A session with UK experts Graham Collins and Wendy Osborne, who debate key updates in lymphoma from the ASH 2021 annual meeting and how the latest breakthroughs could impact clinical practice.

Welcome to The Lymphoma Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc)! This exclusive discussion features leading experts Graham Collins and Wendy Osborne, who debate key topics in the treatment and management of lymphoma from the ASH 2021 Annual Meeting and how the latest breakthroughs could impact clinical practice in the UK.

The topics of discussion include the role of radiotherapy in diffuse large B-cell lymphoma (DLBCL), the use of high-dose methotrexate for CNS relapse in DLBCL, and bisphosphonates for bone protection in patients receiving steroid-containing chemotherapy. The biggest updates on CAR-T therapy and bispeficics are also covered in this insightful discussion. Catch up on-demand!

Methotrexate prophylaxis for CNS relapse in DLBCL

 
 
 

 

“I think one of the things that really struck me, and I think it’s generated a lot of conversation and is potentially practice-changing, was the data on high-dose methotrexate prophylaxis for CNS relapse in diffuse large B-cell lymphoma. We had two studies. One was looking at intercalated methotrexate with R-CHOP, versus end of treatment, and another by the Australian group was looking at the efficacy of high dose methotrexate.”

     – Graham Collins

“We’re going to give less. We’re going to focus on patients with the CNS IPI of six, and really think carefully if they have a CNS IPI of four, and not routinely give it to CNS IPI of four, but think if it’s a CNS IPI of five. We will continue to give it for high-risk sites, and probably just be really cautious with these older patients, because they’re the ones that get the methotrexate toxicity.”

     – Wendy Osborne

The role of radiotherapy & bisphosphonate prophylaxis

 
 

“And I was very interested to see another retrospective data set, but a huge one. I mean, almost 40,000 patients from a US data set, looking at the role of radiotherapy in early-stage diffuse large B-cell lymphoma…It essentially showed that the five and 10-year overall survival was prolonged for patients who received radiotherapy, both for nodal and extranodal disease, modestly, but by about five percentage points. And the other thing I thought was very interesting is the subgroup analyses, looking at the extranodal sites. So, it seemed to be particularly beneficial for testicular, for thyroid, which I thought was an interesting one, and skin and soft tissue, and less so for bone and breast, both of which slightly surprised me.”

     – Graham Collins

 

POLARIX & ZUMA-12

 
 

 

“One of the real highlights, I think, was to hear the POLARIX data. So this was frontline randomized Phase III trial, double-blinded placebo-controlled. I thought really well-designed study in that respect, with progression-free survival as the primary endpoint. It was an R-CHOP plus X study, which many people have been saying will always be negative, as they have been historically. And the X, in this case, being polatuzumab vedotin.”

     – Graham Collins

“So, there was a 6.5% improvement in PFS in the polatuzumab arm. So I think that, in terms of the fact it met its primary endpoint, and therefore reduced the numbers of patients going on to require second-line therapy, is a fantastic outcome for our patients, and we’ve not had an improvement in R-CHOP in 20 years. And I think that that is good news.”

     – Wendy Osborne

CAR-T & bispecifics

 
 
 

“I’m really excited by the bispecific data. I love the fact that it’s off the shelf. I think that, as we’ve already discussed, it’s sometimes quite difficult to get patients to CAR-T, and it’s logistically quite difficult, whereas a bispecific product that you could see a patient in the clinic and treat them the next day, with good response rates and well-tolerated, is really exciting.”

     – Wendy Osborne

 

Full Transcript

Graham Collins:
So welcome to this roundtable ASH 21 discussion. Thank you very much for VJHemOnc for putting this on. We’ll be discussing lymphoma data, and particularly how it applies to UK practice. My name’s Dr. Graham Collins. I’m a hematologist and a lymphoma lead in Oxford, and I’m delighted to be joined by my friend and colleague, Wendy Osborne, from Newcastle. Thank you for joining, Wendy.

Wendy Osborne:
Pleasure.

Graham Collins:
So it was a bonanza, I think, for lymphoma this year. We were completely spoiled. Quite hard to sort of keep it all in our heads, I think. And Wendy, I think one of the things that really struck me, and I think it’s generated a lot of conversation and is potentially practice-changing, was the data on high-dose methotrexate prophylaxis for CNS relapse in diffuse large B-cell lymphoma. We had two studies. One was looking at intercalated methotrexate with R-CHOP, versus end of treatment, and another by the Australian group was looking at the efficacy of high dose methotrexate. I love to hear your thoughts initially, Wendy, if you’re happy to sort of summarize the outcomes, and how you in Newcastle are applying the data.

