Dr. Abramson:
Welcome to Personalizing Treatment Pathways and Relapse Refractory Diffuse Large B-cell Lymphoma, an ASCO Post Roundtable. I'm Dr. Jeremy Abramson from Mass General Hospital in Boston, and joining me today are two of my outstanding colleagues.
Dr. Haydu:
Hi, I'm Dr. Erika Haydu from Mass General Hospital.
Dr. Soumerai:
And I'm Jake Soumerai, also from Mass General Hospital.
Dr. Abramson:
And our final case for discussion today will focus on the management of multiply relapsed diffuse large B-cell lymphoma.
This case is MB, a 44-year-old man who presents with DLBCL GCB subtype. FISH was performed and showed translocations of both MYC and BCL2, a so called double-hit lymphoma. PET scan showed disease involving multiple lymph nodes above and below the diaphragm, spleen, and skeleton consistent with stage IV disease. The IPI score was 2 based on advanced stage and elevated LDH.
Let me first do a quick question to Erika, which is you've got this young patient with IPI-2 stage IV double-hit DLBCL. What's your treatment of choice going to be as initial therapy?
Dr. Haydu:
In this young man, who's only 44 with double-hit lymphoma with MYC and BCL2 translocations, this is a patient I'd be thinking about treating with dose-adjusted EPOCH-R given benefit over R-CHOP, at least in retrospective studies, for this aggressive biology.
Dr. Abramson:
Jake, let me ask a question about initial therapy of double-hit. Let's say this 44-year-old patient had evidence of extensive marrow involvement, leukemic phase disease, and involvement of the central nervous system. Now, the IPI score is much higher and more high-risk features.
Is that a patient you would consider for anything different?
Dr. Soumerai:
I mean, that is really behaving like some of the early patients that really defined this entity. And in particular patients with CNS involvement, I would be considering even more intensive approaches. For example, something like R-CODOX M/IVAC. And given the CNS involvement in a young patient who's transplant-eligible, assuming that we can achieve a complete response, consolidation even with a thiotepa-based autologous stem cell transplant.
Dr. Abramson:
Thankfully, this patient did not have those features. This patient with IPI-2 stage IV double-hit DLBCL was treated, as Erika suggested, with dose-suggested EPOCH-R. This patient got six cycles and achieved a complete remission.
Unfortunately though, a year-and-a-half later, patient was feeling well, was being followed with routine scans every 6 months with a goal to do that for up to 2 years of remission, and their 18-month imaging showed new adenopathy and liver masses. A biopsy of one of those liver masses confirmed diffuse large B-cell lymphoma with double-hit cytogenetics, a relapse at a year and a half. At this time, organ and bone marrow function are normal. The performance status is 0. This is still a young patient, now just turned 46 years old.
Erika, you now have this patient who's relapsing a year and a half out with double-hit lymphoma with a favorable performance status. What would you do?
Dr. Haydu:
Thank you, Jeremy. In case one, we talked about CAR T cells for early relapse within a year of initial chemoimmunotherapy or primary refractory large B-cell lymphoma. Unfortunately, with the 18-month relapse, this patient would not have been eligible for those studies which demonstrated CAR T cells performed better than autologous stem cell transplant proceeded by high-dose chemotherapy. This would be one of the rare patients that I would be thinking about trying to take them to an autologous transplant. I'd be thinking about some sort of chemotherapy approach to then get them in a remission and taking them to autologous transplant.
Dr. Abramson:
And Erika, this is a 44-year-old patient. What if it's a 74-year-old patient relapsing 18 months out with double-hit lymphoma? How would your approach be different?
Dr. Haydu:
Well, that's another great question, Jeremy. For a 74-year-old person relapsing at an 18-month interval, I'd be thinking about CAR T cells for that person if they were otherwise willing to do it and eligible. Like we talked about in case number 2, we have data for liso-cel in that setting based on the pilot study. And if, for some reason, the person was otherwise not eligible for CAR T cells, didn't want to do CAR T cells, couldn't do CAR T cells logistically, then we could think about some of the second-line regimens we talked about in case 2 for someone who, at age 74, I would probably consider not–transplant-eligible unless there was very extenuating circumstances.
