Loretta J. Nastoupil, MD, reviews prognostic biomarkers to advance the timely identification and risk assessment of patients with follicular lymphoma (FL) for prompt treatment and/or referrals. Dr. Nastoupil also describes current treatment options for patients with multiple relapses in the management of FL, and discusses the efficacy and safety data for agents in late stage of development and in patients who have experienced multiple relapses.
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it is now my pleasure to introduce Dr Loretta. Nasty people from University of Texas M. D. Anderson Cancer Center, Dr Nassif all will be giving us a lecture today on therapeutic updates for follicular and marginal zone lymphoma. She is well known for her contributions to the field of lymphoma, and we thank her greatly for taking time out of her busy schedule. To deliver this important lecture to us today. I would like to extend a warm welcome to Dr Nasty Pool, and if you do have questions for her, please use the chat function, and we will address them afterwards during the panel discussion. I'm Loretta Nostril from the University of Texas M. D. Anderson Cancer Center in Houston, and I'll be covering the therapeutic updates for the management of relapsed follicular Marginal Zone lymphoma. These are my disclosures. Over the next 30 minutes, I'll cover the current understanding regarding the prognostic biomarkers to help risk stratify patients and informed treatment selection, particularly as a treatment landscape continues to expand. I'll describe the current options for patients where the unmet needs lie and discuss the safety and efficacy profile of the recently approved or drugs that are anticipated to be approved in the next one year. Currently, our clinical features are how we define those patients who are at highest risk. This is the P O. D. 24 population, which was defined based off of an observation all cohort of patients enrolled between 2004 and 2000 and seven. So there is some historical context here, as that was prior to the introduction of the Mustang and read text map and also prior to the common use of pet scans. Nonetheless, those patients who experience a progression event within 24 months of front line chemo immunotherapy are facing, uh, unfavorable outcomes of the median overall survival in this group approaching five years versus the other patients who experience a progression event. Beyond that, 24 months are facing a normal life expectancy again, suggesting that those outcomes are quite favorable, even with the treatment options that existed in 2004 to 7. So this defines this high risk group, those patients who progress early in the modern era we've seen data emerged, particularly from Memorial Sloan Kettering, that with the use of pet and more commonly, biopsies to explore those high risk features. About 40% of these patients will actually have transformed disease, and that might be driving these poor outcomes. But nonetheless again, patients who progress within 24 months of front line chemo immunotherapy defined currently our highest unmet need. We also know that the best outcomes are observed in those patients with front line therapy. Again, this was an analysis of the same observational cohort defining outcomes with each line of therapy. And even in the modern era, the outcomes are best with frontline approaches. With second line, we see median PFS around 18 months and with 3rd, 4th and even fifth line of treatment. Uh, those median progression free survival are less than one year and actually not dramatically different again suggesting that beyond Frontline, these patients will be anticipated to experience multiple relapses and again, improvement in the efficacy of those treatment options, particularly for second line and later, is needed so again defining our population that needs new drugs. We recognize the chemo immunotherapy is largely used in front line, and the average median PFS is between eight and 10 years. That's quite favorable, but for about 20 to 25% of patients, they will experience a progression event early, currently defined as within 24 months, and those patients are facing poor outcomes. And currently we're trying to enrich our protocols for this poor risk group. Beyond Frontline again, the progression free intervals dramatically shorten, and particularly with third line and later. This is where patients are facing outcomes generally in that less than 12 month period, suggesting that new drugs are urgently needed. Summarize our frontline approach. What's happened in the last few years? Again, we've seen the introduction and rapid uptake have been a Mustang and rituximab, first based off of the steel study, which was a randomized trial versus our chopped for high tumor burden. Patients without maintenance performed primarily in Europe. The American version of this study was the bright trial that looked at either our chop or R CVP versus been the Mustang rituximab, and maintenance was allowed at the discretion of the treating physician. In both of these studies, we see at least the same or better progression free survival with bin the Mustang based approach versus an anthro cycling