase 3 trials that enrolled patients who had relapsed within the first 12 months after first-line therapy. It matters when you finish therapy, how long afterward the relapse occurs, because different treatment options may work better in that early relapsed/refractory population. CAR [chimeric antigen receptor] T-cell therapy might be preferred, but someone who relapses very late, maybe they’ve got other options.

 Dr Saeed, regarding their prior treatment, or their prior tolerance to treatment if they [had] a KPS [Karnofsky Performance Score] of 3 because of their lymphoma that improved and [went] into a CR, how do you take all those factors into [consideration] when the patient does have relapsed/refractory large B-cell lymphoma?

 In addition to the relapsed/refractory patient status, whether they relapse within a year or they’re refractory to their frontline therapy, there are other factors that I usually look at whenever I have patients, especially in the second-line treatment of diffuse large B-cell lymphoma, such as what kind of frontline therapy [is best]. We just heard about the frontline therapy changing, and more and more patients will be treated with pola-R-CHP [polatuzumab, cyclophosphamide, doxorubicin, prednisone, and rituximab] compared with R-CHOP [cyclophosphamide, doxorubicin, prednisone, rituximab, and vincristine]. We have patients who are treated with EPOCH-R [rituximab, etoposide phosphate, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride]. All those things we now have to keep in mind whenever we make our decision for the next line of therapy. Like you mentioned, performance status is essential. DLBCL is a disease of the elderly, and if they can improve their performance status from frontline therapy, we still have those patients who have comorbidities, who are unable to tolerate the aggressive therapy that we wish we can push through. I keep that in mind all the time. I also keep in mind the utility and the logistics for the patient receiving therapy. If they come to see us in the clinic, how far do they live from the clinic? Whether they have the financial means to get their treatment, and whether they can drive all the way to the clinic. All those things are important in making a decision for second-line treatment of B-cell lymphoma.

 Dr Rhodes, we just heard a lot of the intricacies and the operational aspects of this. Let’s say a patient isn’t a transplant candidate and they aren’t a CAR T-cell [therapy] candidate in the relapsed/refractory large-cell lymphoma space. What are their treatment options then? How do you have that conversation with that patient population?

 As you had said before, there’s a lot of excitement because now we have therapies for relapsed/refractory diffuse large B-cell lymphoma that are not just chemotherapy. So we have loncastuximab tesirine, which is our anti-CD19 antibody drug conjugate; I’ve found that is well tolerated in patients who have other comorbid medical conditions, and it has a good dosing schedule. We have polatuzumab, which is more for a patient who didn’t get pola-R-CHP in the frontline setting; that is approved in combination of bendamustine and rituximab. I personally don’t use the bendamustine.

 I think the polatuzumab was probably doing a lot of the heavy lifting.

 I think so, yes. Vedotin is not great as a single agent in relapsed/refractory large-cell lymphoma. We have seen the response rate, it’s 10%, and I don’t know if it adds much, but it definitely adds toxicity. Finally, we have tafasitamab, which is an anti-CD19 antibody in combination with lenalidomide, and I find it is well tolerated and a good regimen for the right patient.

 Those 2 drugs play well in the sandbox together.

Focused discussion on specific patient or disease factors that aid in the selection of therapy for patients with relapsed/refractory diffuse large B-cell lymphoma.

Factors in Selecting Treatment for Relapsed/Refractory DLBCL

 Dr Wang, in your practice, are patients with diffuse large B-cell lymphoma [DLBCL] either primary refractory to their frontline therapy or relapsing quickly thereafter?

 We typically say we cure about two-thirds of patients with standard immunochemotherapy. It used to be R-CHOP [cyclophosphamide, doxorubicin, prednisone, rituximab, and vincristine], and now we just heard it would probably be pola-R-CHP [polatuzumab , cyclophosphamide, doxorubicin, prednisone, and rituximab], and that left us about one-third of the patients who will have refractory disease or will have relapsed after the initial response. The primary refractory disease has different definitions across different literature, but basically they’re either not responding enough to the frontline therapy, or they’ve relapsed early. You can argue about what’s early, but that’s about probably 10% of patients. Then you have probably another 20% or 30% of patients who relapsed within the first 2 years, but [are] not in a primary refractory bucket. Then at the 2-year mark, we usually say, we’ve probably cured most of the patients, but then if you start the clock again at that point, there is still about 9% to 10% risk of relapse in the next 5 years, counting from the 2-year mark. So, adding that together is probably again one-third of patients who will have refractory or relapsed disease.

