Administration

Anthony Perissinotti: Good evening everyone and welcome to this virtual presentation entitled the Importance of multidisciplinary collaboration throughout the BLINCYTO^® Treatment Journey. My name is Anthony Perissinotti, I am a clinical pharmacist specialist in hematology at the University of Michigan. My primary role is to take care of adult patients with acute leukemias.

Andy Ostrenga: And I'm Andy Ostrenga, I'm the assistant director of pharmacy at the University of Mississippi Medical Center. And I've been serving in pediatric oncology for about 15 years and I take care of the wide variety of especially ALL patients that need BLINCYTO^® .

Anthony Perissinotti: Excellent, thanks Andy. And one of the major differences besides being at different institutions, between Andy and I is Andy treats pediatric patients primarily and so you're going to get two different flavors and very different perspectives. There are a lot of things that are going to be very, very much the same throughout the treatment journey, but there are going to be little nuances that we'll explicitly discuss with regards to pediatric patients.

So this program is a promotional program. And it's presented on behalf of Amgen. The purpose of this is really to help you all figure out how to operationalize the use of blinatumomab in various different sites of care. So inpatient, how do you get a patient from your clinic to inpatient, back to outpatient, and to their home.

Now we are not going to be talking about anything off-label today. We also will not be endorsing any particular manufacturer or supplier of pumps, or even home health care providers or institutions.

Anthony Perissinotti: So the way that we have this outlined is, I'm going to start off the presentation giving you a brief introduction of what acute lymphoblastic leukemia is and really highlight the epidemiology and the prognosis. With that, Andy is going to talk about a therapy that was FDA approved back in 2014 called blinatumomab. He'll discuss the indications, mechanisms, and then he'll go over the relapsed/refractory data, which is the Phase 3 TOWER Study.

The bulk of this presentation is really going to be the patient treatment journey. Again, how do we get the patient from our clinics to our hospitals, back home in a very seamless fashion.

Anthony Perissinotti: Okay. So acute lymphoblastic leukemia, there are two primary acute leukemias: acute myeloid leukemia and acute lymphoblastic leukemia.

Acute lymphoblastic leukemia is an issue, a malignancy within our early progenitor cells that affect B lymphocytes and also T lymphocytes.

Anthony Perissinotti: Now it's not that common, it's actually quite rare. There's only 6,000 cases in the United States diagnosed every year. Now Andy will argue that ALL is a pediatric cancer. And I will give it to him, he is probably right for a couple of reasons. One is that, you know, there are a lot of other adult cancers, breast cancer, colon cancer, prostate cancer, that, you know, absolutely are much higher incidence than ALL.

Whereas in peds this is a more common malignancy because peds patients fortunately do not have very many cancers. The second reason why Andy is right, is that the story of ALL in kids is much better than adults. The story for kids is an 80 to 90 percent cure rate. Whereas in adults our cure rates are about half of that.

And so that all being said, even though ALL is considered a pediatric cancer, 50 percent of these 6,000 cases actually happen in adults.

Anthony Perissinotti: Now again, with adults the cure rates are much lower, primarily because they have more resistant disease and they're more likely to relapse. Now when patients are first given their primary induction therapy, even in adults our remission rates are about 90 percent or even greater. However, about 50 percent of our patients will relapse.

When they do relapse, our ability to get them back in remission is half of what it was in their first line therapy. So instead of 90 percent CR rates, we're now half that, 45 percent and this is with traditional chemotherapy.

In second salvage, third salvage, keep cutting it in half. Not only can we not get our patients successfully back into remission, their overall survival, because of this, is quite poor. So, for adults, first salvage patients live for less than six months, unfortunately.

And with that I think I teed up Andy perfectly to talk about a therapy so that we can go beyond just giving chemotherapy and improve upon outcomes.

Andy Ostrenga: Yeah. Thank you, Anthony. So, first of all about BLINCYTO^®’s indication, so we're going to focus on this indication for this presentation.

VO: BLINCYTO^® (blinatumomab) is indicated for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adult and pediatric patients.

BLINCYTO^® is indicated for the treatment of relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients.

Andy Ostrenga: As you can see that BLINCYTO^® targets these malignant and benign B cells. So, it's not just the malignant, its your regular B cells too via the CD19 cell surface antigen. So, this actually engages the CD19 as well as the T cell CD3 antigen at the same time.

So, once it activates that T cell it results in a formation of a synapse between the two and it allows the T cell to actually fight. So, it activates it, and releases perforin and granzymes and it really starts causing apoptosis and attacking the cells, so that's what we want. We want those T cells to attack the living B cells.

It actually persists so the active T cells persists in the blood stream, they stay around and attack multiple targeted cells. So you get some sustained activity beyond just during the actual infusion so that's nice.

