Chapters Transcript Video Best of ASH 2020: Transplantation and Cellular Therapy welcome. Um It's my pleasure to bring you some of the more important abstracts from the ash annual meeting on transplantation and cellular therapy. Um I have divided my talk into um the following categories. To facilitate discussion um role of transplantation, transplant strategies and platforms. Graft versus host disease and transplant genetics. Uh So in the role of transplantation probably the most important abstract presented at the meeting this year was this one which was based on transplantation for myelodysplastic syndrome. This was a multi center biologic assignment trial comparing reduced intensity. Androgyny came out of with Excel transplantation to hyper method dating therapy or best supportive care in patients aged 50 to 75 years with advanced myelodysplastic syndrome. This was a blood and marrow transplant clinical trials network study and was presented by dr Corey Cutler from the F. C. I. On behalf of the um on behalf of the uh authors of the study. So just a little bit of background I'm not sure how well this is coming across. Um But a lieutenant transplantation for high risk and es has been model to predict superior outcomes in at least two studies when compared to best supportive care. These studies were smaller studies. There has also been a study from the dana Farber based on decision analysis, which showed that transplantation for high risk mds uh is beneficial when dan Cody. Um Despite all of this data, um older patients are often not referred for transplantation. Um And more importantly, Medicare actually does not cover the service. So uh so this study was actually done to um The study was essentially done to um to see how transplantation for high risk cambodia's fed. This was an open label multi center biologic assignments study. Um The assignment was based on high resolution typing where basically the patients who had a fully matched donor were assigned to one arm and those who did not were assigned to the other arm so mismatched, happily identical and got blood transplantation was excluded. The donor and subjects were expected to undergo transplantation within six months. Subjects were aged 50 to 75 years and had primary myelodysplastic syndrome with intermediate to a high risk I. P. S. S. Um And we're otherwise candidates for traditional reduced intensity transplantation. Go to the next slide. Um transplant and non transplant therapy were determined for institutional standards. The endpoint of the study was adjusted three or overall survival. Uh we can move on to the next slide. So as you can see, there were 384 subjects were enrolled in biologically assigned. Uh of which 260 were in the army, in which donors were identified and 100 and 24 were in the no donor identified. Um um Seven patients died during the 90 day search. Uh and here's a summary of what happened to the patients in each um, in terms of disposition and move on to the next slide. Uh This is the important slide in the presentation. Uh This is the primary endpoint of three year overall survival. As you can see, the black line is the donor ram. The yellow line is the no donor ram, so the door. So patients in the donor ram had better overall survival. And this was a significant difference with an absolute improvement of 21.3%. The survival in the donor round was 47.9%. This is 26.6% in the no donor arm. Go to the next slide. Uh subgroup analysis also showed that this benefit was, was held through in all subgroups, including patients who were greater than 65 years of age, so both less than 65 greater than 65 years of age had an overall survival benefit, which as you as I'll show you is very important for Medicare and like slide. Uh This is the three year leukemia free survival, which also shows an absolute improvement of 15.2% with the p value of 0.3 survival was 35.8% in the donor arm versus 20.6% in the no donor arm the next slide. Um and because of the nature of the study, which was a biologic assignment study that has treated analysis was particularly important. And even in the has treated analysis, as you can see, there was an absolute survival benefit of 31.4% and the donor rum did much better than the no donor arm. So um even when we took all confounded into a counter was better survival in the donor arm. So in conclusion, the study showed definitely that among higher risk MSs patients aged 50-75 having a suitable donor does lead to improved outcomes. Uh The overall survival improved by 21% the leukemia free survival by 15%. Uh This benefit was seen even in subjects greater than 65 years of age who are Medicare age, there was no decrease in quality of life compared to the no donor controls. And they have treated analysis also suggested a strong advantage for transplantation versus non transplant therapy. And uh this study is particularly important I feel for the community because uh the community oncologists are the ones who see the MDS patients first. So we encourage, based on this study only referral of MDS patients to a transplant center so that they can be evaluated um for transplantation. And we do