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- [00:02]
Podcast Host
Welcome to the American Society of Hematology Conversations with Blood Authors podcast hosted By Associate Editor Dr. Laurie Sen. In this episode, Dr. Sen discusses the topic Validating a Thrombosis risk model for Critically ill children with Dr. Julie Jaffre. She also discusses Trispecific T cell Engager Romantomig in Multiple Models with Dr. Ulrike Filipart.
- [00:26]
Dr. Laurie Sen
Hi, I'm Laurie Sen, podcast editor at Blood and I'm joined today by Dr. Julie Jaffre from Rady Children's Hospital, UC San Diego. She's the lead author of a new blood journal article entitled Multi Site Validation of a Venous Thrombosis Risk Model in Critically Ill Children through the CHAT Consortium. Thanks for joining us today.
- [00:50]
Dr. Julie Jaffre
Thank you for having me.
- [00:52]
Dr. Laurie Sen
Perhaps he can start by providing some clinical background on the risk of hospital associated VTE in critically ill children along with the risk variables that were recognized in the development of this model.
- [01:06]
Dr. Julie Jaffre
What we've noticed in the pediatric thrombosis community is that the rates of VTE, specifically hospital associated in children, has been going up for the last really couple of decades and that's throughout the entire hospital, so not just the pediatric ICU. And we've seen rates now going up by about 120% over the last 10 years. So certainly a really big issue. And we haven't, unlike the adult treaters, really figured out how to prevent blood clots in kids. But the highest rate in the hospital units is in the pediatric ICU. So we see rates anywhere between 2% for symptomatic clots, which we found in our study confirm that. But rates are up to about 16% we've seen in patients with central venous lines and asymptomatic clots. And so our consortium called the CHAT consortium, decided about 10 years ago that it was really time to figure out who is at risk for thrombosis and hospitalized children. And hopefully one day we can really figure out how to prevent clots. We had eight centers at the beginning of the CHAT consortium. We're now 69, which is pretty exciting. But at the beginning with those eight centers, we looked at what risk factors are there for kids in the pediatric ICU and we created a risk model out of that is five main risk factors. So things like being immobile. And we use something called the Braden score, which nurses use usually for looking at pressure ulcers, but can also help us determine mobility. We found patients with inflammation or a new infection were having increased risk of thrombosis, congenital heart disease being in the ICU for Three or more days, and then, not surprising, having a central venous catheter.
- [03:15]
Dr. Laurie Sen
So the current goal then was to prospectively validate this model. Can you summarize your overall study design and the population that you included?
- [03:25]
Dr. Julie Jaffre
The tricky part was this was all done during the pandemic, so a really fun time to do research. And we were luckily able to do validation just through chart review. So we were able to continue through the pandemic, give people work to do while they were home. So we enrolled, we wanted to do our validation two ways that had not been done before in pediatric thrombosis. One, we wanted to do it prospectively, and two, we wanted to do it in many centers around the U.S. so we were lucky enough to get 32 centers to prospectively validate our risk model. So how does that work? We were able to randomly select patients that got admitted to the pediatric icu. And on their day of admission, we took those five risk variables that I talked about and determined whether the patient had that within the first 24 hours of being admitted to the ICU, did they have a central venous catheter? Did they have a new infection? Did they have congenital heart disease? And so then we followed them throughout their hospitalization and after about 30 days after being in the hospital to see if they developed a VT el. And that way we were able to truly validate, to figure out, all right, who is actually at risk, at high risk of getting a clot and who is not at risk of getting a clot. And we were able to enroll over 4,500 patients, patients, which was pretty fantastic feat in pediatric research.
- [05:09]
Dr. Laurie Sen
That is actually very impressive. So what were your findings? Were you able to validate the model?
