Matthew Lunning, DO, FACP

Case Overview: A 64-Year-Old Man with Diffuse Large B-Cell Lymphoma (DLBCL)

History of hypertension (well-controlled)

: Patient began treatment with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) induction therapy

Patient had neutropenic fever and limiting fatigue that was controlled with growth factor support; also had mild neuropathy

Underwent interim CT scan after 3 cycles/9 weeks and again at completion of therapy (6 cycles/18 weeks)

Patient achieved a metabolic complete response at 18-week PET-CT scan

 (6 months post–RCHOP completion): the patient complained of recent weight loss, fatigue

Followup CT scan revealed that the patient had relapsed disease

Patient started salvage chemotherapy with R-GemOx (rituximab, gemcitabine, oxaliplatin)

: 6-month for-cause CT scan and subsequent biopsy revealed that the patient was refractory to GemOx

The patient lives 50 miles from a healthcare facility that administers CAR T-cell therapy and does not have reliable transportation or continuous caregiver support; he and his clinician decided to start 3rd-line tafasitamab/lenalidomide

: The patient remains on tafasitamab/lenalidomide; fatigue has mostly resolved

 The critical unmet need is that chemotherapy-immunotherapy doesn’t work very well in the relapsed/refractory setting. It may. In those for whom it does work, you have a very narrow window of time to do something with it. If you’re considering and have the opportunity to go to an allogeneic transplant in third-line therapy, if you’re bringing out chemotherapy-immunotherapy, you’ve got to target that disease. You have to be ready to go toward an allogeneic transplant if you get that miraculous complete remission [CR]. Because the odds are that either the bone marrow will give out or the disease will recur if you only keep giving those therapy. Obviously, there are anecdotes of people who have had long-term disease remissions to chemotherapy, but I don’t think that’s the majority.

The discussion about the strategy in the relapsed/refractory setting still needs to be had as the data and the field evolve to dichotomizing people between those who relapsed within 1 year of their end of their initial therapy and those who haven’t relapsed after 1 year of therapy. You need to discuss when you’re going to pull the CAR T-cell card out of the deck. The emergent treatment options are around the bispecific antibodies that engage CD3 and CD20. They appear to have interesting data in the relapsed/refractory setting. Similar to what tafasitamab-lenalidomide brings, if you can get those people into a CR, it has the potential for durability.

Nevertheless, if we’re talking about tafasitamab-lenalidomide, bispecifics, or CAR T cell, we have to look at the populations and compare them with the median PFS [progression-free survival] of those therapies. As we find drugs that as monotherapy or as doublets have efficacy and appear to have the potential for durability, we’re always looking to move them into the frontline setting, where we’re trying to challenge the frontline space. One of the interesting things that’s going to come out is where polatuzumab or CHP [cyclophosphamide, doxorubicin, prednisone] fits in. Where does R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] fit in? How do you put all these trials with these novel therapies into that frontline setting? Which regimen do you pair with? Maybe where these regimens are best utilized will become clearer over time.

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Dr Matthew Lunning closes his discussion on DLBCL by highlighting unmet needs in the treatment landscape.

Unmet Needs and Future Directions for Patients with R/R DLBCL

 RE-MIND2 is an interesting twist on how we typically do some observational studies. Here you have them taking the L-MIND patient population and looking at their characteristics and outcomes, pulling from a very large data set of thousands of patients with relapsed/refractory diffuse large B-cell lymphoma and keying out important key characteristics of their disease and trying to do some matching into a retrospective cohort that then matched to the prospective cohort seen in the L-MIND data set. That was the RE-MIND2 data set.

There was a retrospective population being compared with the prospective population in the L-MIND data set. They took those patients who were in the retrospective data set who would have received drugs like pola–BR [polatuzumab vedotin, bendamustine, rituximab]. I believe there were other all-comer second-line salvage regimens, and then interestingly CAR [chimeric antigen receptor] T cell. What bore out over time is that some of the efficacy outcomes were equivalent to utilization of tafasitamab-lenalidomide to those populations, like CAR T cell or pola-BR [polatuzumab vedotin, bendamustine, rituximab]. It’s comparing retrospective to prospective data, but it can be thought generating or hypothesis generating between the 2 populations. In the end, because there’s unlikely to be a tafasitamab-lenalidomide vs a pola-BR [polatuzumab vedotin, bendamustine, rituximab] trial, this is the best data we’re going to get when you try to do age-matched patient populations, noting that the best comparator between the 2 would be a prospective randomized trial between the 2 regimens.