Wendy Osborne:
Thank you, Graham. So I think that, well, for a long time now, we’ve known who the high-risk patients are for risk of CNS relapse. And we know that that’s a devastating outcome for our patients, with the response rates being very poor if patients have a CNS relapse. And I think it’s fair to say that, over the years, we’ve probably given a lot less intrathecal and moved to intravenous methotrexate. And the retrospective data looking at timing of intravenous methotrexate concluded really, that if you give it intercalated, so amongst the cycles of R-CHOP, you can cause a 20% delay of R-CHOP delivery. And obviously, this is of detriment to the patients, and we would be concerned that delaying proven R-CHOP therapy would be a poor outcome. And so now, if you’re going to give it, I think, giving it at end of treatment, so after you’ve completed the R-CHOP is optimal, and these data confirm that. I think that the other retrospective data presented by Kat Lewis gives a lot of food for thought and discussion, and has certainly caused a lot of discussion between lymphoma colleagues around the world. And this was looking to see if, actually, there is any benefit at all of giving that intravenous methotrexate. And it’s a fantastic study, retrospective data, but huge numbers of patients. They had 2,300 high-risk patients, and these high-risk patients had a CNS IPI of four to six or were considered to have high-risk sites. And they looked at these patients as to whether they’d had IV methotrexate or not. And within the group, there were 390 patients who’d had the high-dose methotrexate. And what they showed was that when they compared the patients who’d had high-dose methotrexate, compared to those who hadn’t, there wasn’t a significant difference in relapse risk. So it was about 8%, I think, in the high-dose methotrexate arm, 9% in the no high dose methotrexate arm. So, when you first hear this, or you read the abstract, you think, “Fantastic, we can stop giving this potentially toxic treatment to our patients.” However, I have to say that, when making that decision, I would give caution, when looking at the data. So initially, they were hoping to get 650 patients having a high dose methotrexate, and they’d got less than that, so it was underpowered. And the groups weren’t matched, so there were significantly more higher-risk patients in the high dose methotrexate arm, maybe 10% more with three or more extranodal sites, and 25% more high-risk sites. So, they weren’t matched. And when we go back to that initial Smith data, that CNS IPI four to six was quite varied. So, four had a 10% risk, whereas an IPI of six was nearly a 30% risk. So when you don’t have matched groups, you could say, “Well, maybe we would expect them to be even higher in this high dose methotrexate group. And actually getting down to the same is a good outcome.” And then, one of the other final thoughts, really, is how much high dose methotrexate did they have? Because they only looked at patients who’d had one cycle or more. And obviously, in Newcastle we would give two or more, and we would give a minimum dose of three grams per meter squared, and a third of patients, the dose wasn’t recorded. So I just think, with caution, with a small event rate and with not matched groups, trying to remove it for everyone, for me, doesn’t feel, at the moment, that we’ve got the data to do that. So, you asked what we’re doing in Newcastle. We’re going to give less. We’re going to focus on patients with the CNS IPI of six, and really think carefully if they have a CNS IPI of four, and not routinely give it to CNS IPI of four, but think if it’s a CNS IPI of five. We will continue to give it for high-risk sites, and probably just be really cautious with these older patients, because they’re the ones that get the methotrexate toxicity. So, focus on younger patients. We don’t use age as a cutoff, but biological status of 70 older, we would be less keen to give the high-dose methotrexate.

Graham Collins:
Hmm. That’s interesting, Wendy. I mean, we have very similar thoughts here in Oxford. We’ve actually got our Thames Valley regional meeting this week to discuss what we’re going to do. Because it’s interesting, isn’t it? How it’s so ingrained that you do something, to actually stop doing it is very, very difficult, and slightly goes against the grain sometimes. And particularly when CNS relapse is so devastating. So I think, like you, Wendy, we’ll probably be focusing on the CNS IPI, certainly of six and high-risk sites such as testicular, but probably dropping it for the fours, and probably most of the fives, and making sure that the people we give it to are fit. So, very similar thoughts our end. It’s interesting though, isn’t it, to see the spectrum of how people are reacting to the data? Some saying, “Drop it completely.” Some saying, “Stick with the status quo,” and some saying, “Give more. If high-dose methotrexate isn’t enough, we need to give more, maybe ARA-C as well.” It’s interesting how these data is interpreted by people differently.

Wendy Osborne:
I think that’s true, and I think that, if people were keen to stop it before this, and they probably would use these data just as extra evidence, whereas more cautious people might go through and say, “Well, hang on, what about this? And what about that?” And we need to discuss this with our patients, because the truth is that none of us really know.