Andy Ostrenga: So, also BLINCYTO^® is recommended as a category 1 treatment option for Ph-negative relapsed or refractory B precursor ALL. And in the NCCN guidelines and those are for acute lymphoblastic leukemia. So it's good, it's category 1.

Andy Ostrenga: So, here's our first question here. So BLINCYTO^® targets malignant and benign B cells via the blank cell surface antigen, while simultaneously engaging the patient's own T cells through the blank antigen. So, our options are, A) CD19 and CD3, B) CD22 and CD3, C) CD3 and CD19 or D) none of the above.

The correct answer is A. So the CD19 on the B cell and the CD3 on the T cells.

Andy Ostrenga: Now let's talk a little bit about the data. As Anthony mentioned we'll talk about the TOWER Trial. So, the TOWER Trial was a randomized controlled Phase 3 Trial of BLINCYTO^® versus standard of care chemotherapy for adult patients with Ph-negative for relapsed or refractory B precursor ALL.

Andy Ostrenga: So it was again, a very large trial, so 405 patients over the age of 18 were assigned here. They were assigned to two to one ratio so obviously more BLINCYTO^® patients were received that versus standard of care. And you can see the different standard of care regimens here as the different options and then into consolidation.

Andy Ostrenga: So here's -- I always like curves, so this is a pretty obvious curve here. The efficacy of BLINCYTO^®. So you can see the overall survival was much better in the BLINCYTO^® group. So 7.7 months compared to the 4 months of the standard of care. So again, this isn’t comparing against a placebo, this is standard of care, this is what everybody else is doing. So, you can see a very nice difference in those curves, a statistically significant difference there.

There was some adverse effects.

Andy Ostrenga: There's also more than double median survival when used at first salvage. So, the overall survival was 11.1 months versus 5.5, so again a very nice difference there.

And also, the remission rate was very different, 34 percent remission rate versus standard of care chemotherapy.

Andy Ostrenga: Let's go back to Anthony and talk about the administration.

Anthony Perissinotti: Perfect, thanks Andy. So, one of the things that, you know, is relatively challenging when we first started using blinatumomab is it was administered in a way that we've never administered a drug, and that is as a 28-day continuous infusion. And I remember, I'll tell you a story, it was back in 2014 in December, right around Christmas we got a brand new ALL who came from an outside institution and was relapsed and we thought, this is just FDA-approved. We looked at the data, the TOWER Study.

And so, we decided to give this therapy to the patient. But it didn't just stop right there, we can't just decide okay, we'll give the therapy to the patient. There were a lot of logistics that we had to figure out, and one of the logistics was the 28-day continuous infusion. So, myself and my colleague started outlining okay, who do we need that's involved with this. Who do I need to talk to about our policies and procedures, and we just laid everything out and we successfully gave this patient blinatumomab.

So, you can see on this slide here, initially the patients will start in the hospital. They'll start at a lower dose, 9 micrograms per day and the reason why they start in the hospital and at a lower dose is, as Andy outlined, there is one toxicity called cytokine release syndrome that requires some pretty prudent monitoring for the first week or so.

In my experience the cytokine release syndrome occurs 48 hours into the initiation and then also after the seven days of the 9 micrograms, we actually escalate the dose to 28 micrograms. And 48 hours after the dose ramp up is when I usually see cytokine release syndrome.

And so, as such we keep the patients in the hospital 48 hours after the dose ramp up. And so, patients are in the hospital for nine days on their first cycle. And then they're discharged and we continue this therapy for a total of 28 days as an outpatient.

You'll see also at cycle 2 we will admit the patient again, but this time it's only for 48 hours and we don't do a dose ramp up, we just start right at the 28 micrograms. And then the remainder of 28 days is outpatient. They get a 14-day block and then we come back and we can give up to 9 cycles. And you'll see there's a little bit longer of a gap once you get through cycle 6 through 9.

You'll notice that we have a flat dose. It's no milligrams per kilogram. It's no per meter squared, it's a flat dose and this is for patients that are greater than 45 kilos.

Andy Ostrenga: Yeah, so it's similar to what you said, the strategy. So, we also racked our brains for a good while, but here is an example. We dose 5 micrograms per meter square up to the max of 9 micrograms.

And then all we do is ramp up to the next 15. So, we also do a similar strategy, what you said of bringing them in and monitoring them. We also see that similar timeline of when they actually have the CRS syndrome as well.

So, the biggest difference is finding that specific microgram per day that they need and trying to make that work with the bags.

VO: Patients weighing 45 kilograms or more receive a fixed dose, and for patients weighing less than 45 kilograms, the dose is calculated using the patient’s body surface area.

Let’s review body surface area-based dosing for patients with Relapse/Refractory B-cell Precursor ALL weighing less than 45 kilograms.

