Dr. Jason Westin:
Welcome to The ASCO Post Roundtable Series on Treatment Strategies for Transplant-Ineligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma.
I'm Dr. Jason Westin, Professor at MD Anderson Cancer Center, where I'm the Director of Lymphoma Clinical Research. Today I'm thrilled to be joined by two of my expert colleagues, and we'll start off with Dr. Caron Jacobson.
Dr. Caron Jacobson:
Yeah. Hi everyone. I'm Caron Jacobson. I'm a lymphoma clinician at the Dana-Farber Cancer Institute in Boston, Massachusetts.
Dr. Dai Chihara:
Hello, I am Dai Chihara. I'm lymphoma faculty at MD Anderson Houston, Texas.
Dr. Westin:
Wonderful, well, thrilled to have both of you here with us today. We're going to be discussing the treatment and management of relapsed/refractory DLBCL with three patient case studies. Our final installment will focus on third-line therapy for transplant-ineligible DLBCL.
Our case is Mr. HS, who's an 81-year-old man with a history of hypertension who develops back pain and night sweats. Imaging is performed, showing a 7 x 6 cm retroperitoneal mass causing hydronephrosis, and numerous smaller and large lymph nodes both above and below the diaphragm.
A biopsy is performed and shows DLBCL, non-GCB subtype, with an International Prognostic Index, or IPI, of 3. He receives six cycles of R-mini-CHOP, dose-reduced CHOP based on his age. And at the end of treatment a PET/CT scan shows a complete response.
Six months after completing the treatment, however, a surveillance scan shows a suspicion of relapse with multiple enlarged lymph nodes. You perform a biopsy and confirm that he's got relapsed DLBCL.
You offer a referral to a CAR T-cell center and he declines. He says it's too far away and too disruptive for he and his family to travel to be evaluated at a CAR T-cell center, and therefore you treat him with two cycles of R-GemOx.
You perform a repeat PET/CT scan and identify that some areas have improved. However, there are new areas of enlarged lymph nodes consistent with progressive disease.
Dr. Jacobson, what are some standard of care options available for this scenario?
Dr. Jacobson:
We have now an older patient who is having relapsed large B-cell lymphoma in the third line, who declined CAR T-cell therapy and is not transplant eligible.
And I think this is an exciting time for large B-cell lymphoma in the third line, because we have lots of new options for these patients. So the most exciting new option we have for these patients are the CD20-targeted bispecifics, which of course are antibodies that have two heads, one that binds to a tumor antigen, one that binds to an immune effector cell.
And the CD20-targeted bispecifics that are approved for lymphoma, including epcoritamab and glofitamab, bind to CD20 on the tumor cell and CD3 on the T cell. And both were approved based on phase II studies that showed an approximately 40% complete response rate in these patients.
And while epcoritamab is dosed indefinitely and glofitamab is more of a time-limited therapy, both show that for patients who achieve a complete response, those responses can be quite durable. Although I would say our follow-up on those studies are somewhat limited at this point. So those would be excellent options for this patient.
Of course, the side effects of those drugs are not dissimilar to CAR T-cell therapy, in that they can induce cytokine-release syndrome through T-cell activation, and in rare instances can cause immune effector cell–associated neurologic syndrome.
Thankfully the CRS that is experienced is low grade and usually within the first month, and is mitigated by strategies like either using prophylactic steroids, or prophylactic obinutuzumab dosing for glofitamab, and then also doing step-up dosing before you get to the target dose. So those would be excellent options for this patient based on that data.
Of course, preceding those approvals we saw approvals for polatuzumab/bendamustine/rituximab, based on a phase II randomized study that compared that regimen to bendamustine and rituximab alone. And not surprisingly, it beat BR in terms of progression-free survival, but it was quite substantial. And the CR rate on that study is also around 40%, with about 20% of patients having durable remissions. And so that is a nice option and it's time-limited, it's six cycles of therapy and then time off of therapy.
And then finally, tafasitamab/lenalidomide is approved for large B-cell lymphoma in the second line and beyond for any transplant ineligible patient. And that's based on the phase II L-MIND study, which we did discuss in case two if you've tuned into that case, which showed a very nice complete response rate and a durable CR rate.
But the majority of patients on that study were treated in the second line, and it excluded patients with primary refractory disease, as well as some of the higher risk lymphomas like double-hit and triple-hit lymphomas.