anticipate that the study will lead to Medicare coverage for transplantation for this group of patients. We move on to the next slide. I now wanted to talk a little bit about some abstracts presented on transplant strategies and platforms. Uh There was a definite emphasis on post transplant cyclophosphamide in this year's meeting. Uh So the next three abstracts um are based on post transplant cyclophosphamide, which seems to be the direction in which the field is going in terms of ghd prophylaxis strategies and transplant platforms. So this is a comparison of outcomes after half low identical related donor transplantation and H. L. A matched unrelated donor transplantation with post transplant cyclophosphamide i containing ghd prophylaxis regimens. Um I happen to present the study on behalf of the C. I. B. M. T. R. Just a little bit of background. Um cyclophosphamide is a drug which you are very familiar with in the context of transplantation. It has been used uh for gBh d prophylaxis. First Houston happily identical transplantation pioneered by the johns Hopkins group. Um However um it has made its way into fully matched donor transplantation as well because uh of the of the superior tv HD outcomes that have been seen in half the identical transplants which we attribute to the post transplant cyclophosphamide. Indeed a recent prospect of trial compared matched unrelated donor transplantation with PTC Y. two matched unrelated Donald transplantation with cny based prophylaxis in the reduced intensity setting and actually showed better when you're G. V. H. D. Free relapse free survival with PTC Y based prophylaxis. On the basis of this. Um there are trials being run where PTC YB. S prophylaxis is being compared to standard of care in the match donor setting. The purpose of this study was to evaluate when you have both a half low identical and a matched unrelated donor available, both with PTC Y based prophylaxis, which is the better transplant platform. The study was done in two cohorts a milo a belated and reduced intensity to account for the important discriminatory effect of conditioning intensity on outcomes. Um I'm discussing the results of the milo oblate of co art first, Where you can see there were three different DVD prophylaxis regiments um in the half legroom PTC by Sienna and Michael Fennell. It were used and in the mud group this regiment as well as P. T. C. Y. C. And I only was used. Uh These are the survival curves and as you can see, there was no difference in either overall survival or disease free survival in the milo oblate of setting whatever the transplant platform. Um Similarly, there was no difference in relapse and non relapse mortality When we looked at graft versus host disease. When P T. C. Y C N. A N mmF were used in both arms, there was no difference in acute or chronic tv HD. We did find an increased rate of great 2 to 4 acute tv HD in the mud arm, but only when P. T. C. Y. C. And I alone was used, which is really considered a non standard prophylactic platform but was used in certain centers. So moving on to the reduced intensity cohort. Um Here are all patients uniformly received, P. T. C. Y. C. N. A. And M. M. F. Um These girls show you that the matched unrelated donor cohort actually did better in terms of overall and disease free survival compared to the ap bio identical cohort. Um This seemed to be due to create a non relapse mortality in the half low identical transplants, uh compared to the matched unrelated donor group. Whereas relapse rates was similar. We looked at graft versus host disease and interestingly there was no difference in acute and chronic graft versus host disease, which you would have thought would be the reason for the difference in non relapse mortality. Instead, it looked like delayed neutrophils and platelet and graft mint in the happily identical group, as well as significantly higher rates of fungal infection at six months. Um what could possibly be the reason for this difference and non relapse mortality? The conclusions from the study um really focused on the importance of PTC, why in removing uh some of the differences we have seen in the past between matched and mismatched donors. But in the reduced intensity setting, we should favor a matched unrelated donor over a half. Low relative as the latter is associated with higher non relapse mortality and poorer survival. Um In the milo oblate of setting, it does not seem to matter. And you could use either a model or a capital donor continuing on the theme of post transplant cyclophosphamide. There was a study presented again from the C. I. B. M. T. R on acute lymphoblastic leukemia. Um which was a comparison of different donor sources happily identical match sibling match down related and mismatched unrelated. I want to show you the important calls from the study where basically, as you can see the happily identical donors did better when compared to the match sibling and matched unrelated donors. Remember in this case, the fully matched donors are not using post transplant cyclophosphamide. Um And the seven out of AIDS, which are single Anchorage and mismatched donors did