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 serve as the Director of Clinical Research in the Department of Lymphoma Myeloma. I'm pleased to be joined today by two experts in lymphoma treatment and we'll first start with Dr. Caron Jacobson.
Dr. Caron Jacobson:
Yeah. Hi everyone, I'm Caron Jacobson. I'm a lymphoma specialist at the Dana-Farber Cancer Institute in Boston, Massachusetts.
Dr. Dai Chihara:
Hello, my name is Dai Chihara. I'm also a lymphoma faculty at MD Anderson Houston, Texas.
Dr. Westin:
Wonderful, we're thrilled to have both of you here today. Today we're going to be discussing the treatment and management of relapse refractory DLBCL with three patient case studies. Our second installment will focus on the treatment of a patient with late relapsing DLBCL.
This case is a case, Ms. TK. She's a 77-year-old woman with a history of basal cell carcinoma, moderately well-controlled diabetes, and obesity. She was diagnosed with DLBCL, GCB or germinal center subtype, without MYC translocation. She has an IPI or International Prognostic Index Score of 2 at diagnosis with stage II disease. She was treated with R-CHOP for six cycles. However, she was hospitalized after cycle four with neutropenic fever and required 1 week in a skilled nursing facility for rehabilitation.
Cycles five and six were subsequently dose-reduced and she tolerated those relatively well. She achieved a complete response at the end of treatment on her PET/CT scan and regained her functional status back to baseline over the next 6 months. Two and a half years after the end of treatment, she calls your office describing a new fullness in her right axilla. A PET/CT scan shows FTG-avid adenopathy in both axilla and in the retroperitoneum. The patient had a painful biopsy at the initial diagnosis and asks if we could just treat without a relapsed biopsy. You advocate for the biopsy to ensure the relapse is not a low-grade lymphoma. Based upon the timing of this relapse being 2.5 years after initial treatment, and the biopsy unfortunately confirms this is DLBCL. Dr. Chihara, what are standard-of-care treatment options available for this situation and, along those lines, is CAR T-cell therapy one of the options?
Dr. Chihara:
Yes, thank you, Dr. Westin. So this is a case of an older patient with large cell lymphoma who had relapsed of the disease after 12 months, so late recurrence of the large-cell lymphoma, and then she's likely transplant-ineligible. These are the patients not treated on ZUMA-7 or TRANSFORM study like we discussed in case one. So, in that setting, CAR T-cell therapy was clearly better compared to standard-of-care treatment options such as platinum-based second-line treatment followed by transplant. For those patients who have a recurrence of the disease after 12 months following the first-line treatment, we don't have clear randomized study to show which treatment is better than the other so there are multiple treatment options she can take. She may still have chemotherapy-sensitive disease, so I do think it is also reasonable to consider a chemotherapy regimen like R-GemOx for such patients.
And then, the question is what to do if she responds to that treatment? Do we consolidate the response by sending her to the transplant because that used to be the traditional way of treating the patient, but she may not be eligible for transplant and what to do after achieving the response. There are other targeted treatment options in second-line treatments such as tafasitamab/lenalidomide. It's a little different than targeted treatment, but polatuzumab/bendamustine/rituximab is also a good second-line treatment. And considering the question about is she eligible for CAR T-cell therapy knowing that that recurrence happen after 12 months?
Yes, there is a study called PILOT trial which did lisocabtagene maraleucel in second-line treatment who were not eligible for the transplant. In the PILOT study, I think around 25% to 30% of the patients had lisocabtagene maraleucel as a second-line treatment following over 12 months after the first-line treatment. So there were patients treated in the PILOT trial who had the late recurrence of the disease and that trial did show or confirm the activity of CAR T-cell therapy in second-line treatment. So I do think second-line CAR T is an option for such case in her because she's not eligible for transplant. And then I think the question is even if she still has chemotherapy-sensitive disease, what to do afterwards is still in question.
Dr. Westin:
Thanks, Dr. Chihara. Dr. Jacobson, we just heard about PILOT study looking at lisocabtagene maraleucel in this transplant ineligible population. Are there any data for axicabtagene ciloleucel in a similar patient population? Elderly, not transplant-eligible?
Dr. Jacobson:
So, there are. The French group did a study called the ALYCANTE study that looked at transplant-eligible patients. I still believe everyone in that study had an early relapse of their disease. So they weren't necessarily these late-relapsing patients as opposed to the PILOT study that Dr. Chihara just outlined. The majority of the patients are not transplant-eligible because of advanced age, which is I think what applies to this patient. And I think both studies demonstrated a similar efficacy to each of the CAR T cells and more importantly, a similar toxicity profile to each of the CAR T cells as they perform in younger patients that are potentially transplant eligible and have less comorbid disease. So I think both studies do confirm that CAR T cells have activity and an acceptable safety profile in this patient population. But only one of the studies was reviewed by the FDA and allowed to expand the label, and that was the PILOT study for lisocabtagene maraleucel.
