Novel Treatment Options in CLL

thank you John I will be very impressed if anyone gets that last question correct so usually this is supposed to be great debates and updates I guess there's nothing to debate in CLL because everything is resolved so hopefully I can just have a great update here are my disclosures so on today's agenda what I really want to do is to sort of update everyone on sort of the data that we have from hash and how this really fits in you know we have a lot of long-term data regarding FCR from the FCR 300 which are 300 consecutive patients treated at MD Anderson and you know those data we have up to twelve point eight year follow-up on those patients we also have now from ash some seven-year follow-up data on a Bruton tips Phase two so some very very nice long-term Phase two data which we won't violate any statistical rules and compares side-by-side but we also have two clinical trials looking at chemo you know therapist namely FCR compared to ibrutinib and ibrutinib rituximab in elderly patients and in not elderly patients our young patients that were also presented at the hemotoxin 2018 and so it will be important to sort of look at these data and decide how you want to apply them to your practice so here's a list of approved agents for CLL of course we're certainly not um we're not suffering for lack of agents but I think we are suffering for a lack of knowledge and how to use these agents what I really do want to emphasize is we have this you know 2010 cut where prior to 2010 we only had chemotherapy and chemo immunotherapy and since 2010 there's been array of new agents and it's important to recognize that you know once again we need to evaluate how we treat our patients and how we measure the success of our treatments so we no longer need to measure you know our treatment successes MRD or in terms of depth of response but really PFS is really what's most important and I can foresee a future where we can cycle patients between all these different drugs and as long as they don't accumulate toxicities we can actually get patients a very very long time into their future so here's the FCR curves the progression free survival and overall survival for these 300 patients treated at MD Anderson with FCR at standard doses and you can see their pointer okay no pointer sorry so you can see here that we actually have a median PFS of 6.4 years for the population overall a nemedian overall survival of 12 point 7 years for the population overall now a number that is actually going to be very important to keep in mind is the progression free survival at twelve point eight years of 30.9% and as it turns out there's really been no one who has relapsed beyond year 7.2 so it really looks like that there's a plateau on this curve and the question is you know whether or not this plateau represents a group of patients who are cured and actually if we can identify who these patients are and sort of use this information in pre selecting patients who might be at great or at high likelihood of benefiting from FCR so looking a little bit more at this plateau it turns out that it's seventy four percent of the patients on this plateau are mutated in E globulin genes alright so these are patients with mutated New England genes which normally have a good prognosis thirty point nine percent of them will do extremely well I'm sorry thirty point nine percent of the population but of the mutated immunoglobulin gene patients fifty three point nine percent overall will actually be free from progression at twelve point eight years the comparison for the unmedicated group you can see there is eight point seven years so we now have an ability to identify a group of patients who have a fifty-fifty chance of really doing extremely well with chemo immunotherapy that's the benefits now we got to look at the downsides because one of the problems of course is that we can't choose where we're gonna be on the curve we can't choose whether or not we're gonna be the person on the plateau or the person not on the plateau so first we have to look at sort of the reproducibility so here we have the German CLL study group which that flew Derby and cytoxan and Rituxan compared to flew Dara beam cyclophosphamide and is basically the same regiment as the MDR reg and I'm sorry MD Anderson regiment and what you can see here for comparison purposes because things always seem to work out a little better in Texas so we have a median PFS at six point four years from the MD Anderson group where it's four point seven years for the German CLL study group so I think obviously the four point seven is probably a little closer to the truth but and although the follow-up is still short we certainly would expect there still to be a plateau in these groups of patients so what happens to these patients and these are the data again from the FCR 300 series so 58% of the patients who died died from CLL 18.4% die from other cancers 15.4% die from the Richter's transformation that's not the incidence of Richter's but that's 15 point 4 percent of the deaths 6 point 6 percent of the patients die from infections while in remission and overall 71 percent of the deaths that occurred were in patients who are in first remission so clearly we have to be careful in choosing our regimen because there certainly could be a high cost to pay now looking at secondary cancer specifically what we see is that there's an 8% incidence of Richter's transformation there is a 6.3 percent chance of human to logic malignancy mostly AML and then 21% risk of other cancers excluding non-melanoma skin cancers so I really want to focus on the hematologic malignancies because MDS and AML what are grouped together as secondary myeloid neoplasia really represent an endgame for our patients these really are sort of that that horrible sequelae that we really are unlikely to get our patients back from so we talk about secondary MDS and AML typically being somewhere between two and eight years after people initiate