How I Use Jelmyto™ - Karim Chamie

June 16, 2021

In April 2020, the US Food and Drug Administration approved Jelmyto (mitomycin gel) as the first therapy for low-grade UTUC.  One year later, Jelmyto has become a valuable treatment that urologists can incorporate into their clinical armamentarium. In this conversation with Sam Chang, Karim Chamie provides a state-of-the-art lecture on UTUC and treatment in 2021.  Dr. Chamie summarizes risk stratification of patients, the challenges in the visualization of the upper tract tumor, and how JELMYTO fits into the treatment paradigm. Jelmyto is a novel formulation of mitomycin C that uses a unique hydrogel designed to increase urinary dwell time, and thereby efficacy of treatment. Dr. Chamie shares a video demonstrating the administration of Jelmyto. He and Dr. Chang discuss the safety and feasibility of this agent and how to operationalize this treatment in clinical practice.

Biographies:

Karim Chamie, MD, MSHS, Associate Professor of Urology at Resnick Neuropsychiatric Hospital, Ronald Reagan UCLA Medical Center, UCLA Santa Monica Medical Center, UCLA Health

Sam S. Chang, MD, MBA Patricia and Rodes Hart Endowed Chair of Urologic Surgery Professor Department of Urology at Vanderbilt University Medical Center, Nashville, TN 

Read the Full Video Transcript

Sam Chang: Hello everyone, my name is Sam Chang. I am urologic surgeon at Vanderbilt, but more importantly, we are today with Dr. Karim Chamie, associate professor. Well-deserving of full professorship, and I want to make sure that that gets passed on to his chair. He's at UCLA, he's going to give us actually some insights on, I think what you'll find to be very helpful in terms of how do I actually get started using a new medication that's been FDA approved for upper tract disease. So Dr. Chamie.

Karim Chamie: Dr. Chang, thank you so much for the kind introduction. Briefly before I go into my talk as far as how I use JelmytoTM, I must report that I do have some disclosures. Namely, I am a consultant for UroGen who actually makes Jelmyto. So a little background about upper tract urothelial cancer, cancers of the upper urinary tract are primarily found in the renal pelvis. Twice as common in the renal pelvis, in the calyces, as they are in the ureter. Unlike bladder cancer, upper tract cancers tend to be a little more invasive and they tend to be higher grade disease. So 60% of tumors in the upper tract are invasive compared to about 25 to 30% for the bladder. The incidence of bladder cancer after upper tract urothelial carcinoma is about 40 to 50%. Obviously, there are two studies that have demonstrated that providing intravesical instillation of chemotherapy at around the time of nephroureterectomy can reduce it by about 50%.

The incidence of upper tract urothelial carcinoma, so migration of the ureters, is about seven and a half percent for those with non-muscle invasive bladder cancer, getting BCG patients who have undergone a prior radical cystectomy, the incidence of developing metachronous upper tract disease is about three to 5%. And most of those times, oftentimes it's higher grade, oftentimes variant histology. The EU guidelines really were the first ones to risk-stratify patients with upper tract disease. And they initially stratified it based on high risk and low risk. The things that have changed was the tumor size. So initially tumors that were less than one centimeter, unifocal, low grade biopsy and cytology, and noninvasive appearing images, were the ones that were deemed low risk. And those guidelines came online about 2011. And then in 2015, they kept pretty much everything the same with the exception of increasing the size to two centimeters. So now tumors that are less than two centimeters would be considered low risk.

But remember it's an and statement, so they have to have all these features to be considered low risk. Whereas high risk features, namely hydronephrosis, tumor greater than two centimeters, high-grade cytology, biopsy, multifocal disease, prior cystectomy, variant histology, those are or statements, any of those would be considered high risk. How we manage patients with low-risk non-invasive disease. We have two primary modalities nowadays. One is you ureteroscopic excision and laser ablation of tumors, and the other is chemoablation. Now I'm primarily talking about tumors up in the renal pelvis here, because tumors in the distal ureter can be managed with segmental ureterectomies as well. What makes treating upper tract disease so difficult is tumors are a little harder to visualize in the upper tract. So this is a tumor that's in the bladder, you can clearly see it, you can resect it, you can get your loop, you've got a bladder that's pretty thick.