- [05:14]
Dr. Julie Jaffre
My goal for clinicians who are going to be using the CHAT ICU risk model is that when they have a patient that's admitted to the pediatric icu, they can use our risk model when they first get admitted. And they can really use this as a tool to guide if they are going to be at risk for thrombosis or not. So not only did we create the model, validate the model, but you will also see in the article, we've created risk scores. So not all of those five risk factors have the same weight of being risky enough to get a clot. So some we have weighted at a score score of 1, and some we have weighted at a score of 2. When we looked at a patient who had, you know, 1, 2, 3, 4 of those risk factors, we found that the risk of actually developing a clot with one of those five risk factors was 1%. But once you get up to five, six risk factors, that that is going up to 17% is of those patients to even 30% if you have all of the risk factors. So what does that mean? Well, it's really going to guide us to our next big stage of what we need to do within the pediatric thrombosis community is, okay, we figured out who's at risk for a clot. Now let's actually try to prevent clots. And, and that is our next big step as a community to try to prevent VTE children safely and effectively. And there have been a couple of studies trying to do that. But I do think we have a long way to go in this commentary.
- [07:09]
Dr. Laurie Sen
Paul Monigal from the University of Melbourne actually notes that this model is nicely validated in your paper. But of course it doesn't predict the patient's at risk of bleeding. So which is another important factor when you think about the use of thromboprophylaxis. Can you comment on this?
- [07:30]
Dr. Julie Jaffre
That was a really good point by Dr. Monigal and that what I think has been holding back a lot of our research with pediatric thrombosis is that fear, of course, of bleeding. And so I think most clinicians have been hesitant to start prophylactic anticoagulation because of that potential risk of bleeding. There's been small studies showing that, especially using prophylactic doses of enoxaparin or other low molecular weight heparins, that the bleeding risk is quite low in our children. But this is the pediatric ICU where the risk of bleeding is higher than your average hospitalized child. So that is what we also need to look at when we are doing these randomized controlled studies. So there's the Crete study that was just done by Dr. Faustino, who looked at both thrombosis and bleeding risk using prophylactic anticoagulation in pediatric patients in the icu. And those results will be coming out shortly. But we certainly have a long way to go of looking at bleeding risk. And I think what a person needs to do is not only apply the chat risk model, but hopefully one day we will have a chat bleeding model and we can put the thrombosis CHAT model and the bleeding chat model together to find, you know, the perfect patient that we could put on prophylactic measures that we can protect them from clots and also not add to their bleeding risk.
- [09:08]
Dr. Laurie Sen
Excellent. Well, I look forward to following this as it evolves, but in the meantime, I hope you've enjoyed the conversation today with Julie Jaffrey who's discussed the newly published article multi site validation of a Venous Thrombosis Risk model in Critically Ill Children through the CHAT Consortium. This important study validates the predictive capacity of an easy to use thrombosis risk model, supporting its clinical utility as well as its potential to risk stratify patients patients in future intervention trials. This article is now available on bloodjournal.org so I'm also joined today by Dr. Ulrika Philippar from Johnson and Johnson Innovative Medicine Belgium. She's the senior author of a New Blood Journal article entitled A novel T cell engaging trispecific antibody targeting BCMA, GPRC5D and CD3 in multiple myeloma models thanks for joining us today.
- [10:15]
Dr. Ulrika Philippar
Thank you so much for having me.
- [10:17]
Dr. Laurie Sen
Perhaps you can start by discussing some of the limitations of the currently available BCMA and GPRC5D bispecific antibodies in multiple myeloma and what we know about resistance mechanisms.
- [10:31]
Dr. Ulrika Philippar
In the recent years, two bispecific T cell engages have been developed for the treatment of multiple myeloma. One is focused on BCMA CD3 and the other one is focused on GPRC 5D CD3. Both of these have shown very nice response rates in multiple myeloma patients. Several drugs have been improved in the past years. However, if you look at the disease of multiple myeloma and across patients, it's very clear that even starting there's a heterogeneity and that is something we've described in our paper that there's clones that express BCMA and GPRC5D but then there's also clones that only express BCMA or GPRD GPRC 5D in addition to that having several therapies Targeting BCMA or GPRC5D, not just T cell engagers but also CAR T cells has led to the development of resistance and that mainly comes through downregulation of a tumor associated antigen. So downregulation of BCMA and or GPRC5D depending on the therapy and that can be post translational downregulation can be genetic deletion in events in the tumor, so leading further post therapy to more heterogeneity. And that's why we thought that it would be really nice to have a one molecule that incorporates the benefits of dual antibody targeting. So we picked those two tumor associated antigens and multiple myeloma and designed a tri specific T cell engagers which is targeting both BCMA and GPRC 5D as well as CD3.