treatment and so one would think that you know because we have twelve point eight years of follow-up that maybe we actually have seen the peak or we've seen what we would expect one of the questions though of course and I actually missed this morning so I don't know if we spoke about colonal hematopoiesis but with all that we're learning on clonal hematopoiesis and this sort of bottleneck that's created in your stem cells by something like chemotherapy you know the question becomes you know at 70 years old these persons who had FCR chemotherapy when they're 50 what is going to be their risk of MDS at that point in time there's already a background incidence of MDS and AML in the seven year olds honor the is this group going to be that much higher so a word of caution is I do expect that we need to wait and see what those long-term data are going to reveal and then the other problem of course with FCR is in those patients who progress which will be half of the mutated patients and 92% of the unmutated patients median survival is actually only 51 months and a lot of this is because the CLL comes back very aggressively and also the patient has had toxicities and unable to actually tolerate additional therapy so what other options do we have so the b-cell receptor kinase is you can see the list here phosphor at nib actually was the first one and this was a plenary session done by jonathan freiburg at ash in 2008 for unclear reasons it really never went forward in oncology and is now approved for ITP we have our BTK inhibitors ibrutinib in a caliber – which are both approved XANA Brut nib should be approved shortly and then we have our pi3 kinase inhibitors i della Duvel Lissa and elissa which I expect will be approved within the next 12 months so I want to review the phase 2 data for my Bruton immuno this is the longest follow-up we have on these patients treated with a b-cell receptor kinase inhibitor and really provides us with some helpful information so the patient's initially treated in what's called the 1102 study which was the first phase 2 study were actually in two cohorts there was a treatment naive cohort which was over 65 years of age and then there was a relapsed refractory cohort initially the treatment naive cohort everyone received 420 milligrams in the relapsed refractory cohort patients were actually randomized side that 420 or 840 because we very quickly saw no difference everyone was actually converted to 420 and all the data is presented in aggregate so what I want to point out here these are the baseline characteristics is that the 17p deleted incidents in the treatment of cohorts about 6% which is what we typically see published 3 to 7% as the incidence of treatment naive now interestingly in the relapsed refractory cohort the incidence is 34% which is also fairly consistent with what we see published and for comparison purposes the resonate study which was the air Bruton a pivotal study had an incidence of 17p deletion of 35 percent and the 116 study which was I'd Ellis subs pivotal study had a 17 p deletion rate of 45% and the thing I really want people to think about as we go forward is 17 p deletion really dramatically increases from treatment naive to subsequent lines of therapy and of course the question is is how do you get there how do you get from that 6% to that 34% and the answer is selecting for it with chemo immunotherapy and that's something I think that we need to think about I'll come back to later so here the ibrutinib they're called the 7-year outcomes for some reason but they give you 6-year PFS data little unclear as to why but the treatment naive cohort the median PFS is not reached and the six-year PFS is 88% intent for the relapsed/refractory court you can see the median is 50 months and the six-year PFS is 37% so there's definitely a difference between relapsed CLL and treatment naive CLL and one of the important is going to be if there's something that we can measure that can help predict for the differences beyond just number of prior therapies now I'd like to point out that the first patient who is that tick on the treatment naive curve was a 17 P deleted CLL patient who was diagnosed with a Richter's transformation at month 8 and then the second drop on that curve was actually a 17 P deleted CLL patient who actually had CLL responded to the ibrutinib and then developed progression of the CL out but was still CLL and those were the two 17 p deleted patients in that treatment naive cohort so I really do believe that 17 P deletion is one of the predictors for our patients not doing well and when we look at the relapsed refractory cohort because of course the numbers were much more robust you can actually see here the difference in outcomes reported by the interface fish abnormalities one I want to point out is actually subsequent studies namely an aggregate study which I'll show you in a sec and the resonate studies all showed really no difference for 11q deleted patients so really looks like 17 P deletion is the most important predictor for patients long term outcome on a Bruton tip and here you can see the integrated and analysis of three different clinical trials including the resonate resonate to and Helios and I can really see that 11q deleted patients had no worse outcome compared to non 11q deleted patients on ibrutinib i also want to look at now the 17 p deleted patients because this really represents an important question of what we're going to be looking at so the NIH did a phase 2 study that was consisting of treatment naive patients there were 35 and then I'm sorry treatment naive patients and patients who had p53 dysfunction either 17p deletion or p53 mutation so there are two groups of these patients with abnormal tp53 the treatment naive cohort was 35 patients and the relapsed/refractory cohort was 16 patients overall 47 of the 51 patients had 17p deletion and 4 of the 51 patients had a tp53 mutation without a 17 peta lesion any patients with both were included in the 