For Cycle 1, the starting dose in days 1 through 7 should be 5 micrograms per meter squared per day; not to exceed 9 micrograms per day. For days 8 through 28 of Cycle 1, the full dose of 15 micrograms per meter squared per day, not to exceed 28 micrograms per day, should be administered. Days 29 through 42 (14 days) are a treatment-free interval. For Cycles 2 through 5, for each day of days 1 through 28, start dosing at 15 micrograms per meter squared per day, not to exceed 28 micrograms per day. Days 29 through 42 (14 days) are a treatment-free interval.

For Continued therapy, Cycles 6 through 9, for days 1 through 28, start dosing at 15 micrograms per meter squared per day, not to exceed 28 micrograms per day. Days 29 through 84 (56 days) are a treatment-free interval.

Anthony Perissinotti: So, you'll notice that there are different bags that are available. There's a 24-hour bag, there's a 48-hour bag and a seven-day bag. And I'll show you later how you can kind of mix and match between these. But just know that these are available right now.

You'll also notice that no matter what the dose is, whether you're doing 9 micrograms or the 28 micrograms, you'll notice that the infusion rate is actually dependent upon how long you're infusing the drug over. And what I mean by this is so regardless of your dose, if it's 24-hour bag, you're going to be running the infusion over 10 milliliters per hour. If you're giving a 48-hour bag you're going to be running over 5 milliliters per hour and then there's the 7-day bag which I really, really like for convenience, and that's run at .6 milliliters per hour.

And I know immediately a lot of you guys are like how do you do that? How are you giving such slow infusion rates, 5 mls, .6 mls per hour.

And initially I was worried as well. I was even worried about 5 mls, are you going to have the line that clots off? Are you going to have occlusions? And quite honestly despite my criticism of thinking that that would happen, in my experience we’ve really not had issues with running things at .6 milliliters per hour versus 5 milliliters per hour but it's definitely something to think about.

And so multiple different bags for patients and we essentially mix and match and I'll show you later how we do that. So going into our next question, BLINCYTO^® is administered as a continuous IV for up to blank cycles, for patients with relapsed or refractory B-cell precursor ALL.

It is a little bit confusing but you can give up to a total of 9 cycles.

All right. So, hospitalization is recommended for the first blank days of the first cycle and the first two days of the second cycle. So how many days are patients in the hospital for the first cycle, is it 6 days, 7 days, 8 days, or 9 days?

All right. And so, we do keep the patient in the hospital for nine days.

All right. So, patients have the option to continue administration of BLINCYTO^® at home, at the infusion center or both after their initial hospital stay in cycles 1 and 2. And for the entirety of any additional cycles.

And so, both of the answers are correct, either at home or the infusion center.

Anthony Perissinotti: And this actually segues us perfectly into the next section that we're going to discuss and that's the patient's treatment journey.

Andy Ostrenga: Thank you, Anthony. So we're going to break this journey into four different groups. Obviously it's not as easy as one stops here, one starts there. So a lot of interlapping groups of things.

So first we'll talk about the pre-admission. So that's when you identify a patient as an appropriate candidate for BLINCYTO^®, hospital admission preparations begin. So obviously you need to consult with an academic or community center that is able to do that. And these key stakeholders really need to work together, so that's the oncologist, the pharmacist and also those that are in charge of discharge planning, case managers, social workers.

So, the things we really look at here are, number 1, insurance approval. Are we going to be able to pay for this drug. Benefits investigation, does it have to go through a high cost med committee? There may be needs to be order sets. What's the length of stay, what's our plan, you know, is nine days enough or does it need to take a little bit longer? What's our plan for outpatient infusion and monitoring. We can't just plan for the hospital stay and nothing afterwards.

And also what kind of evaluation and testing do we need. Also, what's the coordination? So how do we work together to do this. So, Anthony, what has been your experience on these preadmission group to get everybody ready for the infusion?

Anthony Perissinotti: Yeah. I mean, this is by far one of the most important aspects, the preplanning of things, right? And you don't always have as much time as you'd like. Typically, at our center what we say is if you know that your patient is going to get blinatumomab, give everybody a heads up about a week prior. Just so that we can start getting rolling on things.

Obviously not every acute [leukemia patient] can wait seven days for us to prepare and so sometimes we just admit not having all the answers, and we have the nine days while they're in the hospital to figure things out.

So typically, what we'll do is we'll start an email chain, and we have an email group just to let everybody know hey, we have a new blinatumomab and these are all the players, and here are all the steps that we want each individual doing. And then we obviously want some email confirmation back when they do some of these steps.

We have an order set that's built, this is really helpful when you're kind of mix and matching your various bags.

We're trying to plan ahead, even before they get admitted things like education to the patient, right? Educating them on the signs and symptoms that they should be worried about. The majority of it is happening in the inpatient hospital stay, but we still educate them on the signs and symptoms of what to watch out for and when to call our clinics as well.

