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Dr. Jeremy Abramson:
Welcome to The ASCO Post Roundtable Series on Clinical Advances in Diffuse Large B-Cell Lymphoma. I'm Dr. Jeremy Abramson from the Mass General Hospital Cancer Center in Boston and Harvard Medical School. And joining me today are two of my wonderful friends and colleagues, Dr. Sehn and Dunleavy, who will introduce themselves.
Dr. Laurie Sehn:
Great. I'm Laurie Sehn. I am from BC Cancer and the University of British Columbia here in Vancouver, Canada.
Dr. Kieron Dunleavy:
I'm Kieron Dunleavy and I'm from MedStar Georgetown University Hospital in Georgetown University in Washington DC.
Welcome both of you and welcome everybody watching. Today, we'll be discussing recent updates in the treatment of diffuse large B-cell lymphoma and integrating new developments into three different patient scenarios. Our first installment will focus on upfront therapy for patients with high risk disease. So I'll present a case of patient LE. LE is a 72-year-old woman who presents with lymphadenopathy, fevers, and drenching night sweats. An axillary lymph node biopsy is performed and shows diffuse large B-cell lymphoma, non–germinal center subtype. FISH is sent to evaluate for genomic translocations and finds no translocations of MYC or BCL2, but with IHC expression of MYC and BCL2, and making this a so-called double expressor lymphoma.
The patient undergoes staging with a PET-CT scan, which shows stage IV disease with nodal involvement, as well as involvement of liver and kidney. LDH is elevated. Her ECOG performance status is 1 and her IPI risk score is 4. Organ and bone marrow function are normal.
So maybe I'll turn this to Dr. Dunleavy to start and say we have a high-risk older patient with diffuse large B-cell lymphoma. Her IPI is 4, she's non-GCB. As of today, Kieron, how would you approach this patient?
Yeah, so thanks, Jeremy. So based on this presentation, this patient would have a pretty poor outcome with standard R-CHOP therapy. So based on the recently published POLARIX study and the fact that polatuzumab is FDA approved, I would treat this patient with pola-R-CHP. So polatuzumab in combination with R-CHP. She's got a high IPI score, she's got a lot of extranodal disease, high LDH, so a lot of really bad prognostic factors. And in the POLARIX study, we saw that patients who had higher IPI scores and the non-GCB subtype did particularly well compared to receiving R-CHOP if they got pola-R-CHP.
Terrific. And Laurie, would you do anything different?
Yeah, no, I would agree. So I think by everybody's definition, this patient is high risk. So she has a high-risk IPI score. She has bad biology with a non-GCB subtype, which tends to have a poorer prognosis when treated with R-CHOP chemotherapy. We spent a long time trying to make improvements upon R-CHOP. So R-CHOP has been the historic standard of care and it's been a little frustrating for these high risk patients because we know that they may not have optimal outcomes with that. But years of trying to juggle around the chemotherapy and even intensify chemotherapy alone has really not improved the overall survival for these patients.
So we finally have a trial that introduces a novel agent into the upfront setting and that agent is polatuzumab vedotin. And as stated, the POLARIX trial really has been the only trial that's demonstrated a significant improvement over R-CHOP with an improvement in progression-free survival. I think the important thing to state about those trial results is that the toxicity of the pola-R-CHP was comparable to R-CHOP. So in my mind, it does become the standard of care and particularly for these higher risk patients where we feel R-CHOP may just not be enough.
Yeah, I agree completely. And to remind all of our viewers, the polatuzumab-R-CHP regimen substitutes the polatuzumab for the vincristine in R-CHOP. And polatuzumab is an anti-CD79B antibody-drug conjugate where the conjugated toxin is monomethyl auristatin E, a microtubule toxin familiar to folks from brentuximab vedotin, for example. And in the POLARIX trial which enrolled patients with previously untreated diffuse large B-cell lymphomas, and IPI scores of 2 or above, the pola-R-CHP regimen improved progression-free survival with an absolute difference of about 6.5%, which amounted to a 27% reduction in risk of progression or death.
There was no difference in overall survival in this study and so, one can't necessarily be dogmatic, but as Laurie pointed out, there was also not excess toxicity. And so with the substitution of polatuzumab, there was an improvement in efficacy without a detriment in toxicity. And particularly in these high risk patients, I think that makes good sense, giving every patient the best possible chance at cure, which is obviously our goal for the initial treatment of large cell lymphoma in all of our patients in front of us. Kieron, are there any patients who you would look at who you would think would not be optimal candidates for pola-R-CHP and you would still favor good old-fashioned R-CHOP?