17p cohort or group so the median follow-up for all these patients was 57 months and the discontinuation a discontinuation rate for these patients was 5.8 percent overall so this was 5.8 for the entire group of patients on the nih cohort not just the tp53 disfunctional patients but that's important that definitely is you know fly it's very different from what we often hear published when we look at data from anthony meadow who shows a number closer to 23 percent and obviously there's going to be a lot of benefits of having one very experienced investigator managing these patients it's also going to be a very big difference when you have a very motivated group of patients who are able to get themselves to the nih but that's something I really want to emphasize is that we can keep people on a Bruin tip with some tricks that people you know basically I think with repeated experiences may actually develop overall in this 17 in the tp53 cohort there were 17 progressives progressor 's v really related to Richter's transformations and 12 were related to seal out progression so what I really want to show here and the important thing is the five-year PFS for the treatment naive 17p or tp53 dysfunctional patients with 74.4% and for the relapsed refractory patients it was 19.4% and i think that this is sort of an important thing to keep an eye on because clearly these are two of patients who both have 17p deletion or tp53 dysfunction be–it we have very different outcomes and I think obviously the major difference between these two groups which we know is just the number of prior therapies probably translates into other genetic changes that have occurred sort of acquired genetic mutations inquired you know resistant mechanisms that the cells obtain that sort of enable them to resist ibrutinib and so I think that this is a very important thing to keep in mind because I've written up front line is gonna really do much better than ibrutinib in relapse disease and it's not just because of the increase in 17p deleted cells and I think so it's really a combination of both the 17p deletion being present and obviously subsequent therapies creating other unmeasurable avenues of resistance and then the other thing I want to mention here is that the adverse events over time really do decrease and that's an important thing obviously because we are currently planning on having our patients on this therapy for a long time I do want to point out that the hypertension is the one adverse event that seems to increase over time so while we haven't yet seen a peak it's about in the phase two study here at about six years it's about 25% now the atrial fibrillation does seem to peak at about two years and so that really speaks there being a biology about the patient or a protoplasm of the patient that sets them up for afib or that they'll be fine and not develop atrial fibrillation so now I want to talk about the two studies that we cited earlier just sort of look at chemo Mina therapy versus ibrutinib the first is an alliance study that looked in elderly CLL these were patients with untreated CLL over the age of 65 there were no Sears score requirements so there are no measures of comorbidity just aged over 65 patients were stratified based upon my stage presence or absence is 17 P and 11 Q deletions and zap-70 methylation in zap-70 methylation is not some commercially available as we all know there's a lot of issues as we also all know with zapped 70 testing expression level testing and so one of the ideas that's being put forth by the OSU group is that methylation where an unmethylated unmethylated promoter really is indicative of zap-70 positivity might be a reproducible measure of zap70 expression so whether or not this could actually replace the ab 70 expression is also being tested as part of the study what I do want everyone to remember is the study did include 17p deleted patients which is part of the controversy around the study remember these were patients who randomized to receive benda Muhsin Rituxan ibrutinib or ibrutinib rituximab and of course we we already know that patients who were 17p deleted are not going to do well with been the Machine rituximab so you can see there the randomizations one two one two one and the doses that were used and statistically the comparisons were BR versus i BR versus ir and i versus our overall the patient characteristics were fairly well balanced but i want to point out once again is the number of 17p deleted patients and tp53 mutation patients so there was a significant number of patients in this group who didn't have 17p deletion but had tp53 dysfunction we don't know but when the data points that will be assessed is whether or not accounting for the 17p deletion actually might change the outcomes of the data overall but in looking at PFS ibrutinib in rituximab and ibrutinib as a single agent had a significant improvement in 24-month progression-free survival compared to BR and you can see the hazard ratios there and you can see that there was no difference between ibrutinib and ibrutinib rituximab of course there was no difference in overall survival and this is actually a good thing because patients were allowed to cross over onto ibrutinib if they actually progressed within one year of completing venomous tok-san now a huge not a caveat but one of the things to keep in mind is I do believe that a lot of people who progress after Benham us in Rituxan would have gotten ibrutinib regardless so even if people are progressing after a year and are therefore our off trial and still being followed for survival that would likely have gotten ibrutinib anyway and so I think what we really are looking at is the overall survival being you know these patients being rescued with ibrutinib as second line that is important to keep in mind because when you look at the resonate to study which was Claire missile versus ibrutinib we actually did see an increased risk of death in the patients who got Claire missile first and