Cancer Topics - New Therapies for Lymphoma (Part 1)

In part one of this two-part ASCO Education Podcast episode, Dr. Sonali Smith (University of Chicago Medicine) and Dr. Paolo Strati (MD Anderson Cancer Center) discuss the application of recently approved therapies for diffuse large B-cell lymphoma through examination of challenging patient cases.

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Air Date: 10/20/21

 

TRANSCRIPT

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SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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SONALI SMITH: Hello, and welcome to this episode of the ASCO Education Podcast highlighting new therapies for lymphoma. My name is Dr. Sonali Smith, and I'm a hematologist and medical oncologist specializing in lymphoma and clinical investigation in lymphoma. I'm also the Elwood V. Jensen Professor and chief of the hematology/oncology section at the University of Chicago, and very excited to be joined by my colleague, Dr. Paolo Strati.

PAOLO STRATI: Good morning to everybody. My name is Paolo Strati. I'm a hematologist and medical oncologist and an assistant professor in the Department of Lymphoma/Myeloma, and in the Department of Translational Molecular Pathology at MD Anderson Cancer Center, Houston, Texas. And I'm also the clinical director for the Lymphma Tissue Bank.

In part one of this podcast episode, we will discuss the adoption of recently approved therapies for diffuse large B-cell lymphoma, such as selinexor, tafasitamab, Liso-Cel, and Lonca-T. These therapies have transformed care for patients with this disease. And we'll start our conversation today with a patient case.

SONALI SMITH: Great. Well, I'll go ahead and present a patient to you, Paulo. So this is a 78-year-old man with diffuse large B-cell lymphoma that is the germinal center-derived subtype. It is not double expressor, it is not double-hit. He has advanced stage disease with a high IPI, as well as the high CNS IPI. Luckily, his performance status is zero and he has no significant comorbidities or other health conditions.

He received frontline dose-adjusted EPOC-R with intrathecal methotrexate for six cycles. But at the end, he had a partial remission. So how do you select your salvage therapy in this situation? Are you concerned about using agents targeting CD19 in the second line, given the potential need to use anti-CD19 cellular therapy, or CAR-T in the third line?

PAOLO STRATI: This is a very interesting and unfortunately not uncommon case. And thank you, Sonali, for asking these very important questions. Technically, a platinum-based regimen followed by autologous transplant will be a standard answer and may be feasible. Because as you mentioned, this patient has a good performance status and non-meaningful comorbid health conditions.

However, patients who are refractory to a frontline anthracycline-based regimen, such as in this case, with achievement only of partial remission at the end of frontline dose-adjusted EPOC, can potentially experience a suboptimal outcome following the standard approach with a platinum-based second line regimen. And as such, alternative strategies may be needed.

To this regard, the combination of tafasitamab that, as you know, is a monoclonal antibody targeting CD19, and lenalidomide, an oral immunomodulatory agent, a combination which is currently approved by the FDA in the United States as a standard second line option for transplant ineligible patients, would be a great option in this case.

Data from the three year follow-up of the phase II study that has brought to the FDA approval this combination, the L-MIND had been recently presented and have showed the complete remission rate of 40% and immediate duration of response of 44 months, including patients who received this regimen as a third line or beyond.

So there is, of course, a biological concern by targeting CD19 in second line. These may potentially impact a third line use of an autologous anti-CD19 CAR-T, because CD19 downregulation may potentially be a mechanism of escape to tafasitamab. And recent data has shown the CD19 levels are strongly associated with the efficacy of CAR-T cell therapy in patients with large B-cell lymphoma.

Small retrospective studies have shown that autologous anti-CD19 CAR-T can be safely and effectively used after antibodies or antibody drug conjugate targeting CD19. But we need a significantly larger and prospective data, including serial tissue biopsy in these patients before considering this combination as a standard practice in patients for whom we plan to use CAR-T as a third line.

Until then, I would be cautious in using second line tafasitamab in patients, again, for whom there is a potential plan for anti-CD19 autologous CAR-T in third line. And if necessary, limited to very selective cases. Finally, recent press releases have anticipated the two autologous anti-CD19 CAR-T products, Axi-Cel and Liso-Cel, are superior to autologous settings transplanted in second line.

