John M. Burke, MD

: What are the potential therapy options for this patient experiencing a relapse of his cancer?

: The NCCN [National Comprehensive Cancer Network] guidelines [for] options available for patients with relapsed/refractory DLBCL include gemcitabine/oxaliplatin with or without rituximab, polatuzumab vedotin [Polivy] with or without bendamustine and rituximab, or the combination of bendamustine and rituximab alone.

 Of course, bendamustine and rituximab have a label for 2 or more prior therapies, which this patient has not had; he has only had 1. But the study included patients in the second line, so it was a bit of an odd label based on the data.

Other chemotherapy regimens include CEPP [cyclophosphamide, etoposide, prednisone, and procarbazine], CEOP [cyclophosphamide, etoposide, vincristine, and prednisone], dose-adjusted EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin], and GDP [gemcitabine, dexamethasone, cisplatin], gemcitabine/vinorelbine, [all with or without] rituximab. Then the new March 2021 | Case-Based Roundtable Meetings Spotlight 17one is tafasitamab [Monjuvi] plus lenalidomide [Revlimid].

In certain circumstances, the NCCN listed brentuximab vedotin [Adcetris] for CD30+ disease. That does not have a label. There’s bendamustine with or without rituximab, ibrutinib [Imbruvica] for nongerminal center B-cell-like subtype. Also, selinexor [Xpovio] is listed as a third-line treatment. Chimeric antigen receptor [CAR] T-cell therapy probably has a separate category, but the American label on CAR T-cell therapy is for third line and beyond. My understanding is that you probably [would have] trouble getting this treatment paid for outside a clinical trial in the second-line setting right now.

What is the rationale for combining tafasitamab and lenalidomide, as this patient received, that led to approval by the FDA?

This patient received tafasitamab plus lenalidomide [after a relapse of his DLBCL]. On July 31, 2020, the FDA granted accelerated approval to tafasitamab plus lenalidomide for relapsed DLBCL.

Tafasitamab, formerly known as MOR208, is an anti-CD19 monoclonal antibody. It has been modified on the Fc portion to increase its antibody-dependent cellular cytotoxicity and also antibody-dependent cellular phagocytosis. That is, it binds the macrophages to allow them to phagocytose the cancer cells as well, which causes some direct cell death. As a single agent, tafasitamab has modest activity, but where it really was thought to be more exciting was in improving the activity of lenalidomide. Lenalidomide can activate T and natural killer cells, and so the thought was that perhaps the increased antibody-dependent cellular phagocytosis and cellular cytotoxicity aspects of tafasitamab combined with lenalidomide would be synergistic. Lenalidomide has some activity in large cell lymphoma and it is proven in other lymphomas, but it was not approved in DLBCL.

Which trial looked at this combination, and what was the design of the study?

The hypothesis [for tafasitamab plus lenalidomide] was tested in a clinical trial called L-MIND [NCT02399085].

This was a phase 2 single-arm open-label study. Patients with relapsed/refractory DLBCL were eligible for the trial, but they had to have received 1 to 3 prior regimens and they had to not be eligible for stem cell transplant.

The trial excluded most patients with primary refractory disease. This was a relatively favorable population because they excluded some of the [patients with worse disease]. Patients who enrolled went on to receive the combination of tafasitamab and lenalidomide. Lenalidomide was dosed—a big dose—at 25 mg daily on days 1 through 21 of a 28-day cycle, 3 weeks on, 1 week off. For the first 3 cycles, tafasitamab was dosed weekly on days 1, 8, 15, and 22. There was also loading dose during week 1 on day 4, but that was just cycle 1. After the first 3 cycles the dosing schedule of tafasitamab was changed to days 1 and 15, so every other week. It was continued through 12 cycles and after those 12 cycles, lenalidomide was stopped and tafasitamab was continued as maintenance long-term treatment until [disease] progression. This is indefinite therapy, as we do with some other diseases, but we are not used to that with DLBCL. The primary end point of this study was objective response rate [ORR], and the secondary end point included progression-free survival [PFS] and overall survival [OS], and duration of response [DOR].