they weren't being rescued by the ibrutinib so that's an important thing to keep in mind and something that we need to actually think about a little bit more a ease of interest and this I think is really one of the most important slides to look at so previously or from the 1102 data we talked about there being a 10% risk of atrial fibrillation in the population overall here in the B R group it was 3% and the ibrutinib group it was 17% and the IR group was 14% and then hypertension only grade threes were 14 29 and 34 percent for Bri and higher respectively which is actually compared to the 25% that was seen in the ibrutinib Phase two data so that's clearly a significant increase and I do believe that a lot of what we're looking at is an impact on age on these comorbid or the age on these adverse events and I'll show you the young seal all data is comparison in a moment the other thing that raised a lot of controversy regarding the studies there was an increased risk of death in the iboot native arms now when you look at the death overall in patients who died on treatment or 30 days post treatment it was 1% versus 7 vs. 7 percent for Bri and I are respectively but of course patients remained on ibrutinib indefinitely until they progressed or died and the patients had gotten been the muscle Rituxan for six cycles so that would be a way that might bias sort of what we're looking at so if we just look at the risk of death based upon or for the first six cycles and n 30 days post cycle six be it been demoscene or ibrutinib the numbers are much closer one percent two percent versus three percent respectively so that would something that would suggest that that sort of normalizes for a lot of the concerns that people first expressed regarding the increased rate of death the only thing to keep in mind is if we do worry about there being a cardiac toxicity with ibrutinib that might sort of be seen as this unwitnessed or unexplained deaths and you can see there that there were two seven and four unwitnessed or unexplained deaths in the Bri and I our group's respectively so now just moving on to the young CLL study this was done by AE cog and patients who were untreated and younger than 70 so 70 versus 65 had to be FCR eligible and 17p deleted patients were excluded so that's obviously an important difference between these trials patients are stratified by age performance status stage and the presence of 70 of 11q deletion and you can see they're randomized to two one two ibrutinib Rituxan or FCR that the doses there and you can see here that there's statistically significant improvement in progression-free survival and overall survival for ibrutinib rituximab as compared to FCR and you can see the hazard ratios and the data there now interestingly and one of the things that I think people will take away from this trial and have to think about is when you look at immunoglobulin gene mutational status as a predictor you know because FCR does worse with the unmutated patients and ibrutinib does equivalent and mutated and uh mutated we actually see the differences magnified in the unmutated population and they actually do go away in the mutated population now this is short follow-up and of course you know happens long-term will be important to see but for now it looks like the benefit of ibrutinib / FC are in the short term really was just in the unmutated population looking at great three adverse events throughout you can see here that atrial fibrillation was in the ibrutinib hour 2.9 percent and hypertension was seven point four percent so really far lower than what we saw and I really like to emphasize that these were patients younger than 70 so this also supports the idea that there really is a very significant impact of age on the development of these adverse events and take chana felt at us a favor and sort of lined everything up side by side and the data that he used were a little bit different but you can see here the comparison between IR and the young versus IR in the older patients for afib being 3 to 6 percent respectively and hypertension 7 to 34 percent respectively so in conclusion ibrutinib better than chemo immunotherapy overall I think that's a debate that every physician needs to have with themselves and with the patient and the patient needs to have with themselves one of the important caveat to consider is whether or not we should consider mutational status when were actually having this discussion a lot of people have actually talked about combining both together there is a slide that Peter home and put together that addresses this once again that violates all rules of statistics and what you can see here looking at the helio study which was B R versus Bri and the resonate study which was I versus both Fatuma mab the curves for I and Bri are superimposable these are both relapsed refractory patients and so it really suggests that maybe the B are added very little to the ibrutinib and then we've focused really in the short-term toxicities and the differences but the ultimate question is what are going to be the long-term toxicity and whether or not we actually can predict those from this point in time so we have twelve point eight year follow-up for FCR and we have seven year follow-up for ibrutinib and then you know the question about sort of this increased risk of death in the align study what does it mean is it something that we need to consider now I do believe very much that we haven't seen this signal earlier and it's always important to not let one study discount all the earlier studies but obviously it's something we need to think about and look into more closely and then ultimately who decides the patient or the physician I mean I really think we all wear our biases on our sleeves and most of the time the patients will actually follow their physician and that's just something important for all of us to keep in mind in this day and age but thank you [Applause]

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