Graham Collins:
Yeah, absolutely. And another sort of fairly hot topic in MDTs is radiotherapy, the role of radiotherapy in diffuse large B-cell lymphoma. And I was very interested to see another retrospective data set, but a huge one. I mean, almost 40,000 patients from a US data set, looking at the role of radiotherapy in early-stage diffuse large B-cell lymphoma. We’ve seen a drift away from using radiotherapy, particularly in PET-negative patients, or end of chemotherapy PET-negative patients. And there’s been some studies, albeit relatively small, certainly compared to 40,000, suggesting that the outcomes from a PET-directed approach are good, but there’s been some concerns raised that we may be throwing the baby out with the bathwater. Yes, it’s good maybe to reduce radiotherapy, but where it’s safe, are we actually potentially omitting a modality which may reduce the relapse risk, albeit modestly? So this was a very interesting data set. It essentially showed that the five and 10-year overall survival was prolonged for patients who received radiotherapy, both for nodal and extranodal disease, modestly, but by about five percentage points. And the other thing I thought was very interesting is the subgroup analyses, looking at the extranodal sites. So, it seemed to be particularly beneficial for testicular, for thyroid, which I thought was an interesting one, and skin and soft tissue, and less so for bone and breast, both of which slightly surprised me. So again, Wendy, I’d love to hear what you do in Newcastle now, and will this inform your practice? Or again, is it status quo for you, do you think?

Wendy Osborne:
So again, I think that this was a really helpful study, and huge numbers, so it was very impressive. And I mean, in Newcastle, we would tend to give a combined modality approach of three R-CHOPs plus radiotherapy, or a PET-guided approach of three R-CHOPs, a PET scan, if that’s negative, give a fourth R-CHOP. We would do that for our early-stage nodal patients without bulk, and really in our MDT, if they fit that criteria, we would have a discussion about what is more risky for the patient: a fourth R-CHOP or the radiotherapy? Now, we’d had a lot of discussion over last year about whether to include extranodal patients within this group, because with extranodal patients, although in the fantastic British Columbia data, and in the SWOG data, extranodal patients were included, there was obviously a broad group, and small numbers in each group. And so, it’s difficult to know whether large numbers of tonsillar extranodal, which I would consider as nodal, and would be quite happy to include that. But what about the risk of bone or thyroid, as you’ve just said? And the retrospective data from Memorial Sloan Kettering also showed that there was benefit, that the extranodal patients don’t do as well if you shorten their chemo. So I have to say that we’ve continued giving our extranodal patients six cycles of R-CHOP and radiotherapy consolidation. So, I think in terms of this, to me, just highlights we need to think carefully about removing radiotherapy. Our clinical oncology colleagues are so important in our MDT about weighing up the risk and benefit. I don’t think that we can say that these data presented at ASH mean that we should be giving radiotherapy to all. It didn’t use a PET-guided approach. And there were no details on the number of cycles of chemotherapy. But again, for me, I’m still less keen to reduce the treatment for our extranodal patients. And we will continue giving six and radiotherapy at the moment.

Graham Collins:
Yeah, I guess it’s a heads-up, isn’t it, as well, that radiotherapy is active in lymphoma, and using it judiciously and in the right patients is important. I even thought, with the bone, it didn’t show a benefit in bone as a subgroup, but of course the numbers, as you go into each subgroup, get lower and lower. And yet often primary bone lymphomas, if it’s in an arm or an iliac bone or something, the risk of radiotherapy is so low that I think, actually any benefit they may derive is low risk. And again, with our clinical oncology colleagues, we still often do irradiate those patients.

Wendy Osborne:
I completely agree. The risk of relapse is devastating. Moving to high dose and then auto is devastating. So, it has to be individualized, that discussion. And I did find this data helpful, because we were talking about whether we should start including our extranodal patients into more of an early-stage group, which many centers do. It’s not the wrong thing to do. But for the reasons I’ve discussed, I think that these data would just mean that we’re keen to keep that treatment intensity up for them, including radiotherapy.

Graham Collins:
Yeah. Thanks Wendy. One thing I really like in ASH is when you get a decent presentation on supportive care, because that, again, is perhaps neglected slightly, in terms of investigation. And there was a really interesting prospective, even randomized study, looking at bone protection. So, alendronate in patients receiving. It wasn’t just diffuse large B. It was patients receiving steroid-containing immunochemotherapy. The Siesta study, small numbers, I think, Wendy, and the primary endpoint wasn’t really a clinical endpoint. It was a bone density endpoint, but it was positive, at least looking at bone density in one part of the skeleton, suggesting that maybe we should certainly be taking bone health more seriously, and potentially intervening. Again, interested to hear your thoughts. Do you think that should change our practice, in terms of bisphosphonates and calcium and vitamin D?

