Oncology Data Advisor: Welcome to the Oncology Data Advisor Fellows Forum, I'm Keira Smith. Today I'm joined by Dr. Sunil Iyer, who is a Chief Hematology/Oncology Fellow at the University of Miami. Dr. Iyer, thank you so much for coming on today.

Sunil Iyer, MD: Hi everyone. It's an honor to be here. I'm Sunil Iyer. I'm a third-year Hematology/Oncology Fellow, current Chief Fellow for the next month and a half, at the University of Miami Sylvester Comprehensive Cancer Center in Miami, Florida. I grew up in the Midwest from Columbus, Ohio. Came down to Miami for medical school. I think it was about -20 degrees when I took off and 75 degrees when I landed. So, I think I made a good decision. I'm personally interested in leukemia, so acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndromes. And I'll actually be joining the faculty at Columbia University, the Leukemia Disease Team, in August of this year.

Oncology Data Advisor: Awesome, and congrats.

Dr. Iyer: Thank you.

Oncology Data Advisor: So, what are the particular areas of leukemia research that you focus on?

Dr. Iyer: One thing I've really noticed working down here in Miami is that there are a lot of patients with a disease called ALL, acute lymphoblastic leukemia, and this is the most common malignancy of childhood. And so, the majority of cases, maybe 60% to 70% of cases, occur in children, so those under 20, and maybe 30% to 40% of cases occur in adults. We noticed here in Miami—a lot of my colleagues come from the Midwest or the Northeast—there are a lot more cases of adult ALL than expected, and it kind of got some of us to read the literature from other countries. It looks like in several Latin American countries, the incidence of this disease is much higher than what's previously reported in the US or in Europe. A lot of these patients are younger adults as well, in their 20s or 30s.

So, as a medical student, I met a lot of these patients; I really bonded with them. A lot of them were about the same age as me. So, I've had this motivation to figure out why this happens and what we can do about it. We also find that the disease is of higher-risk when it comes to their cytogenetics or molecular mutations. When you think about ALL, we kind of divide it into two major categories, Philadelphia-positive or Philadelphia-negative. What that means is that the disease is either driven by the Philadelphia chromosome, which you also see implicated in chronic myeloid leukemia, and that's something we can target very well with modern therapies. So, that went from being a really terrible, pretty much incurable disease to something we can cure in the majority of cases. Or you have Philadelphia-negative disease, which is not driven by this chromosome.

Well, in the Latino population, we find an increased incidence of something called Philadelphia-like ALL. What that means is it has all the badness of Philadelphia-positive, but it doesn't have that Achilles heel that you can target. So, we find that this is much more common in the Latino population. It's unfortunately harder to treat, harder to put into remission and more prone to relapse. One of the major projects I'm working on with Dr. Alvaro Alencar, who specializes more in lymphoma, but he does see ALL as well, is that we have a project which we call GALLEON: Genomic Analysis in Latins with Lymphoid Neoplasia. And what we aim to do is, every new patient who comes to the University of Miami with the diagnosis of B-cell ALL, we do a buccal swab, meaning we take a saliva sample, and do whole genome sequencing. We could actually do this here on campus at the University of Miami. And we also take a bone marrow aspirate sample, and we send that to the Charles Mulligan lab at St. Jude's Children's Hospital. That's actually the group that first discovered Philadelphia-like ALL about 10 years ago. So, he's able to do very sensitive testing in his lab that we don't really have anywhere else, it's proprietary testing, that may pick up cases of Philadelphia-like that we or most centers cannot pick up with standard fluorescence in situ hybridization (FISH) testing. And what we do on our end with the genomic testing is trying to see if there are any mutations that are germline—meaning inherited from parents—that may correlate with higher-risk disease, whether that's Philadelphia-like or just disease that tends to be harder to put into remission or keep in remission. We hope to clarify this. The endgame, I think—which will take several years—is to figure out if we can identify higher-risk patients from the beginning, and maybe we can allocate those patients to get earlier immunotherapy, or earlier stem cell transplant, and cure more of these patients.

And I think really, the endgame would be to develop clinical trials and figure out which patients would be good candidates for these trials to optimize their chance of cure. That's my main project that I hope to take up to Columbia University, and we actually hope to open in many centers because the Latino population's very heterogeneous. The Latino population in Miami is more of Cuban descent than any other descent, whereas in New York you have more of a Dominican and Puerto Rican population, and in Los Angeles over 70% of Latino populations are of Mexican origin. So, everyone has very different backgrounds, and it'll be great to not just get Latino patients, but everyone to really figure out what inherited germline features may portend the risk of high-risk ALL.

Oncology Data Advisor: Awesome. That's definitely such important research, and it'll be exciting to see where it all goes. So, with all the recent changes you mentioned, I know there are a lot of advances in immunotherapy as well as chemotherapy-free approaches. Would you like to describe some of these?

