®, which focuses on relapsed and refractory diffuse large B-cell lymphoma [DLBCL]. In today’s presentation, my colleagues and I will review 3 clinical cases. We will discuss an individualized approach to treatment for each patient, and review key clinical trial data that impact our decision.

I am Dr Kami Maddocks, from The Ohio State University [Comprehensive Cancer Center] in Columbus, Ohio. Today, I am joined by Drs Ian Flinn [MD, MPH] from Sarah Cannon Research Institute in Nashville, Tennessee; Loretta Nastoupil from [The University of Texas] MD Anderson Cancer Center in Houston, Texas; and Jason Westin [MD, MS, FACP], also from MD Anderson Cancer Center in Houston, Texas. Let’s get started on our first case.

The first case is a 63-year-old [woman] who presents with fatigue and worsening, burning back pain. On physical exam, she’s found to have a left posterior cervical, 1.5-cm node; a right anterior cervical node of 2.5 cm; and a left supraclavicular node of 2 cm.

Imaging is pursued and on CT she’s noted to have multiple enlarged mesenteric and retroperitoneal nodes, the largest measuring 5.3 × 3.1 cm. PET [positron emission tomography] is performed, demonstrating hypermetabolic adenopathy above and below the diaphragm with the highest SUV [standardized uptake value] max of 25.

A biopsy is pursued and confirms diffuse large B-cell lymphoma. Immunohistochemistry is positive for CD20; CD10; BCL6, BCL2, including 50% of cells; MYC is positive in over 90% of cells and IHC; and KI67 is 85%. Additional labs demonstrated normal CBC [complete blood count], and LDH [lactate dehydrogenase] is greater than 1.5 × the upper limit of normal.

In this patient, we have a stage III or advanced stage patient with an aggressive B-cell lymphoma, appears to be germinal center type, overexpression of BCL2 and C-MYC by immunohistochemistry, although we don’t have FISH [fluorescence in situ hybridization] results at this time. The patient has a high intermediate IPI [International Prognostic Index], and an intermediate CNS [central nervous system] IPI. Looking at this patient, what are the therapeutic options at this point?

R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone] is generally our backbone of therapy. There are patients that we have cautious optimism surrounding the outcomes of R-CHOP. Particularly in this case, the features that I’m concerned about are the double expression of MYC and BCL2. I’d like to know the FISH results to know that this is a double hit in addition to a double expressor, because I know those patients are likely to do quite poorly with R-CHOP–based therapy. … I might pursue something more aggressive, or clinical trials—that is an option for me.

: I would agree with Dr Nastoupil on that. We know the double expressors are often the nonterminal center subtype. This patient’s a germinal center subtype, and that would raise my concern that this could be an expression on protein because there could be translocations. It’s difficult to know without the FISH if it is a double hit. You can’t tell, you need to have FISH results, but that would raise my concern that this could be a potential translocation-defined overexpression.

 It sounds like … we feel R-CHOP is still the standard, but there is some concern in this patient that we may be looking at a double hit. We don’t have the FISH results.

Case 1: Relapsed DLBCL, Transplant Eligible

 Does anybody treat without those FISH [fluorescence in situ hybridization] results and then possibly change care afterward? Or do you wait for the FISH results to come back? What’s your approach when you have a patient that … could potentially be positive, but the results are not that?

: For many patients, it takes a while to get the FISH back. We’re used to having rapid access to FISH in our tertiary care centers, but [for] a lot of the community hospitals it takes a long time for the results to come back. Community pathologists don’t have in-house FISH testing; they must send it out. They’re doing serial testing to define which group they’re going to do. And for many patients, I think they’re much better just going ahead and treating with R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone]. Or you could treat with dose-adjusted R-EPOCH [rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride], or something along those lines with first cycle, and then adjust your therapy thereafter. Because of the convenience, it’s probably easier just to treat with R-CHOP. It depends on how long you’re going to be waiting and how sick the patient is. I certainly wouldn’t wait for a long period of time for the FISH to come back before treating.

: I agree with Dr Flinn. I think that waiting is potentially harmful to the patient. If they get sicker and their disease begins to progress and now their performance status is limited, waiting for a test that may or may not be informative for your next steps, it’s better to start treatment and change. If you were to start R-CHOP, you could always change in future cycles to dose adjust at R-EPOCH if the patient did have translocations.

The confounder here of these adverse features, their relatively high IPI [International Prognostic Index], we all would love to do something better than R-CHOP for this patient because we know that this person doesn’t have an awesome prognosis with these adverse features. But the randomized trial of R-EPOCH versus R-CHOP didn’t show that there was a clear benefit to escalating therapy. There was a trend to the high IPI patients. In my practice we do give dose-adjusted R-EPOCH [etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride] to people who were fit that have bad features, but that’s not based on a clear win in a randomized trial, at the subset analysis of a big study. There’s not a wrong answer here of R-CHOP or R-EPOCH, but I think most people would use R-CHOP just … because of the convenience while waiting for those results.

 Now we’re even seeing that most trials will actually allow 1 treatment of a cycle of therapy, be it R-CHOP or R-EPOCH, before getting patients on trial. … A sick patient needs treatment. It’s okay to pick 1 and then transition once you have the final FISH result.

Case 1: Waiting for FISH Results in DLBCL

What about working up this patient? Is there any further workup? Is this a patient that you would consider looking for CNS [central nervous system] disease? And if so, how do you do that? Who do you do a baseline brain MRI? When are you thinking about CNS prophylaxis?

In our retrospective series of double-hit patients, not specific to double expressors, we found that the rate of CNS involvement was as high as 13%. Because we’re on the fence about how concerned we should be about double-hit features … we often will perform a diagnostic LP [lumbar puncture] to assess for circulating tumor cells. The timing of that, whether you add in prophylactic chemotherapy, depends on … the CNS IPI [International Prognostic Index], but also whether we’re concerned about the underlying disease histology and whether there are high-grade features. It’s reasonable in this case to perform at least a diagnostic LP and then consider prophylactic—either methotrexate and/or cytarabine.

I agree. It’s hard to argue against getting an LP in this patient who had some high-risk features and then letting your results of the FISH [fluorescence in situ hybridization] my guide, whether I treat this patient prophylactically with either intrathecal chemotherapy or whether they were receiving … day high-dose methotrexate in order to prophylax against CNS involvement. I wouldn’t do a brain MRI. Unless a person had symptoms, that’s probably a low yield.

 What types of patients are you doing prophylaxis besides double-hit patients?

: We have the CNS IPI, which is the regular IPI as well as looking at high-risk sites such as the adrenal gland or kidneys. We know that gonadal involvement does increase the risk, as does spinal disease if somebody has involvement of the bones and the spine, the sinuses if the bone marrow is involved. … As Dr Nastoupil mentioned, double-hit patients have up to 13%. We know that the higher the CNS IPI, it’s going to be up in the 20% risk of having occult disease. If you don’t address it with primary therapy, relapse in the brain is a bad problem. The CNS IPI is a useful shorthand tool to help decide what’s the risk and what’s the tradeoff cost-benefit ratio to give prophylactic therapy.

 Dr Nastoupil had mentioned intrathecal methotrexate or cytarabine while waiting for FISH. Are there other things people are using for prophylaxis? Is there a standard agreement or approach?

: For patients that don’t have the double hit, and for which we’re using dose-adjusted R-EPOCH [rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride], for a lot of our patients, such as … high-risk, adrenal gland involvement … we’ve switched over to using high-dose methotrexate incorporated with R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone] regimen. And we do it different ways and I’m not sure there’s 1 right way, but we’ve been giving it on day 8 of R-CHOP chemotherapy. It’s very cumbersome. We must admit the patient to the hospital. No one likes doing this. But I think that you tend to get better penetration of the CNS and probably better prior distribution. We’ve switched over to doing that from giving intrathecal chemotherapy.

 And when you use dose-adjusted R-EPOCH, do you incorporate that somehow into the treatment, or do you use the intrathecal with that?

: I’d love to hear how other people do it. We do the intrathecal just because I think it’s difficult to integrate methotrexate into that regimen. I know that at some centers they will take a break and then give high-dose methotrexate after several cycles of R-EPOCH. But we’ve been giving intrathecal in that patient population, but it sounds like the group at [The University of Texas] MD Anderson [Cancer Center] has a lot of experience in terms of retrospective analysis of your patient population.