You can get down to lamina, muscle, and potentially even fat and leave a catheter in and no worries. The problem with the upper tract is visualization's poor. And as soon as you get into the tumor and it starts to bleed, you're really working with both hands tied behind your back. So hematuria is a significant detriment in the way you manage upper tract disease. And the instruments aren't quite as good and make resection or ablation pretty challenging. And in fact, if you actually look at recurrence data for patients who've undergone prior ureteroscopic management for upper tract disease, these are in the best of hands. These are people that felt comfortable and confident with their data and they published it. And you look at pooled analysis of ureteroscopic series for low intermediate risk disease, 85% of patients with low intermediate risk disease, you follow them for two and a half years, the recurrence rates are about 58%, so it's pretty significant.

And so because of that, we feel that there was an unmet need and Jelmyto came in. And basically it's a reverse thermal hydrogel polymer where it's liquid in cold temperatures and becomes solid in body temperatures. And urine slowly effluxes the gel out and so you get chemoablation. And so this was pretty novel study, the OLYMPUS study, because in urology, most of the time when we have clinical trials, it's oftentimes either neoadjuvant or adjuvant. We've never really done many studies where we're actually looking at a chemo ablative as a surgeon. You want to go in there and remove a tumor. This was pretty cool in the sense that surgeons were forced to leave a tumor behind, which is a bit of a challenge. And they did, and the study was primarily indicated for patients with tumors that are about five to 15 millimeters in size. If tumors were larger than 15, they can get the bulk down. They got once a week treatment, either in the office or in the OR followed by a four to six week waiting period, and then there was a primary efficacy evaluation. And here the primary endpoint was complete response.

When the company went to the FDA and they asked the FDA what was the clinically significant response, they went in there with the notion of 15%. And the FDA said, "Whoa, whoa, don't tie yourself to that one number because you may end up not meeting it." And so we didn't know what the complete response rate was. So it really was in the dark eras because there's been no precedent of that type of study. And then the secondary evaluation was durability at 12 months after complete response. And the definition of complete response was a normal ureteroscopy, normal cytology. And if there was any erythematous or any abnormal lesion, it had to be biopsied. And what they found was that the complete response rate was 58%, nearly four times what we thought was clinically significant. And then they followed these patients up for a year, and the durability is quite good at 82% probability of maintaining a complete response 12 months later. So it measures favorably compared to ureteroscopic series, where we're talking about 58% recurrence rates in two-and-a-half years.

So the data looks pretty promising thus far. Adverse events, obviously ureteric obstruction grade one was the most common, 25%, grade two 16 and grade three 17%. The median time to obstruction was about two and a half months. Patients who just got once a week induction of Jelmyto, their ureteric obstruction rate was about 40%, whereas those that got induction and maintenance, their ureteric obstruction rate was 82%. And it usually occurs between the third and the fifth installation. If it were to occur in the induction phase, it tends to occur between third and fifth. And I found that giving patients a Medrol pack seems to help with it, and it tends to be transient. Tidbits, in the study 37% of patients had general anesthesia. I would strongly advise that urologists, if they've never used this product, to at least do it, use it the first time in the operating room. Again, we know that sodium bicarbonate potentiates the efficacy of mytomycin C, so we tend to give it the night before in the morning of.