Dr. Iyer: Sure. So, as I mentioned, acute lymphoblastic leukemia is more of a disease in children than adults. Back in the 50s and 60s, unfortunately, the majority of children could not be cured. Now the cure rate approaches 90% or higher in some subtypes. So, we know how to treat this disease, but the problem is that this therapy is very difficult for adult patients. Some of the medications have a lot more side effects, not just the chemotherapy, but pegaspargase, some other treatments that can be well tolerated in children, but we kind of shudder at the thought of giving it to someone older than 40 or 45 because the rate of side effects is so high. What we're trying to figure out in adults is how to optimally treat these patients with something less toxic than standard chemotherapy that can be equally effective. So, we've been using the anti-CD-20 antibody rituximab for many years now, which can improve survival in adults with B-cell ALL.

But there are other immunotherapies such as blinatumomab. So, this is an antibody basically with two arms. It's a bispecific T-cell engager. What that means is with one arm, it grabs onto T-cells in your immune system and with its other hand, it grabs onto the cancer cells, the B lymphoblasts, and it brings them together and creates an immune response. And this therapy has very high rates of inducing remission, and it's currently approved for adults with relapsed or refractory B-cell ALL. So, one really exciting development is that this is being studied upfront in patients who do not really have any signs of refractory disease, meaning they get the chemotherapy, and the bone marrow appears to be well treated. Well, we wonder if you add this immunotherapy upfront, is it possible that you're taking out some of these bad cancer cells that we're not able to detect, some of these cancer cells that may lead to relapse? And data that was recently presented at ASH, the American Society of Hematology meeting, last year, did show that we have improved survival and reduced relapse.

So, unfortunately, based on that one study, it's not enough to get this therapy approved in this setting, but I think it's spurring bigger multi-center trials. It'll be tough to get this past insurance at this point—perhaps for high-risk disease we can make a case for it—but I think that once this really is shown to be beneficial, we can reduce the amount of chemotherapy we give people and reduce the risk of infection, of heart disease cardiomyopathy from chemo. And we can introduce these immunotherapies which are generally well tolerated.

What's even more exciting at this time is the treatment of Philadelphia chromosome–positive ALL. So we know we used to treat this with chemotherapy only and it would relapse a lot more than Philadelphia-negative disease. We know that we can use these targeted therapies, the same ones we use in chronic myeloid leukemia such as imatinib, dasatinib, ponatinib—these oral pills that are also generally well tolerated. And we know that when we give this to these patients with Philadelphia-positive ALL, these pills do a lot of the heavy lifting. So, it made us wonder, in older patients—60s, 70s, 80s—can we reduce the amount of chemotherapy? And we found that we could. We can still induce remission by using these pills with less chemotherapy.

Now the question is, can we forego chemotherapy entirely? So, some really exciting research, the D-ALBA trial, which came out of Italy within the past couple years, show that you can induce patients with B-cell ALL using pills such as dasatinib or ponatinib combined with this blinatumomab immunotherapy that I described without systemic intravenous infusion (IV) chemotherapy. And you get really high rates of remission—remission that lasts a long time. Potentially, you don't even need to transplant these patients. They may be cured with this therapy alone. So, I think that's extremely exciting that now our patients who are 70 and 80, who are not great candidates for intensive chemotherapy, have a real shot at cure.

Oncology Data Advisor: Great. Those are such exciting new treatment directions. You touched on genomics and how this can be used to help detect and treat patients with higher-risk disease. Would you like to share more about this?

Dr. Iyer: Sure. So, we know that in certain countries—in certain Latin American countries—where more indigenous genotype prevails, meaning if you go to Cuba, for example, and you do a genomic analysis of people, you'll see a large amount of DNA that originates from Spain or Western Europe. Whereas if you go to other countries, specifically Guatemala and Peru have been tested, there's been a higher percentage of DNA that comes from indigenous American ancestry. And we found that in these nations with more indigenous DNA, there is a higher risk of ALL and a high risk of high-risk ALL. So we've been trying to study what genes may be responsible. There's a gene called GATA3, which is involved in the maturing of lymphocytes, and we found that there are certain germline mutations, meaning inherited from parent to child, that can cause problems, that can cause leukemogenesis, and we notice this in children and adults.

So, what we hope to gain from our studies is to figure out there must be other genes that we don't know about. So, if we can find patients with a new diagnosis and we can do genomic sequencing on them, we may be able to identify, oh, you have this mutation in GATA3 or Ikaros zinc finger or some other gene. And we know that this tends to correlate with very high-risk behavior, so we can go ahead and do a consultation with their stem cell transplant team earlier. And if we can get you into remission earlier, we know, hey, for people like you, statistically the best shot of cure is to go for transplant as soon as possible.

The goal is to identify high-risk patients by looking at genomics. And we may not know at first why certain genes cause certain things to happen, but I think the first step is making the association. If you know that a patient has a certain gene variant, and we know that's associated with high-risk disease, it'll help us decide where in the algorithm the patient falls and what treatment we should pursue.

Oncology Data Advisor: Awesome. This is such interesting research, so thank you so much for explaining all of it.

Dr. Iyer: My pleasure.

About Dr. Iyer

Sunil Iyer, MD, is a third-year Hematology/Oncology Fellow and current Chief Fellow at the University of Miami Sylvester Comprehensive Cancer Center in Miami, Florida. This August he will be joining the Leukemia Disease Team faculty at Columbia University, where he will continue his extensive and passionate research in leukemias such as acute lymphoblastic leukemia, acute myeloid leukemia, and myelodysplastic syndromes.