Wendy Osborne:
Yeah, I think that this is practice-changing, and if practice hasn’t already changed in your center, then I do think it should include bisphosphonate prophylaxis. I mean, we knew from retrospective data presented at ASH couple of years ago that the fracture rate is high. This was just looking at patients over 70, but it was something like an 11 or 12% fracture risk for patients who’d had steroids-containing regimes for lymphoma. And we’d audited our data in Newcastle and found almost exactly the same. And it’s these things that you’re often unaware about. You think, “Fantastic, I’ve cured the lymphoma. This is all great. The patient’s fine.” And then they have significant morbidity after their treatment, and they’re going to different centers for their hip replacement, for example. So this randomized trial of about 30 in each arm, showing that there was a benefit in that mineral density weighted score, T2 score, in the patients who had weekly alendronate, without toxicity. I think we should be doing this for our patients, and I think what’s going to be interesting is who we do it for. So, the study was all patients age 18 and over, with R-CHOP-like regimes. Before this study, in our center, we were looking at patients who were over the age of 65 to 70 with another risk factor, such as bone involvement with lymphoma or previous fractures. And for those, giving them bisphosphonates. However, again, we need to have a discussion whether we broaden that out, in view of this data. Small numbers, but bone protection is really important, and provided their renal function is okay, and there isn’t going to be sort of dentition concerns, in terms of osteonecrosis of the jaw, I think that more and more bone protection is standard of care sort of prescribed alongside the chemotherapy is important.

Graham Collins:
Absolutely. Yes. I mean, we’ve sort of adopted the approach of giving everybody Calci-Chew, essentially, with calcium and vitamin D, and then bisphosphonates, as you say, Wendy, for the higher-risk patients. We’ve actually gone with a single dose of zoledronic acid IV when they come for their first R-CHOP. But the risk groups, as you say, came out of that study that my colleague Toby Eyre led. So yeah, we’re sort of targeting the higher risk too. So yeah, I absolutely agree. And I can think of some patients. I mean, there’s only one or two, but who really have crippling pain from their osteoporotic vertebral fractures. I mean, it’s really impaired their quality of life. And I think beforehand, we just thought maybe this was coincidence, but I think now we appreciate it’s actually a lot of steroids you get with six cycles of RCBP or R-CHOP. So, very important to think about it. Yeah.

Wendy Osborne:
And we give so much bisphosphonate for myeloma patients, and it’s something that we’re all quite experienced at doing and most patients tolerate it well. So, to me, this is something that should be practice-changing.

Graham Collins:
Yeah, absolutely. And another really interesting study I thought presented, looking at the more holistic approach to our patients, was the use of psychodynamic drugs. This was as a surrogate for, essentially, depression and anxiety in patients treated for non-Hodgkin lymphoma. And this was not just treated actually, diagnosed with non-Hodgkin’s lymphoma. This was high and low grade, and this was a big Danish population study. The Danes have excellent databases, not just for cancer, but also for primary care and drug use pharmacy data sets. So, I thought it was a really nice example of a project linking two data sets together, the primary care data set, looking at what drugs were prescribed, and also the cancer data sets, and showing an increase, certainly in the first year after diagnosis of psychodynamic drug use for all lymphomas. And I think, Wendy, what I found particularly interesting. I don’t know if it’s surprising or not, but was the low grades where, actually, they didn’t seem to go back to baseline, in terms of their risk of psychodynamic drug use, but the risk was increased over a number of years, and actually there was an increased risk of self-harm and even suicide attempt. There was no intervention in this, but I think just a really important study highlighting this issue. What were your thoughts on that, Wendy?

Wendy Osborne:
Yeah, again, I think that this shows that we mustn’t just focus on the lymphoma and the treatment for our patients, and the fact that there was that increased risk across all subtypes of patients requiring psychodynamic drug therapy is really significant. And we do need to address this as part of our whole assessment of the patient, and make sure that we’ve got good support. And I think we’re getting better at that. I think that, certainly where I work, we have our Maggie Center, which is fantastic, for the psychological support for patients. We have our specialist nurses who are fantastic, and clinical psychologists. But it’s often not the primary thing that we consider, and we should be bringing it up and discussing with our patients. But the data from the low grade really was concerning, and the data showing that it doesn’t ever normalize. So it did for high-grade within five years of treatment. So, it seems that if a patient is treated and cured, then the patients, they come off their antidepressants or whichever psychodynamic drugs they’ve had, whereas for low grade, it stays, as does that risk of self-harm and suicide. And so, I often say this to our registrars in clinic; we often follow up a patient with follicular lymphoma and say they’re a quick watch and wait review. And actually, I don’t think they should be. I think that we should be spending time with them, because many of these patients watch and worry. They may never need treatment for their follicular lymphoma, but for many years, they might have low mood and anxiety. So, their mental health is impaired, even if their physical health doesn’t require treatment. So I think that, again, highlighting this study, I’m pleased it got an oral at ASH this year, because it’s a really important aspect of making sure we look after our patients properly, and not just about delivering chemotherapy or targeted therapy.

