FDA-Approved Rytelo a ‘Game Changer’ for Some Patients with MDS

The approval by the Food and Drug Administration of Rytelo (imetelstat) for the treatment of some patients with myelodysplastic syndromes (MDS) could mark a significant improvement in the quality of life for those patients with MDS who are dependent on blood transfusions, an expert said.

“Half the people who responded to [Rytelo] actually went a whole year without needing a transfusion. I think that for that group, it's a game-changer,” said Dr. Mikkael A. Sekeres, chief of the division of hematology for the Sylvester Comprehensive Cancer Center, part of UHealth, University of Miami Health System, in an interview.

The FDA approved Rytelo to treat adults with low- to intermediate-1 risk MDS with transfusion-dependent anemia, requiring four or more red blood cell units over eight weeks who did not respond to, have lost response to or are ineligible for erythropoiesis (red blood cell)-stimulating agents (ESAs).

The approval of Rytelo was based on results of the phase 3 IMerge trial, which included Sekeres among its researchers. The trial enrolled 178 patients with MDS who received intravenous infusions of Rytelo or placebo in 28-day treatment cycles until they experienced disease progression or unacceptable toxicity.

“Typically, a patient [with MDS] who develops anemia is treated with an [ESA] — and that, on average, works somewhere between 25% and 40% of the time, and the amount of time it usually works on average is about a year,” Sekeres noted. “So, it's a limited-term solution for something that plagues people with lower-risk MDS. … After [ESA] fail patients, then if they have ring sideroblasts [an iron-rich immature red blood cell], they can try [Reblozyl (luspatercept)], which also was recently approved both in their setting after ESAs and also as upfront therapy. It works particularly well in patients with ring sideroblasts, not any better than ESAs in patients who don't have ring sideroblasts. And again, that's a limited-term option. In patients who've already been exposed to ESA is [Reblozyl] works for about, on average, 31 weeks, and then it stops working.

“So, what do you turn to? And for these folks, we often pivot to low-dose chemotherapy in the form of hypomethylating agents. Well, now we have a drug we can turn to that works pretty well, has manageable side effects and when it works and tends to work for a decent amount of time.”

Sekeres discussed how Rytelo works, its benefits for patients and the unmet needs that persist.

CURE®: Can you explain the science behind this drug?

Sekeres: This is a new class of drugs that's known as telomerase inhibitors. And it has to do with how the cell copies all of its genetic material to make a new cell. Remember, MDS is a type of cancer. So, the cells are constantly growing and dividing and making copies of themselves. So, if we can give a drug that interferes with their ability to copy themselves, then we've crippled the ability of the cancer to continue growing and dividing. So that's how these drugs work. And it represents a totally new approach to therapy in MDS.

What exactly does it mean when a patient has low- to immediate-1 risk MDS?

In general, we divide the severity of MDS into two major branches. Patients either have a lower-risk MDS, or higher-risk myelodysplastic syndromes. With higher-risk MDS, they're at an increased risk of developing acute myeloid leukemia, of their disease worsening to the point where they have leukemia. Folks who have higher-risk MDS have an average survival that's often less than a year and a half. So it's a very serious diagnosis, and we tend to treat it very quickly.

With lower-risk MDS, our focus is on improving transfusion needs and improving the patient's quality of life. People will live for years with a lower-risk MDS, so, it's less urgent than higher-risk MDS. Our approach is to really make people's lives better. No drug that's been approved to treat lower-risk MDS has ever been shown in a randomized prospective trial to improve overall survival.

What does red blood cell transfusion independence mean?

To be eligible for the trial, a patient had to have a disease that required red blood cell transfusions regularly. In other words, somebody had MDS that caused profound anemia to the point where they needed blood transfusions just to survive. And typically, blood transfusion dependent is defined as somebody who needs two bags of blood in an eight-week period. So, these folks started the study requiring at least two bags of blood every eight weeks. So, imagine about a bag of blood a month. Actually, if you look at the average patient on this study, they needed at least four bags of blood over an eight-week period. So they were getting a bag of blood essentially every two weeks.

The success rate of [Rytelo] was defined as somebody who then became transfusion independent for at least an eight-week period of time. In other words, they started the study needing at least two bags of blood every eight weeks. If [Rytelo] worked, they no longer needed any blood transfusions for at least an eight-week period of time.

That's, for some folks, needing a bag of blood every other week.

Yeah, imagine what kind of time investment that involves. The typical person with MDS is in his or her 70s, that person has to wake up in the morning, get into the car, drive to the cancer center, park, walk to have their labs drawn to determine whether or not they need a transfusion that day, meet with a doctor, then go to an infusion center and sit there for at least a couple of hours while they get a bag of blood. So you're talking about a period of time that may take an entire day just to get a blood transfusion. And they're doing that every two weeks. So having the drug that eliminates that investment in time and effort is a big deal.

In terms of patient quality of life, and how you spend your day, how you spend your week, this is huge. This sounds like a game changer for a lot of these folks.

For 40% of these folks [Rytelo] was able to give them at least an eight-week break in those transfusions. Now, you may reflect back to me, “Gee, is it really worth coming in for an injection of a drug every four weeks to get one two-month period without transfusions?” and I would argue probably not. For something that's truly valuable to patients, I think they need to go at least at least 16 weeks without a transfusion, about four months, or ideally even six months without a transfusion.

So, 40% of patients who got [Rytelo] went at least eight weeks without a transfusion. And then if you focus instead on that 16-week period, it's about 31% of patients. And then the 24-week period, so almost six months, it's 28% of patients. So in general, we can say between one quarter and four out of 10 patients respond to [Rytelo]. And if somebody does respond, if they get this period of time without a transfusion, on average, that period of time lasts actually about a year.

Now that this option’s on the table, what unmet needs remain for this patient population?

We don't have enough tools in our toolbox. And we now have another tool, but I still need more tools in my toolbox. So for somebody who has anemia with myelodysplastic syndrome, [they] might try an erythropoiesis-stimulating agent, [they] might try [Reblozyl] now I can try [Rytelo]. For patients who have a deletion 5Q mutation, [they] can try [Revlimid (lenalidomide)]. That's it. Then [they’re] turning to low-dose chemotherapy. ... So we're still looking for other drugs we can use to treat anemia in lower-risk MDS and extend the periods of time — by using one drug after the next after the next — that patients go without needing a blood transfusion.

What is the side effect profile of this drug?

The biggest side effects with [Rytelo] and the ones that really kind of emerged in the FDA report were that it can cause cytopenias (lower levels of blood cells) in other bloodlines. So while it improves anemia and transfusion needs, in four out of 10 patients who are treated with the drug, it can make the platelets go lower and make the white blood cells go lower. So, patients have to be monitored for those drops in blood counts, and occasionally it could cause things like liver abnormalities, or joint aches. So, again, patients need to be monitored for the side effects; we can always do reduce the dose of the drug, spread out how often it's given, there are ways to mitigate that.

Transcript has been edited for clarity and conciseness.

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