The kit comes with a 5-French catheter, but you can use a 7-French, just make sure it's a molded Luer lock, otherwise the gel has a consistency of peanut butter, and as you're trying to torque it, it potentially can explode and spill chemotherapy everywhere. So the urethral catheter has to be molded. And then the median time to first urination was about 1.3 hours. We did this study in a pig model back in the days before any of the study was in the clinical phase. And we instilled it both in a retrograde and in an antegrade fashion in bilateral kidneys. And the gel obviously has a purple dye. And within seconds, you would see discolored urine in the catheter. So even though it fills up the renal pelvis, urine is able to drain around the gel. As far as toxicity, median plasma concentration of mytomycin C from the clinical trial was 0.5 nanograms per milliliter. You see myelosuppression once you have a concentration of 400 nanograms per milliliter, so about a thousand times higher than what we found in humans.

Route of delivery, we know that the paper published by one of our residents, [Matt Pollard 00:09:24], looking at what's the best way to deliver chemotherapy to the upper tract or immunotherapy to the upper tract, retrograde is superior to antegrade with regards to liquid. In gel, when we did the pig models, retrograde gel would stay up into the kidney for about six to eight hours whilst antegrade is about five to six hours. Absorption is better with retrograde, so it's less absorption of mytomycin C into the bloodstream. Retrograde is about four nanograms per milliliter, and antegrade is about 25 nanograms per milliliter. This is peak mytomycin, this is not median concentrations. So to summarize, when you're treating a patient with upper tract urothelial carcinoma, just make sure you get an adequate biopsy. The last thing you want to do is go in there and assume that the patient has low-risk disease, meanwhile they've got underlying high risk disease and you're treating them with a drug that may not be all that beneficial. And then do selective cytologies to confirm it's low grade.

If there are any high risk features then obviously nephroureterectomy, unless of course they've got a solitary kidney or CKD, then you got to have a shared decision-making conversation with the patient. One of the things we're finding out now is that whenever we do ureteroscopies, doing a biopsy can actually see the ureter and the bladder. And there's talk about maybe potentially putting perioperative chemotherapy to reduce the risk of seeding in the bladder, not just for nephroureterectomy, but also from ureteroscopy. One of our fellows published a paper, the Mayo clinic series, where patients who got a ureteroscopy and a biopsy had a higher rate of seeding the bladder than those who just got a ureteroscopy alone. With regards to Jelmyto, induction therapy I think is associated with a lower ureteric obstruction rate compared to induction and maintenance.

Transient edema tends to occur between the third and fifth instillation. I found that there's a good response with a Medrol pack. As far as nephrostomy tubes, I've done Jelmyto with a nephrostomy tube delivered in an antegrade fashion. I place nephrostomy tube, I wait at least a week, or at least for the hematuria to resolve. The dwell time is a little less than the retrograde, but I think it's more than sufficient. There may be higher mytomycin C absorption, but still it's one 20th of the levels that you would see to see myelosuppression. And if you're doing this for the first time, consider your first treatment in the OR, and if you need to place a stent, you can pass a urethral catheter adjacent to the stent. You'll just need a dual working port whereby you would grab the stent with one port and then advanced urethral catheter with the other. And with that, I'd like to thank you.

Sam Chang: Great. Thank you so much. I know you've got some videos that you want to share. So as you're loading up the first video, I think that those last two summary slides in your tidbits really, I think, would prove helpful for those that should just start initiating this whole process. Looks like the first video is from Dr. Shabsigh, so let's get that started.

Karim Chamie: Yeah. So this is a video that we presented at the AUA a few years back. And Ahmad shows a video where he actually does this in the clinic, you'll see the step-by-step approach. [Brian Who 00:12:53] shows his way of delivering it by actually doing more targeted delivery into the calyce where the tumor was, where he uses a [inaudible 00:13:04] catheter. And then I show you a way of administering it in a patient who has a Boari flap and has an indwelling stent. So three different ways of administering this. So the equipment usually comes with a UroGen injector. It's titanium, trying to push these Jelmyto through with a syringe is a little bit of a challenge. So you'll need the titanium injector, and basically you twist it about a clockwise every three quarters of a second. So you should be done in about 15 seconds with administration of the gel. Make sure you have a Luer lock that's molded. And here.