Andy Ostrenga: Yeah, and you really also have to assess whether the patient is a good candidate. Can they handle that? Can they call us, is there a language barrier? What do we have to work through to make it safe for this patient to get it, when they’re in the hospital and go home?

You don't want to have somebody come in for BLINCYTO and think they go home after a week and oh, wait, I still need to be infused. I live four hours away. So it's really important to get the whole picture. Sit down with the patient and the family and have these frank conversations of this is what it is, these are the side effects, we need to make sure we can handle it.

Anthony Perissinotti: Yes. And then, the last piece I'll say is when, we're still talking about prehospital planning is we do think about what day of the week we're starting. Our infusions base can't do bag changes on a Saturday or Sunday, well then you have to do some math and we can't start on a Thursday or Friday, because day nine will be a Saturday or a Sunday. So, there is some thought on the logistics of when to start as well.

The other thing that we really try to do is start them early in the day, because we don't want them to have to be discharged at 10:00 at night. Many home care agencies may or may not want to come out at 10:00 for their bag changes. So, we try to be considerate and start at, you know, in the early morning to midafternoon at max.

Andy Ostrenga: Yeah, so that segues great into this next part of the in hospital stay. So, we're still having those conversations, still trying to organize but now you can see a few different people are brought in. Obviously, they're admitted as Anthony says, but this is where you really bring in to make sure your inpatient pharmacist is involved, your oncologist, but also your nurse.

So, once we come into the hospital you make sure that everybody is on the same page for monitoring for side effects, grading these side effects and trying to manage them. So that's very important in this period because if you delay in it, it may delay discharge.

Also, education for pharmacy staff. How do we compound this, how do we evaluate or as Anthony said, to make 24-hour bags, 48-hour bags, that's all very important to have those conversations work with the team.

And also, this is where you still work with coordination of when is the discharge date. When we bring them in, what's the plan so we always have a plan when we bring them in when they're going home. Anything Anthony, that you want to add to this?

Anthony Perissinotti: No, I agree.

Andy Ostrenga: Well next, the continuation of care so that when the patient is being evaluated for a transition to outpatient setting, again it's this core group that really needs to work together to determine how we get them there. So, when we're at this point, it's really a big thing, it's communicating with home health and the infusion site.

So, number 1, you have to pick out where you're going to infuse after the day, is it home, is it in a clinic, is it home health? So all these things are very important to us as far as communication.

You also need to make sure you have the contacts. So, the family needs to know who to call when something goes wrong. But in the beginning, they need to be educated, what can go wrong? If we're talking about pump issues, we're talking about side effects. The family needs to know ins and out of how to handle this when they go home.

Also dispensing size. So, this is again where we figure out the nuances and the logistics of which bags we dispense first, which ones we dispense towards the end. These are all the things that you need to communicate to the home health agency or your own hospital clinic so everybody's on the same page with that.

And also, continue with the post hospital stay stuff. So, it's monitoring for toxicity, tracking your therapy schedule, making sure you're on point and on schedule. And then educating anybody that could be around these patients. Anthony? Do you have something to add? 

Anthony Perissinotti: Yeah. I mean there's quite a bit of steps. And I know many people are probably, you know, if you've never given blinatumomab are very overwhelmed. But honestly, when you do what I did in 2014 in my office and just started organizing all of this, right. Putting things into a policy, a procedure, a guideline. You are going to feel so much better. And actually, you're going to look at it and be like wow, this is not really that daunting at all. There are a lot of steps but there are so many team members that play a role that each individual's role is not as time consuming as you might think. Because there's just so many people that are helping with patients, so.

Andy Ostrenga: In the post hospital stay we've already touched on a lot of things. But this is where the patient continues on their journey outside of the hospital setting. So, these are at the outpatient clinic, maybe it's an infusion center, maybe it's at home. So, there are a lot of different options, which is a good thing for the patient, but also a lot of things you need to plan for.

So, travel distance back and forth as they're getting to come into the clinic. If they're getting it outpatient or in their home, well how do we get the drug to them? How do we get it mixed? Those are important things. Again, it's continue to track side effects, schedules, and keeping that line of communication is very important. So, you want to have a really good conversation. Have your social workers or case managers calling those home infusion companies, ensuring that patient is doing well.

Anthony Perissinotti: One of the things that our pharmacist will do is they'll write a note with the bag change plan so that the patient knows exactly when to expect a nurse to show up at their doorstep or when the patient needs to come to the infusion center. And obviously that note changes if anything changes.

But that's really helpful for our discharge planner. Our nurse, we have a couple of nurses that are involved. One is our inpatient nurse and they will help with PICC line care and access care. So they'll educate the patient on how to do that properly at home.