Walking through this patient’s case, there are lines and then you have to color the lines. That’s where you have to know what the frontline R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] and the tolerance were. You have to understand the logistical factors that affect this patient’s life and their family’s lives. Some patients choose to travel hours, sometimes days, to get to a CAR T-cell center, and others won’t. The important thing is the discussion that led to the decision to not get therapy that was potentially amenable to going toward a transplant, or utilizing the data in the second-line CAR T cell of what led to not going toward CAR T cell in the second- or third-line setting.

In this case, there wasn’t the opportunity to travel, have good care support, or have good caregiver support before and after CAR T-cell therapy. That led to the decision to give tafasitamab-lenalidomide. Given that this individual fell within those criteria, given the data, tafasitamab would be a reasonable third-line treatment regimen. My only question is if you had the CAR T-cell question in the second line and you knew that you weren’t going to go toward CAR T-cell because of logistical concerns and whatnot and this patient had recurred within 6 months of R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] chemotherapy. If I could have given them tafasitamab in the second line rather than in the third line and spared them what I felt has a very low chance of efficacy and durability with R-gem-ox [rituximab, gemcitabine, oxaliplatin], I would have rather given them tafasitamab-lenalidomide in the second line of therapy than wait until they had refractory disease in the second line.

Matthew Lunning, DO, FACP, shares data from the RE-MIND2 trial and explains how it compares to the L-MIND trial.

R/R DLBCL: Data from the RE-MIND2 Trial

 Tafasitamab-lenalidomide pairs a drug that not many people had used before—tafasitamab, a CD19 monoclonal antibody—with a drug that we’ve used in many areas, in not only non-Hodgkin lymphoma but also multiple myeloma. You have a drug with a lot of name recognition in lenalidomide and a new drug targeting something that probably hadn’t been targeted before in the relapsed/refractory diffuse large [B-cell] lymphoma [DLBCL] space.

Tafasitamab given in IV [intravenous] is front-loaded with multiple intravenous doses during the first couple of cycles. In the study, lenalidomide was dosed at 25 mg and given every 21 days, with an 8-day break. In my experience, lenalidomide at that dose can be difficult for patients to tolerate. However, in this study, the dose intensity is very interesting. About 8 of 10 individuals were able to stay at 20 mg or more of lenalidomide during their treatment course. Obviously, dose reductions occur—mostly with lenalidomide because of cytopenias, in my experience. But if you can find the right dose for that individual, then tafasitamab has some activity by itself.

It appears that when you add tafasitamab to lenalidomide that you increase the potential for efficacy. In relapsed/refractory diffuse large B-cell lymphoma, when you look at the data with tafasitamab, if you aren’t going toward second-line platinum-based therapy to try to get to a transplant, starting tafasitamab-lenalidomide in earlier lines of therapy—potentially even 1 prior line of therapy if you can get those individuals into a complete remission [CR]—is where the curves of the duration of remission in people in a CR has showed a substantially high percentage of people remaining in CR over time. That’s one of the encouraging signs of this drug and regimen. That’s not to mean that if you’re second line or beyond that you don’t have the potential to derive benefit. But that benefit, at least in the curves, are in people who can get into a CR. You can see some people who go from PR [partial response] to CR over time, but it’s important with this drug, as I was alluding to about dose intensity, and getting those doses of tafasitamab in early to gain disease control.

When you introduce lenalidomide at the dose that it was introduced in, one thing I’m very cognizant about with this regimen as they’re starting therapy is their creatinine clearance. In this study, everybody had a creatinine clearance greater than 60 mL/min. Because if you’re borderline or below that, you’d be talking about dose reductions. There could be some tolerance issues. Cytopenias were one of the things that stuck out and may require dose holds or dose reductions with the lenalidomide fatigue. As in this case, fatigue was one of the issues. But then you start to figure out what’s disease-related fatigue vs lenalidomide-related fatigue. You can see diarrhea being one of the issues. Then we’re thinking about infections from that standpoint.

When I look at the AE [adverse event] profile of tafasitamab-lenalidomide, for that first year of therapy, when you’re giving lenalidomide plus tafasitamab, the toxicities are being driven mostly by the lenalidomide. That is foretold because after 1 year in those individuals who are still in response and continue on the tafasitamab given every other week, you see a lot of the cytopenia grading scale back. I see a lot of the fatigue and diarrhea fall off. As far as single-agent tafasitamab in individuals who are doing well, we don’t know because we don’t have randomized studies of stopping after 1 year vs continuing tafasitamab. But I truly feel in relapsed DLBCL when you look at the disease space that the tafasitamab at 1 year and beyond is likely adding to that durability.