Eighty-one patients were enrolled on [L-MIND] and their median age was 72. The median prior lines of therapy was 2, but about half of patients have received only 1 prior line of therapy. The other half had received more than that. So as relapsed large cell lymphoma trials go, you can compare this with the others, but this was a relatively less heavily pretreated population. Eleven percent received a prior stem cell transplant, 44% were refractory to their last prior therapy, and although I [mentioned] that they excluded primary refractory disease, they actually included a few. Nineteen percent looks like kind of a complicated story, but they actually changed the trial design a little bit as the trial was going on.

What were the efficacy data seen in the L-MIND study that led to approval of the therapy?

The ORR was 60% [95% CI, 48%-71%], which is high in a relapsed/refractory DLBCL trial, and the complete response [CR] rate was 43% [95% CI, 32%-54%]. The median DOR was 22 months and the DOR, broken down by whether it was partial response [PR] or CR, [showed] patients who achieved a CR had much better duration of response than those who achieved only a PR. If a patient achieved a CR, the median duration was not even reached at 2 years, whereas if you had a PR, the median duration was 4 months.

Median PFS was 12 months [95% CI, 5.7%-not reached]. The median OS was not yet reached [95% CI, 18.3–not reached]. At 12 months, 74% of patients were still alive, at 18 months it was 64%, and the number of deaths between 12 and 18 months was pretty low.

What was the toxicity profile of this therapy that oncologists should be aware of?

The key toxicities [found on the L-MIND study] are neutropenia, anemia, and thrombocytopenia. Grade 3 neutropenia was 27% and grade 4 at 21%, so a total 48% of patients [were] getting grade 3 or 4 neutropenia. Any-grade febrile neutropenia was only at 12%, so it was not significant, but that’s one of the key hematologic toxicities to keep in mind.

The [most common] nonhematologic toxicities were fatigue, diarrhea, cough, fever, edema, respiratory infection, and loss of appetite. Grade 3 and 4 rash sticks out at 9%, and most of the rest are pretty uncommon. Diarrhea was common at 32%.

Fifty-one percent [of patients on the trial] had serious adverse events [AEs], with 12% discontinuing combination therapy due to an AE. Nineteen of these serious AEs were thought to be related to treatment and 13% of these events led to death. Upon discontinuation of lenalidomide after cycle 12, or earlier if they had toxicities, the rate of these AEs went down during tafasitamab monotherapy.

Toxicities that occurred during the first 12 cycles of combination therapy and toxicities with tafasitamab monotherapy in 37 patients, who either made it to a year or they came off lenalidomide because of toxicities, [went down]. The number of patients with grade 4 neutropenia went down [to 19 with the combination therapy and 5 with the tafasitamab monotherapy] as [did the number of] patients with anemia, [34 patients grade 1-3 compared with 10 patients with grade 1 anemia, respectively]. Basically, everything went down. This indicates that most of these toxicities are due to lenalidomide, and when the patients can get through that first year again on tafasitamab monotherapy, the toxicities go down.

1. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 4.2020. Accessed February 16, 2021. https://bit.ly/35H3YW0 

2. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. FDA. Updated August 3, 2020. Accessed February 16, 2021. https://bit.ly/34Emq2z 

3. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. 

. 2020;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4

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The NCCN guidelines options available for patients with relapsed/refractory DLBCL include gemcitabine/oxaliplatin with or without rituximab, polatuzumab vedotin with or without bendamustine and rituximab, or the combination of bendamustine and rituximab alone.

Toxicities From Tafasitamab Monotherapy Are Less Severe After Discontinuing Lenalidomide in R/R DLBCL

 We have seen tremendous progress in diffuse large B-cell lymphoma in the last 4 or 5 years, with 2 FDA-approved CAR [chimeric antigen receptor] T-cell products, and perhaps a third to come. Polatuzumab vedotin was approved last year in combination with bendamustine and rituximab. This followed the first randomized trial in relapsed large cell lymphoma in recent memory to improve overall survival. That’s a big deal.

We’ve talked a lot about tafasitamab and lenalidomide today. Selinexor is a recently approved oral drug. This is an inhibitor of exportin 1. In the study, there were lower response rates, but in the high 20% range, and responding patients did pretty well. So that’s a new option for patients. There’s a lot going on, we have a lot of new options.