So I think for diffuse large B-cell lymphoma patients with an IPI score of 2 to 5, as per this study, I would offer those patients at polatuzumab in combination with R-CHP. A number of patients who recruited onto the study actually had high-grade B-cell lymphoma, whether they had high-grade B-cell lymphoma with MYC and BCL2, rearrangements or high-grade B-cell lymphoma NOS. And one question out there is how should those patients be treated? There's a lot of controversy about this particular subgroup. Historically, in many studies they have had an inferior outcome compared to other DLBCLs when they receive R-CHOP.
They did okay in this study. There were different analyses of that in the initial paper, and a subsequent FDA analysis, as well, looked at the outcome of this subgroup. I would treat that subgroup differently. I would treat them with dosage adjusted EPOCH-R. One aspect of the POLARIX study was the time from initial diagnosis to on treatment, it was 26 days in one arm and 27 days in another. And a lot of the high-grade B-cell lymphomas that we see in general can't wait around a long time before initiation of therapy. So for that subgroup, I myself would offer them an alternative regimen, but understanding that we need more data and we need more experience with this regimen in subsets of aggressive B-cell lymphoma.
And Laurie, go ahead.
Yeah, I guess I would just comment, another thing that comes up with the POLARIX data is that there was subgroup analysis done and presented in the way of a forest plot that we're used to looking at, which is really just pulling out a number of risk factors and seeing whether or not the regimen offers benefit across all the different patient subtypes that we see. These analyses are always difficult because they're not powered and they're certainly singular looks at individual features and they don't take into account the multitude of features that patients may present with. So I think we have to take some of this with a grain of salt.
But from the forest plots and the subgroup analysis, there was a suggestion that patients with an IPI score of 2 may not have benefited as much from the use of the polatuzumab. And interestingly, the GCB subtype may not have benefited much. So I think people are raising the questions, are there unique subtypes of patients that maybe benefit more or less? In the case of this particular patient with the IPI score being high and the non-GCB subtype, I think there's a lot of argument to be made for the use of polatuzumab where the forest plot did suggest even a stronger benefit for that group of patients.
So Laurie, if this patient had been GCB, would you have treated any differently?
And again, I know this debate is going on, but I would say no. So again, I think that the subgroup analysis that was presented are really univariate looks. And for this patient, if she was GCB but had high risk IPI score and a lot of other high risk features, I don't think we learned from those forest plots how this patient may fare. So I would say that I'm looking at the trial inclusion criteria and that's really what it was powered for. And unless there was a contraindication in a particular patient for the inclusion of the polatuzumab, I would say that right now, if the patient meets the trial inclusion criteria, it would be my preferential treatment.
I agree 100%. I think there's no doubt that I'll be most enthusiastic about a high IPI risk, non-GCB patient like the patient in this case. That patient seems to be right in the wheelhouse to garner the maximal benefit, but patients are made up of multiple variables that none of them are univariable. So I don't think we can interpret patients on a single variable by variable basis. I think the IPI 2 patients are just lower risk patients. And so in this, study we just didn't realize a benefit doesn't mean they can't get this treatment. And at worse, it appears that it's no worse in those patients.
And I suppose I'll err on the side of treating based on the eligibility criteria and try and offer optimized therapy. I think it is clear, a limited stage patient, an IPI of 0 to 1, those are patients who should still get R-CHOP. I think we'd all agree. And Kieron, you mentioned the double-hit lymphomas where I would also typically favor dosage adjusted EPOCH-R in a double-hit patient, which isn't the subject of this case. This case was a double-expressor. Do you approach a double-expressor large cell lymphoma differently than any other DLBCL-NOS?
Yes, sir. In terms of therapy, I don't. I mean, there's no doubt that if we look at retrospective data, especially this subgroup that have double expression of MYC and BCL2 have a much worse outcome than DLBCLs that do not have a double expression of these two proteins. But they're almost always of non-GCB origin, so non-GCB and double express or status in those that don't have double hits go along together. So really, I think double expression is capturing the non-GCB subgroup and probably some other clinical characteristics that often go along with that as well.
Yeah, absolutely. And then Laurie, British Columbia has been a real leader among groups in looking at risk for CNS recurrence. And this case has several risk factors. This patient has a high IPI risk score. She has renal involvement. How do you use CNS risk stratification and do you offer prophylaxis? And I recognize that's a controversial question.