We did do a small retrospective series looking at high-dose methotrexate mid-cycle with dose-adjusted EPOCH-R [rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride], and it can be done. It can be done safely, albeit in our hands and a small series. But you bring up a good point in terms of the cytopenias that are likely to happen. How do you handle growth factors knowing that these patients are likely going to be neutropenic? It’s cumbersome and something that probably is not generalizable to everyone’s practice.

 I think the important thing to remember when trying to do that is that if you’re giving the curative therapy, you don’t want to risk the curative component for the prophylactic component for that, that’s done right.

Case 1: Identifying Patients for CNS Prophylaxis in DLBCL

This patient was started on R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone] therapy. FISH [fluorescence in situ hybridization] was negative for rearrangement of BCL6, BCL2, and C-MYC. She completes 6 cycles of therapy. She undergoes a posttreatment PET [positron emission tomography] and it demonstrates a complete response by Deauville, and with a Deauville score of 2. Ten months after completion of therapy, however, she complains of fever, night sweats and back pain and has a palpable lymph node in the left groin, which was discovered on physical exam. She undergoes restaging with PET and CT and is found to have a new left inguinal node, and increase in size of a residual node as well as multiple metabolically active lesions and lymph nodes in the retroperitoneum, the abdomen and the pelvis. A biopsy is pursued, and it confirms recurrent diffuse large B-cell lymphoma [DLBCL].

 Now we’re back to our 63- … 64-year-old patient, relatively healthy, completed 6 cycles of therapy, had a CR [complete remission] to therapy but relapses in less than a year. What is the prognosis for a patient like this?

Based off of the CORAL study [NCT00137995] we know that patients who progressed within 12 months of CHOP-based chemotherapy, the outcomes with standard therapy such as salvage and high-dose therapy, autologous stem-cell transplant, are poor and only 20% of patients are likely to have a good outcome. This is a patient that falls into that category of poor prognosis with standard chemotherapy options.

Now we have other options at our disposal. We have trials that are enrolling, particularly with high-risk patient population, looking at CAR [chimeric antigen receptor] T[-cell] versus salvage and high-dose transplant, that would be an option that I would pursue in this setting.

 I would echo what Dr Nastoupil just said, that in that CORAL study the EFS, the event-free survival, at 1 year for those patients that had Rituxan [rituximab] and relapse was 25%. That’s kind of a historical benchmark we’re up against. And CAR T-cells are exciting but they’re not yet proven in the second line, so those studies hopefully will read out in the coming years, but as of now it’s a poor standard of care we have for salvage chemotherapy and transplant.

 Ideally, this is a patient we’re looking at getting on a trial, but right now our standard outside of a trial is the salvage chemotherapy and autologous stem cell transplant if they respond.

The patient receives 2 cycles of R-ICE [rituximab, ifosfamide, carboplatin, and etoposide phosphate], and PET scan after 2 cycles demonstrates disease progression. They had a progression of it within 12 cycles of their frontline R-CHOP therapy. … Based off … a retrospective analysis, including data from the CORAL study from Mayo and from MD Anderson, we know that patients who have either primary refractory disease, or refractory to second-line, or progress within 12 months of autologous stem-cell transplant, their outcome in the era of chemotherapy-based approaches was quite poor.

Now I must note that this was prior to the approval of CAR T-cell therapy; it was prior to the approval of targeted therapy such as polatuzumab, tafasitamab, and selinexor, but this just highlights that in the era of rituximab and CHOP-based frontline treatment, patients who failed to achieve a meaningful remission are facing poor outcomes.

Case 1: Outcomes in Chemotherapy-Treated Patients With DLBCL

 We know that this patient, as described, is facing poor outcomes. What are the treatment options?

 CAR [chimeric antigen receptor] T[-cell] therapy is an option for patients who failed at least 2 lines of therapy. I think [it] has been one of the most transformative options of the patients with chemorefractory disease. I recognize that it is underutilized and there may be many reasons for this, including patient identification. You must refer them to a designated center to administer this treatment. About 40% of patients will have good outcomes, and 60% unfortunately will not. And there are lots of factors playing into why this is underutilized. But for chemorefractory patients in third line it is my preferred choice, and something I would consider for this patient.

I agree. The biggest decision you’re making at this point is: Do you think that you can cure this patient? Or is this a patient for whom cure is still a goal? CAR T-cells are the only therapy that offers … at least that hope. All the other options that we’re talking about … other salvage regimens, other new therapies that have been proven, are largely trying to palliate the patient and improve their survival and their quality of life if they aren’t cured. In my mind, the only potentially curative option for this patient is a CAR T-cell. And this patient seems to be fit enough to undergo that type of therapy.

 I agree with the other panelists. CAR T-cell therapy is underutilized but it is potentially curative. And the reason it’s underutilized is it’s challenging to administer and somebody has to usually travel to a faraway academic center. And, how do you refer, and how does the logistics work? … Treating physicians shouldn’t try to guess which patients are eligible for CAR T-cells—that’s the job of the CAR T-cell center. A lot of times it’s unclear if you’re not transplant eligible, are you CAR T-cell eligible? … But their referral to a center early on, if somebody’s had additional therapy their chances for CAR T-cells may diminish. Their chances for success with CAR T-cells may diminish, the more lines of chemotherapy that they got, especially if they were to get bendamustine or other T-cell toxic therapies. Referring early for an evaluation for CAR T-cells is important for these patients.

 Is this a patient that anybody would ever still offer an autologous stem cell transplant if maybe CAR T weren’t available or it seemed hard? I think probably prior to the availability CAR T you may have said this is a patient you might try a second salvage in, and if they get a response to a second salvage, go to auto-transplant? But I’m not sure would anybody consider that with the therapies available today.

 I wouldn’t think there are practices that you have to use what’s available to you. Part of our job, particularly in this session, is to educate and identify. There are other options. CAR T is my preferred option. … If you have a curative option, pursue that first. But there are several options that I think are probably safer and more effective than attempting a second salvage attempt.

 In the CORAL study [NCT00137995] that we mentioned earlier, there was a crossover where people would go on to get the other salvage therapies. If they didn’t respond to R-ICE [rituximab, ifosfamide, carboplatin, and etoposide phosphate]or R-DHAP [rituximab, dexamethasone, cytarabine, cisplatin], they’d crossover. And the response rates aren’t 0, but they’re low and it’s toxic and because we have other options it doesn’t make a lot of sense in the modern era to continue to beat up somebody and potentially cause renal issues, neuropathies or other cytopenias when you’ve got these other smarter options. I agree, I would not likely pursue that if I had other options available.

 Dr Westin, you alluded to this, but when people are referring for CAR T therapy, when is the ideal time to refer the patient in, or question if this might be a potential therapy?

 The ideal time is the first time you think that this might be an ideal therapy, the sooner the better. CAR T-cells are logistically challenging. They take time to get a financial approval. They take time to get the apheresis arranged. They take time to make the cells and then have them sent back. … Dr Nastoupil just recently published a beautiful paper in the 

looking at real-world evidence for CAR T-cells. Patients who need to get so-called bridging therapy, or chemotherapy, radiation-targeted therapy to hold them over don’t do as well, and that’s probably a surrogate for advanced disease. The sooner, the better.

If somebody has a relapse or doesn’t respond to a therapy and is now eligible for CAR T, the time to refer is now, not trying to think of other options or trying to evaluate a third-line therapy. If they’re a CAR T-cell candidate, my bias is to refer. And if it doesn’t work, if they don’t go or the patient doesn’t want to travel, at least you’ve given them [the] option. But if you wait, sometimes you can miss your window.

It’s hard to overestimate some of the logistical issues that surround giving CAR T-cell therapy. And I agree, getting people in as early as possible is key. Otherwise, just sometimes the financial clearance, all the issues that go through getting a patient a CAR T-cell therapy, that timeline is long. And even if you haven’t already done the scans, you’re sensing that something is not going well, a lot of our referring doctors will refer at that time, just in the notion that they might need us in the future. And I really think that’s … an appropriate approach.