worse than the half blood donors as well as did umbilical God Blood mirroring the results we have seen in the past with God blood transplant. Um This is the non relapse mortality and uh the seven out of AIDS had higher non relapse mortality. Not surprising once again, as did the God blood transplants, there was no difference in relapse rate. Uh you know, underscoring the fact that the transplantation platform may not have that much to do really with the relapse rate. And it's more about the leukemia genetics, which you're about later uh in this morning. So in conclusion for acute lymphoblastic leukemia patients, it seems that you do not lose out if you have a happily identical doctor donor. However, I think it's uh it would be uh not correct to say that they are the superior doner sauce until you compare to match unrelated or related donors who will also use post transplant cyclophosphamide. And finally this was a single arm study looking at the effect of uh cyclophosphamide as geechee prophylaxis. Um in mismatched unrelated donor transplant. The group you saw in the previous abstract did very poorly with standard of care prophylaxis. Uh and when you use post transplant cyclophosphamide, these patients actually do quite well. The one year overall survival was in the range of 84%. Which is really very um encouraging. So again the conclusion from all of these three abstracts is to pay attention to where post transplant cyclophosphamide is going because that's the direction in which the field is going. Um I wanted to present this study from the M. D. Anderson group. It was a negative study but I just wanted to highlight because this was an attempt to improve on conventional fluid. Arab in yourself and conditioning by adding cloth paraben to the conditioning regimen. It was a randomized study. The Patients uh were aged 3-70 years of pediatric populations were also included. Um and you can see the conditioning regiments as outlined on the slide. Uh These were the survival curves from this study. As you can see there is no difference in the progression free survival and overall survival. Uh They did break out some subgroups where there was um an improvement in survival. These were very young, fit patients with um you know, higher risk disease, but we don't really see this crossing over um to our practice at this time. So moving on to the third section, which is graft versus host disease. Um This was a very good year for Gbh D at the Ash Animal meeting because we have two abstracts which are potentially practice changing. So let me start with uh doctors, easels, presentation of the Reach three. Study rock solid and versus best available therapy in patients with steroid refractory uh chronic graft versus host disease. A little bit of background, chronic graft versus host disease occurs in approximately 30-70% of patients undergoing transplantation really seems like a huge number. Um and um you do see some of these patients in your own practice when they show up with crowding tv HD symptoms. Standard for slain therapy is systemic steroids. However, approximately 50% of patients do become refractory or dependent and there is no standard second line treatment because a number of drugs which have been promising even in phase two studies have not really been successful in phase three trials. That's further the importance of this trial. This is the study design for the reach three study where steroid refractory patients each greater than 12 years were randomized to rocks, a litany of 10 mg twice a day to best available care. And both groups could be on steroids and calcium, urine inhibitors, Crossover was allowed at 24 weeks uh to Iraq's elite in. Um and this is why a lot of the outcomes have been looked at at 24 weeks. These are the baseline characteristics of the patient's. Um Most of the patients had moderate and severe chronic TV HD. Uh This is the primary endpoint, which was overall response rate at week 20 for the primary endpoint was met and the R r. Was significantly higher in the Rocks militant group with a significant p value 49.7% versus 25.6%. And it is something we would consider a very good response rate for GBH for chronic Tv HD. The failure free survival at 24 weeks was also very impressive and was significantly better in the rock solid and improve, which is the blue line was not reached uh in that proof of this 5.7 months and the best available therapy group in chronic TV HD uh just as important as the response rate is uh did we improve symptoms or not? And this is shown in this slide with the N. L. S. S. Response and uh there was a significant improvement and symptoms and this is actually very important for our patients. So the slide, I think is very important piece of data. The best overall responses you can see was actually even higher than the overall response at 24 weeks, 76.4%. Which does show you that some patients do develop tolerance to the drug. So, you know, the response rate did fall off a little. However, overall the duration of response was very impressive with Rocks Religion. So in conclusion, this is the first successful randomized phase three trial in a dollar