And so in the near future, CAR-T cell therapy may become a standard second line option. And that would be an ideal option in primary chemorefractory patients as the case that you presented here.

SONALI SMITH: Yeah, I agree. There are a tremendous number of options. And having anti-CD19 products as well as autologous stem cell transplant, the sequencing will be an evolution. So going back to this patient, he received tafasitamab and lenalidomide for two cycles with no significant toxicity, but unfortunately, he had further progression after two cycles based on a PET/CT scan.

So what are your next steps? Would you move directly to an autologous anti-CD19 CAR-T cell therapy now? Would you re-biopsy before that? And how would you select among the three available CAR-T products?

PAOLO STRATI: These are not easy questions, particularly the selection of one out of three available CAR-T products. As you said, there are currently three autologous anti-CD19 CAR-T products approved by the FDA in the United States for the treatment of large B-cell lymphoma in third line or beyond. And these are Axi-Cel, Tisa-Cel, and Liso-Cel.

For all of them, the best outcome is observed for patients who have a low turmor burden at time of CAR-T infusion. And they need to either select patients with no bulky disease or to decrease it through bridging therapy. And as we define bridging therapy given between leukapharesis and CAR-T infusion.

Unfortunately, there is currently no standard bridging therapy and all FDA products approved in third line can potentially be used in this specific scenario that you described, including polatuzumab with bendamustine/rituximab, selinexor, and Lonca-T, of course, beyond tafasitamab and len that has already been used in this case.

Of course, when selecting a bridging therapy, there are many disease-related and patient-related factors to take into consideration, including the need to preserve the host immune microenvironment that we all know is crucial for the subsequent activity of CAR-T cells. And also, we need to give into consideration the need to preserve as much as possible, as we discussed previously, in CD19 expression.

To this regard, and going back to one of your questions, I strongly recommend to re-biopsy patients if any bridging therapy is used between bridging therapy and CAR-T infusion in order to document CD19 expression before CAR-T infusion. When it comes to CAR-T product selection, as I said, it's a really difficult decision to do. And we don't have at this time randomized trials in third line. And as such, the decision is really left to the treating physician based on multiple factors. But all of the limitations of inter-study comparison, efficacy seems to be pretty much the same for the two products, maybe slightly higher based on the recent second line data.

But Axi-Cel and Liso-Cel as compared to Tisa-Cel, and also as suggested by recent press release. However, due to the fact that Liso-Cel and Tisa-Cel have less potent co-stimulatory domain for 1BB instead of CD28, the rate of CRS and ICANS, the two main toxicities associated with CAR-T cell therapy, is usually lower with this to the point that some centers are able to infuse them in the outpatient setting, whereas Axi-Cel is almost always infused in the inpatient setting so the toxicity can be monitored more closely.

So with older patients or those who have comorbid health condition, Tisa-Cel and Liso-Cel may be a safer option, though there's a lot of research going on trying to mitigate toxicities associated with Axi-Cel. Finally, it's important to keep in mind manufacturing time. Axi-Cel is manufactured in an average of 17 days, whereas Tisa-Cel and Liso-Cel take typically longer than three to four weeks. This can be itself a determining factor, particularly for patients who are quickly progressing and where immediate treatment is needed.

SONALI SMITH: Yeah, I agree. I think there are going to be many patient product and disease-based factors that will impact both the effectiveness as well as the toxicity. And you did a really great job of explaining the role of the co-stimulatory domain potentially in some of that, as well as all of the products that are out there. It's definitely a complicated area.

Going back to our patient, so he did undergo leukapharesis for Liso-Cel and received third line polatuzumab and rituximab without bendamustine. The restaging PET/CT after two cycles showed a PR with a significant decrease in tumor burden, and repeated biopsy showed high expression of CD19 by flow cytometry.

He then proceeded with Liso-Cel, which was relatively well tolerated. There was only grade 1 cytokine release syndrome and no ICANS, so no neurotoxicity. And his day 30 PET/CT showed a complete remission. Unfortunately, the 90 day PET/CT showed progression. So Dr. Strati what is the outcome for patients who relapse after CAR-T? Do you recommend to re-biopsy? And what are the efficacy data for FDA approved agents for these patients? And I know this is a long question, but is there any role for repeated CAR-T or allogeneic transplant now?

