As the landscape in acute myelogenous leukemia changes, consultations with top-tier experts have become a necessity, said John Byrd, the principal investigator of Beat AML, Distinguished University Professor, the D. Warren Brown Professor of Leukemia Research at The Ohio State University, a member of the NCI Leukemia Steering Committee, chair of the Leukemia and Correlative Science Committee within the Alliance for Clinical Trials in Oncology.
“Even as somebody who does this every day, physicians really have to be on their feet with emerging data that’s coming forth,” Byrd said. “But I think it’s becoming more and more necessary, as treatment decisions are made, to consult with an expert who really deals in that disease, because it is complicated, and things are moving, particularly when you get beyond first-line therapy. It’s a team effort.
“Local hospitals and hematologists in the community might treat this disease, particularly in the elderly, but it’s probably best getting help from somebody that focuses in AML, say, on a daily basis.”
Byrd spoke with Paul Goldberg, editor and publisher of The Cancer Letter.
Paul Goldberg: AML used to be a quiet little corner of medicine. What happened?
John Byrd: I know. It’s amazing—after probably 40 years of the same therapy being used in this disease.
It’s a pretty common theme—people in their 50s and 60s saying, “Well, I treat AML the same way that I did when I was a fellow.”
We’ve seen all of the investment that Congress and the taxpayers and philanthropic groups, such as The Leukemia & Lymphoma Society, have invested in basic science research of leukemia, to understand its pathogenesis.
That has led to a disease that was treated at one time just with one therapy, 7+3 chemotherapy and transplant, to one where we have a burgeoning number of targeted therapies—and where we recognize it’s probably not one disease, but 12 or 15 diseases.
We’re talking about a lot of drugs in the pipeline, and a lot of drugs approved—three in the frontline, two in refractory. How many are in the pipeline?
JB: There are many. I don’t have the exact number of clinical trials and targets, but as I said, Paul, there are probably at least 15 and probably more subtypes of AML.
Some will be able to be treated the same way, but many will have different paths that ultimately lead to a targeted therapy.
For some, targeted therapy may not be the path; it may be immunotherapy. But I think, really, what’s going to limit us in our exploitation of the science of AML now is the ability to get sufficient patients on clinical trials to ultimately isolate these small groups of patients, such as the one with the IDH1 and IDH2 mutations that respond really well to targeted therapy.
Do physicians now know which drug to use when? Is that a problem yet?
JB: Yeah. It’s very similar to CML. I also work in CML, and the AML field is becoming very similar in that the field is moving so quickly, and you have a whole set of physicians who trained before the genomic era.
And even as somebody who does this every day, physicians really have to be on their feet with emerging data that’s coming forth. In general, I would say yes, because the U.S. breeds a very confident group of hematologists and oncologists that keep up with the field.
But I think it’s becoming more and more necessary, as treatment decisions are made, to consult with an expert who really deals in that disease, because it is complicated, and things are moving, particularly when you get beyond first-line therapy. It’s a team effort.
Local hospitals and hematologists in the community might treat this disease, particularly in the elderly, but it’s probably best getting help from somebody that focuses in AML, say, on a daily basis.
So, one shouldn’t go to a garden variety oncologist with AML; one should go to someone like you?
JB: Right. Or to a specialist who works predominately in leukemia.
What’s the rationale and the ultimate goal of your trial, Beat AML? In terms of design, how is it distinct from, say, NCI-MATCH?
JB: The Beat AML study is distinct from MATCH in a couple of ways. It is an umbrella study that encompasses untreated AML right now over the age of 60, although we’re broadening to under the age of 60 to select genetic groups, and it builds upon several things that are different than MATCH.
AML is different than most solid tumors. With the majority of solid tumors you can wait a couple weeks to get your results back to decide on therapy. AML tends to move quicker.
A big part of the initial study was, can we actually assign genomic cytogenetic, biochemical therapy within seven days, because that’s probably the time period you need to do it. We move much quicker to assigning therapy.
Say, we’re really focusing on the hypothesis that AML starts with, a trunk lesion or a primary mutation, and so we’re going after the dominant clone with our targeted therapy.
Another difference between our study and MATCH is that it encompasses all patients. We have our targeted arms, but then patients who are marker-negative, in other words, who don’t have a genomic marker that we target, still include an arm for that group.
We call it the marker-negative group. It’s not exactly marker-negative, but it has a marker that we don’t have an agent for right now. Everybody that goes on our study knows that they are going to get access to a new and exciting approach.
The other thing that we are doing in our trial—and we are moving toward right now—is doing novel-novel combinations, because AML and most cancers are not going to be cured with one therapy. It’s going to be a targeted approach.
We are moving to giving several targeted drugs together, to build upon synergy and really try to get away from chemotherapy when it’s appropriate—when chemotherapy isn’t curative.
How many arms does Beat AML have now?
JB: There are 11 treatment groups, and we have seven pharmaceutical sponsors. Since the study opened in November of 2016, and as of yesterday, I believe we’re up to 332 patients enrolled.
The study has gone well thus far. It’s a multi-center study, which with one presupposition, and the presup that has allowed to move along the quickest is that in our initial bylaws, the principles we put together, the Number One bylaw is: If you want to participate you can’t care about credit.