or CVP based approach. Though no difference in overall survival has been reported to date. The galleon trial looked at replacing Rituximab with Obinna Tuesday mob, which is a second generation, fully humanized antibody that should have enhanced properties. And sure enough, we see that there's a progression free survival improvement if you replace for tucks a map with a big Natuzzi mob. However, there are some caveats. The first cycle. There's more dose intensity with amenities mob administered weekly. And there are rates of Grade three or higher infusion reaction, particularly with the first dose and similarly, some, uh, increase in toxicity, particularly cardiovascular events and grade three or higher neutropenia. Non chemotherapy approaches in the front line included little intimate and rituximab, at least in the U. S. Based off of N. C. C N guidelines. That was based off of the Relevance trial, which was another randomized trial for high tumor burden patients looking at little intimate accommodation with rituximab versus our chemotherapy, and that was designed to show a significant improvement in both complete response rate at 30 months and progression free survival. The outcomes were essentially similar, suggesting that it did not meet its primary in point, and therefore it's listed as an option for those patients who prefer to avoid chemotherapy with a slightly more favorable toxicity profile with the R squared arm and then, lastly, maintenance. Rituximab is something that is still generally pursued following front line chemo immunotherapy based off of the prima study, which has been updated recently. Now, with about 10 years of follow up and the median PFS among the patients who received two years of maintenance, Rituximab approaches 10 years versus four years for those patients who were observed. Despite this dramatic difference in their initial progression free interval, the overall survival between these two groups remains the same, suggesting that even though that first remission is dramatically shorter among those patients who do not receive maintenance, uh, subsequent lines of therapy do catch these patients back up. So to summarize our front line again, peut 24 currently defines our highest risk patient population. It does not currently correlate with stage of disease, although there is some correlation with flippy score, and it is encouraged that patients undergo pet, particularly to examine potential for transformation that's driving these early failures. We don't know what the current preferred approaches In the second line space, though there is a randomized cooperative group trial, the swag 16 Oh eight trial that is strongly encouraged to consider, which is a three way randomization between a little item ID based approach appear three kinds based approach and then chemotherapy. Either been the Mustang or chopped, depending on what their front line, uh, strategy was again. We're lacking those predicted by markers to inform that treatment selection, but we are trying to enrich trials with this high risk group. What's changed? Your emerged in the relapse setting well in the past two years now we've had the approval of Little Item ID and Rituximab, based off of the Augment trial, which is a placebo controlled randomized study that enrolled both relapsed follicular and marginal zone patients not powered to distinguish the outcomes among these two subgroups and not surprising, based off of prevalence, much larger numbers of follicular lymphoma enrolled on this study than Marginal zone patients. It's also important to note the dozing schedule and sequences. This varies across trials and the augment study. There were 12 cycles of little item ID administered, starting at 20 mg on days one through 21 of a 28 day cycle. The dose reduction could be pursued as encouraged for patients with a creatinine clearance less than 60 down to 10 mg. Rituximab is essentially loaded in the first cycle with four weekly doses, and then continued only on day one of cycles two through five and then beyond cycle. Five rituximab is not continued, and then this is again was randomized placebo. But at 12 cycles, patients were discontinued with the primary endpoint of progression free survival. This study did meet its primary and point with a significant improvement in PFS 39 months. Among those patients who received little itemized and rituximab versus 14 months for those patients who received rituximab plus placebo. Similarly, we see an improvement in overall survival among the follicular lymphoma patients who received R squared versus where. Toxin that placebo, which is not a common occurrence, particularly in follicular lymphoma studies. Given that most of these patients will receive additional treatments. But again just suggesting that that significant improvement in PFS did hold up, uh, and even transitioned into improvement in overall survival was not powered to address this again. This is just seen in the follicular, uh, cohort among this population, but again, very promising efficacy. The conclusion of the augment studies we saw higher response rates longer progression free survival Among those patients who received R Squared