Dr. Abramson:
Unlike that case, this patient clearly is transplant-eligible, and the young, fit, transplant-eligible patient with relapsed disease more than 12 months from frontline chemoimmunotherapy should still be considered today for high-dose chemotherapy and stem cell transplant. Indeed, that was the plan for this patient. The patient would receive a second-line platinum-based chemoimmunotherapy regimen. In this case, the patient received R-DHAP with a goal of inducing remission and taking them to high-dose chemotherapy and autologous stem cell transplant.
Patient received two cycles of R-DHAP. Tolerated it reasonably well. A restaging PET/CT scan, however, after two cycles of R-DHAP showed progressive disease. And at this point, the LFTs are actually increasing because that progressive liver disease is now seems to be causing some compression and elevation of the bilirubin. The kidney function remains normal as does the marrow function and the ECOG performance status. But this patient now has rapidly progressive disease despite second-line therapy and some early hepatic impingement.
Jake, this patient has had a shot at chemosensitivity. This patient is now progressing. They're young, and there appears to be some urgency based on some early impact on hepatic dysfunction. What would you do?
Dr. Soumerai:
I mean, the first thing to remember is that refractory disease with organ involvement should always be taken very seriously. This is a patient where clearly the best approach is CAR T-cell therapy. This was its initial indication, and large cell was in the third-line setting. And this patient clearly would've been a candidate for those studies.
You're targeting either axi-cel or liso-cel. For this patient, I would target axi-cel. I think that there's urgency here to having access to the product in hand. And manufacturing is shorter with axi-cel than it is with liso-cel generally. I would favor axi-cel for this patient.
And I would also administer bridging therapy urgently. For a patient who's already received frontline dose-adjusted EPOCH-R, second-line and more intensive chemotherapy with a DHAP regimen, I would recommend, in this case, typically polatuzumab and rituximab as a bridging option. If there is a single site of disease that's responsible for the worsening liver abnormalities, you might also consider some targeted radiation. Again, the key thing here is to get this patient to the CAR T-cell therapy which has the potential for curative outcome.
Dr. Abramson:
Absolutely. For this patient with clinical urgency, axicabtagine ciloleucel was selected. This particular patient did, indeed, undergo leukopheresis for axi-cel manufacturing and, as you suggested, Jake, received a cycle of bridging therapy with polatuzumab and rituximab but unfortunately did not respond to polatuzumab and rituximab.
The patient then got a pulse of high-dose steroids to try and prevent further worsening of the liver function and did get to the point 18 days later when the axi-cel was returned and underwent axi-cel therapy. The patient underwent the standard 3 days of lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by axi-cel infusion.
This patient then developed grade two cytokine-release syndrome and grade three immune effector cell-associated neurologic syndrome. The tocilizumab and dexamethasone were administered for treatment of the CRS. And as the CRS was getting better, the ICAN started and progressed to the point where the patient was significantly debilitated and having difficulty communicating and speaking and understanding commands.
Dexamethasone was resumed for this, and the drug, anakinra, was added when the patient was not improving on dexamethasone alone. With those two therapies and a tincture of time, the patient did ultimately recover, but it took about 10 days to recover from ICANS. It can, indeed, be a gradual recovery process. Despite that, the patient recovered nicely. And at day 30, the patient achieved a complete remission.
Let me ask Erika. This patient is now in a remission at day 30. How do you follow a patient? Certainly they're at high risk for relapse, but there are also some ongoing potential side effects even after day 30.
How would you counsel this patient and monitor a patient following CAR T-cell therapy?
Dr. Haydu:
I think that that's a great point. I mean, the risk for CRS and ICANS has generally passed by day 30. This person is pretty heavily pretreated at this point and then received additional immune suppression to treat the CRS and ICANS. I would be watching out for infections. They might have prolonged cytopenias. If they're having issues with infections and the IgG level is low, I'll think about giving IVIG. And then I typically re-image around 3 months and then 6 months and would probably have the patient checking in potentially even more frequently than that, depending on if there's any other lingering toxicities after the treatment.
Dr. Abramson:
That's exactly what happens with this patient. And at 6 months, the patient unfortunately has disease progression. They have nodal disease as well as recurrent disease in the liver and now with soft tissue and skeletal involvement. And as we always recommend, doing a biopsy is repeated, and this biopsy does confirm diffuse large B-cell lymphoma.