certain adult patients for a new drug for product graft versus host disease, which is steroid refractory. Um We do expect that this will change practice in fact at our institution and many others. We have already started using Rocks a little um as the first line agent for steroid refractory graft versus host disease. Um there are some safety issues in terms of sight opinions and infections, but most of the time quite manageable. Um so moving on to the other important that abstract in chronograph was a supposed disease. This was the follow up analysis of the rock star study evaluating a drug which we will call Katie 025213 It was a Phase two randomized multi center study and was presented by DR Cutler from D. F. C. I. On behalf of the investigators. Um so what are these rock inhibitors? The Rock pathway, as shown, is involved dominantly in uh five process and matrix stiffness and in chronic TV HD. The final common pathway uh involves five process in various organs. So this drug video to five of Bellew Massoud ill, is an oral selective rock to inhibit or small molecule and it targets with the immune and the vibe robotic battle physiology of chronic graft was supposed disease. The preclinical data in a mouse in mouse models was very striking and in the face to a studied overall response rate was 59% in patients with chronic graft versus host disease. After receiving 123 prior lines of systemic therapy, leading to FDA breakthrough therapy designation for this drought. So this was the Phase two randomized study and patients were randomized to two doses of KD 025 200 mg once a day, or 200 mg twice a day. With the primary and point of overall response rate, just like in the rocks. A little of study patients were stratified by prior brutal nip and severe chronic TV HD And 2-5 prior lines of systemic therapy were allowed. Um this is the slide showing the primary endpoint, which was overall response rate. Both arms achieved extremely impressive response rates of 73% and 77%. An average of 75%. Um and there was really no significant difference between the two doors. Uh oh, heart. Um, Seven patients achieved the cr the median time to response was four weeks. Um And importantly, responses were observed across all key subgroups and in fact, overall organ systems, including in long graft versus host disease, which is a very difficult uh entity to treat in general. This slide shows the duration of response. The median duration of response was 50 weeks, and 60% of patients maintain responses for greater than 20 weeks, which is again something which is very impressive. Um this is the failure free survival curve um and also looked very impressive in this study. Overall survival was in the range of 89%. So the conclusions from the Rock Star study was that Bellomo suited Loki, due to five was well tolerated, achieved its primary and point as well as clinically meaningful outcomes. Um, I have not shown that slide here, but in addition to the response rate, it also actually led to significant improvements and symptoms uh when we looked at it with the early symptoms score. Uh So this is another drug which will likely be approved by the FDA by the end of the year for chronic graft versus host disease. Just adds another agent to our armamentarium to treat what is a very debilitating long term uh toxicity of transplantation. I think we have a little bit of time to go into the last section, which is not really practice changing but was very provocation. And so I wanted to show you this data. Um This was a study on clonal him atop voices and older donors, which is an area that has become an area of focus in recent years. Um with the abstract title D. N. M. P. Three A clonal hematoma. Voices in older donors is associated with improved survival in recipients after allergenic transplantation. This was presented by Christopher Gibson from the dana Farber group uh from the Lindsley lab. So clonal him a trip oasis um is defined us um When when we see there are clonal mutations present um without the presence of clinical disease. And we do define it by a particular variant elite fraction Uh which in this which is generally defined as greater than 0.005. Um So based on that cut off when we looked at donors for stem cell transplantation um they had a higher incidence of the mutations that you see on the screen. D. N. M. T. Three A tattoo S. XL one. Um And uh these uh and as you can see uh the ones which were greater than 0.1 D. N. Empty three particularly predominated. The next question was does the presence of these mutations in the donor affect outcomes in the recipient? So this slide shows you that when the valve was greater than 0.1 there was a significant interaction with survival outcomes at lower vast this effect was not really seen. So patients who had the NMP three a mutated donors tended to do a little better. And the reason for this is not clear and it's something that we are investigating. But uh it does have uh implications about the role of D. N. M. P. Three mutations in t cell biology. And if we can understand this, we may be able to better understand how to choose the right donor for the right patient