versus Rita Kaufman mono therapy. Now the criticism is that reduction in mono therapy was the control arm, so this inherently selected out for less heavily pre treated patients, less refractory patients. Nonetheless, for patients where you would consider Attucks Madam mono therapy R squared is significantly better in terms of efficacy without a significant change in the safety profile. What are the other classes in this, uh, setting the relapse, particularly follicular lymphoma setting? We know there are three P I three kinase inhibitors and more on the horizon for third line or later. And that's based on the fact that the P I three kind of signaling pathway particularly the Delta Ice a form when inhibited, results in significant efficacy, particularly in B cell lymphoma subtypes and as monotherapy, particularly effective in relapsed follicular lymphoma. There are four Aisa forms of the P three kind of enzyme, so the degree of inhibition of these various Aisa forms may differentiate the available agents, particularly when you're looking at their safety profile. The first FDA approved pediatric kinase inhibitors I'd elicited, which primarily inhibits the Delta ice a form. It was approved based off of a single arm, Phase two trial, enrolling a double refractory patient population, which was defined as refractory to both the CD, 20 antibody and and calculator. This did take several indolent lymphoma. Histology is a follicular was the most common subtype in this trial. The overall response rate among the 72 patients with silicone foam was 54% which again was similar to the entire patient population. The median PFS was 11 months, with a median overall survival of 20 months. However, one of the potential limitations to uptake of idealism has been the toxicity profile and outlined. Here you see grade three or higher diarrhea reported in 13% of patients. There is, in my experience, two types of diarrhea. You have the early onset diarrhea, which is usually occurring within the 1st 12 weeks of treatment. It's usually self limited and rarely results in severe, significant toxicity. And then there's the light onset diarrhea that generally occurs after six months of continuous therapy that can be associated with the colitis and even the bowel perforation, which is a black box warning. Generally, these are the patients that have been on therapy, meeting their diseases, responding. So it's important to educate both patients and staff, particularly with this late onset toxicity. Hopin listed is a PAN P I three counties inhibitor that we see most of the activity against the Alpha and Delta Aisa forms. It, too, was approved based on a single arm, Phase two trial, though less refractory patient population. But they did have to have at least two prior lines of treatment. The overall response rate again over 100 patients on this study was 59% which again is very similar and fake, compares favorably to what was reported with idealism. Median PFS of 12.5 months. We do see a differentiated safety profile here, outlining again. The difference in terms of the inhibition of both. The Alpha Delta is a form with transient but notable hyperglycemia and hypertension, which was not reported with idealism and lower rates of Grade three or higher diarrhea. GI toxicity in general, which may also be due the fact that this is an I V formulation that's administered on days 18 and 15 of a 28 day cycle. The third FDA approved Patrick kinase inhibitor is Douville ism, which is an oral inhibitor that inhibits both the Delta and gamma Aisa forms. If you look at the efficacy and safety on this side, in my opinion, it looks to be most similar to Idella. Listen, the fourth that's anticipated be approved as early as this spring is umbrellas it, which is again, an oral Delta inhibitor that does have an additional component of inhibiting CK one epsilon. Uh, the clinical implications of this, in my opinion, are unclear. Maybe approved first for the treatment of relapsed refractory marginal Zone lymphoma as a single agent based off of the Unity NHL study, which was updated at Ash this year, showing an overall response rate of 52% in Marginal Zone lymphoma patients again as a single agent but quite impressive as a complete response rate of 19%. And they did see responses across all three Marginal Zone lymphoma subtypes, including extra nodal, nodal and splenic. Okay, there has been healthy criticism of the numberless of data because most of it has been reported with relatively short follow up. However again it ash this year, we've seen an update to the safety profile umbrellas it with now, more patients being on therapy again, median duration of drug exposure, surpassing six months in some patients on as long as five years. And with this longer follow up in larger sample size, we still see a favorable toxicity profile, with only 2% of patients discontinuing treatment as a result of diarrhea. Colitis. However, a larger percentage discontinued as a result of any toxicity that was thought to be drug related, and that included 14% of patients with 9% resulting in dose reduction. Some of the most common adverse events include diarrhea, despite only 2% having either