Our clinic nurse will educate the patient on the pump and how to use the pump. Who to call if there's any issues with the pump. Our clinic nurse will also call the patient about 24 to 48 hours after the patient was discharged just to touch base. See how things are going, see if they have questions. And obviously the patient can always reach out to us if they ever have questions as well.

Andy Ostrenga: Yeah. I think the really key to all this is like you said, is organization, early collaboration. You cannot work in silos and expect for this to happen. You can't, as a pharmacist just take care of your job as a pharmacist. You need to speak to the nurse, you need to speak to the oncologist, the discharge planner. All those things must be worked as a team to really be successful.

So again, this just goes over the Association of Community Cancer Centers. It's really outlines these considerations. So really what we talked about is really having a structured communication. Effective patient education. Again, you really need to speak to the patient and their family so they understand everything. And appropriate follow up, are really the key elements to optimal patient care.

Also, the clear instructions for the outpatient treatment regimen. The points of contact. That information is really important for follow up points, but really just the middle of the night call. Who do they call if the pump starts beeping or if they start feeling a little bit funny? It's really important to have those.

And then detail discharge information as well. So that really should be sent to providers in outpatient clinics like Anthony said. Those notes are very important to make sure everybody's on the same page.

Andy Ostrenga: Next, Anthony will take us over a patient case.

Anthony Perissinotti: Perfect. Yeah. We talked a lot of sort of from a very general view on those various sites of care, right? Prehospital, during the hospital, continuation, post. And it was quite general, so I want to actually look at this from a patient perspective. So, let's do a patient case.

So, we have a 60-year-old male with relapsed refractory B-cell ALL. He's in first relapse. This is a challenging patient to treat. He has a KMT2A rearrangement, formerly known as MLL.

Definitely a challenging patient from the cytogenetic perspective. And so, they're presenting now from a community center to your center for blinatumomab.

Some important social aspects. Social aspects are always important to look at. The patient lives alone. However, has a daughter that is close by, as their primary care giver. Other important points, he lives in a rural area. He's a 40-minute drive from a community hospital and obviously, he enjoys gardening and spending time with family, so we want to keep the patient out of the hospital for as long as possible.

Now, preadmission what we notice at our institution is that he lives six hours away from us. So, Andy, let's kind of talk through this. What are some barriers here, gaps that you might think can occur and how would you work through this scenario?

Andy Ostrenga: Yeah, so this distance and rural nature is something we're very familiar with in Mississippi. So, we may be the only academic center in the state. So, they may be traveling long distances. So, it's having that conversation early on of how do you think you can make it through this journey, this month-long infusion. And then after, is it coming back and forth, is it getting somewhere more convenient? So that's really important to us is having that conversation thereof.

Number one, where do you want it, but if you want it closer to home is there support for you?

So, we can utilize the seven-day bag. And this is going to be absolutely great, not only because he's six hours away, honestly even a 40-minute drive can be quite a lot, right. So, a seven-day bag is going to be fantastic for a patient who wants to be in his garden and hanging out with his family.

And so that's one of the considerations that we would do for this particular patient. Now, him being six hours away usually we try to treat the patient at our institution. So, we'll admit the patient. We'll help this center set them up with whatever needs that they have, whether it's trying to do prior auths, insurance approvals, helping them manage, you know, the initial CRS and monitoring for neurotoxicity.

And we will help them develop an entire plan of how to get the patient in and out of the hospital. Now being six hours away even with a seven bag, having to drive six hours is still quite a bit. So, one of the things that we would do instead having the patient come to our infusion center is to try to have our home health agency come out to this individual's house.

Now with six hours away our home health capture area is not even that far. And so likely wouldn't even use our own home health, what we would do is we would have our care manager start looking for home health agencies around that patient's community center or around that patient's house to hopefully, you know, allow nurses to come in and out of his house a little bit more easily.

So, some tips for y'all that there are multiple avenues. There's not always just one way of doing it. There are 20 different ways that you can do things that's best for the patient.

Andy Ostrenga: So, it's really having that plan and ensuring we understand what's going to happen. And if we need to think outside the box and look at other resource which we'll cover later, we need to know that ahead of time.

Anthony Perissinotti: Yeah. And then Andy will talk about Amgen 360 and some resources that Amgen has, but that's in scenarios where you're having issues. They certainly can help you with that.

So, let's get into some specifics of what you tell patients and their caregivers during the hospital stay to help them prepare for discharge. Andy, I'll throw that question back to you.

Andy Ostrenga: Yeah, like I said, we really sit down and explain the possible toxicities to look out for. So, the signs and symptoms of CRS, the signs of neurologic toxicity. So especially in pediatrics, that runs the gamut. So, if I have an infant, it's going to be a little bit harder for me to explain the neurological effects to the parents of what to look out for. They can't complain of headaches, they'll just cry because they're babies. So, it's really tailoring that conversation to the patient and what to look out for as far as toxicity, number one to the patient but also their care giver and then that way they can monitor whether at home or an outpatient infusion center as well.