at this time. This remains exploratory. Um The second question is, does presence of mutations in the donor lead to increased donor cell leukemia in the recipient? Um And it seems to depend on the kind of mutations. So if you had P 53 mutations or splicing factor mutations, uh then recipients from transplantation from those donors Did have a higher risk of donor cell leukemia, but it did not seem to be true for the NRP three a. And for the other mutations. So in conclusion, um D N M t three mutated donors should definitely not be excluded from stem cell donation. And at this time we cannot say that they should be preferred. But this is an area that we are exploring donors with rare high risk mutations such as B 53 splicing factor mutations are jOHN or other oracle jOHN Dean risk leans uh They are dangerous and they should be excluded from donation due to the higher risk of donor cell leukemia. Um So I'll that's my last light. I'll stop here. Thank you for your attention. Um and I'll be happy to take questions. All right, thank you sweater. That was really an outstanding presentation and a lot of excitement I think in in transplant this year. And how would you say that these results are going to directly impact how our group practices at Dana Farber? Maybe starting with uh M. D. S. Yeah. So I think the MDS study uh is a validation of what we have known for a long time that patients with high risk Gambia's need transplantation and transplantation results in better outcomes than best supportive care or chemotherapy alone. Um We we do want to we hope that the study encourages or leo referrals to us so that we can even if they are low risk patients that we can make the evaluation and say that, you know, this patient would be uh would would benefit from transplantation. But more importantly, hopefully this will get Medicare to approve transplant in that age proof. Which will be huge since we deal with a lot of insurance issues for these patients and will allow them to get the best therapy that they didn't. We sometimes if a patient is free and they automatically get differed from transplantation referral but that is not necessarily the case. So we hope this will encourage earlier referrals for patients with myelodysplastic syndrome from the community. Okay thank you. And then we had two questions from the audience with regard to this. You include CMM L. Uh in this in this group and is there an upper age limit for transplantation for MDS? Um Right so we we ECM member was included in this group. We we do treat them at least from the point of view of transplant like MDS patients. Uh the other question um and could you repeat the other question, Is there an upper age limit? Yeah so there is no upper age limit in the United States for transplant for M. D. S. We have transplanted patients after the age of 78 years and they have done okay. But that doesn't mean every 78 years old should get transplant. But it really is the biologic age and we do a very careful evaluation both in terms of testing as well as their performance status and their frailty before we decide to take them to transplant. So there is no upper age limit if you think a patient has M. D. S. And it's not someone who's automatically deferred because they are you know they have multi organ failure or whatever they should be referred so that we can make the evaluation. And then maybe one last question we had was regarding the role of cord uh cells and stem cell transplant. And would you consider the use of I need. Do they sell to expand cord cord sell amount in advance? And how do you incorporate cord blood transplantation in uh in light of all this new data? Yeah. So cord blood transplantation has been used for many years now and truthfully is used successfully by centers who do more cord blood transplants than centers who do not. So outcomes are much better in high volume blood transplant centers. But in a randomized study presented last year which compared happily identical to cord blood transplants in the realm of alternative donor transplantation, the cobbler transplants did not fare as well as the happily identical transplants and it was mostly due to increase non relapse mortality. They tend to have poorer immune reconstitution, which leads to higher rates of viral and fungal infections. Um And so with post transplant cyclophosphamide making these inroads into every donor platform really. Um And happily identical transplants being much easier and cheaper to perform. I mean you just need a first degree relative and cyclophosphamide doesn't cost anything while God blood transplants are very expensive. So given that they don't have meaningfully better outcomes and that they are logistically much more cumbersome. I don't see I I really don't see them playing a dominant role in transplant in the next decade. Uh There are still studies ongoing to better God Blood Trust that we have the night got study and other studies but um most centers will be doing happily identical transplant if they had the choice between half. Great. All right, well thank you so much. I really appreciated your insights. Published May 27, 2021 Created by