 It sounds like if you have a patient with relapsed large-cell lymphoma, it’s a good time to at least send a referral to a CAR T center to help decide whether they’re transplant eligible, whether they’re CAR T eligible, that might mean something different. Even if they’ll go for transplant, maybe they’ll end up with CAR T. Right away when you have that relapse might be the ideal time to be sending them and thinking about it.

Dr Westin also referred to bridging therapy. In the bridging, I know there is not great data here, but is there a time when you think about giving bridging therapy? How do you find this? Is there a therapy that’s more ideal in the bridging therapy setting?

 I don’t think that there’s a standard, nor do I think there should be a standard here because every patient is different. Sometimes radiation may be an option if it’s a localized disease that’s causing significant pain or other comorbidity. The short answer is I don’t like giving bridging therapy unless I must. And it’s those patients … where you have to choose, is it going to be chemotherapy, radiation, some other targeted therapy? But the less bridging you can give, the better for the patient, they’re sicker. You’ve got greater risk for infections that could potentially derail the ability to administer CAR T.

Back to the idea of timing. The sooner you start the process, the less likely you are to need bridging. Some patients can’t wait, and it doesn’t seem like it matters what bridging therapy you give. Those patients who need it don’t do as well. I don’t think it’s the bridging therapy itself that does that, although it could contribute. It’s the underlying disease biology, but everybody’s got their own sort of preferences for what types of bridges they use. I like using systemic chemotherapy, if it’s not localized disease, but there’s not a right answer to what bridge to give.

Case 1: Therapy for Relapsed DLBCL in Transplant-Eligible Patients

ZUMA-1 [NCT02348216] was the pivotal phase 2 study that led to FDA approval of Axi-cel, or axicabtagene ciloleucel, based off this study design. What’s unique about this trial … is that it primarily enrolled refractory patients with diffuse large B-cell lymphoma [DLBCL], primary mediastinal, or transformed follicular.

They reported out two different cohorts, cohort 1 with refractory large cell, and cohort 2 with the refractory primary mediastinal and transformed follicular. There’s some notion that the patients with primary mediastinal transformed follicular do slightly better. … This is a relatively small sample size of 101 patients. The dosing and conditioning regimen is unique to this study and that patients received 500 mg/m2 of cyclophosphamide, and 30 mg/m2 of fludarabine for 3 consecutive days starting day -5. They received a flat dose of 2× into 6 cards/kg.

And the other important thing about this study is that there was a high successful manufacturing in administration of these cells, and 99% of patients who were enrolled had successful manufactured product, 91% were dosed.

This is the updated analysis with a median follow-up of 27.1 months, and you can see the median progression-free survival had not changed, it remained at approximately 6 months. But the median overall survival at this time point had still not been reached. It settled out with 3 years of follow-up right around the 26-to-27-month period. … This was a significant improvement in the survival for these patients that were, again, facing dismal outcomes.

In contrast, this is a JULIET study [NCT02445248] that is, again, a single-arm phase 2 study that was the pivotal trial that led to FDA approval of tisagenlecleucel.

This was different in terms of study design and conduct, so this is a large international multicenter study. There was a lapse in time from screening and enrollment until infusion of cells, which primarily just dealt with the fact that they were trying to get this therapy out to a much larger patient population. And as a result, bridging was allowed because of that time delay from enrollment and to infusion itself.

There’s also a difference in the lymphocyte-depleting chemotherapy that was administered in this cycle. And as a result, there were fewer patients that received cell infusion in comparison to the ZUMA-1 study. However, for the patients who achieved a complete response, that was quite durable. And you could see here, as outlined by this progression-free-survival, it’s much better for patients who achieved a complete response versus all patients. At 12 months, our relapse-free survival was 65%, and the median overall survival was about 12 months. That does take into consideration there was a higher proportion of patients who never made it to cell infusion as a result of the difference in this study design.

Though it’s hard to compare the efficacy across these studies because the patient populations were clearly different, the conduct of the studies were different. The most important thing to recognize is this is an effective strategy, and that you see higher complete response rates than we’d ever seen in third-line large-cell lymphoma, and much higher overall survival than we had seen to date.

In addition, the toxicity is hard to compare across these studies because different grading systems were applied. However, there are some notable differences, and that has to do with the construct. Axi-cel is a CD28 costimulatory CAR, which leads to more rapid T-cell expansion, which is mediated and driven by cytokine production, and as a result we do see shorter time to onset of cytokine release syndrome [CRS]. If we’re applying the same grading criteria, you see slightly higher rates of grade 3 or higher CRS, and particularly higher rates of neurotoxicity.

Liso-cel, which is a 41BB construct in the third that’s anticipated to be FDA approved, may have the most favorable toxicity profile, but I think that’s also the evolution of our ability to recognize and mitigate some of these toxicities, which is why you see much lower rates of grade 3 or higher CRS in neurotoxicity. Comparably, the 41BB constructs are just safer, particularly about neurotoxicities in the CD28 construct.

Case 1: Trials in CAR T-Cell for Patients With Relapsed/Refractory DLBCL

 Prior to CAR [chimeric antigen receptor] T-cell, the most difficult population similarly were those patients … who were refractory to salvage chemotherapy or relapsed after transplant. As was mentioned … somewhere probably about 40% of patients that were given CAR T will have good outcomes, but we still have 60% of patients who are going to progress or not respond. This is probably 1 of the more difficult populations for us to treat. How do you … approach treatment?

 If they’re a trial candidate … I have the luxury of a number of trials. I think what looks intriguing currently is data presented by Steve Schuster at the last ASH [American Society of Hematology 2020 meeting] incorporating a CD20 bispecific antibody. We do see some complete response rates in post-CAR T-Cell. That is a strategy that is only available on trial but may be available in the next 1 to 2 years that might be an effective strategy.

We have explored using checkpoint inhibitors because we have seen T-cell exhaustion as a particular mechanism of resistance. We have an investigator-initiated study looking at the incorporation of [pembrolizumab], plus lenalidomide and rituximab, specifically for these CAR T failures, the phase 1 dose-finding study. … We see some patients have meaningful response and durability of that response. There are several targeted agents…. But we have new immune modulators. We have other agents targeting the microenvironment that might be strategies, in addition to other CARs that might be either bispecific or dual antigen targeting.

There are so many different options for this patient, but unfortunately … this patient population has a very poor outcome. … This is the group of patients that were chemotherapy refractory before going into CAR T-cells and now often have this highly follicular relapse after CAR T-cells. There are standard options for this patient population, and while there are many different ones, from BR polatuzumab to MOR208 and lenalidomide, to a variety of selinexor, there are a variety of different options. Unfortunately, their success rate is low. Loretta’s point about getting patients on to clinical trials is important.

That 1 clinical trial that she mentioned with mosunetuzumab with CD20 bispecific antibody .... T-cells really took me by surprise. I would not have thought that someone who just failed a CAR T-cell therapy would respond to, was commonly sort of a lesser cellular therapy approach to patients with relapsed disease. That was an important outcome and I think we’ll find more pointed outcomes from some other clinical trials.

 I completely agree with all that’s been said. This is a dangerous situation. If somebody progresses after CAR T-cells, often they still have cytopenias or frail; this is a dismal prognosis. However, as Dr Nastoupil mentioned, we’ve had some home run responses in this group. The clinical trial that she mentioned of the checkpoint antibody plus lenalidomide. I’ve enrolled a few patients of mine on that study and I have a couple of them that are more than a year out now doing well. It’s not hopeless, but it’s something where clinical trials are needed.

The only other thing I would add to the discussion is that there are a new generation of CAR T-cells coming that show great promise that don’t use the patient’s own cells. It’s a donor cell. It’s an allogeneic CAR T-cell. Many of these cells are modified in a way to avoid graft-vs-host disease. The T-cells are genetically crisper or other genetic modifications modified to reduce their ability or prevent their ability to have a reaction versus the host cells. But they show incredible responses.

And at the ASCO [American Society of Clinical Oncology] meeting in 2020, Dr Neil Abu from our group presented a trial with early results showing that these might be as good or potentially even better than the autologous cells. The data is still very immature, but the current CAR T-cells we’re talking about may not be the final result for what we use for these patients in the future.