Anthony Perissinotti: Fantastic. And again, I can't stress enough, and I think Andy really stressed this as well, is we need to be a team, we need to be a multidisciplinary team. We really need all hands on deck. And the process will be very seamless if everybody is doing their thing. If you got me as a pharmacist trying to figure out how to schedule appointments you would go nowhere. If you had the physician trying to do that you would go nowhere. We really need people that, their specialty is really put in the spot that we need them.

Anthony Perissinotti: And so, we talked quite a bit about the multidisciplinary team prior to discharge. And again, I would highly encourage, whether it's an email chain, or whatever's best at your institution.

So, one of the things that we actually do, and this is religious, 11:00 a.m. every single day we have discharge rounds. And all of these key players are there. It's not just for blinatumomab, it's for every single one of our patients. Because every patient that has acute leukemia is complex, and there are a lot of logistical considerations for these patients.

Anthony Perissinotti: And so, because of that we religiously have an 11:00 a.m. meeting with all these key players that Andy kind of outlined previously so that we can help facilitate the safest discharge for patients so that we're not forgetting things.

Anthony Perissinotti: All right. And then, you know, so what are some steps you may take to address this patient's concerns about their frequent visits. So, this is a patient that doesn't want to come in every two days. And we would definitely want to utilize a seven-day bag for as much as possible.

I'll show you some schedules in a bit that you can mix and match. Unfortunately, there are going to be some days where he is going to have to use a 48-hour bag. But Andy, I guess this is probably a bigger challenge for you for some of your infants and whatnot that you can't use your seven-day bags.

Andy Ostrenga: Yeah.

Anthony Perissinotti: Any words of advice?

Andy Ostrenga: No. So again, it's setting that expectation for the family so they know what to expect. But also trying to work with some smaller community hospitals that may be willing to do it. Now, a lot of times it's harder for pediatric patients. They don't want to touch a peds patient but especially our AYA patients that we can talk them into hey, you know, you're two hours away, you're on the coast of Mississippi, perhaps you can get a bag change there and not have to come up here a couple of times.

Or work with the home health company that we want to handle that as well.

Anthony Perissinotti: You hit the nail on the head and that's setting expectations for the patient.

Andy Ostrenga: Next, we go back to Anthony to talk about the infusion pumps.

Anthony Perissinotti: With regards to pumps, use what your nurses are comfortable with. That is by far the most important thing. So, if you're already using a pump, and the nurses are comfortable with that, there's no reason to recreate the wheel, okay. So, if your institution already knows that you have this pump available and, you know, you have enough in stock and you have your home health agency or your nurses that have the ability to answer phone calls and understand how to triage questions or answer questions for patients, that's by far the most important thing.

Anthony Perissinotti: All right. So BLINCYTO^® must be delivered at a constant flow rate using an infusion pump that is programmable, lockable, non-elastomeric and has an alarm. The infusion bags are admixed to infuse over, A) 24 hours, B) 48 hours, C) seven days or D) all of the above?

All right. And we got 100 percent so we successfully taught you that there is a 24-hour bag, a 48-hour bag and there is a seven-day bag.

Andy Ostrenga: All right. Next, we'll talk about the considerations for pharmacists, so this really focuses on the definite things as a pharmacist you need to be looking at during the treatment journey.

Andy Ostrenga: So, number one, preadmission. Make sure you have the correct equipment and also like we said order sets. Admission, this is the nuts and bolts. How do you mix it, how do you prepare it, how do you reconstitute it and then afterwards the equipment availability for outpatient administration as well as outpatient order sets.

Andy Ostrenga: So this information again is in your package insert, but we'll briefly go over what the contents are. So each box will contain one vial of BLINCYTO^®, the blinatumomab, and one vial of the IV solution stabilizer. So, this is not a solution to reconstitute. It's for the IV solution. So it's a 10 mL glass vial that you actually put in the bag prior to injecting the reconstituted BLINCYTO^®.

So again, we don't reconstitute with IVSS, we put it in the bag beforehand. This package should be refrigerated so kept between 2 and 8 Celsius. Do not freeze it and try to protect the vials from light as well until time of use.

Andy Ostrenga: So, this goes over supplies that you need, so we'll break it into those that are fixed dose and a BSA dose. So, if they're fixed dose you need one package, that preparation you get up to 28 micrograms per day for a 24 bag and 10 mLs and then two packages if you're actually going to do a 48-hour bag. If the patient is less than 45 kilo it depends on their weight and their BSA, but you'll either need one or two packages to make a 24- or 48-hour bag.