PAOLO STRATI: Unfortunately, currently, the outcome of patients with large B-cell lymphoma relapse or progress after autologous anti-CD19 CAR-T is suboptimal, with a life expectancy, unfortunately, shorter than six months. Hence, the need to be creative and customize treatment based on biological data.

To this regard, I think it's crucial to repeat a tissue biopsy to guide subsequent therapy. As mentioned previously, there are currently four products approved by the FDA for patients with large B-cell lymphoma in third line and beyond. Two of these target CD19, tafasitamab plus lenalidomide and Lonca-T One targets CD79B, polatuzumab combined with bendamustine and rituximab. And one is an SPO1 inhibitor, selinexor.

While we have no data for selinexor in patients who relapse or progress after CAR-T cell therapy, limited prospective data showed that a progression-free survival in the order of weeks is usually observed for patients who receive polatuzumab with or without bendamustine and rituximab after CAR-T cell therapy. So I would not recommend that.

However, there's some interesting activity in the post-CAR-T setting for Lonca-T and for tafasitamab/len is limited to patients who still express CD19 in time of relapse. And of course, it needs to be largely and prospectively further investigated before becoming a standard approach for patients who relapse or progress after CAR-T cell therapy.

When it comes to cellular therapy, repeated anti-CD19 CAR-T infusion is not shown to be successful in the original registration studies. So it is not currently something that I would recommend and is not definitely a common practice. And very limited retrospective studies have shown the use of allogeneic stem cell transplants in the post-CAR-T setting may be associated with quite elevated treatment-related mortality. So I don't suggest this as a standard practice in large B-cell lymphoma at this time. This is different from B acute lymphoblastic leukemia, where instead, allogeneic stem cell transplant is becoming progressively a standard approach. And we definitely need more data before using this consistently.

While we strive to identify the optimal cell batch therapy for large B-cell lymphoma patients who relapse or progress after CAR-T cell therapy. I think the priority should be given to clinical trials, including CAR-T targeting molecules other than CD19, such as CD20, CD22, CD79B, allogeneic CAR-T there are immediately available, so without the need to wait for manufacturing times. And K-CAR, that may be less toxic than CAR-T and other non-cellular therapy biological agents. So definitely, clinical trials are, at this time, the best approach in patients who relapse after CAR-T cell therapy, as the case that you described.

SONALI SMITH: Thank you Dr. Strati. As an update, this patient had repeated biopsy showing a CD19 positive relapse. He consented for a clinical trial with a novel NK-CAR targeting CD19, achieving CR which is still ongoing at nine months. And this case really does represent some of the most exciting advances that we've had for this disease for patients who can tolerate aggressive therapies and have access to clinical trials.

PAOLO STRATI: Dr. Smith, I'd like to hear your opinion about another patient with diffuse large B-cell lymphoma. This patient is an 81-year-old man with a history of coronary artery disease and well-controlled diabetes mellitus, who noticed a right cervical lymph node while shaving that seemed to have popped up. He was evaluated by his primary care physician and given a course of antimicrobials. 10 days later, the lymphoma seems to be enlarging and he is referred to ENT pharyngeal biopsy.

The specimen is small but shows follicular lymphoma in a portion of the sample. However, there is also concern for larger cells and possible transformation. The patient is also beginning to note night sweats and a decreased appetite. And labs are notable for elevated LDH, 500, and thrombocytopenia with a platelet count of 110.

So Dr. Smith, in your opinion, is this specimen sufficient to start treatment? Or should treatment be delayed to get a larger and maybe excisional biopsy?

SONALI SMITH: Yeah, thank you for this question. I think this is a challenge we have in the clinic all the time, which is what is a sufficient biopsy specimen to make a diagnosis that allows us to subtype lymphoma? As we know, every lymphoma subtype, the treatment is really guided by the histology and not so much the stage or some other factors.

