Dr. Abramson:
Welcome to Personalizing Treatment Pathways and Relapse Refractory Diffuse Large B-cell Lymphoma in ASCO Post Roundtable. I'm Dr. Jeremy Abramson from Mass General Hospital in Boston, and I'm joined today by two of my wonderful colleagues.
Dr. Haydu:
Hi, I'm Dr. Erika Haydu from Mass General.
Dr. Soumerai:
Hi, I'm Dr. Jake Soumerai from Mass General Hospital.
Dr. Abramson:
And it'll be our pleasure to talk you through some cases today. Our first case will focus on the management of early relapsed, diffuse large B-cell lymphoma.
Our first case is patient D.B., a 64-year-old woman with diffuse large B-cell lymphoma, not otherwise specified. It's the GCB subtype based on the Hans algorithm using immunohistochemistry. Staging PET/CTs shows stage III disease. The IPI score is 3, and cytogenetics show no double-hit lymphoma rearrangements.
Now, while our focus today is on relapsed/refractory diffuse large B-cell lymphoma, I'm going to go to Jake for our first question, which is you've got this patient with advanced stage, IPI 3, GCB, DLBCL. What would your typical front-line regimen be?
Dr. Soumerai:
It's a great question. We currently have two standard frontline options that we would consider for this patient. The first would be six cycles of R-CHOP chemoimmunotherapy.
The second would be Pola-R-CHP, which was evaluated in a randomized phase III study called the POLARIX trial, comparing Pola-R-CHP with R-CHOP for patients with advanced stage diffuse large B-cell lymphoma with higher IPI risk scores.
Either option for this patient would be entirely appropriate. However, we have to look at specific pretreatment factors, including cell of origin, IPI risk, and others. For this patient with an IPI score of 3 with germinal center–derived diffuse large B-cell lymphoma, I would typically use R-CHOP chemoimmunotherapy as my standard frontline treatment, although again, either option would be entirely appropriate.
Dr. Abramson:
Yeah, I agree with that. In this particular case, the patient did receive R-CHOP. Patient had an interim PET/CT after three cycles of chemoimmunotherapy, which shows a mixed response. Some areas were better, but there were new areas and existing areas that had progressed in size.
Now, to confirm that this was indeed refractory disease, a biopsy was performed, again, confirming diffuse large B-cell lymphoma GCB subtype. Now, the patient looks and feels well. The ECOG performance status is 1. Organ and bone marrow function are all entirely normal. The LDH is modestly elevated at 255, with upper limit of normal in the laboratory being 212.
So here we are now at the end of six cycles of R-CHOP with evidence of persistent primary refractory DLBCL. So now we'll turn the question over to Erika and say, what would you do now in this scenario?
Dr. Haydu:
Yeah, thanks, Jeremy. So I'd be thinking about for this patient who's otherwise fit and healthy, what's the best possible chance of curing her? And for that, I would say CAR T-cells. And that's because we have two randomized studies demonstrating that liso-cel and axi-cel, which are both anti-CD19 CAR T-cells. When compared to the prior standard of care of high-dose chemotherapy and autologous stem cell transplant, have improved response rates, progression-free survival, and now overall survival. And so, I would be thinking about one of those two options for this patient.
Dr. Abramson:
Great. Jake, how would you choose between axi-cel and liso-cel?
Dr. Soumerai:
Both of these C19-directed CAR T-cell therapies have been compared against chemoimmunotherapy. They've not been directly compared, and so it's important just to recognize that we're relying on, really cross-trial comparison data here, and both achieve high rates of response and similar rates of long-term event-free progression-free and overall survival.
The key differences really relate to, again, acknowledging cross-trial comparison data to the safety outcomes, with higher rates of cytokine-release syndrome and ICANS or neurologic events for neurologic toxicity, and as well as higher rates of severe ICANS in CRS with axi-cel when compared with liso-cel again across trials.
And so, in many patients, given similar efficacy outcomes with these two agents, I tend to select liso-cel for most patients in whom I'm considering second-line CAR T-cell therapy.
I would say that for patients who have very active, rapidly progressive, extensive disease, patients in whom I need rapid turnaround manufacturing, I will reach for axi-cel given more reliable early manufacturing with this product for those patients.
Also, age and other comorbidities contribute to the decision. Younger patients, patients who are more fit, in whom I'm less concerned about potential severe CRS and neurologic toxicity, these are patients in whom I may be more comfortable using axi-cel.
Dr. Abramson:
Yeah, we get axi-cel manufactured about a week quicker than liso-cel. And while for most patients, that week doesn't necessarily make a difference. There are those occasional patients just need that product yesterday, and you'll want to prioritize the axi-cel even if it is a slightly more toxic product.