 Could you rank [the] risk factors [you assess] when you see a new patient to say, this person is at a high risk of having primary refractory or early relapsed large-cell lymphoma?

 There are high-risk features that predict less chemotherapy-responsive disease but may not necessarily differentiate when they will relapse or become refractory to the disease. Certainly, the high-risk features, the traditional clinical risks like high IPIs [International Prognostic Index scores], disease bulk, and then, from the molecular standpoint as we just mentioned, the MYC and BCL2 expression or the 

 rearrangement, some of the high-grade B-cell lymphomas, those are the ones. With more sequencing, we’ll probably know [of more] high-risk mutations like 

. Then as you go to frontline therapy, in the first couple of cycles, probably the kinetics 2 response in the interim, may have some implication, [to] identify those who may relapse later as well.

 Dr Saeed, we just heard about the up-front treatment, [that the] paradigm may be changing. There’s been an absolute explosion of treatments for relapse/refractory DLBCL. How has all that energy, all that therapeutic energy that’s been put into the relapse refractory large-cell space, changed your practice over the last several years?

 It changed the way I look at patients right after treatment with the frontline therapy. At this point it’s important to recognize those patients who have refractory disease, who have positive imaging findings that might need follow-up right after finishing chemotherapy. It changed how I follow up on them right after treatment for the first year or two. It’s important to recognize those patients who relapse early. Unfortunately, I still feel that we don’t have good guidance on how we check and find those patients. I think we still, in clinical practice, must wait for them to have symptoms that would indicate disease relapse. I look forward to hearing more and more about the use of genetic markers in the blood, such as minimal residual disease or cell-free DNA, because I think those will help down the road to recognize those patients earlier so that we can find the best treatment for them earlier. As Dr Wang mentioned, we cure around two-thirds of those patients, but for the last one-third, we must do a better job in recognizing and finding them early because we will open many more doors for them rather than waiting for them to present with significant disease burden before we can intervene and treat them.

Key opinion leaders share a broad perspective on relapsed/refractory diffuse large B-cell lymphoma and the current treatment landscape.

Overview of Relapsed/Refractory DLBCL and Management Strategies 

 titled, “Translating Recent Evidence to the Real-World Management of Relapsed/Refractory Diffuse Large B-Cell Lymphoma.” I’m Matthew Lunning, associate professor, Division of Oncology and Hematology, and assistant vice chancellor for clinical research. I’m joined today by a panel of experts in diffuse large B-cell lymphoma. I would like to welcome my esteemed fellow panelists to introduce themselves.

 I’m Dr Joanna Rhodes, and I’m at the Rutgers Cancer Institute of New Jersey.

 My name is Yucai Wang, I’m a lymphoma doctor in Rochester, Minnesota, working for the Mayo Clinic.

 Hi, I’m Dr Jason Westin from MD Anderson Cancer Center in Houston, Texas. I’m the director of lymphoma clinical research and section chief for aggressive lymphomas.

 I am Ian Flinn, director of the Lymphoma Research Program at the Sarah Cannon Research Institute in Nashville, Tennessee.

 And I’m Hayder Saeed. I’m a lymphoma doctor at Moffitt Cancer Center in Tampa, Florida.

 Welcome, everyone, and thank you for joining me. Today we’re going to discuss several recent updates in the treatment of diffuse large B-cell lymphoma. We will discuss the data in the context of the treatment landscape and its impact on clinical practice. Let’s get started on the first topic. Dr Rhodes, I’d like you to walk us through your thoughts on when you see a pathology report or the clinical history that gets sent to you by a new patient coordinator about a [patient with] large-cell lymphoma. What are the characteristics that you’re looking for in the disease as well as in the patient?

 Outstanding question. I think any of us at this table would say that no two diffuse large B-cell patients are alike. Whether or not it’s from the clinical perspective or even from the pathologic perspective, when I’m looking through everything, I’m looking for things that give me pause about perhaps having high-risk features or concern for relapse after frontline therapy; genomic markers like 

 rearrangements. I know we don’t call it double-hit lymphoma anymore, but the new classification system is a little bit more challenging. If you get NGS [next-generation sequencing] panels, things like 

 mutations, and then clinically bulk of disease, whether or not there’s extranodal disease, and also just the rapidity with which someone comes in and the sort of cadence of their lymphoma progression.

 Are you now calculating an IPI [International Prognostic Index] score for everybody, or is that still something that you’re doing just to help your fellows out in retrospective reviews?