So having a needle biopsy is unfortunately often insufficient. In this case, we have a very strong concern for a possible transformation. And as we know, both follicular lymphoma and diffuse large B-cell lymphoma can mark very similarly when it comes to immunophenotype. Certainly, the germinal center type of diffuse large B-cell lymphoma or any transformed follicular lymphoma will be CD20 positive, CD10 positive, and it really requires architecture to be able to tell whether or not there are sheets of large cells.

So the ideal outcome for this patient would be to have a biopsy that is done promptly that allows us not only to confirm whether or not there is histologic evidence of transformation, but also to conduct FISH studies to determine if there's acquisition of a MYC rearrangement. At its core, all follicular lymphoma patients essentially have a transformation of 14;18, leading to BCL2 rearrangement and BCL2 overexpression.

During the transformation process, there can be an acquisition of a MYC rearrangement, which would then make this a double-hit lymphoma and certainly has a much worse prognosis and may also prompt a change in treatment if the patient can tolerate more intensive therapy. So my recommendation would be to have a biopsy.

Now one other aspect is that sometimes, we don't really have the time to proceed with a biopsy, or the lymph node may be in an inaccessible area. And in that case, there are some other criteria that we can use to assume that somebody has a transformation. Symptoms such as profound B symptoms and elevated LDH, and sometimes, a PET scan with multiple areas of very high avidity, can lead you to feel or suggest that this person has a transformation.

There is some controversy over the use of PET and we know it does not confirm a diagnosis of transformation. But in my opinion, this is very suggestive if there are many areas of high SUV.

PAOLO STRATI: Thank you, Dr. Smith. I agree completely about the importance, when time allows, to perform either a larger core biopsy or an excisional biopsy, because as you very well-outlined, this has not just a mere diagnostic purpose, but can meaningfully affect treatment planning for patients.

And actually, in this case, as you suggested, the patient eventually had multiple core biopsy that showed transformed follicular lymphoma with very evident areas of diffuse large B-cell lymphoma. FISH, as expected for follicular lymphoma, was positive for translocation for TN18, but luckily negative for MYC rearrangement. So fortunately, we didn't have to deal with a double-hit lymphoma.

The remainder of his staging showed he had diffuse lymphadenopathy. And PET scan, as you mentioned, has a controversial role in the diagnosis of transformation. So there's some areas that had high avidity with an uptake with an SUV of 1215, whereas other areas were less intense with SUV 618. And usually, heterogeneity in SUV actually helps further supporting diagnosis or transformation. While meta-maps showed follicular lymphoma, no large cells. So movement was isolated in the B-cell lymphoma.

So Dr. Smith, at this point, based on the provided information, what's your treatment approach in this older patient and also a patient with comorbid health conditions, but with diffuse large B-cell lymphoma?

SONALI SMITH: Yes. The goal of treating any aggressive lymphoma is to obtain remission, and if the remission lasts, to hopefully offer cure to the patient. And when somebody has a transformed lymphoma, of course, there is a dual concern, which is that the aggressive component can potentially be put into remission in a durable way achieving cure. But the indolent component will always need to be monitored, although hopefully, will not be life threatening the way the aggressive component can be.

Treating an octogenarian is really challenging, particularly due to comorbidities in this age group and the potential toxicity of chemotherapy. So the standard of care for diffuse large B-cell lymphoma is anthracycline-based chemotherapy. But this, of course, can have significant toxicity in older patients. And in addition, the vincristine can aggravate neuropathy. And I've personally found that the high dose steroids that are part of CHOP can also cause toxicity in older patients and patients who are frail.

So unfortunately, the literature is somewhat sparse. But we do have several data sets that can guide management in this particular patient situation. The French published, over a decade ago, the development of R mini CHOP, that includes an attenuated dose of cyclophosphamide, doxorubicin, and vincristine, and leads to some durable remissions and cure. Unfortunately, the long-term overall survival is less than 50% with R mini CHOP. And so although this is an appropriate backbone, there's certainly a lot of room for improvement.

And there's also toxicity even with R mini CHOP. So in their initial phase II trial, there was actual deaths related to the R mini CHOP, particularly in the first cycle or two, really necessitating some type of pre-phase help ease patients into the chemotherapy. One of the challenges that we face in the clinic is that when we meet an older patient, we both want to maximize our chance for cure, but also minimize the toxicity that is particularly pronounced. And there is very little data in terms of how to guide this at the bedside.