Sam Chang: And when you mean by molded, do you mean just fits well? Because I know you said you could use a 5-French and be able to take a look, but do your Luer lock that needs to molded, you mean just fit very tightly to the catheter, or the one that's already attached? Is that what you mean?

Karim Chamie: That's right. It's the one that's pre-attached that comes as a single unit where you can't separate the attachment from the actual catheter.

Sam Chang: Understood. And that 5-French is just easier in terms of maneuverability? Okay, got it.

Karim Chamie: Yeah. The 5-French allows you to administer it in a patient that may have a little bit of transient edema around the third to fifth installation. I always use 7-French even with a patient that had an existing stent. You're able to still get around it, just giving them a little bit of Metro ELPAC. So this is Ahmed, he's doing here in the clinic. You could see the injector, the syringe is Guidewire. You could see the molded catheter right here.

Sam Chang: Yes.

Karim Chamie: It's green, and it's a single unit. He's got another one there. This is a patient who's awake. He first uses the five French regular open-ended catheter to get the wire into the ureter.

Sam Chang: Pre COVID?

Karim Chamie: Yeah, this is pre COVID. Those were the days.

Sam Chang: So he's basically using that combination, he's got fluoroscopy there as well as obviously [inaudible 00:15:36]. Okay.

Karim Chamie: And you've got a C-arm. If you're going to do this, obviously you should have a C-arm in your clinic. I'd probably advise doing it with a C-arm and performing a retrograde to confirm that you didn't have a perforation in the UR, in the renal pelvis.

Sam Chang: Yeah.

Karim Chamie: So once he gets his wire up, he confirms its location. Then he removes the catheter and places his five or seven French molded, Luer lock. Here he's performing a retrograde Pyelogram, confirming he in fact is. You can see the ureter there on the left.

Sam Chang: At this point, is he estimating the volume then that it takes to fill that renal pelvis or at this point no?

Karim Chamie: No, really, really good question. Very insightful question, Sam. So in the study what we had to do was when we biopsied the patients, we'd have to take an average of three volumetric measurements. So you do a retrograde pyelogram in the operating room, do three different measurements and get the average of the three. Then that average would be how much you instilled in the clinical trial.

Sam Chang: Okay.

Karim Chamie: I don't know if you need to do three in real-world practice, but that's how we did it in the clinical trial.

Sam Chang: Okay. And so when you do it either retrograde or antegrade, and you may show in upcoming videos, is there a certain way that you guesstimate the volume then? Is there a certain best way, technique?

Karim Chamie: In general, it's about 10 to 15 milliliters.

Sam Chang: Good to know.

Karim Chamie: That tends to be the average amount. Here he is advancing his molded Luer lock catheter up into the renal pelvis. And I find that just advancing the urethral catheter into the renal pelvis is more sufficient. Brian Who will show you a video where he's actually able to target an individual calyce. I don't think you need to do that, I think you can probably get away with simply just getting it into the renal pelvis. Here he is, he's emptying the contrast out of the renal pelvis, because obviously you don't want to put a gel in addition to contrast, because then you can get a perforation. So you have to make sure you empty the contrast out. It impacts your volumetric measurements. Here. He is instilling Jelmyto. Again, you don't want to grab the syringe because you've got body temperature, it'll solidify. You'll see it filling up in there like goop. You see, he's not grabbing the syringe, he's grabbing the bottom.

Sam Chang: Good point as well. Okay. And this is all obviously still chilled and they're made as cold as possible.

Karim Chamie: Yeah. Yeah, it's on ice here and it's removed off ice and he puts it into the titanium injector.

Sam Chang: So as you do this, I am assuming you want to move along pretty quickly.

Karim Chamie: That's right. That's right. And the administration of this should take seconds, it should not take a minute. It should take something on the order of 10, 15 seconds. And you twist it in a clockwise fashion.