Dr. Westin:
Excellent. Thank you. And as mentioned by Dr. Chihara, we don't have randomized data comparing CAR vs other treatments in these settings. As we just heard for PILOT and the axicabtagene ciloleucel study that those data look impressive. But as are in single-arm clinical trials, we know that patients generally who have late relapse of their disease tend to be more sensitive to next treatment as opposed to those who were refractory. And Dr. Chihara mentioned tafasitamab/lenalidomide. That was a study that was looked at in the L-MIND clinical trial. And in patients who are not refractory to their initial treatment but had later relapse, response rates looked pretty promising. More than half of the patients achieved an overall response and a complete response rate around 50%.
And that is in the population of patients who are not refractory. So I think the key finding for this particular patient, although older, is this patient is different from our first case who is primary refractory. This patient had a relapse more than 2 years after initial treatment and therefore potentially has a chance to respond to lots of different treatment options including chemo. Although chemo certainly is going to be more toxic than some of these new targeted therapies. So back to our case, you discuss tafasitamab/lenalidomide, you also discuss R-GemOx, polatuzumab/bendamustine/rituximab, R-ICE and autologous stem cell transplant. Your patient considers all those options and opts to receive tafasitamab/lenalidomide and achieves a complete response after three cycles. Dr. Chihara, what's known about patients who have a CR after tafasitamab/lenalidomide in terms of their long-term outcomes?
Dr. Chihara:
In the L-MIND study, the treatment was designed as indefinite treatment. So even after achieving CR, it was not time-limited treatment. Patient continued to receive at least tafasitamab maintenance. But in that study, those patients who achieved complete response had a very long-term remission. I think the median progression free survival for all patient was about a year. But for those patients who achieved complete response, the duration of response was quite remarkable. And then 46% continued to be in remission at 5 years with the long-term follow-up data. I think what was interesting to me was that those patients, there were some patients on L-MIND study who needed to discontinue the treatment for different reasons. There were 26 patients who discontinued treatment, during achieving response. I don't recall the number of the patient, but at least five or maybe a little over five patients who were off treatment for over 2 years, even after discontinuation of the treatment.
So as long as they achieve complete response by the tafasitamab/lenalidomide, I think it's a very good treatment that can induce durable remission. Here though, just like Dr. Westin said, there are patients who may not respond well to tafasitamab/lenalidomide. The Memorial Sloan-Kettering team led the real-world evidence study in tafasitamab/lenalidomide, and then they collected around 180 patients who received tafasitamab/lenalidomide in real world. What was striking from that study is that the 90% of the patients they collected were not eligible for L-MIND study. And then for those patients who had refractory disease, had very poor outcome and then almost no response from tafasitamab/lenalidomide. So there are selected patient who respond well to the tafasitamab/lenalidomide, and those are probably the patient who had long-term remission from the first-line treatment have relatively less aggressive disease. And then I think obviously the second-line treatment seems to be better than giving this treatment in the third line, but it's not, I don't know if it's because of tafasitamab/lenalidomide works as a second-line therapy or it's just the biology, more aggressive disease in third-line treatment.
Dr. Westin:
Wonderful. Great. Thanks for that summary of the “real-world” data set looking at tafasitamab/lenalidomide, which was different than the clinical trial and resulted in different outcomes. So I think for those patients who would fit the L-MIND study and have a late relapse of their disease, as you just heard from Dr. Chihara, that may be a good option and potentially can provide long-term clinical benefit in folks who otherwise might not have been eligible for more intensive treatments.
So the key clinical takeaways from this scenario of a late relapse of DLBCL include that relapse beyond 2 years is rare, but it can occur and it's slightly more common with stage I or II DLBCL of the GCB subtype. Getting a biopsy is absolutely essential, especially for these patients that have late relapse to ensure that there's not an undiagnosed or a previously diagnosed indolent lymphoma, which obviously may have a very different treatment management than an aggressive large B-cell lymphoma.
Tafasitamab/lenalidomide can achieve durable responses in patients with DLBCL that's not refractory to initial therapy. And CAR T-cell therapy is approved as second-line therapy for patients who are within 12 months from completing their first-line treatment. Or as Dr. Jacobson mentioned, lisocabtagene maraleucel has got an indication for patients who are ineligible from transplant even if they are more than 12 months out based on the PILOT clinical trial.
And 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. Thank you.