A review of the methods and data from a clinical trial investigating a combination therapy for relapsed/refractory DLBCL.

R/R DLBCL: Safety and Efficacy Data from the L-MIND Trial

 With third-line therapy, at least in my practice, at the time of relapsed/refractory diffuse large B-cell lymphoma, we’re having a discussion about second-line therapy. I’m already starting to introduce the spectrum of therapies that could be used in the third-line setting, because the odds are against the patient to obtain a response that allows them to go to consolidative autologous transplant, often regardless of when they relapsed.

Many times, anti-CD19 CAR [chimeric antigen receptor] T-cell therapy may be in the discussion, but it takes an army to have 1 CAR T cell done. It doesn’t mean that it can’t be done. It just needs to be a well-oiled machine, and there are very important steps along the way. That’s a partnership between the community oncologist and a CAR T-cell infusing center. Sometimes they’re already at the CAR T-cell center, but there are very similar checkpoints along the way. There are 3 approved CAR T cells in the third-line setting: axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel. In the third-line space, none of them have been compared head-to-head against one another, so to look at the efficacy and toxicity data, you have to look at the individual constructs and what best fits for your patients and their timelines.

In regard to non-CAR T-cell therapies that could be used for this patient, after 2 prior lines of therapy, polatuzumab plus or minus bendamustine plus or minus rituximab could be used. With pola–BR [polatuzumab vedotin, bendamustine, rituximab], if you’re going to use BR [bendamustine, rituximab], then polatuzumab in that third-line treatment setting would be reasonable. Because the heavy lifting in that study and what led to the survival advantage was likely because of the polatuzumab vedotin, which is a CD79B antibody-drug conjugate, with the warhead being an MMAE. That’s a warhead similar to what’s carried with brentuximab vedotin in Hodgkin lymphoma, lymphoblastic large cell lymphoma, and very rarely some CD30-positive diffuse large B-cell lymphomas.

In this patient’s case, they received tafasitamab-lenalidomide, and we can go into further detail about that regimen and the intricacies that I see with that regimen. There’s also a newly approved drug called loncastuximab tesirine, which is a CD19 antibody-drug conjugate. Different from polatuzumab vedotin, this warhead is a pyrrolobenzodiazepine, or PDB, dimer. It’s a different warhead, and there are potentially some different adverse effect profiles. A lot of the adverse effect profiles are at least mitigated by some of the experience of using this drug, but also the dosing strategy of this drug, where in the initial 2 cycles, the dose is higher and then cut by 50% for the remaining every-3-week doses for up to 1 year of therapy.

Selinexor is an oral therapy. It’s an XPO inhibitor, a fairly new class of medicine. We’re trying to figure out how to use this drug in relapsed/refractory diffuse large B-cell lymphoma, but it has been seen and is going to be used in later diffuse large B-cell lymphoma. Clinical trials are always a good option for those who have clinical trial access and meet the eligibility criteria. We’re seeing some drugs being put in combination, whether it’s with chemotherapy or other more targeted therapy approaches in clinical trials. Bispecific antibodies are 1 type of clinical trial drugs in the relapsed/refractory setting that’s garnering a lot of attention. Best supportive care comes down to a long discussion about the disease biology and whether we could do palliative radiotherapy to areas that are causing pain or threatening organ function.

While they were retrospective data, if there’s anything that SCHOLAR-1 taught us, it’s to have very low expectations for that third-line chemotherapy-immunotherapy regimen. We’ve seen across the board what gem-ox [gemcitabine, oxaliplatin] has done in that setting, where you may see responses, but the median PFS [progression-free survival] is very short. Even in those individuals who are obtaining a response, at the next response evaluation, they’re already progressing. That’s in older data sets. Now we have third-line CAR-T cell, where you’re seeing curves plateauing around 40% at 4 to 5 years post-CAR T cell in the clinical trial arena, and we have real-world data in CAR T cell showing similar initial outcomes and hopeful durability over time.

There’s still space for other therapies, because CAR T-cell therapy is having difficulty accessing all available patients who may be amenable to CAR T cell or may not be willing or in the right situation to get CAR T cell. In that case, there are third-line therapies like tafasitamab-lenalidomide, loncastuximab tesirine, and polatuzumab–BR [bendamustine, rituximab]. If I’m going to use polatuzumab-BR [bendamustine, rituximab], it’s going to be in a population that I’m going to potentially have something for afterward.