severe diarrhea or colitis. And you don't see on here rates of trans am in itis, very low rates of pneumonitis and again resulting in efficacy that looks to be similar to what we've seen with other PS three counties inhibitors suggesting this might be the preferred agent just given the more favorable safety profile what's emerging, including recent approvals in the management of relapsed follicular lymphoma? Well, the most recent approval is to as a metastatic, which is an oral easy. H two inhibitor epigenetic modifications inflict lymphoma have been implicated, particularly for gcb lymphoma, Genesis and Easy H two as a regulator, both gene expression and self fate decisions and so gain of function mutations, which occur in about 20% of patients with follicular lymphoma, lead to arrest a maturation. Uh, in this Gina toxic environment and increased proliferation. However, there's probably another important role of Easy H two, and that's in the micro environment that is sort of manipulated to be very pro tumor. And so inhibition of easy H 2 may also lead to this less pro tumor micro environment. And that may be important based off of the results of the single arm Phase two trial that lead to accelerated approval of Tasmania Stat enrolling both easy H two mutant and wild type populations. And they received 800 mg of Tasmania stat orally B i d. Until disease progression or intolerance broken down here, the patient characteristics according to whether or not they were in the mutant cohort or the wild type cohort there are important differences. The wild type cohort was more heavily pre treated, more likely to be refractory to re tucks a mob and had a longer time from their last exposure to going on to therapy. This was not a randomized comparison. In some of these differences in the baseline, characteristics might impact some of the efficacy that was observed. Not surprising. The overall response rate is significantly higher in the patients who have the mutation about 78% according to Investigator, 69% by an independent review committee. And only about a third of patients with the wild type had an overall response rate. Complete response rates are relatively low, but again not substantially different between the mutant and wild type population. And I'll draw your attention to the medium duration of response of 10.9 months, um, in the mutant population, versus 13 months in the wild type population and similarly median PFS of about 14 months and the mutant population versus 11 months in the wild type population. So despite this disparate response rate, there was reasonable disease control and PFS. It looked to be more similar than different, suggesting that again, easy H two inhibition may not be simply directed at that gain of function mutation and may also be impacting the micro environment again. We've covered this quite notable duration of response again in both cohorts Even more impressive to me is the safety profile, which outlined here suggests very low rates of Grade three or higher toxicity. Very low rates of treatment discontinuation. You see 5% as a result of toxicity. 9% had a dose reduction, no treatment related deaths. So we now have a single agent with response rates in the 30 to 70% range median PFS 11 to 14 months, which compares quite favorably to what's currently available in third line, uh, space, but with maybe a more tolerable safety profile and an agent. That may be important in targeting the micro environment, suggesting that with the safety profile you'll be able to build on this with combination strategies. Again, this is now FDA approved for patients who have the mutation and two prior lines of therapy, but also available for patients without an acceptable standard of care option, suggesting that we recognize with the safety profile and the reasonable efficacy seen in the wild type population. This should not be just restricted to those patients with the mutation. Other agents that are on the horizon include the by specific antibodies, so these are generally proteins that are infused into patients and will engage both the tumor and T cells and by bringing them into close proximity and activation. This is a stronger T cell. Engage er than, say, passive immune responses with things like Rituximab at Ash. This year, we had four agents reported as oral sessions. These are phased one dose. Finding studies with now longer follow up in a few of these trials looking at dose expansion, particularly in relapsed follicular lymphoma. There are difference in terms of whether there i g antibodies, where there's an I G M that was reported at Ash this year. Also, differences in terms of whether they're administered ivy or subcutaneous in the ramp up strategies during the first cycle to mitigate some of the side of kind release syndrome. That appears to be a class effect. But it is too early to identify a preferred by specific, uh, and again further drug development is underway most into sin. Mob is one of the largest sample size we've seen reported to date, and they are reporting their expansion study in relapsed, refractory folic lymphoma. And these are patients who had at least two prior lines of therapy and you