And so those good results seem to be more applicable to patients that met the L-MIND criteria, and so this patient now having refractory disease after R-GemOx may not, and also being treated in the third line, may not exactly meet that criteria, so the results may not be quite as good in this patient.
Dr. Westin:
Excellent, thank you. Dr. Chihara, we just heard about tafasitamab/lenalidomide targeting CD19. Tell us a little bit about loncastuximab tesirine, another CD19-targeting therapy, in patients with relapsed/refractory DLBCL.
Dr. Chihara:
Yeah. So the loncastuximab tesirine was tested in a single-arm phase II trial called LOTIS-2. I think they treated around 70 patients or so. The overall response rate was around 50%. 25% to 30% of the patient achieved complete response. And then that was I think the time-limited treatment, every 3 weeks for 1 year.
Those patient who achieved complete response, so it's not a large portion of the patient, but those patient who achieved complete response actually did quite well. The response was durable. And a 2-year progression-free survival for those patients who achieved complete response was, I remember, 70% or so. So that treatment can also provide some durable remission for those patient who have such disease not eligible for CAR-T, or even post CAR-T.
I think the toxicity, there is some learning curve. I did have some patient who had massive pleural effusion, or edema, and then photosensitivity from the treatment. These are the concerning or some toxicity that unique to the loncastuximab.
But it is very convenient for a patient because it's only one infusion every 3 weeks, compared to other treatment like tafasitamab/lenalidomide where patient needs weekly infusion for quite some time.
Dr. Westin:
Excellent, great. So it sounds like there's lots of good options for our patients in third-line therapy with relapsed/refractory DLBCL. Dr. Jacobson, you mentioned specifically the bispecific antibodies and how they've got some challenges with toxicities. For a doctor in practice who doesn't do a lot of bispecific antibodies, what are some of the challenges in terms of having to admit patients, or having to manage expectations for patients for when toxicities might occur, that patients might experience if they're doing this in a setting where there's not a lot of CAR T-cell experience in a community practice?
Dr. Jacobson:
Yeah, this is an excellent question. And I think we're all still sorting out how to manage these logistics.
But I think for both epcoritamab and glofitamab, again, the bispecifics that are approved for large B-cell lymphoma, on the clinical trials that led to their approvals, patients were admitted for the first full dose of those bispecifics for observation thereafter.
And as a result, the labels don't mandate that patients be admitted for the first full dose, but they do recommend or suggest that patients be admitted. So that's one thing.
But you have to realize that the first full dose is not the only dose where patients can develop cytokine-release syndrome. And for epcoritamab, which uses dexamethasone at 16 mg/d for 4 days, with each step-up dose until you get to target dose, that risk of CRS might actually be on day 5 after they finish the prophylactic steroids.
And so I think a lot of people were excited about these bispecifics because they offered a very effective therapy for patients that could be done in the community, where CAR T-cell therapy is more limited to CAR T-cell treatment centers.
But the first month is actually quite logistically challenging, and a lot of these patients are still being referred into centers that have experience. Because while the incidence of higher-grade CRS is still very low, you just need to have one patient who has grade 3 CRS to understand that you don't have the experience or just the clinical experience to manage it confidently.
So I think a lot of centers, especially smaller centers, are still sending these patients to a tertiary center for the first month of treatment. And then, of course, they're able to resume the treatment thereafter at home. But I think that does make it not quite as seamless as was anticipated, and not as much of an advantage over CAR T-cell therapy then we might've otherwise thought.
Dr. Westin:
Excellent, well said.
Back to our case, the patient's treated with a bispecific antibody and develops grade 2 CRS, with the first full dose prompting 3 days in the hospital. She's unsure if further treatments with a bispecific antibody are safe enough and asks what's known about the risk of CRS recurring with each cycle.
Dr. Chihara, Dr. Jacobson mentioned a little bit about this, but tell us a little bit more. Is this something that each subsequent cycle has the same risk? Or is there a difference over time?
Dr. Chihara:
No. So, this is also a learning curve for us. I think the risk or possibility how likely patient get CRS differs by the product, like Dr. Jacobson mentioned.
So for the glofitamab it's a first dose, first step-up dosing 2.5 mg on cycle one, day 8. And then for epcoritamab it's cycle one day 15, the first targeted dose, so the last dose during the step-up dosing.