 And not only is it difficult to find treatment that works in these patients, but these patients often have residual toxicity from their other therapies, cytopenias, and it can even hard if you have treatment for it, for the patient to tolerate. This is an area where we need better treatments and better options.

Case 1: Therapeutic Options After CAR T-Cell in Relapsed/Refractory DLBCL

The second case is a 78-year-old man who presented with fever, a 7-lb unintentional weight loss and occasional chest pain. His past medical history is significant for diabetes, which is medically controlled. A physical examination he was tired appearing. He would have had palpable bilateral cervical lymphadenopathy. On laboratory examination he was anemic with a hemoglobin of 10.8. His creatinine was elevated at 1.7, and he had an elevated LDH [lactate dehydrogenase] of 300. All other of his labs was within normal limits.

A lymph node biopsy revealed a CD 10-positive, CD 20-positive diffused large B-cell lymphoma. His FISH [fluorescence in situ hybridization] testing was negative for rearrangements of 

. On imaging a whole-body PET [positron emission tomography] scan showed activity in multiple lymph nodes above and below the diaphragm. And the largest lymph node was 3.9 cm.

He also had evidence of subcutaneous tissue involvement. An MRI of the brain showed no evidence of lesions. And he had stage IV disease with an ECOG performance status of 1.

His treatment was initiated with R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride (Hydroxydaunomycin), vincristine sulfate (Oncovin), prednisone] and he tolerated it well. But an interim PET scan after 4 cycles unfortunately showed progressive disease.

Here we have an advanced stage aggressive B-cell lymphoma. The patient may be a little bit older, has some underlying comorbidities, diabetes, although well controlled. Goes on to get standard therapy with R-CHOP. And then on receiving PET shows progression of disease.

Are you guys using interim staging in diffused large B-Cell lymphoma? And if so, when are your using it—after 2 cycles, after 4 cycles—don’t do PET?

I tend to do it after 2 or 3 cycles. I generally use a CT scan. If someone has obvious nodes that I can feel and know that the person’s responding, then I might delay it to the third cycle and just do a CT scan at that point. But if I have nothing to follow, then I generally do it after 2 cycles.

I’d like to hear what other people have to say. I don’t often do PET scanning in patients with large-cell [disease] and my experience in Hodgkin disease, mostly because I’m not sure I know what to do with the data. In this case the person had progressive disease but they probably could have seen that from the CT scan. And patients who don’t become PET-negative after 2 or 3 cycles of R-CHOP, there’s a lot of controversy about what the best course of action for that patient is. Clearly it’s not a good prognostic factor, but how to act upon it is less clear to me.

 I agree that it’s controversial and there’s not a right or wrong answer here. For patients that don’t have palpable lymph nodes, if I can’t tell what they’re doing I’ll get a PET CT scan either after two or three cycles. There’s not a consensus of what to do. If it’s not a CR [complete response] I agree with Dr Flinn that we have troubles with false-positive PET Scans, the residual abnormality, which is improved but not resolved. It does help to give confidence that the therapy is working if someone does have a CR on interim PET. Lack of a CR [complete response] is concerning but it wouldn’t be something I would necessarily change treatment off protocol.

We do have a clinical trial that is allowing patients with certain high-risk features who do not achieve a good response on an interim PET to go on to receive CAR [chimeric antigen receptor] T cells. There’s ZUMA-12 trial [NCT03761056].

The ZUMA-12 Trial enrolls patients after 2 cycles of frontline chemotherapy without a good response if they’ve got high-risk disease such as this patient coming in. But off the trial there’s not really a right or wrong approach, and it’s more of if you’re not sure if the patient is responding or if you’re concerned that they’re progressing early, getting that scan to confirm and not waste any more daylight of getting toxic and effective frontline therapy.

The only thing I’ll add is that for our double-hit patients, sometimes having an early glimpse that they’re likely to fail may help you line up that next course of treatment. Because in my opinion most patients do quite well with frontline R-CHOP. But those that don’t, you have a narrow window intervening before they succumb to their disease. Those are the patients that I generally will get a PET after 2 cycles and may act on. Outside of that, I 100% agree with all the comments that have been shared about the challenges of interpreting those interim scans in large-scale lymphoma.

 I use the same approach. I typically do them. It’s reassuring if somebody’s in a complete remission. It’s obvious if they’re progressing that you need to do something else but it’s challenging when they’re responding but there’s still disease. You think they probably are not going to do well but there’s no real great change or great option at that point.

Case 2: R-CHOP Refractory DLBCL, Transplant Ineligible

: This was mentioned by Loretta. You said that most patients are going to do well with R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride (Hydroxydaunomycin), vincristine sulfate (Oncovin), prednisone] and that’s true. What percentage of patients in your practice do you find are refractory to front-line, either progressing in therapy or don’t get into remission, versus those that relapse within the first year or two?

: Rare. I was going to say, it’s rare to have totally refractory. This patient progressed during therapy, that’s uncommon. And that is a pattern we do see with patients with double hit lymphoma, that they’ll have an early response and then a progression, and perhaps there’s a chemotherapy refractory clone that just took time to grow out to be the dominant clone. But primary refractory or progressing during therapy, it happens. I’d say it’s less than 10% of cases, but it’s a poor prognosis.

The second scenario you mentioned, Dr Maddocks, is somebody progressing after achieving response is more common and would have a better chance to respond to second chemotherapy. These people that are primary refractory to R-CHOP, they’re unlikely to respond to salvage chemotherapy because there’s something innately chemo-resistant about their disease.

 No. Jason’s analysis is correct. We often feel obligated if someone has primary refractory disease to try to salvage it with a second-line treatment. And that’s generally unproductive and doesn’t work. If they’re trying to get that patient to CAR [chimeric antigen receptor] T cells is where we would go next, if the patient was eligible. In this case this patient is probably not a great candidate for intensive therapies in the future given his complaining of chest pain. He’s 78, he’s got renal insufficiency, and he may not be the best candidate for the next line of treatment.

: What option for treatment does this patient have? He is older, maybe some more medical comorbidities. How do you approach this patient?

 It’s similar to discussions we had before—is the goal still cure? Or is the realization that it’s not likely to happen in this patient? Given the primary factor, the nature of this disease, the patient’s comorbidities, we’re probably not talking about a curative therapy in this patient population. The next generation of CAR T cells are getting easier and easier. But, the ones we have today are still quite difficult to administer to this patient.

I would, think some of the other options that we have are relatively new approved options, and some old ones. For instance, you could go to a second-line perhaps less intense salvage therapy such as R-GemOx [rituximab, gemcitabine, and oxaliplatin]. You could switch to one of the newer approved therapies such as BR [bendamustine] polatuzumab. There is the tafasitamab and lenalidomide that’s recently been approved. There are a number of options for this patient, but you have to make a decision what the goals are for this patient.

: We’ll talk about a little later what is the auto eligibility, a patient who is eligible for auto-transplant versus CAR T. Is it the same thing, is it different? And there’s no boxes that you can check to ensure that a patient is going to be eligible for one or the other. But what are some of the things that you look at when that patient is sitting in front of you to make a decision but you’re thinking, 1 of that type of curative therapy versus a more palliative approach?

 Someone like this who’s progressing amid CHOP, my enthusiasm about salvage chemotherapy, age aside, is quite low. Then you throw in a 78-year-old who is going to be particularly nervous about heading down the path of platinum-based treatment. Am I really going to pursue high-dose therapy. Though we don’t have an age limit, and I recognize that it is a functional status and we decide who is going to move forward with auto-transplant in the US, I have not taken may 75-plus-year-olds to transplant because I haven’t seen many of them, particularly in this setting, do well with salvage chemotherapy.

This is someone I would start thinking about CAR T. I think the eligibility is quite different. You have chemotherapy sensitive disease; you go forward with transplant. If you have a patient who’s not chemotherapy sensitive or chemorefractory, I think CAR T. But, even without knowing the results of the randomized phase 3 studies, this is a patient I might have to cool off or stabilize before I get to a CAR, particularly from an autologous T-cell situation.

This is a situation where I might try one of the newer agents that are available. We have, Peter had played around a little bit with the polatuzumab-rituximab and hold the bendamustine until you capture or collect those T cells. That might be a strategy I might employ.