Graham Collins:
Absolutely. Yeah. Thank you. Now, moving on to the more therapeutic approach in frontline diffuse large B-cell lymphoma, one of the real highlights, I think, was to hear the POLARIX data. So this was frontline randomized Phase III trial, double-blinded placebo-controlled. I thought really well designed study in that respect, with progression-free survival as the primary endpoint. It was an R-CHOP plus X study, which many people have been saying will always be negative, as they have been historically. And the X in this case being polatuzumab vedotin, the antibody-drug conjugates targeting CD79B. So R-CHOP versus R-CHOP plus polatuzumab. Wendy, are you okay to summarize the primary endpoint data, and what your thoughts are? Obviously, we can’t use it yet. It’s not licensed, but it will be, imminently, I’m sure. And then NICE will be saying whether we can use it in England, and obviously the respective authorities in Scotland, Wales and Northern Ireland. So, interested to hear your thoughts.

Wendy Osborne:
So like you, I thought this was a really well-designed study. There were about 440 patients in each arm, so good numbers and double-blind placebo-controlled. So it felt like a good design of study. And the primary endpoint was a two-year progression-free survival, and it showed that it met its primary endpoint. So, there was a 6.5% improvement in PFS in the polatuzumab arm. So I think that, in terms of the fact it met its primary endpoint, and therefore reduced the numbers of patients going on to require second-line therapy, is fantastic outcome for our patients, and we’ve not had an improvement in R-CHOP in 20 years. And I think that that is good news. I think the big concern really, is that there has not been an overall survival advantage shown. And the overall survival, is that because patients who relapse after they’ve had polatuzumab are harder to get into response second-line, and that’s why we’re not seeing survival benefit? Is it that it’s a bit early? Is it that our second and later line therapies are getting better? I think that’s difficult. So for me, if there’s a PFS benefit, I would then go on and look at the toxicity. And the toxicity was pretty similar in both arms. The main difference is that there was more febrile neutropenia in the polatuzumab arm. I think it was 8% up to 12%. But there wasn’t an increase in neuropathy, which was my worry with polatuzumab. Is that going to be a problem? So for me, if there is an improvement in PFS with minimal change in toxicity, would I give it to my patients? The answer is yes. Will it be funded? The answer is I don’t know. I think that this is going to come down to health economics, and this needs to be reviewed by NICE, looking at, by reducing numbers of expensive second and third-line therapy, in terms of car T. Will that be of health economic benefit? So therefore to allow approval, and that needs to be assessed by health economists. That isn’t me. If I’m able to give it to my patients, to try and reduce them having that not great second line high dose therapy on auto, then I would, and I am disappointed there wasn’t a survival benefit shown, if I’m honest, but it’s whether we see that later. I don’t know. So would you be giving it to your patients, Graham, if it’s approved?

Graham Collins:
I mean, you’ve mentioned already, but I’m so glad to live in a country where I don’t even have to worry about the cost of the medicines. That’s worried about by someone else. And likewise, if I had diffuse large B, I would want the treatment with the highest PFS. I think we do have to remember, as well, the trial wasn’t powered for overall survival. Therefore, there might be an overall survival benefit that’s just hidden by the numbers, hidden by the inadequate power of the trial to show it. And is the PFS a fluke for some reason? Well, I think no, because they did show, as you said, the reduction in second-line treatment. So, it is translating to another beneficial outcome. I think the other thing that was interesting, Wendy, and I’m sure NICE will look at this as the subgroup analysis, we’re all rightly trained to be very cautious interpreting subgroup analyses, but it did seem that the higher IPI groups, three plus, the whole drug population was two plus, but the three plus particularly seemed to benefit more, if you just look at the forest plots and take them at face value. So, there were some other subgroups as well that seemed to benefit more perhaps older patients, perhaps the ABCs. But if I had a crystal ball, I would be predicting that NICE might restrict availability to make it more health economical, perhaps, to the higher IPI groups. I feel it always a bit uncomfortable when that happens, because of the lack of power in subgroups. Maybe that that our use is limited to a higher risk group, in which case, so be it. As I say, I’m just glad that I’m not the one who has to make these decisions.

Wendy Osborne:
Yeah, I think that’s true. And I think that the sub-groups weren’t powered, so it’s frustrating sometimes, when NICE make their decisions depending on that when it’s not powered for it. But I can understand that, if trying to get availability on an economic ground, then I think that’s probably what will happen as well, if I’m honest.