I'm excited that SWOG, with the US Intergroup, is conducting a trial, S1918, which prospectively includes a frailty assessment tool that was developed by the Italian group in lymphoma, and then also includes serial comprehensive geriatric assessment so that we can get a better idea about quality of life both during and after treatment.

So there is no great standard of care right now, but I would say that R mini CHOP, outside of a trial, is a very reasonable way to proceed.

PAOLO STRATI: Dr. Smith, thank you for outlining so well what we can do to minimize toxicity and to better select patients for this type of treatment. And as an Italian practitioner in the United States, I am very excited that the Italian frailty tool will be used in this SWOG trial. Are there any other ways to further improve safety when we use chemo immunotherapy in older patients or patients with comorbid health conditions?

In particular, there is a lot of concern about potentially infectious complications in these patients. And so I'm wondering if there's any routine antimicrobial prophylaxis that you recommend.

SONALI SMITH: Yes. I think it's really important to maximize supportive care for our older patients with aggressive lymphomas getting intensive therapy. I did mention the pre-phase, and I would just like to mention that one more time because I do think there's data that providing a brief pre-phase can minimize toxicity with the first cycle.

And how this pre-phase is given is highly variable. Again, the data is somewhat limited, but it typically includes steroids given for five to seven days with or without a dose of vincristine. And steroids themselves can have toxicity. And the dose of the steroids, I think, is somewhat controversial. In my personal practice, I use somewhere between 40 to 60 milligrams per day for five to seven days. And I do not typically use vincristine, although a prospective French trial recently did and showed that this significantly improved toxicity.

Other complications that can occur really are related to infection. And so, of course, all patients should have growth factor support as per ASCO guidelines. But I also routinely give VZV prophylaxis with acyclovir or valacyclovir. And for the first cycle in particular, I have patients come back to clinic after the first dose one week later to ensure that the counts are stable and that they are doing well. This is really where our team of nurses and other providers who are part of the care team are so important and communication is also very important.

PAOLO STRATI: So Dr. Smith, as you suggested, also, this patient actually received mini R-CHOP without any complications. And end-of-treatment PET/CT can showed a VL score of 3, so a complete metabolic remission, potentially. How do you interpret these findings?

SONALI SMITH: So response criteria in clinical trials, and then of course, extrapolated to the clinic, have evolved in lymphoma. And the Deauville or the International Prognostic Scoring System that has been used typically defines a uptake relative to liver and mediastinal blood pool. And those patients who have a Deauville 1 to 2, which is less than that bar, is considered negative. And 4 to 5 is positive, with five being the emergence of new sites of adenopathy.

The interpretation of a Deauville 3 can be somewhat more complicated, but this really outlines the limitations of just using the SUV or the PET scan uptake to measure response. For my patient and for this patient, the lymph nodes all substantially decreased in size. And having some type of combined interpretation of the uptake, as well as the size that has decreased, I think is going to be a very important part of how we approach patients going forward. So for this patient, I opted for close observation after the completion of therapy and felt that his Deauville 3, along with the decrease in the size of the lymph nodes, was very significant.

PAOLO STRATI: I completely agree with that. Where PET scan is an extremely helpful tool, particularly for the management of aggressive B-cell lymphoma, can also become a major challenge when it comes to its interpretation for these borderline scenarios. And as you said, it's very important to add into the equation multiple parameters, including CT findings and overall patient performance status symptoms.

So that's all we have for today. Thank you, Dr. Smith. This was a great conversation. We have learned and discussed a lot about diffuse large B-cell lymphoma, including novel biological agents, CAR-T cell therapy, management of elderly patients, and patients with comorbid health conditions and interpretation of PET/CT scan.

I think this will be very helpful. And the conversation will continue beyond this podcast. In part 2 of this episode, airing in November, we will discuss new therapies for mantle cell lymphoma and for follicular lymphoma. Thank you so much to all the listeners tuning into this episode of the ASCO Educational Podcast.

SONALI SMITH: Thank you. It's been a pleasure to speak with you today.

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