It’s interesting to think about what the right algorithm is right now. As you asked, how do you sequence these new drugs? I don’t think there’s a right answer right now. A lot of it is going to come down to sitting with an individual patient and thinking through the pros, cons, risks, and benefits with them and making the best decision for that patient. Again, if the patient is transplant eligible, the standard remains using a salvage chemotherapy regimen followed by stem cell transplant. If they are transplant ineligible but your goal is to get them to CAR T-cell therapy, then, I haven’t talked to my CAR-T doctors who I refer to about this, but I suspect they’re going to favor something like rituximab, gemcitabine, oxaliplatin, although tafasitamab, lenalidomide may be reasonable. I know there are concerns about bendamustine pre-CAR T-cell collection, but polatuzumab vedotin with bendamustine, rituximab or polatuzumab vedotin with rituximab without bendamustine could be used. So we have a number of different choices there.

If you feel the patient is not headed toward CAR T-cell therapy because of performance status or comorbidities, the field is wide open. Polatuzumab vedotin, bendamustine, rituximab, tafasitamab, lenalidomide, and selinexor are all available in the third-line setting, plus good old-fashioned chemotherapy.

You can sit down with your patients. I think each of these options has pros and cons to think through. With polatuzumab vedotin, a pro is the survival advantage that was seen in a randomized phase 2 trial. Tafasitamab/lenalidomide has a great response rate and a manageable toxicity profile. One disadvantage of tafasitamab/lenalidomide is that we don’t have a chemotherapy comparator arm. We only have the lenalidomide-alone comparator arm. My understanding is that there are some retrospective data going on with an effort to do a chemotherapy comparator study. So, stay tuned on that.

As third-line therapy, CAR T is preferred if your patients can get to it. Not only does CAR T have excellent response rates, but we’re seeing prolonged disease-free survival in about a third of those patients. There are a lot of complex choices to make, and you have to sit down with your patients and go through some of those pros and cons.

In this era of rapidly changing options for diffuse large B-cell lymphoma, doctors certainly need to familiarize themselves with these new drugs and their risks, benefits, and adverse effects. I think having early discussions with transplanters and CAR T-cell therapy providers to whom you refer patients is really important, if you’re not doing those treatments yourselves. It’s important to get them involved in helping map out how to proceed and get this patient to the best available therapy.

Then, it’s important to move quickly, I think it’s conceivable with all these new options that we can turn this disease into a bit more of a chronic disease than it’s been. In these patients who can’t get transplants or who relapse after transplant, relapsed large cell lymphoma has a terrible prognosis. From retrospective studies, we know the median survival is on the order of months. So, it’s essential that we move quickly, get them on some of these effective treatments soon, and again, have those early conversations with your transplant and CAR T doctors you work with to make sure you make as many of these options available to your patients as you possibly can. That’s going to give your patients the best outcome.

A 77-year-old woman presented with loss of appetite, fatigue and shortness of breath

PMH: post-menopausal; DM, medically controlled

PE: palpable inguinal lymphadenopathy; splenomegaly

Core needle biopsy of the inguinal node: CD20-positive diffuse large B-cell lymphoma, non-GCB subtype. FISH panel: t(14;18) with a BCL2 rearrangement; no MYC or BCL6 rearrangement

Whole body PET/CT scan showed FDG avidity the inguinal lymph node region, largest node 3.3 cm; splenomegaly; and a small suspicious lung lesion

Bone marrow biopsy: involvement with DLBCL

Conclusion: stage IV DLBCL, non-GCB subtype

IPI score high-risk; CNS relapse score intermediate risk

End-of-treatment PET/CT demonstrates a Deauville 2 complete remission

1 year later while in surveillance she presents with new cervical, axillary, mediastinal, and abdominal lymphadenopathy

Core needle biopsy of an axillary node confirms a relapse of DLBCL, non-GCB subtype

Based on her age of 78 years and performance status, you consider her to be transplant-ineligible

You elect to initiate tafasitamab + lenalidomide

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Progress Made in Treating R/R DLBCL

 In regard to this particular patient case example, this was an elderly patient who had relapsed 1 year after completing R-CHOP [rituximab with cyclophosphamide, doxorubicin, vincristine and prednisolone] chemotherapy. The options, in theory, would have included stem cell transplant. Right now, CAR [chimeric antigen receptor] T-cell therapy is only approved as a third-line treatment.