Graham Collins:
Yeah. Yeah. And another frontline study that I thought was perhaps just a little glimpse into the future. I mean, this isn’t practice-changing, but was ZUMA 12. I mean, I really liked this study in many ways, because it was focusing on high-risk diffuse large B-cell lymphoma. And I think they were proper high risk, so you had to have a double hit based on cytogenetics, albeit that the MYC translocation partner wasn’t defined, or a high IPI, and you had to have an interim PET-positive scan after two cycles of R-CHOP, with a good number actually being Deauville five. And then, for those patients, they were taken off their frontline R chemo. I mean, they weren’t all on R-CHOP, but R-CHOP or R-CHOP-like, perhaps . and given a CAR-T approach, using axi-cel. The data as it stands, it was small numbers of patients and it’s relatively short follow-up, but showed essentially a PFS of around 75%. And a response rate, obviously, higher than that. So, in my mind, I’m always comparing with the PETAL data, which took interim PET-positive patients, and gave them a Burkitt-like chemotherapy regimen, much bigger trial, though, and probably a much less select patient cohort and showed really dismal results. So, it was just very intriguing, I thought, that potentially using a CAR-T approach for this very high risk frontline setting is certainly worth investigating further. And maybe the way where we’re heading, thought it was also very interesting that they looked at the CAR-T product and it seemed to be a more T-cell fit product, compared to those used in third-line, which is of course where the current license is for CAR-T use. So I’m interested to hear your thoughts, Wendy. I just wondered if, in 10 years time, maybe even less than that, we might be seeing the randomized trial suggesting we should be using CAR-T upfront in high-risk diffuse large B.

Wendy Osborne:
So, like you, I think that the future will be that we will be able to understand who the high-risk patients are, whether this is defined, as was defined in ZUMA 12. I’m not sure yet, but I think that we will also use a risk-adapted approach, as we do in Hodgkin. So looking at the PET scan, probably using different PET parameters, as we understand PET scanning more and more. It did take a long time to get the patients into trial for ZUMA 12. So, the screening period was long and you would think, “Right, although they’re high risk in terms of their definitions, they’re obviously good enough risk patients to get into a frontline trial.” But the fact that significant numbers have progressed on that PET scan. I agree with you, the outcomes are better than I thought. And it makes sense, doesn’t it, that if we take these T-cells of patients earlier, before we’ve exposed them to lots of chemotherapy, that they will be fitter and you would think, therefore, more CAR-T expansion, less CAR-T exhaustion. And I wonder if the future might be that, at diagnosis, we can just take everybody’s T-cells off them and stick them in the freezer in case we need them. It might be that we’re not going to need them for everybody frontline, but it feels that the earlier we can get those T-cells, the better in terms of the efficacy of CAR-T later on. So, small numbers, one to look out for. But yeah, I agree that ZUMA 12 is certainly something that we’re discussing, but not practice-changing yet.

Graham Collins:
So, if you’re an investor watching this, you should invest in apheresis machines, maybe.

Wendy Osborne:
Yeah.

Graham Collins:
Okay. And, talking about CAR-T. There was a lot of really interesting data in CAR-T. Not one, not two but three randomized clinical trials, looking at CAR-T versus a conventional approach. So, chemotherapy with autologous stem cell transplantation in first relapse diffuse large B. Two big trials, so ZUMA 7, looking at axi-cel, Belinda, looking at tisa-cel, and one interim analysis, the Transform study, looking at, I’ll call it liso-cel, just for clarity and ease. The bottom line here was that ZUMA 7 was a positive trial, Belinda was a negative trial, and Transform, again was a positive trial. This has led to much discussion about whether this is due to differences in the product or differences in the trial design. And there were some significant differences. I mean, the basic similarities is that they were all one-to-one randomizations of a CAR-T approach versus a chemo with autologous stem cell transplant approach. In each trial, around a third of patients actually made it to their autograph, which I thought felt about right. That’s sort of what we see in practice. Maybe even less, actually, in practice. The toxicity was what we would expect. So for axi-cel there were higher neurological grade three plus events at around the 20%, just north of that mark, whereas with tisa-cel and liso-cel, it was both significantly less than that. And there was a big difference though in time from apheresis to CAR-T infusion. So, it was down in the 20s for axi-cel. It was just over 50 for tisa-cel. So big differences there, and differences in the bridging that was allowed. So, a lot of bridging was used in Belinda, sometimes even two lines of bridging chemo, whereas the only thing that was allowed in ZUMA 7 was steroids, and it was a more select group. They did exclude more patients in ZUMA 7 with very aggressive disease that may be imminently leading to clinical deterioration. The primary end point in all three was event free survival, which is slightly confusing, because there were subtle differences in that definition. And there was no overall survival in any of the trials, albeit I thought in both ZUMA 7 and Transform, I always want to say a significant trend. That’s a contradiction in terms, but there was a marked trend. You think, “Wow, they’re close,” and in all three trials as well, there was significant crossover. In ZUMA 7 that was off protocol, but in the other two, it was on protocol, but around 50%. Again, it was give or take in the standard arm crossed over to CAR-T, so that may explain why the overall survival was not affected. So Wendy, again, interested to hear your thoughts. I guess ZUMA 7 being the positive one, axi-cel is the one that’s likely to get a license in that setting, tisa-cel, less likely. liso-cel, it’s a bit too early to say yet. Do you think this is the approach to use for a high-risk relapse? That’s other thing; they were all high-risk relapse patients, but is this the way to go, do you think?