It’s been an effort of a lot of centers, of The Leukemia & Lymphoma Society, a lot of different organizations rolling up their sleeves, doing the work, and moving it along quickly.
It’s run like a pharmaceutical company trial, not a cooperative group study, in the sense that we have monitoring. We have a CRO—all the data is being collected with the intent that if a study is positive, it can be filed as an NDA.
It’s looking for big differences. We aren’t looking for small differences, we’re looking for big responses in these small groups, with the decision to move forward with therapy or not.
So, this could be, in principle, a whole series of registration trials, right? Eventually?
JB: That’s correct.
But just to delineate that the most recent approval, the Agios [IDH1] drug; do you have it in one of the arms?
JB: Yes, we do.
But their registration study was not your study?
JB: No, that registration study was done in relapsed disease. And, Paul, as I said, our study only is looking at upfront disease, and in patients who have not had prior therapy.
We do have an arm where we’re testing new combinations, where we need to look at the safety before moving forward to untreated patients, where they could be previously treated.
But really, as a team we believe that targeted therapy will probably have a modest effect—with very, very good drugs—in the relapsed setting.
Because in most cases of AML, by the time patients have relapsed, particularly when they’ve received chemotherapy, it’s very likely that you have seven or eight diseases.
The clonal evolution as the disease moves on makes it, probably, many diseases within a patient, and targeted therapy there is not going to work.
But with the IDH1 and IDH2—they’re moving towards front-line, does Beat AML play a role in that, or will it? Does it need to?
JB: Yes, Beat AML has a study with both the IDH1 and IDH2 inhibitor. The IDH2 inhibitor that Celgene is marketing was one of our first studies, and has accrued well.
And we have a trial with the [Agios] IDH1 inhibitor that was just approved in the upfront setting. Our study is different from a typical registration study. For instance, the study that recently got midostaurin approved had to enroll hundreds of patients and went over the span of eight years.
Our study is single-arm, and we are looking either at monotherapy or combinations of these targeted drugs. The big difference is, hopefully, the FDA and regulatory agencies where you see big differences in safety data, will consider these for upfront registration.
Why did you go with LLS sponsorship as opposed to NCI?
JB: The full scope of the Beat AML Master Trial will be at least $55 million, which includes funding from pharmaceutical companies and private donors.
And that’s come from organizations like The Harry F. Mangurian Foundation, that have contributed dollars, from patient donors, from others, including the pharmaceutical companies and institutions that are participating.
This is run similar to the cost of a pharmaceutical company, but they very much are partners in trying to help underwrite a cost, but the cost is considerably more [than a cooperative group trial], because you’re doing it for registration intent, which is somewhat different than the NCI studies.
So, that’s sort of how the funding is handled.
While I’m a professor of Ohio State, I’m also the chief medical officer of the study, and I work with the Leukemia & Lymphoma Society.
The society is an honest broker. They can bring together the different companies, the FDA, the institutions, and really we’re a patient-focused organization.
And while the NCI has supported a lot of the research, we interact with the NCI, and hopefully our study is going to inform some of the NCI studies. By doing it this way, the opportunity just arose to move this very quickly.
And that’s an incredibly important part of drug development, as you know, Paul—to be able to move quickly. We’re a very nimble team. We’re using a lot of novel technologies, such as Protocol First, myClin, and other platforms that minimizes the need for detailed on-site monitoring. And by doing that, and being very nimble, as you would be with any patient-focused organization is going to be, we’re able to do it at less cost and quicker.
That’s fascinating. But a massive amount of planning must have gone into designing this thing. Who was at the table? How did you put it all together?
JB: It started in 2014, when The Leukemia & Lymphoma Society looked at what they were investing their research dollars in, and they saw that about a third or more of their research budget was going to AML, yet that was the only disease where in the past decade their research dollars had not led to something being approved.
They met with the FDA to talk about the concept of this, and there was discussion that the NCI was doing this at the same time. And they brought together experts in the fall of that year.
Brian Druker [director, Knight Cancer Institute at Oregon Health & Science University and JELD-WEN Chair of Leukemia Research], who led the development of Gleevec, was there. I was there as somebody that has been very involved in ibrutinib, and acalabrutinib, and Ross Levine had done a lot of the work with Jakafi in myeloproliferative disorders.
They had people that had done drug development successfully and other diseases, as well as AML.
There were two sessions including a session at ASH. After this ASH session—Brian Druker called me, and we came to the conclusion that, well, let’s get a small group of us together—and we agreed.
I do drug development, and Brian is a big-thinker and a big leader, and also is a kinase person. And we decided to bring Ross Levine [Laurence Joseph Dineen Chair in Leukemia Research; director, MSK Center for Hematologic Malignancies] who did genomics, and we started having weekly telephone conferences, often on Sunday, because that’s when our schedules would allow.
We put together this document that we talked about and presented it to The Leukemia & Lymphoma Society. Amy Burd [LLS vice president, research strategy] started getting on our calls. And it really sort of started off that way, and we worked through a document, a vision statement, and went and met with the FDA. And the FDA loved the concept of this type of a trial.