- [12:03]
Dr. Laurie Sen
So with that as background, can you hone in on the rationale for developing this trispecific antibody?
- [12:09]
Dr. Ulrika Philippar
Well, the rationale was to have one molecule that is addressing the heterogeneity, so leading to higher overall response rates but also durability and hopefully prevention of resistance because the tumor would have to mutate or downregulate both tumor associated antigens to escape romantomic this novel trispecific.
- [12:30]
Dr. Laurie Sen
Your paper has some really nice elegant preclinical experiments supporting the use of this trispecific. Do you want to summarize some of the key experiments as well as the key findings?
- [12:42]
Dr. Ulrika Philippar
Yes, I'm happy to talk about our preclinical experiments. We have tested remantamic across a panel of multiple myeloma cell lines expressing different amounts of either BCMA or GPRCA 5D or CO expressing both tumor associated antigens. In addition, we have generated isogenic pairs where we knocked down or knocked out either one of the two antigens. So again we have generated then a panel with dual expressing or single expressing targets and we have shown that ramantamib can efficiently bind to these multiple myeloma cell lines. We have also shown that it can lead to cytotoxicity of these multiple myeloma cell lines independently of whether both targets or single target is expressed, as well as leading to the affected mechanism of action by showing T cel cell activation and cytokine release. We also further went into multiple myeloma patient samples where we looked at several primary derived multiple myeloma patient samples and again we saw nice activity across different patient samples which had varying degrees of expression of BCMA or gprsfd. And last we went into in vivo models and here we elegantly lose the isogenic saline pairs and we even had a mouse model where we had two tumors in one mouse, one flank with a GPSFD port positive tumor and the other side of a flank with a BCMA positive tumor and then just treatment with romantomic. In this mouse model we can see that both tumors shrink, so we see very potent efficacy if one of the targets is expressed and of course also efficacy when both targets are expressed. And that's differentiated from the bispecifics where you would have to have one treatment for this tumor type and another treatment for the other.
- [14:26]
Dr. Laurie Sen
Do you think it'd be rational to treat someone if they'd already proven fully refractory to bispecifics targeting either one or both of these targets?
- [14:38]
Dr. Ulrika Philippar
Yeah, I mean clinical trials, the formantomic are still ongoing, but we have presented early clinical data where we do also see activity in patients that have already been exposed to BCMA or DPRC5D targeted therapies. And ultimately, while these trials are ongoing, it depends on the mechanism of resistance. If it's mediated by downregulation of one of these tumor associated antigens, we expect that Ramantamic would still work because it's targeting the dual tumor antigens.
- [15:06]
Dr. Laurie Sen
In her commentary, Holly Lee from the University of Calgary stated that it'll be important to clarify that this trispecific format offers more than simply administering two separate bispecifics together or sequentially. Would you like to comment on this?
- [15:24]
Dr. Ulrika Philippar
Multiple trials are ongoing in the multiple myeloma landscape, including combinations of different assets, including the Clinical Trial Division of Ramantamic. What I can say is that the early overall response rate for Ramantamic were 100% and responses continue to deepen. I also can say that Ramantemeg demonstrated a favorable safety profile compared with BCMA or GPRC5D targeting bispecific antibodies, which is leading to a convenient single step up dose which is also suitable for use in an outpatient setting.
- [15:59]
Dr. Laurie Sen
Well, you know, I think it's an exciting time. It's exciting to see that this agent actually is in clinical trials with phase one setting and that other trials are planned and I look forward to seeing that data as it emerges. I hope that you've enjoyed the conversation today with Ulrika Philippar, who has discussed the newly published article A novel T cell Engag trispecific antibody targeting BCMA, GPRC5D and CD3 and multiple myeloma models. This important study highlights the potential clinical value of a novel trispecific antibody for multiple myeloma and this article is now available on bloodjournal.org
- [16:46]
Podcast Host
thank you for listening to this episode of Conversations with Blood Authors. To read the articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.