Wendy Osborne:
I hope so. I mean, when we see our patients having second-line therapy it’s such a different conversation, isn’t it, to our frontline R-CHOP discussion, which is quite positive, 60 to 70% chance of cure, well-tolerated treatment. When we meet our patients to have that second-line GDP and auto discussion, it’s a really breaking bad news discussion. And we are hoping for long-term responses in about 20% of patients. So, most of us are thinking second-line that they’re probably going to go onto CAR-T third-line. And in fact, we prepare that. We make sure we’ve got the biopsies ready to get the patient through the panel. We just are really ready to go third line. So, if we could change that standard of care second line approach, I think that that would be a really positive thing for patients. And I think that, when we looked at ZUMA 7, I was concerned initially that no bridging was allowed. I thought, “Well, hang on, is this that they’ve really selected good risk patients, low volume disease, who often do well with CAR-T?” But then, when you looked at the numbers of patients that got to auto, it was similar in the ZUMA 7 and in the Belinda study. So, that suggested that the groups were reasonably well matched, in terms of the numbers of patients that got to auto. So, will it change practice? I think that, as you’ve highlighted, there are difference in the trial designs, and the difference in what was considered in the event in both arms. But I think that, for ZUMA 7 data, which is the one that is most likely to go forward for approval, if patients relapse within 12 months and it goes through the health economic model, because if the patients don’t get through second-line in the UK, most of them would go to CAR-T third-line. Then I would really be hopeful that this will be a change in the future.

Graham Collins:
Hmm. Absolutely. I guess the one thing that worries me, actually, thinking about how this is going to be applied, is obviously this was by definition, the eligibility was you had to be autograph fit, because the standard arm was chemo and an autograph, but the people I’d really liked to give T-cell to at first relapse, CAR-T, rather, to at first relapse, are those who are CAR-T fit, but not auto fit, because at the moment we have to go through a line of therapy that we know is not curative, just so that they fail it and go on to CAR-T. So, I assume these trials won’t affect that group, which I think is a real shame.

Wendy Osborne:
Yeah, I agree. But it’s interesting, isn’t it? They were deemed to be auto fit in the studies, but then when you looked, they had patients, I think the oldest was 79 in one of the experimental arms, and we wouldn’t give a patient who is 79 a beam auto. So, we start being quite cautious once patients reach the age of 70. Obviously biological age, not chronological age, but there are definitely patients within the study who it would feel would be not auto fit, but would be CAR-T fit. So I agree with you that, at the moment, we give these patients Gem-Ox second line to get them to CAR-T third-line, it would be fantastic to try and bring that CAR-T, which is well tolerated, earlier in the treatment pathway. But possibly, I think people will be saying that their patients are fit, even when they’re in their early to mid 70s, to try and get them CAR-T second line. And for us in the UK, it will depend on how NICE stipulate the approvals as to who we can get into that group.

Graham Collins:
Yeah, what the blue tech form is going to look like.

Wendy Osborne:
Yeah, and I think that we think a lot about the blue tech form and what we are going to consider, and those patients that have to relapse within 12 months of end of R-CHOP therapy, I do wonder whether we’ll be doing more scans. I mean, would you start scanning at 11 months to make sure that you’re not going to miss a potentially better second-line option for your patients, or at present as we all do, just do clinical follow-up? What do you think?

Graham Collins:
Yeah, I do. I think I will be scanning more of my high-risk diffuse large B cell lymphoma patients, even if they’re asymptomatic, because we’re going to have a treatment which is time-dependent. So time-dependent, as in, if you relapse after, if you miss it by a month, they’re 13 months, then we won’t be able to tick the blue tech form and use it. But that the evidence suggests if you get in quickly, so if your patient’s well, performance status 01, that’s when it’s a particular benefit. So it’s time-dependent, in that you don’t want them to relapse and become unwell, because then, this therapy is going to be less effective. So I think there’s two reasons, really, why I think I will be doing more scans, not across the board maybe, but certainly for select patients. Yeah.

Wendy Osborne:
Yeah, and I think when we’re thinking about changing UK practice, so in the UK, we’ve never done surveillance scans, and we do the end of treatment scan and then say, “Okay, clinical follow-up and contact us if you have X, Y, or Z symptoms.” But there were other data at ASH this year also showing that, actually, it was a trial looking for circulating DNA and CT scanning to try and predict relapse. And it showed that the DNA wasn’t, in the test that they had, sensitive or specific enough. But the CT scanning picked up 40% of asymptomatic relapses. Now, in the past, I would have thought, “Well, it’s not really going to change. We’ll treat them when they’ve got symptoms.” But now that we have CAR-T options, and now that we see a lot of patients not getting to CAR-T because of disease progression, it does feel that we may benefit from knowing about a relapse earlier. And so maybe practice would change that we do do more regular imaging. I’m sure that the radiology department are all groaning inside at this suggestion. But I think that if it means that we can get patients to the next line of therapy more successfully, then maybe that additional imaging will be of benefit. Who knows?