 I calculate the IPI. I don’t know if it’s always something that I necessarily take into consideration when I’m choosing [a regimen] again. Most of the time we are still going with an R-CHOP [cyclophosphamide, doxorubicin, prednisone, rituximab, and vincristine] backbone, but it is something that I think about when I am counseling my fellows. I don’t really talk about IPI scores with my patients. I think it gives them too much anxiety.

 Dr Flinn, when you get a diagnosis of diffuse large B-cell lymphoma in your clinic, what are the diagnostic strategies that you’re looking for? Are you always going for an excisional biopsy or an incisional biopsy, or can you get away with a core [biopsy] nowadays?

 An incisional or excisional biopsy is the preferred approach, but on a practical basis, that’s often not possible. Generally, when patients come to me, a lot of times they’ve had core biopsies, so [it is about] making sure that the pathologist has enough material to do all the appropriate studies. In this case, to me, in the most appropriate studies, you want to rule out a double-hit type of lymphoma, making sure they have enough material for FISH [fluorescence in situ hybridization], enough material for flow cytometry, and so forth. If that’s true, then I can often get by with a core biopsy.

 Does that change if a patient is a concern for relapse or refractory disease? Do you do less? Could you go with an IR [interventional radiology]-guided biopsy or are you still considering going with an excisional biopsy for the same purpose?

 If you already have a well-documented large-cell lymphoma, from the initial diagnosis, then you can often get by with less material. The question is, [what if] someone has a transformed follicular lymphoma, follicular 3A, follicular 3B? Sometimes it’s important to get more tissue at that time.

 Very good. We’ve talked a little bit about IPI score and getting at double-hit versus non–double-hit diffuse large B-cell lymphoma. Dr Westin, we know that a monumental shift or paradigm shift in frontline large-cell lymphoma treatment has possibly occurred. Could you walk us through your thoughts on the recent POLARIX [trial] data [NCT03274492] and how it’s impacted your practice?

 The longstanding frontline therapy of R-CHOP, which is CHOP, was developed in the 1970s, and rituximab was added about 20 years ago. It looks like it might be shifting to the polatuzumab-R-CHP [polatuzumab, cyclophosphamide, doxorubicin, prednisone, and rituximab] regimen based upon the POLARIX data set. In [patients with ] IPI [scores of] 2 to 5 there was a small but statistically significant improvement in progression-free survival without a significant increase in toxicity. That’s basically a trade-off of getting a little bit more activity, but not losing anything in terms of toxicity. So I think the effect size was smaller than most of us would have liked; 6.5% percent at 2 years translates to maybe 1 out of 15 patients having a different outcome [when treated] with R-CHOP versus polatuzumab-R-CHP, but at the end of the day, that is a statistically significant improvement, and I think that will be used in a frontline setting in IPI [scores of] 2 to 5.

Expert panelists open their discussion on diffuse large B-cell lymphoma by reflecting on diagnostic strategies and the frontline treatment armamentarium.

Diagnosis and Frontline Management of Diffuse Large B-Cell Lymphoma

Joanna M. Rhodes, MD, director, the Chronic Lymphocytic Leukemia (CLL) Research and Treatment Center, Northwell Health Cancer Institute, discusses evaluating the unmet needs of elderly patients inCLL.

Despite advancements with targeted therapy, the adverse event (AE) profiles of such agents are still not widely understood, Rhodes says. Moreover, elderly patients and those with comorbidities are more likely to discontinue treatments with targeted agents due to these AEs, Rhodes explains.

Although dose reductions or adjustments can help manage AEs, there is a lack of prospective data on the impact of these strategies on patient outcomes, Rhodes continues. Additionally, ibrutinib (Imbruvica) and venetoclax (Venclexta) discontinuation data were gathered from patient cohorts, Rhodes notes. However, these data were not an accurate representative of the elderly patient population and may not lead to an accurate prediction of outcomes, Rhodes concludes. 

Joanna M. Rhodes, MD, discusses evaluating the unmet needs of elderly patients in CLL. 
 

Joanna M. Rhodes, MD, MSCE

Articles

Tafasitamab + Lenalidomide Therapy in Relapsed/Refractory DLBCL

Factors in Selecting Treatment for Relapsed/Refractory DLBCL

Overview of Relapsed/Refractory DLBCL and Management Strategies

Diagnosis and Frontline Management of Diffuse Large B-Cell Lymphoma

Dr. Rhodes on Evaluating the Unmet Needs of Elderly Patients in CLL