Sam Chang: That's what you showed there. I see. So we are hoping to start offering this to patients [inaudible 00:19:36] but we've not yet started. So these insights are very helpful as are these videos that you're showing. So does the material that you get, does it come basically already with a contrast loaded on it so that you can-

Karim Chamie: That's right.

Sam Chang: Okay, so you don't have to do anything extra there. Okay.

Karim Chamie: Yeah, it's pre-mixed, and it's got the dye instilled and ready to go. That's it, and you remove everything.

Sam Chang: That's it, he's finished. Okay.

Karim Chamie: That's it, he's finished. I usually disconnect the syringe from the injector first.

Sam Chang: Okay.

Karim Chamie: But they're just small little variations. This is Brian Who doing it in the operating room. He's trying to target a middle calyce here.

Sam Chang: Okay.

Karim Chamie:And he uses a [inaudible 00:20:22] catheter.

Sam Chang: Oh, to help guide the wire in there. I see.

Karim Chamie: Again, I don't think you need to do it unless of course you've got a patient who has maybe infundibular stenosis. If you don't have a patient with infundibular stenosis, I think just simply instilling it into the renal pelvis is more than sufficient, whether it be an antegrade or retrograde fashion.

Sam Chang: So I guess to further maximize, like you were talking about, these are all obviously hypotheticals, we don't have data, but for this patient, would you give them a couple amps of sodium bicarb while they have an IV?

Karim Chamie: Mm-hmm (affirmative).

Sam Chang: Okay.

Karim Chamie:  Yeah, we give them sodium bicarb pills the night before and the morning of.

Sam Chang: Mm-hmm (affirmative). And then if they were asleep then with an IV, would you go ahead?

Karim Chamie: Sure.

Sam Chang: I guess there's little harmed. Yeah.

Karim Chamie: Yeah, absolutely.

Sam Chang: And then what chemotherapy, interestingly enough, are you considering to give during peri-operative... Not necessarily here, but for the [inaudible 00:21:20], you've been doing chemotherapy and we've been using gemcitabine. For these patients here, would you routinely, because you're manipulating that type of thing, do you leave chemotherapy in their bladder as well or no?

Karim Chamie: Well, for this one, no, because the chemotherapy will actually dissolve and get into the bladder. So in essence, not only are you chemo-blading, but I think you're also reducing the chance of seeding the bladder as well.

Sam Chang: That's a good point.

Karim Chamie: Yeah. With nephroureterectomies, we're currently using gemcitabine, you just got to make sure that your bladder closure's pretty water tight and there's no leak. And you can potentially do a cystogram before you give it. I could tell you from my experience and we're writing a multi-institutional series with some other specialists in the field, peri-operative installation of gemcitabine at the time of TRBT, we're finding a significant number of patients actually have developed alopecia from intravesical gemcitabine. Which wasn't published in the JAMA paper by [Ed Messing 00:22:28]. So maybe they really didn't do deep resection. So I suspect that it's probably related to maybe micro-perforations, but in my hands I've seen it twice.

Sam Chang: Interesting.

Karim Chamie: And so I'm a little more cautious. So this is my video of a patient who's had a low grade upper tract cancer and the distal ureter that was pretty nice size, was around two and a half centimeters. And so I did a distal ureterectomy and a Boari flap on him. And so he ended up developing recurrence of low-grade disease in the upper urinary tract and I enrolled him in the study. The reason why I decided to do this in the operating room is because I tried to pass the five or seven French catheter into the Boari. And it's pretty redundant, it was a little hard. So what I decided to do was place a stent. And the stent seemed to straighten out the Boari, and it allowed it to pass the stent much easier. And this is my way of showing how to instill the gel with an existing stent in place.

Sam Chang: That's good.

Karim Chamie: So he has the stent in place.

Sam Chang: No stenosis there, Karim. Good job. Good job.