You’ve heard about tafasitamab, lenalidomide. We don’t know how well that performs in a refractory situation. I mean that’s another tool in our toolkit that we might start exploring, can we stabilize these patients? And if they respond, do you even need to go down the path of CAR or something that might be more definitive?

I would not even pursue salvage in this case. I would pursue one of the available targeted agents in the second line hoping that a different mechanism of action might turn this around. And I don’t think I would pursue transplant even if I got into a complete response situation.

: I agree. And the only thing I would add is that there’s not an upper age limit for CAR T-cells. This patient is medically frail with a chest pain, as Dr Flinn mentioned, the renal insufficiency. Those are factors that are going to potentially increase the morbidity from a CAR T cell. The eligibility for this patient to go for CAR T cell is going to be borderline. But we’ve treated patients into their late 80s with CAR T cells, none of whom is completely; you know an Olympic athlete, they all have challenges. They’re usually quite fit for their age. However, the CAR T cells are not the same patient population as the transplant patients. Evaluation by a CAR T-cell center, if you’re even considering it, is a good idea. But the targeted approach is probably the best for this particular patient.

Case 2: Therapeutic Options in Patients With Transplant-Ineligible, Treatment-Refractory  DLBCL

 In your practice what are you seeing as the most common reason for patients not receiving a transplant? It was mentioned if a patient refractory, had chemotherapy, you’re not really going to want to consider them for salvage chemotherapy and a transplant, regardless of age or eligibility. But what things are you guys most commonly seeing as reasons that patients—either not eligible or do not get transplant?

 Probably the number one reason is lack of chemosensitivity of their disease is the number one reason. But if you get beyond that, it’s more of a physiological issue in terms of do they have good heart function, do they have good pulmonary function? For most people that if they have chemosensitive disease and they otherwise physiologically are capable of undergoing the transplant, I think most of, at least our patients, would be willing to have the transplant. It seems to me it comes down to would most patients rather than not if it’s a potentially curative option for that patient.

Again, back to some of the organ function part in pulmonary and renal are the number one reasons for ineligibility in our center once you get beyond the chemotherapy sensitivity issue.

 It’s probably rare that once you educate them well, you know, they’re going to decline a transplant if they’re really eligible and get a good response to salvage. That’s probably less likely to use them than not, not getting a transplant.

We’ve discussed this, although not maybe in great detail, but we know patients that are not candidates for transplant are still eligible, or maybe a candidate for CAR T. What are the differences in these patients, or what may make somebody ineligible for auto besides the progression but able to be treated with CAR [chimeric antigen receptor] T.

 We’ve struggled with identifying clear criteria that select out CAR T patients. We know it’s not the same criteria that we often apply for auto-transplant. Though in my general practice if I have a patient who has measurable disease, I know there’s some data that you could proceed in the setting of CR [complete response]. But you probably need some antigen for those T cells to be, or CAR, to be worthwhile and to be effective. Having some measure of disease, and being able to withstand the acute toxicity, cytokine release syndrome, and neurotoxicity. It’s a little bit of in the eye of the beholder currently, but I there should be some reasonable performance status, some reasonable controlled comorbidities. We don’t take patients with active infection. There are some other sort of nuances in terms of pleural effusion and acute thrombosis. Though again we have some small numbers that suggest that those may not be that strong of a predictor of toxicity. It remains to be defined— who is an optimal candidate for CAR? If I have a patient with active disease and is going to tolerate the acute toxicity, I consider it in those patients.

: Agreed. And the take-home point from today’s session should be, it’s difficult for a physician who doesn’t do this for a living, doesn’t see patients and decide CAR T cell or not to make that determination. If you think there’s a potential this patient could have a curative option, refer them to a CAR T-cell center to have somebody who does CAR T cells all the time to help make that decision, because it is a bit of an eye-of-the-beholder thing. There’s not really clearly defined criteria either.

One thing that Dr Nastoupil mentioned about needing some antigen, needing to have a measurable tumor. We did publish a small series of patients that we treated on the JULIET study [NCT02445248] that had a complete response to bridging therapy that went on to subsequently get CAR T cells, not waiting for a relapse, and they had outcomes that were similar to other patients on the JULIET study. One of my patients is now 3 or 4 years out and is too healthy to come back to see me. She had a transient response to hyper-Cytoxan [CVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride (Adriamycin), dexamethasone)]. I guess I shouldn’t say transient. She got hyper-Cytoxan and then went on to get tisagenlecleucel on that study, and never relapsed. And obviously hyper-Cytoxan is not going to give you 3 years of response. Everything else was said, I completely agree with it. It’s referred to a CAR T-cell center to decide who’s eligible for these advanced therapies.

 What are treatment options for patients who don’t want or can’t repeat CAR T? I guess the other thing would be even in a patient who can receive CAR T, this patient is going to need some sort of therapy regardless if eventually it’s decided that they would be a candidate I know was mentioned—polatuzumab. Are there other options in this setting or what’s your approach to these patients?

 There’s a lot of heterogeneity about what is the best approach here. I don’t think we know what the best approach is. There are upsides and downsides of pretty much any therapy you might choose. For instance, if you were to get away from chemotherapy regimens for patients because, chemotherapy are refractory to begin with, then our options are things such as tafasitamab and lenalidomide. The problem with tafasitamab is that it’s a CD19-targeting agent. I don’t know that we have any data but we certainly worry about using a CD19-targeted therapy if you’re going to try to get them to CAR T cells. If you’re going to take a patient to a CAR T-cell therapy, then I think the options are much broader. Of course, the tafasitamab and lenalidomide, polatuzumab and bendamustine—rituximab, the new agents like selinexor that have been approved. I don’t know that anybody has, there’s any 1 answer for a given patient, and sometimes you’re going to go to more than 1 agent, or one therapy for a given patient.

 Probably in this setting you’ll end up going through a number of therapies where, again, the patient unfortunately.

Case 2: Considerations for Choosing a Second-Line Therapy for DLBCL

 As you mentioned, there are a number of therapies if you look at NCCN guidelines [National Comprehensive Cancer Network] ranging from GemOx [gemcitabine and oxaliplatin] to, and rituximab, to BR [bendamustine] plus polatuzumab. There are a bunch of other older chemotherapy regimens that are not very realistic such as using the very aggressive regimens and dose=adjusted EPOCHs etoposide, prednisone, vincristine (Oncovin), cyclophosphamide and doxorubicin hydrochloride (hydroxydaunorubicin hydrochloride)], EPOCH plus rituximab. And then some of the newer agents that we’ve already talked about.

This patient, because it was deemed that this patient was not really a candidate for CAR [chimeric antigen receptor] T cells went on to receive tafasitamab and lenalidomide. Tafasitamab and lenalidomide was recently FDA approved. Tafasitamab is a CD19-directed antibody that has had the Fc enhanced, Fc portion of the antibody enhanced to improve ADCC [antibody-dependent cell-mediated cytotoxicity] as well as ADCP [antibody-dependent cellular phagocytosis]. We know that it works well in combination with lenalidomide, which of course has a number of effects, including direct cells, but that also with the effect on the immune system to achieve a NK [natural killer] cell activation.

There was a study that led to the approval of this combination of tafasitamab and lenalidomide. It was known as L-MIND [NCT02399085]. It was a single-arm phase 2 trial that looked at the combination of this drug—tafasitamab, given days 1, 8, 15, and 22, in combination with lenalidomide at 20 mg PO, days one through 21, similar to what you might expect with an R2 regimen. And then, of course tafasitamab was given less often for the monthly, or days 1 and day 15 for the next cycles through cycle 12. And then patients went on to receive single-agent tafasitamab after that and lenalidomide was dropped out.

It was an interesting study. The patients I failed to mention that were eligible for this trial were patients who had one to three prior regimens, they couldn’t have been eligible for a transplant, they couldn’t have been primary refractory. Not the worst of the worst but patients who had, truly there’s a need here for new agents. And in this study there was an overall response rate of about 60% and many of these patients had a complete remission, 43% of the patients achieved a complete remission.