Other supplies you need are, you need to be able to make a 270 mL of normal saline IV bag. So, this is a combination of an empty bag, so a DEHP-free bag, as well as normal saline to inject into it. Preservative-free sterile water to reconstitute and then also a DEHP free IV tubing that's sterile and including of low protein binding filters. So those are all the supplies you need to gather up and get ready before you mix the BLINCYTO^®.

Andy Ostrenga: Supplies for a seven day bag are a little bit different.¹ The biggest difference here is the volume.¹ It also depends on the BSA, you’ll make a 110 mL bag so the volume of normal saline will be a little bit less.¹

But here you need bacteriostatic normal saline. That's the biggest difference that you need that bacteriostatic. And also, you do not have a filter in the tubing if you're doing a seven-day bag, that's the biggest difference as well. So, the bacteriostatic normal saline, as well as no filter are the biggest difference between just the number of vials.

Andy Ostrenga: This talks a little bit about the key considerations of the actual infusion rates and things. So again, this just really summarizes what I discussed here and the little nuances between the 24- and 48-hour bag, and the seven-day bag.

Andy Ostrenga: So, here's our next question. It says do not use IV solution stabilizer for reconstitution of BLINCYTO^®, A) true, B) false. Please make me proud here and select your answer.

Yes, we'll go with 100 percent. You heard me say it several times, do not reconstitute with solution stabilizer, that's important.

Next, we'll go back to Anthony to discuss the infusion flexibility.

Anthony Perissinotti: Yeah. So, this is essentially the schedule that I promised that I would show. And, you'll notice here it's essentially pick your own adventure, right. You have a 24-hour bag, 48-hour bag, 7-day bag and really you can mix and match depending on your patient's schedule and depending on what the day of the week is.

Now what would I recommend while the patient is inpatient is not to use a seven-day bag, just in case the patient has CRS and you have to hold it and then you have to throw it away.

Typically, what we'll use is a 24- or 48-hour bag for the first nine days. And then a 24- or 48-hour bag for the next two days. Once they get discharged that's when we'll use seven-day bags. And then ultimately, you're going to have to mix and match with a 48-hour bag and a 24-hour bag to get you to a completion of  a 28-day schedule.

So ultimately your goal is a 28-day schedule and you have flexibility with a variety of bags here.

And so just to kind of summarize the presentation here and I think the biggest take home message is that team work, team work, team work, team work makes the dream work. There are multiple key players, specialties that are working on this. What I would say is have one champion. One person that takes the lead that kind of herds all the cats together, have them be that role, but ultimately multiple people are going to play roles. And initially it can be relatively overwhelming but once you have all your policies, procedures and your work flow is all documented and everyone is ready to go, you're going to find that the process is actually quite seamless.

And when you do this, you're going to find that you're not recreating the wheel every single time you have a new blinatumomab, you're just going to look at your policy or your work flow and you're going to say oh, I know what I'm doing, fire off some emails, everybody have at it and the magic just happens.

VO: Let’s take a few minutes to review the Important Safety Information for BLINCYTO^®.

INDICATION AND IMPORTANT SAFETY INFORMATION
INDICATION
•   BLINCYTO^® (blinatumomab) is indicated for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adult and pediatric patients. •   BLINCYTO^® is indicated for the treatment of relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients.

IMPORTANT SAFETY INFORMATION
WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES •   Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO^®. Interrupt or discontinue BLINCYTO^® and treat with corticosteroids as recommended. •   Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO^®. Interrupt or discontinue BLINCYTO^® as recommended.

Contraindications
BLINCYTO^® is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

•   Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in 15% of patients with R/R ALL and in 7% of patients with MRD-positive ALL. The median time to onset of CRS is 2 days after the start of infusion and the median time to resolution of CRS was 5 days among cases that resolved. Closely monitor and advise patients to contact their healthcare professional for signs and symptoms of serious adverse events such as fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO^® overlap with those of infusion reactions, capillary leak syndrome, and hemophagocytic histiocytosis/macrophage activation syndrome. If severe CRS occurs, interrupt BLINCYTO^® until CRS resolves. Discontinue BLINCYTO^® permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS.

•   Neurological Toxicities: Approximately 65 percent of patients receiving BLINCYTO^® in clinical trials experienced neurological toxicities. The median time to the first event was within the first 2 weeks of BLINCYTO^® treatment and the majority of events resolved. The most common (greater than or equal to 10 percent) manifestations of neurological toxicity were headache and tremor. Severe, life-threatening, or fatal neurological toxicities occurred in approximately 13 percent of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO^® as outlined in the PI.

Infections: Approximately 25 percent of patients receiving BLINCYTO^® in clinical trials experienced serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO^® as needed.