Both have risk of CRS in around 50% of the patients, majority of them are grade 1 to 2. After the highest risk of CRS each subsequent doses get lower, and the risk will continue to get lower and lower. Particularly for a glofitamab from cycle 2, I believe the risk of getting cytokine-release syndrome will go down to 27%. And then from cycle 3 and beyond it's less than 5%. So as patient go through all the treatment, the risk of CRS continue to get lower.
But just like Dr. Jacobson and Dr. Westin mentioned, the cycle 1 is the most, therefore, intense treatment period for us that we need to monitor the patient closely.
So for this question, I think the risk of CRS will continue to get lower from the subsequent cycle, and can be manageable in community setting, too.
Dr. Westin:
That's right. I think that's something that's been discussed a lot. As Dr. Jacobson mentioned, this is a great option, however the logistics are tricky in that first cycle.
And so there've been a lot of discussions about referring patients for one cycle or two cycles to a tertiary candidate center that's got CAR T-cell experience or bispecific experience. And then having the patient come back to receive what almost looks like rituximab maintenance. When you get out of those initial cycles the risk of CRS really gets to be so low that it really is kind of a maintenance approach.
And we also heard from Dr. Jacobson the differences between epcoritamab and glofitamab and the duration of therapy, the glofitamab being a fixed-duration product and epcoritamab being treatment until progression or intolerance.
The last thing to say about that is the route of administration. Epcoritamab is a subcutaneous product, it's injected under the skin vs glofitamab, which is an IV product. And there are clinical trials looking at different routes of administration, but the FDA approval for them as of now, in 2024, epcoritamab is subcutaneous. And if that's something that's advantageous for your practice, potentially could be a reason to select one of the antibodies over the other.
Fixed duration is often an attractive thing for our patients, to know that they'll have treatment for a period of time but then we'll be able to potentially stop treatment.
Dr. Jacobson, you mentioned something I wanted you to come back and highlight one more time, about what's known for long-term follow-up for these patients? We think for CAR T-cells we're likely curing patients with a one-time treatment. Do you have confidence that we're curing patients with bispecific antibodies?
Dr. Jacobson:
Yeah, this is a great question. I think one that is unanswered at this point, but I think we largely have 1 to 2-year follow-up either after the completion of glofitamab or after the attainment of complete response with epcoritamab.
And it does look like there are still some patients at 1 and 2 years that are having ongoing response. Although I would say that those progression-free and duration-of-response curves continue to have a slope, they have not yet plateaued.
So unlike the CAR T-cell PFS curves that seemed to really plateau at around 12 months, we're not quite seeing that plateau yet. Now it may be because our follow-up is too short and we need to see more patients reach longer follow-up, or it may be that these are not curative.
I think we saw this experience with the checkpoint inhibitors in Hodgkin lymphoma. We saw these patients that had 1.5 and 2 year responses after the completion of checkpoint inhibitors, but eventually relapse. And I think I fear that that's going to be the pattern here.
I did want to say one other thing about long-term experience with these bispecific antibodies, because, Dr. Westin, you had pointed out that this is getting maintenance rituximab. We always think about maintenance rituximab as being immune-suppressive, but I do want to call out just the degree of immune suppression from these bispecifics.
We are not just seeing B-cell aplasia, but we're seeing effective T-cell lymphopenia as well, because the T-cells are being redirected away from their normal job to do a different job. So we are seeing sort of unique and long-term infections in these patients, and it's especially important for when you're thinking about indefinite dosing.
And so I do keep my patients on PJP and herpes virus prophylaxis with these therapies, and do have a high index of suspicion for things like CMV and other infections.
Dr. Westin:
Yeah, well said. I think infectious prophylaxis certainly is an important consideration for patients receiving bispecific antibodies.
Wonderful. All right, well, the key takeaways for this scenario are patients with refractory or early relapsing DLBCL are not likely to benefit from additional chemotherapy-based approaches. So if chemo does not work once or twice, it's not likely to suddenly work very well in the third or fourth time around.
Patients who are transplant-ineligible with refractory or early relapse large B-cell lymphoma have multiple options for targeted therapies, including bispecific antibodies like epcoritamab and glofitamab, antibody drug conjugates like loncastuximab tesirine or polatuzumab vedotin, and tafasitamab-lenalidomide.
Toxicities for bispecific antibodies can include CRS, but this is typically seen within the first few cycles and it's quite rare after those initial step-up doses.
This brings us to the end of this case. Please see the others in this segment for further discussion about the latest research in DLBCL, or visit ascopost.com. Thank you.