And the duration of response in the progression-free survival will also, were also impressive with progression-free survival about a year, and overall survival about at 18 months, and 64% of patients were still alive. This is better than you might expect with what we saw with the SCHOLAR-1 data, but this isn’t the same patient population that we saw in that dataset as well, definitely not the very refractory patients that went on this.

The adverse event profile is not that dissimilar that you might see with R2 regimen. And of course there’s the hematologic toxicity that’s generally seen with lenalidomide. But beyond that it was a well-tolerated regimen. The most common nonhematologic toxicities were fatigue and diarrhea. Again, things that you might see with the addition of lenalidomide to pretty much any antibody.

So the number of patients that had serious adverse events was about half of patients, not unexpected in this patient population with relapsed and refractory disease. And some of these were thought to be related to the therapy, but that was a minority of the adverse events.

Case 2: Phase 2 L-MIND Clinical Trial for Relapsed/Refractory DLBCL

 The outcomes are better than you would have expected in this population butalso a select population in some, in regards to some of the inclusion- exclusion criteria. Now that this is an approved regimen, under what circumstances are you likely to use or not use this regimen as second-line therapy, for example, in eligible?

 For me it has to do with what the performance status of the patient is, and perhaps how old they are and that’s why they’re not a candidate for second-line therapy. If someone is very frail, you don’t think can take chemoimmunotherapy, such as the BR [bendamustine] polatuzumab [POLA] regimen, then that’s to me the ideal candidate. If a patient has rapidly progressed a disease, who’s very sick, then this would probably not be my first choice. But those patients that, just by age alone or perhaps other organ function are not transplant candidates, but otherwise doing well and have more, less peripheral disease, to me that’s a candidate for this regimen.

One of the interesting things that I’m facing right now in my practice is we don’t have the results yet of the randomized studies that took these patients that are primary refractory or progress within 12 months of frontline treatment, CAR [chimeric antigen receptor] T is currently approved in the third line. And so this is the exact patient where I’m sitting really kind of nervous because the L-MIND study [NCT02399085] didn’t address them, but it is probably my preferred approach for a patient in second line that is not a candidate for salvage chemotherapy. I’d like to go to CAR T but I don’t have it available from an insurance approval standpoint.

What we need to do as a community is collect some real-world data and see how this regimen performed in this patient population because it fits very nicely right now in my treatment landscape. Second line patients are not transplant candidates, but I’m also nervous about how well it’s going to perform in a patient that was not included in the trial.

: I agree. And this population on the study is not super refractory, but it’s not a cherry-pick population in the sense where there aren’t sick people here. A lot of these people were refractory for their most recent therapy, not initially primary refractory. This is perhaps not every patient in the clinic fits in to the eligibility criteria for this study, but it is an ineffective therapy. And as Dr Flinn mentioned, those that get a CR [complete response] have an awesome durability of response. The duration of response is almost CAR T cell-like for these patients. This is a therapy that has a big future. The concern that we’re all dancing around about, if this person were to get this and not respond, could you potentially go to CAR T cell having used a CD19- targeted therapy and another CD19-targeted therapy. We don’t know, but I don’t think there’s a huge risk that you’re going to be CD19 null afterward. Antibodies aren’t for the same selection pressure that CAR T cells are for selecting out CD19 or CD20 or whatever the target is null.

We’ve seen patients with prior Rituxan who are CD20 negative, but you just need a tiny bit of antigen for CAR T cells to work on the cell surface. And you’ll notice in the labels for CAR T cells, there’s no requirement for checking for CD19 expression because it’s there in nearly every patient, at least at some level, and that’s all you need for CAR T cells to work.

Capecitabine, lenalidomide would be an appropriate option to consider for this patient, even if you were potentially considering therapy down the road with CAR T cell.

 You guys have highlighted the challenges of a patient who’s refractory to chemotherapy. You know they were excluded from this trial, at least primary refractory, so is there concern using that but at the same time just giving them more chemotherapy is very unlikely to work so maybe this a reasonable choice in that setting. And then also the concerns about targeting CD19. Hopefully we’ll have more data on the antibody, the ADCs [antibody-drug conjugates] that are being developed. Is it really, is CAR T cell a reasonable option after those therapies are used?

Does anybody have any feelings or comment second line versus third line? Is this something that you’d say, “Well, I’d use it but I’d prefer to use something else as a second-line agent versus a third-line agent.” Does this define a difference in this treatment versus our other treatments like selinexor or BR-POLA, CAR T. Do you have to fail a second-line treatment whereas this approval was in the second-line setting. Does anybody have any hesitancy or feelings regarding that?

There was a large portion on this study that did include patients at second-line. My general thought is we want to reproduce the great overall survival of PFS [progression-free survival] seen. It’s probably going to perform better in second-line, though I agree with Ian’s comments earlier. If I’m really headed to CAR T, even though we don’t have any proof that you’re going to lose CD19 or have selective pressure for a CD19-negative clone, I probably would reserve it for a third line if I clearly am moving straight to CAR T. But otherwise I think it probably will perform better in second-line.

 It’s always a challenge, do you want to save a therapy because it might interfere with CAR T, but you have a patient sitting in front of you and you have to be able to get them into response because CAR T is not going to be an option. It certainly is a challenge and I think you’re right, we need more real-word data on the best way to sequence these or what we can treat, how we can treat patients with these regimens.

I’m looking at the regimen, is there anything that schedule can be intense? Are there pros and cons or barriers that you foresee to patients receiving this treatment?

This might be an ideal patient, it might be an ideal therapy, it’s relatively less intense. This patient’s older, primary refractory disease, and it’s a relatively ideal therapy for this patient.

You know there are pros and cons of any therapy. The cons here are that it’s combined. There are some IB elements of it, and the patient’s constantly coming back into the office for an unedited period of time. I mean the pros are, other than some hematopoietic toxicity, by and large it’s pretty well tolerated. Andit’s almost a kinder or gentler therapy for this older patient, that’s a plus.

 In this trial they did treatment until progression, how do people feel about using this maintenance in diffuse large B-cell lymphoma? I mean I think one could argue maybe though CR [complete response] patient didn’t need the maintenance because once they achieved CR they were going to stay in a CR, and those were most of the patients that stayed on. But any comments or feelings from your perspective, or maybe a patient perspective, thinking about that maintenance?

I have never been a fan of maintenance in large-cell lymphoma. However, the overall survival is hard to argue. But I 100% agree with you that for those CR patients, it would be interesting to see what a treatment holiday results in. And then if you rechallenge those patients, do they respond. I struggle with it in terms of the duration of treatment, particularly for younger patients who are going to need to resume somewhat of a normal life and get back to a normal work schedule. Every 2 weeks indefinite is challenging.

For our older patients, the alternative may not be great, it’s death, they might be more amenable to that, frequent visits to the office. But the schedule is challenging.

: I agree with Dr Nastoupil. There’s no historical precedent for maintenance therapy for large-cell. Lenalidomide potentially in this frontline study had some benefit, but it wasn’t inclusive. The challenges here are there’s still disease and we just don’t have the tools yet. As we get circulating tumor DNA assays that are more robust, can measure, does this patient have cancer that you’re suppressing, or potentially could there be a cure? We don’t yet know.

In patients that I’ve had on other therapies which are relatively well tolerated which should go forever that have stopped and had treatment holidays, I’ve had some good success with people staying in remission for a long period of time off of a therapy. And if there’s intolerability or the patient just gets tired of doing it, I don’t think it would be unreasonable to stop. Potentially you could rechallenge the patient if they had a good treatment holiday without relapse, you could go back to the well a second time.

 That’s a great point and this may be great for circulating tumor DNA where if there’s no evidence of any disease at all by any measure, then they probably, or maybe are okay to not continue on that where maybe it’s helping a small percentage of patients.

Then would you consider CAR T after tafasitamab? We kind of answered that. I mean there is no great answer for this. There were a couple patients treated on the trial who went on to CAR T but that’s very minimal data, and I think we’ll have more, more information in the future as we use this in the real world on patients to see if this is an effective option.