Mm-hmm. Yeah, I think it is super controversial, but I think the one thing we could all admit is over the last several years, there's been a building dataset. So mainly from retrospective analyses and registry analyses to really call into question the utility of CNS prophylaxis. So there's no doubt that some patients are at higher risk for this event, but across the board in diffuse large B-cell lymphoma, it's still a relatively rare event. This patient falls into a higher risk category because of the high risk IPI score and particularly the renal involvement. So if we plotted her out on the CNS IPI score, she would undoubtedly fall into a high risk category, in which case, we might say that she falls into a group of patients that might have as high as a 10% to 12% chance of CNS recurrence.
The real question is can we actually change that natural history? It's been a while now since we've dropped the use of intrathecal methotrexate from prophylaxis here where I treat patients. And that's primarily because I think many of these patients present with parenchymal disease, and we don't think intrathecal prophylaxis really offers much. We had been offering systemic methotrexate. So I'm trying to intermingle them between the cycles of R-CHOP. But again, I think there's less and less compelling evidence that that offers value.
This is the one patient where I probably would consider it, but I probably have to have a detailed discussion with the patient. I think the renal involvement does significantly impact the risk. Overall though, I think that we're using it very infrequently now, but it still probably involves a discussion with the patient. At 72 years of age, I think the methotrexate does bring in a lot of toxicity. And the goal here really should be to focus on the systemic therapy for what we know is high risk systemic disease.
Yeah. We certainly do prophylaxis a lot less than we used to. Retrospective data such as we have it is never definitive. And so at a case by case basis, it still warrants a discussion, I think. Although what I would say is I really now only have that discussion with the highest risk patients, the high IPI, non-GCB patient and I should say the high CNS IPI, non-GCB patient or the primary testicular patient. But even then, I'm very upfront in saying I really don't know if we're going to offer value with methotrexate. And I think very carefully about a patient's risk, their age, their comorbidities, their renal function, because in the absence of a definitive benefit, I also don't want to cause harm.
The one thing I would state is that the one piece of evidence I think that's been valuable that's come out is that I mentioned that we used to intermingle the high dose methotrexate in between the cycles of R-CHOP. There is a retrospective study that looked at the timing of methotrexate if you were going to use it for CNS prophylaxis. And the suggestion was there was no value of doing it during the upfront chemotherapy as opposed to on the heels after chemotherapy is over. So the one thing I do now is if I do use it, I wait till all of the systemic therapy is over. And it's only going to be of value obviously in those patients who've achieved a complete remission. So it lets us bring it into the patients where it seems most appropriate, but also, we'll minimize the toxicity and not hopefully derail the induction chemotherapy, which still is the most important component.
Absolutely. Kieron, last word on CNS prophylaxis?
Yeah, I think I would agree with all that has been said. I mean, the one thing that I think is really important in these patients is to check their CNS diagnosis before institution of therapy. So in this patient, I would do a diagnostic LP. I would do cytology. There's some controversy about flow cytometry and the reproducibility of that, but a significant percentage of these patients will have CNS involvement diagnosis. So you want to know that before starting out. But I agree with all that has been said. It's a really difficult question. The implications of getting CNS relapse are, as we know in diffuse large B-cell lymphoma, are terrible.
It's extremely difficult to cure these patients if they do develop CNS recurrence. So it's really critical for us to identify if there are any patients who we can intervene on in terms of CNS prophylaxis. But as Laurie has said, as especially retrospective studies recently have shown, it's not clear that for the vast majority of these patients, even the ones that we thought would benefit from CNS prophylaxis, that it makes a big difference in the end.
Absolutely. So that's a great discussion. Why don't I put up some clinical takeaways for this initial case? I think first off, patients with newly diagnosed diffuse large B-cell lymphoma should be risk stratified by IPI score as well as FISH testing to look for rearrangements of MYC, BCL2 and BCL6, since we use that data to think about their induction therapy. R-CHOP has been the standard initial treatment for diffuse large B-cell lymphoma for over 20 years and remains so in many patients, particularly those with limited stage disease and low risk advanced stage disease. But polatuzumab, R-CHP is a new standard treatment option now for patients with advanced stage diffuse large B-cell lymphoma and an IPI score of 2 to 5 based on the POLARIX trial, which showed a progression-free survival benefit over R-CHOP, as you heard.
There are still some uncommon subsets of disease where we will consider the intensified dose-adjusted EPOCH-R regimen and that includes double-hit lymphoma as you heard about, as well as primary mediastinal B-cell lymphoma.
And that brings us to the end of this first case. Please see the other segments for further discussion about the latest data in diffuse large B-cell lymphoma or visit ascopost.com.