Dr. Haydu:
I would also say that this patient I think was primary refractory, and is symptomatic from their disease. And that might be a different person than who has maybe a small relapse detected incidentally on a scan and thinking about how you're selecting a product and managing that person, taking that into account as well.
Dr. Abramson:
So Dr. Haydu, this patient says she's feeling well, organ function is normal, marrow function is normal, the LDH is elevated. When you're preparing a patient for CAR T-cell therapy, how do you consider the role of bridging?
Dr. Haydu:
Yeah, I think that's a great point. And so, in some ways with this person being asymptomatic and otherwise organ function is okay, you don't necessarily have to bridge. I would look at what the disease state looks like.
If there's a single site or even two sites of disease that could be readily treated with radiation, I really like that for bridging. It's quite effective, and doesn't have the risk of systemic toxicity that other treatments might have.
It also depends what the patient has already received. One of the other regimens that I really like for bridging is polatuzumab in combination with rituximab. I don't include the bendamustine because that's just additional immune suppression that I don't want to necessarily expose someone to before going into CAR T-cells.
If someone hasn't been exposed to a polatuzumab-based upfront regimen, and they have systemic disease and I do want to bridge, I think that's another great option.
Dr. Abramson:
Yeah, I think this is an interesting case here, because this patient is otherwise not particularly symptomatic, has multifocal disease, but not a very high tumor burden, but the LDH is elevated.
And it's interesting that one of the more predictive biomarkers, pretreatment, in terms of outcome is LDH. And so I always love it when patients go into receiving their CAR with a normal LDH, because across studies that has suggested better outcome. So I might be inclined to consider bridging therapy, even in a minimally symptomatic patient, if their LDH is elevated, suggesting sort of a higher tumor burden. And I think thinking through systemic options as you did is appropriate.
So you do elect, continuing with the case, to bridge this patient with a single cycle of polatuzumab and rituximab due to multifocal disease. The palpable lymphadenopathy decreases on physical exam. The LDH does decline, and she receives lisocabtagene maraleucel or liso-cel.
She has no cytokine-release syndrome or ICANS, and in this particular case, the patient achieved a complete remission, which is obviously a great outcome.
Why don't we, if we adjust the case ever so slightly though. Jake, if I come back to you, let's say this patient is now day 5 and they develop a fever of 100.8. They're otherwise feeling well. They at this point are still neutropenic related to the fludarabine and cyclophosphamide lymphodepletion, so their ANC is 400. Take us quickly through how you would generally approach an isolated fever on day five in this patient with neutropenia.
Dr. Soumerai:
Thank you. So first things first is, you can't assume this is cytokine-release syndrome. So this patient has neutropenia and fever. And so, certainly the first thing you want to do is do a rapid infectious workup, including obtaining cultures, a standard approach for febrile neutropenia, initiate certainly broad spectrum gram-negative coverage and if appropriate gram-positive coverage, including MRSA coverage. And in parallel, think about cytokine-release syndrome.
And so this patient with an isolated fever without hypotension, without hypoxemia or other organ manifestations of severe CRS, is someone in whom I would typically observe. I would observe without initiating either of our standard approaches, including, for example, tocilizumab, or steroids, in the absence of worsening CRS, prolonged CRS.
I would say that there are patients in whom I would initiate treatment for CRS sooner. These are patients, for example, with very early CRS in a day or two out from administration of CAR T-cells, for example. You might consider initiation of early tocilizumab in that patient, or in patients who are perhaps at greater risk for severe complications of CRS.
For example, much older patients, patients with much higher disease burden, these are patients in whom you really want to get on top of their cytokine release syndrome sooner.
Dr. Abramson:
And do you consider the product in that regard? Let's say this were axi-cel and it were occurring on day two.
Dr. Soumerai:
Certainly. So we know that rates of severe CRS and severe ICANS are higher with axi-cel as opposed to liso-cel, and so I have a lower threshold to initiate treatment for early CRS management in patients receiving axi-cel.
Dr. Abramson:
Great. Well, this patient, as with a large proportion of patients on liso-cel, had no CRS or ICANS and achieved a complete remission, I think confirming the curative intent of CAR T-cell therapy in second-line management of DLBCL.
So let's review our key clinical takeaways from case 1 is that relapse diffuse large B-cell lymphoma should be treated with curative intent first and foremost.
Patients with primary refractory disease or relapse within 12 months, like the patient in this case, should be considered for CAR T-cell therapy, whether or not they're considered transplant eligible, because these patients all have access to CAR T-cell therapy with curative intent in second line.
Bridging therapy may be used for disease control during the CAR T-cell manufacturing period, particularly in symptomatic patients or patients with high tumor burden.
So that brings us to the end of this first case. Please see the other segments for further discussion about the latest research in DLBCL, or visit ASCOPost.com.