I’ve started to use polatuzumab-rituximab more as what I call pre-apheresis bridging or as a pre-apheresis holding therapy to hold the disease in check while I try to get them to their CAR T-cell therapy. Clinical factors and prior treatment regimens may influence this a little more as CD19-engaging technologies move into potentially the second-line space, like tafasitamab-lenalidomide, and even in the third-line space with loncastuximab tesirine. If a patient has received a CD19-engaging agent prior to CAR T cell, that doesn’t necessarily mean that I’m not going to give them CAR T cell. We’re going to see data of the situation that I just described come out of the real world. We’re going to have to learn what having gotten a CD19-engaging agent means to the efficacy of cellular therapy. There are in vitro data looking at this that say it may not be as big of a deal as we’re concerned about, but that often has to bear out in experience over time.

Dr Matthew Lunning describes the available third- and subsequent-line treatments for patients with relapsed/refractory DLBCL (R/R DLBCL) who aren’t eligible for transplant.

Available Third- and Further-Line Treatment Options for Transplant-Ineligible R/R DLBCL

 In second-line therapy, chemotherapy-refractory disease is much more common than we think, especially in the era of receiving rituximab as first-line therapy. I’d argue that responses amenable to going on to an autologous stem cell transplant account for maybe 20% to, at most, mid-30% of the patients. When you’re meeting a patient with second-line diffuse large B-cell lymphoma [DLBCL], the odds are that with chemotherapy-immunotherapy or platinum-based chemotherapy-immunotherapy, they’re more likely not going to obtain a response amenable to consolidative high-dose therapy and autologous stem cell transplant. Taking that away from other regimens that classically wouldn’t be used as a bridge or salvage therapy toward stem cell transplant in that transplant-ineligible population, I’d argue that the response rates are in the 30%-to-40% range, but you’re looking at a much lower complete remission rate.

The challenges include that we often want to ignore the history of their prior lines of therapy and how they tolerated it, because we were hoping that with subsequent therapies that we’d be able to tweak or fine-tune the chemotherapy regimen. But historically, in my experience, with patients who’ve had difficulties with prior lines of therapy with chemotherapy, giving chemotherapy again will often have the same or similar difficulties with chemotherapy. Even if you try to massage the regimen, they’re likely to still have similar issues, especially if those issues were more nondescript, like progressive fatigue or difficulty with cytopenias that allow them to continue on their second-line or beyond therapy as more on schedule.

One of the difficulties with aggressive non-Hodgkin lymphomas is that you want to keep them on schedule. What DLBCL and other aggressive lymphomas love is a break in therapy because of toxicity. The double whammy is when you have people who have aggressive lymphomas who are getting treatment delays and the odds of the chemotherapy being ineffective are quite high. They’re not only progressing through the therapy but also having toxicities to that ineffective therapy.

There’s a cadre of patients, a very small percentage of patients, who we consider as having primary refractory or primary progressing lymphomas. Those patients are rolling into immediate second-line therapy because they still have active disease. There’s a difference between patients who are typically relapsing within a year of their diagnosis or about a year from the end of first-line therapy. Those patients may not do as well.

We know from the SCHOLAR-1 data looking at primary refractory or relapsing, or those refractory to second-line therapies, that those patients do quite poorly with subsequent lines of therapy with overall response rates of 27% and CR [complete response] rates of 7% in CT-based response criteria. But the median overall survival in that population is around 6 months. I’d think that would be a population of interest. Even though some of us don’t do surveillance imaging, perhaps that’s why the NCCN [National Comprehensive Cancer Network] Guidelines allow surveillance imaging every 6 months for 2 years. But there’s a big difference between surveillance imaging and for-cause imaging, at least in my opinion.

An expert explains the options for patients with DLBCL who develop chemorefractory disease in second-line treatment.

Chemorefractory Disease in Second-Line DLBCL Treatment

 Hi, my name is Matthew Lunning. I’m from the University of Nebraska Medical Center and I’m here with 

™ to talk about a case of diffuse large B-cell lymphoma. This is a 64-year-old man who presented with stage III diffuse large B-cell lymphoma. What’s interesting about this situation is patients with diffuse large B-cell lymphoma can present with all different flavors of their disease.

In this individual, their disease was causing them to have significant reduction in their performance status. They had been quite an active individual, but with the onset of their large cell lymphoma, their performance status declined. At the time of diagnosis, their performance status was 2. They had an elevated LDH [lactate dehydrogenase], which was nearly 4 times the upper limit of normal. Based on their NCCN [National Comprehensive Cancer Network]–IPI [International Prognostic Index] score, they were high risk with a total score of 6. Looking into their past medical history, they had hypertension but no other comorbidities of interest. Their hypertension was well controlled.

