Dr. Abramson:
Welcome to Personalizing Treatment Pathways in Relapsed/Refractory Diffuse Large B-cell Lymphoma and 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.
Dr. Soumerai:
And I'm Jake Soumerai, also from Mass General Hospital.
Dr. Abramson:
Our second case today will focus on second-line management of relapsed diffuse large B-cell lymphoma. This case is L.R., a 74-year-old woman with DLBCL non-GCB subtype. Stage on PET-CT is IV, based on multifocal extranodal involvement. The IPI score is 4, and FISH testing for MYC BCL-2 and BCL-6 do not show double-hit rearrangements. Let me first ask Dr. Haydu, you've got a 74-year-old patient with non-GCB, DLBCL with advanced stage and a high-risk IPI score. What initial therapy would you select?
Dr. Haydu:
Yes. Thank you, Jeremy. This patient is a ideal candidate for Pola-R-CHP, which when compared to R-CHOP in patients with an IPI score of 2 or higher for DLBCL, had a progression-free survival benefit. The non-GCB subtype had a particular benefit in that study, and this is very high-risk disease, a high IPI score, advanced stage. This is the ideal person that I would think about treating with Pola-R-CHP.
Dr. Abramson:
Terrific. That's exactly what happens in this case. This patient receives six cycles of Pola-R-CHP and achieves a complete remission. Patient is then followed with surveillance, and unfortunately 9 months later, she develops abdominal distension, abdominal discomfort, and is found to have a symptomatic relapse with diffuse peritoneal lymphomatosis. Imaging shows diffuse peritoneal studying and mesenteric studying, along with some adenopathy as well above the diaphragm. This patient is now 75 years old and has a high tumor burden relapse of DLBCL. Let me ask Dr. Soumerai. Jake, without knowing anything else about this case, you've got a 74-year-old patient. I guess I would first ask, is she a candidate for curative intent therapy in the second line?
Dr. Soumerai:
The answer I would say is yes. Obviously you'd have to evaluate the patient, but it's very important to remember that CAR-ineligible and transplant- ineligible are not the same thing. That although this patient is clearly not a transplant-eligible patient, the vast majority of patients who are transplant-ineligible remain CAR-eligible. For a patient like this, I would really focus on trying to overcome whatever barriers exist to try to ensure that we can deliver this patient curative intent therapy in the second-line setting.
Dr. Abramson:
Then, Dr. Haydu, Erika, following up on that question, what are the questions you would ask about this patient to determine whether in fact she is CAR-eligible?
Dr. Haydu:
Yeah. I think one thing that makes someone CAR-eligible or not is if the logistics for CAR T-cells are possible for them, including being able to travel to a CAR center to receive the cells, how long they would need to stay close to the center, having someone, a caregiver who can help support them through this process. I think there's no clearly defined medical footprint for what a CAR-eligible person looks like, but you have to look at the whole picture. Are there significant medical comorbidities? You want to think about renal function. Cardiac function by itself is not a comorbidity, but I'd want to make sure the person could tolerate the lymphodepleting chemotherapy, any sort of fluid shifts that might occur with CRS, although I don't have any strict cutoffs for cardiac function here.
Then also what their course was through chemotherapy. Do they have ongoing infections right now that make lymphodepleting chemotherapy a little bit more challenging? But I think every patient should really strongly be considered for CAR T-cells because that's really the best evidence we have for a potentially curative therapy. We have evidence for liso-cel for people no matter how long the relapse has been from their initial therapy based on the PILOT study in this non-transplant-eligible population where the therapy is effective and safe. I think that can provide some extra reassurance for this particular patient.
Dr. Abramson:
Yeah. I think one essential point is there's no upper limit of age to undergo CAR T-cell therapy, and there is moderate organ comorbidities are appropriate for CAR T-cell therapy. Now, Erika doesn't have an absolute limit for cardiac function, but you probably wouldn't take a patient with an EF of 10% and uncompensated congestive heart failure.
Dr. Haydu:
That's fair.
Dr. Abramson:
Dr. Haydu has her limits as we all do, but moderate cardiac renal and hepatic comorbidities are entirely appropriate for CAR T-cell therapy where they might be limiting for something like an autologous stem cell transplant. Yet, one thing we know is that a great many patients in the United States, and in fact the majority worldwide of patients who are eligible for a CAR T-cell therapy don't necessarily ever get to a CAR T-cell center. A lot of that is based on geography and logistics.
Jake, this is one such patient. This patient is getting their treatment in Northern Maine. They live a long distance from a CAR T-cell center. Multiple hours of driving, would require relocating for about a month to that treating center to undergo therapy. The patient just says, "I'm not interested in that at all. I want treatment that I can get closer to home within a half hour of where I live." The key question now in the modern era is what can we offer a patient like this today if she's not going to be able to access a CAR T-cell?
Dr. Soumerai:
We have a number of very active regimens that can be used in the second-line setting for patients who are not able to tolerate or access CAR T-cell therapy. I would really focus on three regimens. One is glofitamab with GemOx. This is a regimen that has been compared with our GemOx in relapsed refractory large cell lymphoma in the STARGLO study. This was a positive study with improved survival outcomes in this setting. The median progression-free survival in patients receiving Glofit-GemOx was 13.8 months with 54% of patients still alive at 2 years.