Certainly, there are other chemotherapy regimens that could have been chosen here. This patient would have fit into the L-MIND study criteria, having had relapsed disease and because her physician did not feel that she was transplant eligible based on her age and performance status. I think this was a reasonable choice for this patient. You could use it in the second line, or you could use it as third-line therapy or beyond.

One of the questions about this drug is whether it should be used before CAR T-cell therapy. Why? Well, the drug targets CD19. The theoretical concern is that maybe the targeting of CD19 will remove that protein from the cell, and thereby make the CAR T-cell therapy, which is also targeting CD19, ineffective. Of course, you don’t want to do that.

We don’t have a tremendous amount of data on the answer to that question. There are some in vitro data that were presented at ASH [the American Society of Hematology annual meeting] suggesting that removal of CD19 from the cells probably doesn’t happen. That has been looked at in CLL [chronic lymphocytic leukemia] as well. It does not appear that there’s a big reduction in CD19 on the surface of the cell in CLL after tafasitamab exposure. There have been a few case reports, but not a lot, on successful CAR T-cell therapy after tafasitamab. But again, the data are a bit sparse. That’s one of the theoretical concerns about using tafasitamab in the pre-CAR T-cell therapy space. We don’t yet know the answer, and hope that more data forthcoming will help us understand that impact and relationship better.

R/R DLBCL: Treating With Tafasitamab Plus Lenalidomide

 I think Re-MIND is a really interesting trial. A lot of people may not know about it just yet. It was presented on at ASH [the American Society of Hematology annual meeting] in 2019 and more recently at some of the summer meetings. This was a retrospective study. The scenario here was that we have a combination of tafasitamab plus lenalidomide that appears to be effective, but the question was, what are the individual contributions of the different drugs? We don’t really have great data on the outcomes with lenalidomide alone. So how much of the benefit here is from the lenalidomide, how much is from the tafasitamab, and how much of it is from the combination?

There are a couple of ways to answer that question. One is to do a randomized trial where you compare the individual arms and the combination arm. Or, you can do what they did instead, which was really innovative. They went back and did a retrospective study. They found more than 400 patients who had been treated with lenalidomide alone, as monotherapy, for relapsed large cell lymphoma. This is more commonly done in Europe, so most of the patients on this trial came from Europe. They did a matched comparison between the L-MIND patients and the patients in this retrospective cohort. So of those 400 patients, they matched them for these covariates, including age, performance status, white blood cell count, and a whole bunch of other factors, to get as close of a matching between the 2 groups as possible. They came up with 70-something patients in each group who were sort of head-to-head comparisons. Of course, they weren’t identical, but when you look at the data they were pretty darn close to being well matched. Then they compared the outcomes in those, I think, 76 patients in each group.

When you look at the overall response rate in the L-MIND cohort, again it was 67%, whereas in the lenalidomide-alone cohort, it was 34%. So, basically almost double the response rate with the combination regimen. The complete remission rate was 40% with the combination regimen versus 13% with single-agent lenalidomide. And the overall survival was significantly improved with the combination regimen compared with single-agent lenalidomide.

As best as we can tell using this innovative design, it would appear that the combination significantly improves outcomes compared with lenalidomide alone. This indicates that the addition of tafasitamab is clearly providing a benefit above and beyond what one would get with lenalidomide alone. I’m sure it was not an easy study to conduct, but they were able to do that without having to conduct a randomized phase 2 or randomized phase 3 trial, and saved a lot of time and money. They were able to make this treatment available to patients more quickly. It’s a neat design, and I’d encourage folks to take a look at the study.

John M. Burke, MD | Authors

Articles

Toxicities From Tafasitamab Monotherapy Are Less Severe After Discontinuing Lenalidomide in R/R DLBCL

Progress Made in Treating R/R DLBCL

R/R DLBCL: Treating With Tafasitamab Plus Lenalidomide

R/R DLBCL: Observations From the Re-MIND Study