Case 2: Role of L-MIND Regimen as Second-Line Treatment in Transplant Ineligible DLBCL 

 This is the third case in our series, and this is a patient with relapsed large cell double hit. Our patient is 72 years old, and 15 months ago had stage IIIB large cell lymphoma. He didn’t feel well at presentation, with fatigue, night sweats, and a neck mass. The past medical history was notable for a cardiomyopathy with a relatively good ejection fraction of 48% percent. However, the creatinine clearance is impaired at 45 mL per minute. Your staging evaluation shows multiple sites of lymph nodes, including the neck, the mediastinum, the abdomen, and the retroperitoneum. The biggest site is 8 cm, so a rather significant disease burden.

Laboratory test results are notable for an elevated LDH [lactate dehydrogenase], and the lymph node biopsy shows large cell lymphoma, with the Hans algorithm showing the germinal center B-cell [GCB] subtype being present. FISH [fluorescence in situ hybridization] is performed, and you find the patient has both a 

 rearrangement. This would be reclassified as the so-called high-grade B-cell lymphoma with 

, double hit. CSF [cerebrospinal fluid test] is performed, evaluation with lumbar puncture, and is negative for lymphoma. The performance status is 1, and the IPI [International Prognostic Index] score is 3.

The patient is treated with a frontline approach of dose-adjusted R-EPOCH [rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin] for 6 cycles, and received CNS [central nervous system] prophylaxis with 4 cycles of intrathecal methotrexate. He has a complete response at the end of therapy by a PET [positron emission tomography]/CT, but unfortunately within a year develops a new mass, symptomatic, has night sweats. Performance status declines to 2; mild anemia, elevated LDH again; and your scan shows, again, significant adenopathy in the neck and the abdomen, with another bulky mass at 7 cm.

A biopsy is performed which shows, again, the same subtype of lymphoma, large-cell lymphoma, GCB subtype, which is likely the same double hit disease that this patient had earlier that year.

You treat the patient with R-GDP [rituximab plus gemcitabine, dexamethasone, cisplatin], and after 3 cycles perform a PET scan showing, unfortunately, progressive disease in the site seen previously, and again perform a biopsy showing the same disease: relapsed/refractory double-hit diffuse large B-cell lymphoma.

Case 3: Relapsed DLBCL, Double Hit

 Here we have a patient who’s a little older than the first patient, younger than the second patient. Age, however, if this was a healthy 72-year-old, probably still a candidate for curative therapy. This patient’s issue may be more in that they have some cardiomyopathy, not a horrible ejection fraction [EF] but lower, and renal insufficiency. So more than 1 comorbidity.

What are the challenges in treating this patient? In the first-line setting, say this patient had a lower EF,of 30%. What are options in that setting? And then in this patient, what are options in second- and later-line settings when maybe they can get R-EPOCH [rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin] or R-CHOP [rituximab plus cyclophosphamide,hydroxydaunorubicin, vincristine,prednisone] for frontline treatment, but then struggle with the comorbidities in later treatment?

 This is not an uncommon scenario in our clinic, to have a patient who has these comorbidities of mild heart dysfunction, mild renal dysfunction. What I would note is the patient was able to tolerate dose-adjusted R-EPOCH [rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin], so they’ve kind of declared themselves able to tolerate a relatively aggressive frontline approach.

EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin] is not super toxic. It’s easy for me to say that, I’m not the one receiving it, but it’s slow infusion chemotherapy. So I don’t think this is something we need to shy away from, to try for a cure in a patient like this who’s got double-hit lymphoma. You can always start at a lower dose. It’s dose-adjusted. Dose adjusting is a 2-way street, you can go up or down. Sometimes we’ll start at a lower dose and escalate up to full dose in somebody we’ve had concerns about.

The challenges in patients who have heart dysfunction or renal dysfunction go beyond which chemotherapy to choose. It’s what do you do after chemotherapy? If this patient had achieved a complete response to GDP [gemcitabine, dexamethasone, cisplatin], they might have had a challenge to go on to receive an autologous transplant. Some transplant centers have hard cutoffs for ejection fraction or creatinine clearance. This is a patient where CAR [chimeric antigen receptor] T-cell therapy and/or targeted approaches likely will be better tolerated than further aggressive platinum chemotherapy.

Case 3: Later-line Options to Treat Double-Hit DLBCL

 Let’s now review the pivotal study that got polatuzumab FDA approved for a patient such as this. This is a phase 2 study that had the lead in of polatuzumab, bendamustine, rituximab. And then the randomized phase 2 portion was a 1:1 randomization of patients to receive [bendamustine, rituximab], or [bendamustine, rituximab] with polatuzumab. It was a 40-patient per arm study, and the outcomes are shown on our screen with an objective response rate clearly favoring polatuzumab, bendamustine, rituximab, more than doubling the overall response rate at 45%, with 40% of patients achieving a complete response. This is an impressive benefit for adding in the antibody-drug conjugate polatuzumab. For those who aren’t familiar with this drug, it is targeting a B-cell surface marker called CD79B, part of the B-cell receptor, which is nearly ubiquitously expressed on patients with large B-cell lymphoma.

The response rates here are impressive favoring the experimental arm of polatuzumab, bendamustine. You’ll also note that the duration of response is favoring, 7 months versus 12 months. And when we look at progression-free survival both by the central review and by the investigator, we don’t need a 

value to see this difference is favoring the addition of polatuzumab.

We’re not going to review all the data on this drug today, but if we look back at the trial of Rituxan, polatuzumab, the one that was comparing it versus another antibody-drug conjugate that didn’t advance, pinatuzumab, the outcomes in that study look similar to me without bendamustine. Similar to this trial in the sense that the [polatuzumab, bendamustine, rituximab] arm looks about the same as the [polatuzumab, rituximab] arm. I’m not sure how much bendamustine adds here. In my practice I don’t tend to use much bendamustine for patients with large cell. It may be a toxic placebo.

There was a trial done in Japan a few years ago looking at [bendamustine, rituximab] for patients with relapsed large-cell lymphoma. And those patients who relapsed within 12 months didn’t respond to bendamustine. All of the responders were late relapses after primary therapy.

In this trial, the overall survival clearly favors polatuzumab, bendamustine, with nearly a year for median overall survival versus effectively the first or second restaged for the overall survival, 4 months for the bendamustine arm.

Looking at the forest plot, there’s not much to call out here other than there’s no group that does better with [bendamustine, rituximab]. Across the board, everybody benefited from the addition of polatuzumab, regardless of what variable you wanted to look at, this was favorable.

When we look at the toxicity, it’s not surprising, neutropenia is more common when we add an extra agent. The antibody-drug conjugates we know do have the tendency, even though it is a targeted chemotherapy, to have some off-target effects and have the cytopenias with the greater incidence of grade 3/4 neutropenia.

And similar to other antibody-drug conjugates such as brentuximab, the peripheral neuropathy is more seen in the polatuzumab group although it’s limited grade, grade 1/2 and in 40% of patients. No severe neuropathy was noticed on this clinical trial.

Another interesting agent that has been FDA approved, again in 2020, just like tafasitamab, lenalidomide, is selinexor. Selinexor is a novel drug that targets the nuclear export protein, effectively trapping tumor suppressors within the nucleus. Cancer cells often use that as a mechanism to avoid tumor suppression or death by ejecting these proteins from the nucleus, and therefore theoretically could have an increased toxicity against cancer cells over normal healthy cells.

The trial that allowed this drug to be approved was SADAL, which was a phase 2 single-arm study. And the eligibility here, something I want to highlight, is a little bit different than what we see in everyday practice. Patients who went on to this trial had to have at least a PR [partial response] to their most recent therapy. Or, if they did not achieve a PR or CR [complete response], they had to be without therapy for more than 14 weeks, or 3-1/2 months, which is a little bit different than what we see in our typical practice; patients who relapse or are refractory often need to have therapy relatively soon.

There were multiple dosing schedules looked at on this trial, and the higher the dose, the more frequent the drug, the more toxic it was. The group that was analyzed for the manuscript mentioned on the slide, published in 

, was focused on this group that received 60 mg twice weekly, days 1 and 3, for a 4-week cycle. The primary end point in this trial was overall response, which found an overall response rate of 28% and a CR rate of 12 %. There was a slightly higher response in the GCB [germinal center B-cell] subtype, 34% versus 21% in the non-GCB subtype, although this was not a powered analysis. It’s unclear what this means, if this will hold up in more patients in the future.