Graham Collins:
Absolutely. And then perhaps one final abstract, just to briefly pick up on. And I know we’ve been very much focusing on high-grade lymphoma. There was so much data in high-grade lymphoma this year, but I want to pick up on one low-grade lymphoma abstract, and there was a lot out there on low grade, but that’s the bispecific data, because bispecifics are looking like a very active group of drugs, and we heard some longer follow-up data on the phase two study of mosunetuzumab in relapse refractory follicular lymphoma, showing very good response rates, an overall response rate of 80% in relapse refractory group. Quite a high proportion of pod 24 patients, a complete response rate of 60%. And what we’re really waiting for is the more mature follow-up and survival data, and the median progression-free survival was just a little bit more than 17 months. And again, when I’m interpreting this data, I always have the idelalisib data in my mind, because that was one of the first novel agents in this group, and that progression-free survival was around the eight, nine-month mark. So, very healthy-looking PFS. So really, just interested to hear your thoughts on how the follicular lymphoma pathway is shaping up. How might that change, assuming this gets NICE approval and funding, because hopefully we will hear whether we’ll be able to use mosunetuzumab within the next year or so for this indication.

Wendy Osborne:
So, I’m really excited by the bispecific data. I love the fact that it’s off the shelf. I think that, as we’ve already discussed, it’s sometimes quite difficult to get patients to CAR-T, and it’s logistically quite difficult, whereas a bispecific product that you could see a patient in clinic and treat them the next day, with good response rates and well-tolerated, is really exciting. And I think that most of these patients received it as an outpatient as well, so that again is encouraging, not having to go to a treatment center and spend at least two weeks as an inpatient, as they do for CAR-T. So, if this does get approval, to me, I just want durability of response, which is really important, because we need to know that to be able to discuss with our patients. And it feels to me that there is still the bispecific versus CAR-T race, so to speak. At ASH this year, we had more up on the ZUMA 5 and the ELARA trial as well. Again, showing good response data in heavily pretreated patients. But if something’s easier to give and less toxic, it may be that we give bispecific ahead of CAR-T. And I think that, out of all of the patients with lymphoma that I look after at the moment, the most complex treatment pathway is follicular. And I think that we’re all R chemo frontline, but where does R squared fit in? Where do we decide that we’re going to do more chemo and an auto? And where will these bispecifics fit in if they’re approved? So as well as understanding response data, again, they’ll have to understand response data, after which prior lines of therapy, because that will affect it as well. But I think that this will be a fantastic option for our patients with low-grade disease.

Graham Collins:
Yeah, absolutely. And the thing that I’ve come to realize more is of course the bispecifics are also fixed duration, aren’t they? Most of the trials, you don’t just stay on it forever. So, I think it was eight cycles and stop if you’re an CMR, and if not, up to a total of 17 cycles. So, even though obviously it is more visits or a longer treatment duration than CAR-T, it is at least fixed duration. And like you, Wendy, because it’s such a long journey, the follicular lymphoma journey, it really does get complicated. But I wonder if we will start seeing, as you suggest, frontline R chemo. I can’t really see that going anywhere for a while. Second line, maybe R chemo or R squared. I’m still an R chemo fan. Perhaps R-benda first line, R-CHOP second line, then I think we’ll be seeing bispecifics for sure. Maybe in combination with lenalidomide, that may be where it’s going, and then fourth-line CAR-T. So we may be seeing a much more standardized pathway, which is very exciting, because obviously each of those regimes is so active. Yeah, so I think there’s really good news on the horizon for follicular lymphoma patients, which is great.

Wendy Osborne:
Mhmm. I agree.

Graham Collins:
So I think let’s draw stumps there. Wendy, it’s been fantastic. Thank you very much for all your wisdom and insight into the data at ASH. It’s been great discussing it with you. Thank you very much again, for VJHemOnc, for asking us to do this, and for educating us all. And thank you very much for listening. It’s been great. Thanks, Wendy.

Wendy Osborne:
Thank you, Graham.

Watch the full session

Disclosures

Wendy Osborne – Roche, Takeda, Pfizer, Servier, Kite Gilead, MSD, Novartis, Beigene, Astra Zeneca, Syneos, Autolus, Kyowa Kirin, Abbvie, Incyte, BMS Celgene.

Sign-up for our Newsletter!

Keep up to date with all the latest news with our monthly newsletter