At that point, you asked about the NCI, they asked us, well … the NCI has been talking about that, and we all decided at that point that if we got to the end, and we were ready to start our study and the NCI had a trial like this going, because they were talking about it, that we would stop ours, because we didn’t want something to be redundant.
In the spring of that year, after meeting with the FDA, we identified a genomic sequencing organization that ended up being Foundation Medicine, and met at ASCO with about 40 companies, and presented the idea to the companies, and several of them were interested.
After that, we identified a CRO that would partner with us, and some of these model technologies that I was mentioning, such as Protocol First. And we moved forward to write the trial.
The IND opened in the late summer of 2016.
Because we’re treating patients with AML in the untreated setting, we had to really nail down our diagnostic– that delayed us a little bit. This trial actually opened in November of 2016.
It’s phenomenal how it started. If you’d have asked me in November of 2016 if we’d be at this point on, say July 25, 2018, with well over 300 patients on study and things really cranking, I would have said, “I don’t know.”
But again, coming back to what we said, everything has moved in this trial quickly, because of that presup that if you want to be part of this trial, you can’t care about credit.
The only people that can care about credit, we’ve decided, are the junior investigators that are leading the different arms of the trials, because they need to get publications for when the study’s done for their promotion.
That’s sort of a neat thing about this study as well: the studies are led by junior to mid-level investigators at the different sites. We’re facilitating clinical investigations for these individuals. So, it’s been a lot of fun.
What’s really interesting is there are so many pieces of it that it’s easy to lose sight of something gigantic, which is a new endpoint that the FDA is recognizing here for full approval. They’ve just approved two drugs based on single arm trials, and they gave full approval based on reducing the need for transfusions. Is it something that they designed in cooperation with you?
JB: I think the FDA has been a great partner in our trial. And for our trial we’ve had incredible dialog and input from them. But I think Brian Druker’s my hero, but also, I would say Rick Pazdur [director of the FDA Oncology Center of Excellence] is one of my big heroes.
I think that the FDA has really adopted an approach with new medicines, that if it really makes a big difference for patients … And the transfusion endpoint—that is a big difference, and they look at everything.
Still, if you have a drug that causes a lot of side effects, the answer to that would probably be no.
This may sound disrespectful to statisticians, but I think drugs where you can really see clinical benefits where there’s an acceptable safety, that you don’t really need a statistician even to tell that you have a winner are what we are all looking for.
I’m sure that in our study, if we get to the point of talking to them about a registration, their comments would be, “Well, we want to see the data.”
With Agios and other companies, they’ve shown that they’re very open to new ideas for medicines that are going to help patients. It’s refreshing to see that this approach is moving to AML.
We saw the same thing with ibrutinib, where they approved ibrutinib in CLL where just on a phase II study. By approving it on a single-arm before the phase III studies were done, probably thousands of patients are alive today that wouldn’t have been alive.
Again, the medical officers in the FDA are physicians, and they’re really looking at the data in an open way. It’s very facilitatory to patients.
I don’t know of another area in medicine where a single trial might actually inform the entire future development; has that ever happened before?
JB: Lung cancer is probably the other disease. But, as I said before, I think what’s sort of unique as AML is not common; there are only 20,000 cases a year. I think that this study, Beat AML, is the first umbrella study run by a charitable organization, a patient-focused organization.
What will the world look like five years from now in AML?
JB: All of us hope there are a good number of young patients that are going to still be getting 7+3 chemotherapy maybe, with one of the new drugs—because that cures them.
In the patients over the age of 60 and a small subset of the younger patients, Paul, what I hope that five years from now, that we will have moved away from chemotherapy and be using targeted or non-chemotherapy drugs to get AML patients into remission.
Hopefully, when chemotherapy is not essential to cure, we will be moving away from that to a more precision medicine-based treatment approach.
And then a neat part of our trial is that all of us acknowledge that allogeneic stem-cell transplant is still curative for these patients. So, when we have an older patient, there’s nothing more gratifying than being able to get them into complete remission with their targeted therapy.
With an outpatient, in some cases, it’s just a pill, and not being in the hospital for months at a time with toxicities from chemotherapy. And then, getting them onto transplant, if they’re a candidate for that.
And a hot area that we’re really excited about, too, is after patients get this, is if they have still a small degree of evidence of their disease after transplant, is continuing targeted therapy after transplant.
And so, that’s where I see things going. Hopefully, when chemotherapy is not essential to cure, we will be moving away from that to a more precision medicine-based treatment approach.
Is there anything we’ve missed? Anything I didn’t ask that I should have?
JB: No. I think we’ve covered things. The only thing I would say is that Dr. Lou DeGennaro who is the CEO of The Leukemia & Lymphoma Society, and their board, the leadership at the founding institutions (The Ohio State University, Memorial Sloan Kettering, Oregon Health Sciences University) and everybody, how they stuck out their neck to do this, and believe in this approach.
I think that really set us up for a chance that we’ll get to impact AML in a different way. I know from the patients, the investigators, everybody that’s been involved in that, we’re just really appreciative of that.