can see an overall response rate of about 63%. But also important is a complete response rate of 43% and based off of how this is administered for patients who have a complete response. After eight cycles of therapy, they can discontinue treatment and then be observed, suggesting that these CRS are durable. The toxicity profiles outlined in this study and as mentioned side of kind release syndrome, is toxicity that's been reported across all these by specific Phase one studies. Uh, though not head to head comparison, are slightly different characteristics as what we've seen reported with Carty cell therapy, meaning most of these, uh, A s were reported during the first cycle with shorter time to onset. Very few great two or higher, and most were managed with supportive medications. There are strategies, as I mentioned, to mitigate this, to try and minimize the need for drugs like toast, realism, AB or even inpatient stays to monitor for this toxicity. And those strategies include subcutaneous administration, with most enthusiasm at being one that is being explored in this route, more aggressive decks and methadone pre meds and then again does ramp up, particularly during the first cycle. Additional toxicities reported across these agents include neutropenia grade three or higher, reported in about 22% of patients. The Virginia, in 1979 also is now approaching larger sample size. We've seen phase one dose escalation data reported previously, and it asked this year again, we saw follow ups with larger sample size again looks to be quite favorable in terms of, uh, efficacy and quite similar in terms of toxicity. Profile by specific antibodies are anticipated to be FDA approved in the next 1 to 2 years, based off of the phase one data suggesting quite impressive response rates that also appear to be durable. The ability to have this more readily available to patients outside of tertiary centres, Uh, and the ability to meet unmet needs again, suggesting that these response rates in this third line spates are quite favorable. The next wave is to move this into combination strategies and then inflict coma. It's not surprising to see combination strategies with Linda Linda Meid in large cell lymphoma dash. This year we saw combination strategies with chop, suggesting that any, uh, regimen that you would have a CD 20 antibody. There's potential to replace that with these T cell engage or by specific antibodies and then again in the third line or later space. Will this now replace therapies that are also being explored, such as car T cell therapy and along those lines? The Zuma five study was first reported at ASCO and then updated at Ash. This year, Zuma five explored Accessible, which is an autologous CD, 19 directed car T cell therapy with a CD, 28 co stimulatory molecules. 151 patients with either relapsed follicular marginal zone lymphoma have been enrolled to date. The study scheme is quite similar to what we've seen with taxi sell in large cell lymphoma, the duration of response broken down here, according to follicular in the Blue Line and Marginal Zone. And the Green Line again looks to be different but quite impressive, particularly for the follicular cohort, which is a larger sample size. And what we see with the Marginal Zone patients, similar to what we've seen in aggressive histology is those patients who achieve a complete response have even more impressive duration of response than those who only achieve a partial response. What's notable is again this took patients who've had at least two prior lines of therapy. They did enrich for the P O. D 24 patients and those double refractory patients. Uh, and even with these higher risk patients, the median duration of response has not been reached. Median PFS, particularly the Marginal Zone patients, has not been reached, and so again, for a third line with over a median follow up of about 18 months. This is now better than any other therapy that we've seen reported in this third line or later. Space. Recognizing the cartoon cell therapy will be administered to likely a subset of patients. In my opinion, it should be considered and potentially replace any patient you'd be considering stem cell transplant. So, to summarize, is my message. Today. Non chemotherapy options, particularly relapse directory follicular Marginal Zone lymphoma, are rapidly expanding. In addition, we see efficacious therapies, particularly for these purity 24 patients, including the by specifics and car T cell therapy that's anticipated to really change that natural history of disease and should be available to patients in the next 1 to 2 years. The next wave is how we now move these treatments into earlier lines of therapy. I can envision that being done more easily with the by specific antibodies. And the real question is, will we ever replace chemo, immunotherapy and front line? And my expectation is, as these therapies improve in terms of efficacy, as long as the safety profile and ease of use remains reasonable than yes, I do foresee in the future non chemotherapy options across all lines of therapy for both follicular and marginal zone lymphoma patients. And I appreciate your time today.