Interestingly, CD20 is now negative in this patient who's previously received multiple rituximab-containing regimens. CD19, however, continues to be expressed by immunohistochemistry. We now have a patient relapsing after frontline dose-adjusted EPOCH-R, progressing on R-DHAP, and then responding but relapsing after a CD19-directed CAR T cell axi-cel.
Jake, how would you go through thinking about treatment for this multiply relapsed patient with now CD20-negative DLBCL?
Dr. Soumerai:
Thank you, Jeremy. There are a number of options that you could consider in this setting. Obviously, a lack of CD20 expression is concerning when it comes to CD20 directed by specific antibody therapies such as epcoritamab and glofitamab, so I'm going to focus here on some of the alternative approaches that we have in this setting. For example, we have polatuzumab vedotin. This is an antibody drug conjugate targeting CD79B which utilizes MMAE as really the critical component in tumor killing. Polatuzumab vedotin has been combined with bendamustine and rituximab and would be an option in this patient. However, of course, rituximab you could ... I would have some discussion about its utility in a patient with CD20-negative disease. There are multiple CD19-directed therapies in this setting. Most notably, the first would be loncastuximab tesirine. This is a humanized anti-CD19-directed monoclonal antibody which is targeted to PBD with dimertoxin. And this is an agent which, on its own, can achieve high rates of response in multiply refractory patients of about 50%. About a quarter of patients will achieve a complete response, and these can be quite durable.
Alternatively, you could give the other CD19-directed monoclonal antibody, tafasitamab in combination with lenalidomide. This also would be an option in this setting for this patient as well.
Dr. Abramson:
Perfect. Erika, we saw some data not too long ago in a randomized trial and third line and later looking at brentuximab vedotin combined with lenalidomide rituximab compared to len-r alone.
When would you consider that particular regimen?
Dr. Haydu:
I think it's an interesting choice. It turns out that you don't necessarily need to express CD30 to respond to that regimen.
I think it is something that hasn't been targeted yet here. I do think this person, for bridging at some point, received polatuzumab vedotin. That's the same chemotherapy moiety that's on brentuximab vedotin. However, it has a different target, so I wouldn't necessarily consider that a reason not to consider it.
And we know that lenalidomide has activity, in particular, a non-GCB subtype. I believe this person was a double hit, so probably GCB subtype not as important here. But at the same time, I think it's something to consider, particularly in a multiply relapsed person who has had a lot of chemotherapy. Something like antibody drug conjugate or a CELMoD agent, I think, are interesting ways to avoid further chemotherapy and try a different mechanism.
Dr. Abramson:
In this particular patient, we've gone through a number of options. Erika, what would you give?
Dr. Haydu:
I would probably lean toward tafasitamab/lenalidomide. I mean, no CD19 is still expressed. I know they just had a CD19-directed therapy. They had some response, although then progressed. And maybe the lenalidomide after the CAR T cells, if they are still circulating. It's only been 6 months. Might help, maybe help, the CAR T cells work a little bit better. But I also like that it's not particularly marrow suppressive compared to some of the other things you might be thinking about.
Dr. Abramson:
Jake, what would you give?
Dr. Soumerai:
I agree completely with my colleague, Dr. Haydu. I would also give tafasitamab and lenalidomide in this setting.
Dr. Abramson:
I like tafasitamab/lenalidomide as an option with the possibility of maybe jazzing up those emergent CAR T cells that are still in circulation with a lenalidomide while also targeting CD19. But loncastuximab tesirine would also be, I think, a good option for this patient at this point as well.
Going to our key clinical takeaways, options for treating multiply relapsed DLBCL include CAR T-cell therapy and bispecific antibodies, but patients with multiply relapsed DLBCL have often already received CAR T-cell therapy and bispecific antibodies and need additional options for therapy. Those options continue to include polatuzumab vedotin, loncastuximab tesirine, tafasitamab plus lenalidomide, or brentuximab vedotin plus lenalidomide, rituximab, and others. It's important that when selecting a given treatment in a multiply relapsed patient, that we think about what they've previously had to try and select non-overlapping regimens as defined by their mechanism of action, and also be guided in part by patients' comorbidities, underlying biology of disease and disease characteristics.
Antigen loss is important to look at, particularly in terms of CD19 and CD20 because patients can lose either or both antigen expression, and that can certainly help guide our selection of our numerous available options and relapsed DLBCL.
That brings us to the end of this third case. Please see the other segments for further discussion about the latest research in DLBCL or visit ascopost.com.