Looking at the waterfall plot, we see that the majority of patients did have some degree of tumor suppression, but not all. This was a study where not every patient received benefit, and not every patient was able to stay on this drug for a long period due to some toxicities.

Similar to the polatuzumab study, the forest plot here favors the use of this drug in every patient. There wasn’t one particular group that jumped out as, this is the ideal candidate, or this is the subtype, or this is the scenario you would use this in. It worked in patients across the spectrum relatively evenly without anything that I would call out as a highlight of a better response in a particular subgroup. I’ve alluded to a few times, the toxicities were not trivial, and if we look at the thrombocytopenia, the majority of patients had some degree of thrombocytopenia, with about half, 46%, having grade 3/4, and this often required dose hold or dose adjustment, sometimes requiring TPO [thrombopoietin] drugs to try and stimulate platelet recovery.

Nausea, fatigue, anorexia were other concerns that were seen on this study, which could generally be managed, but were not trivial. And 17% of patients required stopping therapy because of toxicities.

Case 3: Pivotal Trials for DLBCL

 The first question for discussion, would you continue to use anti-CD20 therapy after first relapse? And if so, would you choose rituximab or another agent?

 We don’t have a lot of data on other CD20 antibodies being better than rituximab. We had the frontline GOYA trial, which compared R-CHOP [rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone] versus G-CHOP, [obinutuzumab plus cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone]. It showed an equivalence—it wasn’t better or worse; it’s more expensive. There’s not a clear reason to switch to a different CD20 for patients with large-cell lymphoma. If they don’t respond to R-CHOP [rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone], it’s not clear that they would do better with other CD20 antibodies plus other chemotherapy in the future. I generally continue rituximab for these patients if I plan to give them salvage therapy.

 We’ve answered the next question on experience and challenges of using CAR [chimeric antigen receptor] T-cell therapy in this type of patient. If we were not able to get this patient to CAR T, what would be your preference? One of these regimens that we’ve talked about, or something else from the NCCN [National Comprehensive Cancer Network] guidelines? And then looking at these different treatment options, what would you choose for this patient, or how would you sequence these therapies? I know there are no great data. But what would your approach be to this patient, and what would be the key benefits or challenges for each of these therapies?

My preference would be to take this patient and give them tafasitamab and lenalidomide rather than one of the other options, at least on the next line of therapy. As we talked about earlier, this patient has a chemotherapy refractory disease, and then there’s an appeal to using a different mechanism of action. The tafasitamab and lenalidomide serve that need.

Polatuzumab vedotin, the data there, not exactly in this patient, are impressive. But ultimately, that’s giving the patient targeted chemotherapy mediated through the antibody. Giving this patient tafasitamab, lenalidomide would be attractive. There isn’t any right or wrong for which order to give this drug to this patient. I don’t know. I’m less excited about selinexor. As we saw, the results are not nearly what you see with the other drugs, the less than 30% overall response rate, the median progression-free survival was low. I would put that therapy further down the line.

What’s most impressive about the tafasitamab, [lenalidomide] data is overall survival. It looks good, particularly in relapsed large cell lymphoma. Now the caveat is they excluded primary refractory patients, they excluded double hits. We don’t know how this patient would have performed on that regimen. But it is the most interesting to me among the options we have. Again, one other exception that I might consider, polatuzumab, rituximab, and CAR T, if I can get that patient here. Again, bendamustine, I agree with Jason, is not my most exciting drug in the relapsed large cell space. I don’t know how well polatuzumab, rituximab performs without it, but it is something that I’ve tried a few times and have had some success with.

The toxicity profile with selinexor, and the way the study was conducted where they completely excluded any of our refractory patients, has dampened my enthusiasm around it.

 Just to defend selinexor, even though I did say it’s quite toxic, it’s an oral agent, which is the advantage there for patients who don’t want to come in for an infusion, or don’t live near a center, or have to drive 4 hours each way to get there, that’s one advantage for it. But otherwise, I agree with the comments that there are potentially better options for these patients. There’s not a clear way yet for us to choose among these agents. Sometimes it becomes a bit of muscle memory of which one you have used before, which one you have experience with. But it’s great to have this problem, that we have multiple agents approved in this space. There are more to come. There are plenty of promising agents, so this is a problem that’s going to grow over time. Hopefully we’re curing more patients in the front line with novel therapy, so we don’t have as much need in third line. But clearly it’s good to have these problems.

: I agree. Right or wrong, I look at selinexor as one of those options that if a patient is not eligible for a clinical trial, you’ve use other things, and they want to try something. It’s an oral therapy, it’s something that is potentially going to work, and so why not go ahead and try it if the patient wants to?

In our other discussions, we’ve made it clear that we look at this as 2 different populations of patients. If a patient is eligible for a curative therapy, be it transplant or CAR T, they should be evaluated in an attempt at that curative therapy. If they’re not going to be candidates, or progress after, or you’re having trouble getting them there, then these are the times that we want to think about these other options. The overall survival in tafasitamab and lenalidomide is very promising, and maybe with more follow-up that will be a more frequently used treatment, including with more data on some of these more refractory patients.

I look at this as 2 different populations of patients. There are 2 different goals of the care or treatment. I don’t know if everybody would agree with that to some extent, or have other thoughts.

: I agree with you, Dr Maddocks. CAR T-cell therapy is such a transformative therapy for this patient population in the sense that we can now confidently say we’re curing people with relapsed/refractory large cell lymphoma with chemotherapy refractory disease, where before this was a dismal prognosis. These new therapies do have incredible promise, and there is hope that some of these impressive progression-free survival curves may mean some patients could be cured with these therapies. But we don’t know. And you’re right, that if you can give CAR T cell, you really owe it to your patient to refer them to a CAR T-cell center to have that discussion. Patients will come back to you, they don’t stay with us. They get CAR T-cell therapy, and then we help care for them afterward. There are no compelling reasons not to offer CAR T cell to somebody, or at least have them be screened for it, if you think they’ve got a potential for going for a cure.

 Yes, we certainly have much better options than we did even 2, 3 years ago, and it’s made it nice to be able to offer these to patients. But we have a long way to go, and hopefully some of the bispecific antibodies and other therapies we’ll see will help us further improve outcomes.

In closing, I would like to thank all the panel members for your thoughtful case presentations and lively, informative discussion. To our viewing audience, thank you for joining us for this 

 presentation, and we hope you acquired some practical knowledge that you can take back to your clinic.

Case 3: Third-Line Treatment Options for DLBCL 

Clinical Cases in Relapsed and Refractory DLBCL

Experts review clinical cases and best practices for managing relapsed/refractory DLBCL.

Clinical Cases in Relapsed and Refractory DLBCL | Expert Perspective Tumor Board

EP 1: Case 1: Relapsed DLBCL, Transplant Eligible

EP 2: Case 1: Waiting for FISH Results in DLBCL

EP 3: Case 1: Identifying Patients for CNS Prophylaxis in DLBCL

EP 4: Case 1: Outcomes in Chemotherapy-Treated Patients With DLBCL

EP 5: Case 1: Therapy for Relapsed DLBCL in Transplant-Eligible Patients

EP 6: Case 1: Trials in CAR T-Cell for Patients With Relapsed/Refractory DLBCL

EP 7: Case 1: Therapeutic Options After CAR T-Cell in Relapsed/Refractory DLBCL

EP 8: Case 2: R-CHOP Refractory DLBCL, Transplant Ineligible

EP 9: Case 2: Therapeutic Options in Patients With Transplant-Ineligible, Treatment-Refractory DLBCL

EP 10: Case 2: Considerations for Choosing a Second-Line Therapy for DLBCL

EP 11: Case 2: Phase 2 L-MIND Clinical Trial for Relapsed/Refractory DLBCL

EP 12: Case 2: Role of L-MIND Regimen as Second-Line Treatment in Transplant Ineligible DLBCL

EP 13: Case 3: Relapsed DLBCL, Double Hit

EP 14: Case 3: Later-line Options to Treat Double-Hit DLBCL

EP 15: Case 3: Pivotal Trials for DLBCL

EP 16: Case 3: Third-Line Treatment Options for DLBCL