•   Tumor Lysis Syndrome (TLS), which may be life-threatening or fatal, has been observed. Preventative  measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO^® treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO^® as needed to manage these events. •   Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO^® infusion and interrupt BLINCYTO^® if prolonged neutropenia occurs. •   Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO^® are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO^® is being administered. •   Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO^® treatment with a median time to onset of 3 days. In patients receiving BLINCYTO^®, although the majority of these events were observed in the setting of CRS, some cases of elevated liver enzymes were observed outside the setting of CRS, with a median time to onset of 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7 percent of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1 percent of patients. Monitor ALT, AST, gamma-glutamyl transferase, and TBILI prior to the start of and during BLINCYTO^® treatment. BLINCYTO^® treatment should be interrupted if transaminases rise to greater than 5 times the upper limit of normal (ULN) or if TBILI rises to greater than 3 times ULN. •   Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO^® in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO^® and dexamethasone as needed. •   Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO^®, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy. •   Preparation and administration errors have occurred with BLINCYTO^® treatment. Follow instructions for preparation (including admixing) and administer in the PI strictly to minimize medication errors (including underdose and overdose). •   Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO^® treatment, during treatment, and until immune recovery following last cycle of BLINCYTO^®. •   Benzyl Alcohol Toxicity in Neonates: Serious adverse reactions, including fatal reactions and the “gasping syndrome,” have been reported in very low birth weight (VLBW) neonates born weighing less than 1500 g, and early preterm neonates (infants born less than 34 weeks gestational age) who received intravenous drugs containing benzyl alcohol as a preservative. Early preterm VLBW neonates may be more likely to develop these reactions, because they may be less able to metabolize benzyl alcohol. Use the preservative-free preparations of BLINCYTO^® where possible in neonates. When prescribing BLINCYTO^® (with preservative) for neonatal patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO^® (with preservative), other products containing benzyl alcohol or other excipients (e.g., ethanol, propylene glycol) which compete with benzyl alcohol for the same metabolic pathway. Monitor neonatal patients receiving BLINCYTO^® (with preservative) for new or worsening metabolic acidosis. The minimum amount of benzyl alcohol at which serious adverse reactions may occur in neonates is not known. The BLINCYTO^® 7-Day bag (with preservative) contains 7.4mg of benzyl alcohol per mL •   Embryo-Fetal Toxicity: Based on its mechanism of action, BLINCYTO^® may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with BLINCYTO^® and for 48 hours after the last dose.
Adverse Reactions
•   The most common adverse reactions (≥ 20%) are pyrexia, infusion-related reactions, infections (pathogen unspecified), headache, neutropenia, anemia, and thrombocytopenia.
Dosage and Administration Guidelines
•   BLINCYTO^® is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non‐elastomeric, and have an alarm. •   It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).

Please see BLINCYTO® full Prescribing Information, including BOXED WARNINGS, at www.BLINCYTOhcp.com.

Anthony Perissinotti: So Andy, we have some really great questions and I'll pose the first one to you. So, for inpatient administration if you're making multiple bags at the same time, what logistics do you have to work through to educate the IV room? For example do you print all your labels at once?

Andy Ostrenga: We’ll batch individually so we push one through at a time when it comes to BLINCYTO^®. Again, luckily our institution is not huge that we don't have this happen very often. But we much prefer to start one, end one, instead of doing them all at the same time.

Anthony Perissinotti: Okay. Yeah, I mean we do something very similar as well. Second question is, what is the lower and upper age limits for this treatment? You know, when you look at the studies, the youngest patients treated were about ten infants. One of them was one month of age, so I think, Andy, have you treated anyone, you know, that young or even younger than one month?

Andy Ostrenga: No. Not personally, no.

Anthony Perissinotti: Yeah, so I mean one month is…

Andy Ostrenga: That's pretty quick to be relapse or refractory.

Anthony Perissinotti: Yeah, so that patient was included in the trial so. And then, as far as upper age limits in the studies it's a small proportion as you get older, right, 65, 70-year-olds, 75-year-olds.

Another question that we had was do you have to use a particular pump? And the answer to that is no. Again, like I said, use what your nurses are comfortable with. There are specific criteria that are listed inside of the blinatumomab package inserts, and essentially what they say is, you know, use a pump that can run at a constant flow rate, that is programmable, that's lockable, that's non-elastomeric and that it has an alarm. So, with that criteria, you know, use whatever manufacturer again that your nurses are comfortable with. And I'm sure you're giving many other chemotherapies via continuous infusion in your infusion center that you're already using a pump.

Fantastic. And with that I want to thank everybody who took the time out of their day. We understand how busy things are right now. So, thank you very much, hopefully we taught you a few things. And this presentation should be available for you if you need to kind of go back. So, thank you very much again. Have a good evening, everyone.

Andy Ostrenga: Thank you.