Karim Chamie: Thanks. And this is us passing the 7-French adjacent. And here, what you're seeing me do is grab the stent with one working element while we advance the urethral catheter with the other.

Sam Chang: That's slick.

Karim Chamie:Yeah. Otherwise around the third or fourth cycle, you'll notice that when you pass the 7-French next to the stent, the stent will start to migrate up. So you need to actually grab this. And it tends to occur about the fourth or fifth treatment.

Sam Chang: With the edema that you're talking about. I see, okay.

Karim Chamie:Yeah, when you give that Metro pack, it goes away. So this patient had a tumor in the renal pelvis. I did a retrograde. After I did the retrograde, I emptied the renal pelvis. And here's my assistant. Again, it was on ice.

Sam Chang: Ice. Glad you're do the workout, you're able to pull that pretty easily there, a lot quicker than doctor [inaudible 00:24:57], I'll have to mention that to him. That's filling up there.

Karim Chamie: Yeah. And so you'll see how fast I instill it.

Sam Chang: Okay. I see.

Karim Chamie:That's it. So there's various ways of instilling it, obviously in the clinic using a comfy catheter to target a specific helix or placing an adjacent, a urethral stamp. And again, the lesson is try to do this first time, first couple of times in the OR, in a controlled setting where the patient is not uncomfortable because it'll just add undue pressure and stress on you.

Sam Chang: Great.

Karim Chamie:So these are the tips that I've learned.

Sam Chang: So Karim as you start a program, pretend you're me and you're burdened with that difficulty, sorry about that. What would be some of the key points? You gave us so many tidbits. Tell us what were the most difficult things for you as you started this process. And so tell me the three most difficult, and then how you overcame those three difficult points for someone about to start using Jelmyto.

Karim Chamie:Well, there are a few challenges. One is obviously getting it approved at your institution. We have a value added committee here at UCLA, you have to go to some meetings to make sure that they'd be willing to support it. Two, you have to have a pharmacy that would be able to get the drugs. So sometimes not being able to do a 7:30 case can be a little bit of a challenge. Our pharmacy, we couldn't do this any earlier than nine o'clock. So little things like that.

Sam Chang: Nobody ever told us about that. Understood just to help prepare it, make sure it's okay. Good point. All right.

Karim Chamie: Probably not a first case.

Sam Chang: I'll give you two more. I'll give you two more because those are two good ones. Yep.

Karim Chamie: Other parts is, from a urologic perspective, bringing patients in and delivering this in the clinic in a busy workload clinic is a little bit of a challenge. So again, there's two ways about it. Either make it on a separate clinic day where you're not seeing 40, 50 patients in a day, probably a day where you're seeing only a few patients, you can devote more time and attention because this thing may take a little longer than you anticipate. If you get a little bit of edema in the ureter, you got to be prepared to either boarding or taking the stent out, if they don't have a stent. Or if they do have a stent, trying to go with a smaller one. And so trying to do that in a busy clinic day is a little bit of a challenge.

Or use a nephrostomy tube. When you're giving it through a nephrostomy tube, you eliminate a lot of the heterogeneity in anatomy and you eliminate a lot of the heterogeneity in edema. And I find that you really don't get all that transient edema and strictures and ureteric obstructions from a nephrostomy tube. And I think the reason why is that there's less instrumentation of the ureter, and the less you irritate the ureter, the better I think. And so giving it through a nephrostomy tube probably reduces the incidence of ureteric obstruction, above and beyond just induction course. But also you could probably get away with delivering it on a busy clinic day, just because it's so predictable when you give it through a nephrostomy tube.

Sam Chang: Oh, Dr. Chamie, Karim, fantastic, I think, insights as people started initiating this process. I very much appreciate your time and I look forward hopefully soon to introduce you as full professor grand champion from UCLA. Again, thank you for your time and really great insights on what we can do as we initiate this into our practice. Thanks again.

Karim Chamie: Thank you, Dr. Chang. Bye-bye.

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