This is a very encouraging regimen for patients who are not able to access CAR T-cell therapy. I would just highlight that we don't yet know whether this regimen has curative potential. I think that there is hope that with longer-term follow-up, that we will establish that a number of patients are cured with this approach. But unlike with CAR T-cell therapy where we have a number of years really establishing that we're curing patients in the relapsed setting, this treatment, I think that at the current time, we can state that this is achieving long-term disease control in a high proportion of patients.
Dr. Abramson:
Yeah. I will highlight that we just updated that data at the 3-year time point at ASH, and the median progression-free survival on the Glofit-GemOx arm is now 14.4 months for the overall population. About 40% of patients in the overall population remaining progression-free at 3 years. If we look just at those patients with primary, refractory or early relapsed disease, this high-risk population which this patient would fall into, the median progression-free survival even in that population was 9 months with a CR rate of 56%.
I think even these high-risk, early-relapsing patients can achieve a durable remission with glofitamab GemOx and potentially even cure. I agree, I think we need a longer time to tell, but at 3 years, there is some suggestion of some flattening on that curve. I'm optimistic that those remissions will be durable in a good number of those patients, and it is indeed off the shelf. Dr. Haydu, other than Glofit-GemOx, other second-line options that have been more recently studied or presented?
Dr. Haydu:
Yeah. I would think of two other regimens, both were compared to R-GemOx, which was also the comparator arm in the Glofit-GemOx study. One would be polatuzumab, R-GemOx, and the other was mosunetuzumab with polatuzumab. Both of those were also positive studies. The Pola-R-GemOx regimen had improved response rates, progression-free survival and overall survival, and the most in Pola regimen had improved response rates in progression-free survival with the least amount of follow-up of all of these three studies.
I think those are both really nice options for someone who's already received polatuzumab in the frontline, especially if someone's primary refractory or the relapse is relatively recent. I don't think that's particularly appealing. We'll need more study to understand about re-treatment in that setting. I think I'd be thinking about something that didn't include polatuzumab for this particular case, but I think those regimens are important to think about overall.
Dr. Abramson:
Yeah. For patient like this who was progressing within a year of Pola-R-CHP, Glofit-GemOx among those three regimens probably does make the most sense. Jake, all of a year or so or 2 years ago before we had all of these randomized trials, we talked about things like Pola-BR and tafasitamab/lenalidomide. Do you still think about those regimens in the second-line setting?
Dr. Soumerai:
Not currently. In most patients, those have really become third-line or later regimens for me. I'd say that I typically select those patients only after I've either used or been unable to access CAR T-cell therapy and use and unfortunately have the patient failed by a bispecific approach. I really use those therapies in the multiply relapsed refractory setting.
Dr. Abramson:
Based on this discussion, we did elect to treat this particular patient with glofitamab GemOx or recommended that for this patient's treating team in Northern Maine. One question from the primary oncology team who had less experience administering glofitamab, Erika, this is a bispecific antibody that can cause CRS. How do you administer glofitamab in this regimen in a way to try and minimize the risk of CRS?
Dr. Haydu:
Yeah. I think that's a great point, Jeremy. We've been successful using a prophylactic steroid approach, which has lowered CRS rates with glofitamab monotherapy by about half. That's what I would recommend, prophylactic steroids with this regimen. I also think depending on where the patient lives and the resources, an admission for observation with the first dose of glofitamab when CRS risk is highest could be considered. Then I think a really robust system for if the patient calls with a fever after hours so that the on-call is triaged appropriately and there's a plan for the patient to be seen expeditiously to evaluate for cytokine-release syndrome.
Dr. Abramson:
Yeah. It's very important in the Glofit-GemOx regimen, everybody actually gets a dose of obinutuzumab a week before the first dose of glofitamab to clear out some of the CD20 with the goal of reducing the risk of CRS. Then the glofitamab is escalated weekly from a very low dose to an intermediate dose to the full dose over a three-week period. That does minimize the risk of CRS quite significantly, as does combining it with the gemcitabine and oxaliplatin. With that approach, the risk of CRS in the STARGLO study was 44%, almost entirely low grade and almost entirely occurring during the first cycle of step-up dosing. That is lower than the incidence of CRS, as was seen with glofitamab monotherapy probably reflecting this combinatorial approach, as well as the prophylactic steps that Erika highlighted. This patient completed 12 cycles of Glofit-GemOx. That's eight cycles of glofitamab, gemcitabine, and oxaliplatin, which is followed by four cycles of glofitamab monotherapy to complete 12 total cycles.
This patient did achieve a complete response and is currently monitored in surveillance. Key clinical takeaways for this case, patients with second-line DLBCL without access to CAR T-cells can be treated with glofitamab GemOx and achieve durable remissions. Other non-CAR second-line regimens for non–transplant-eligible patients with DLBCL include polatuzumab, rituximab, and gemcitabine, oxaliplatin, Pola-R-GemOx, or the chemotherapy-sparing mosunetuzumab, polatuzumab vedotin combination from the SUNMO trial. Both of those you heard about a moment ago. Selection of the optimal therapy for patients should really consider the underlying disease, their comorbidities, their patient characteristics, and the prior treatments that they'd been exposed to. This brings us to the end of this case. Please see the other segments for further discussion about the latest research in DLBCL or visit ascopost.com.