At the time of diagnosis, it was felt that there was significant disability due to the disease. We felt very confident that if we could get the disease under control, this individual could hopefully return to their prior performance status 6 to 12 months from their diagnosis. In this setting, there was no MYC, BCL2, or BCL6 rearrangements, so this wasn’t a high-grade B-cell lymphoma with double-hit or triple-hit biology.

Given these findings, despite the high-risk IPI score and the fact that the patient didn’t have double-hit or triple-hit biology, he was started on R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] chemotherapy. This was given at full dose because his performance status was mostly driven by the disease and not necessarily because of any underlying comorbidities. During the induction therapy, he had some issues with toxicity related to the neutropenia. He had neutropenic fever and was given growth factor support with subsequent cycles of therapy. There was also the onset of fatigue that limited giving the regimen on an every-3-week schedule that we’d prefer, as well as some mild neuropathy.

Fortunately, after 3 cycles, a CT scan in the interim portion showed a very good response based on CT criteria. After 6 cycles of R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] via a PET [positron emission tomography]–CT, there was evidence of a metabolic complete remission based on the Deauville scoring system. At that point, he was transitioned from the chemotherapy portion into active surveillance, where we’d see him every couple of months and reassess physical examination, how they’re doing, and laboratory values.

In my practice, I don’t do surveillance imaging routinely in those who are in a complete remission. I ask them how their symptoms are. I’m very mindful to tell them that if they have any symptoms even reminiscent of when their disease was starting, one of the goals is that if they’re going to relapse, to never to let them get as sick as they were at the time of their primary diagnosis. In this case, about 6 months later, shortly after the completion of the induction R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] therapy, they called in with complaints of recent unintentional weight loss and fatigue that they were having difficulty discerning whether it was a lagging chemotherapy fatigue or the fatigue that was driving them down at the time of their diagnosis.

Given that I don’t do surveillance imaging, I’d consider this for-cause imaging. A follow-up CT scan unfortunately demonstrated that there was likely evidence of relapsing disease. We got a biopsy because, very rarely, you can have retrograde transformations. We got another biopsy confirming diffuse large B-cell lymphoma. At that time, we had a long discussion about whether they’re a transplant candidate. I take into consideration not only the disease at the time of diagnosis but the tolerance to the frontline therapy. Basically, we wanted to consider our treatment options to go either toward transplant or against transplant, with my reservations about whether they’d be a transplant-eligible candidate given their prior induction experience.

In this setting, they were given R-gem-ox [rituximab, gemcitabine, oxaliplatin]. I like this regimen when I’m on the fence about transplant eligibility. Because if the patient goes into complete remission and their performance status improves, then you could consider consolidating with an autologous transplant. Whereas if they have chemotherapy-refractory disease, then you’d move on to potentially a third-line therapy.

With the recent approval of axicabtagene ciloleucel in the second line in the CAR [chimeric antigen receptor] T-cell space, that throws a wrinkle here regarding patients who have relapsed within 12 months. Unfortunately, with a couple of cycles of R-gem-ox [rituximab, gemcitabine, oxaliplatin], the patient’s disease was growing, his symptoms didn’t improve, and his neuropathy was slightly worse, so he wasn’t a candidate for consolidative stem cell transplant. We had a long discussion. The patient lived 50 miles away from a health care facility, didn’t have reliable transportation, and was unable to obtain continuous caregiver support. That made it very difficult to give CAR T-cell therapy. At that time, we had a long discussion about next lines of therapy, and the patient decided to proceed to third-line tafasitamab-lenalidomide. At this point, the patient remains on tafasitamab-lenalidomide and his fatigue has mostly resolved.

Matthew Lunning, DO, FACP, presents the case of a 64-year-old man with diffuse large B-cell lymphoma (DLBCL) and shares his initial impressions.

Matthew Lunning, DO, FACP | Authors

Articles

Unmet Needs and Future Directions for Patients with R/R DLBCL

R/R DLBCL: Data from the RE-MIND2 Trial

R/R DLBCL: Safety and Efficacy Data from the L-MIND Trial

Available Third- and Further-Line Treatment Options for Transplant-Ineligible R/R DLBCL

Chemorefractory Disease in Second-Line DLBCL Treatment

Case Presentation: A 64-Year-Old Man with Diffuse Large B-Cell Lymphoma