Dan Pollyea, MD, MS, Clinical director of Leukemia Services at the University of Colorado Cancer Center at the Anschutz Medical Campus talks about a potential cure for AML that is showing good results.
What is AML?
POLLYEA: AML, acute myeloid leukemia, is a type of cancer that affects the bone marrow. Your bone marrow is the organ in your body responsible for making all of the cells of your blood; your white blood cells that fight infection, your red blood cells that carry oxygen and make you feel strong, and your platelets that clot the blood. AML is a cancer that affects the bone marrow and your ability to produce blood; since blood travels to every organ and tissue in the body, AML can impact the entire body.
How does it affect people?
POLLYEA: The way people present with AML varies from patient to patient. Some have very dramatic presentations where they’re acutely ill and very sick and need to be treated in the intensive care unit. Other people can smolder along for a longer period of time, weeks to months, before they feel sick. Common symptoms include fatigue, easy bruising, or even increased infectious complications.
When you think leukemia, you usually think young people. This can happen to older people?
POLLYEA: The most common type of cancer in children is a type of acute leukemia called acute lymphoblastic leukemia, or ALL. That is a type of a cancer we don’t see very often in adults. Acute Myeloid Leukemia is the most common acute leukemia in the adult population. It really is a disease of older patients. The median age of diagnosis is around sixty-eight. So, there are all different types of leukemias, and they all have different populations that are affected.
Are all leukemias the same in the fact that most cancers have cancer cells, but leukemia has leukemia stem cells?
POLLYEA: Right. Some types of leukemias don’t even need to be treated. Other types of leukemias can be treated with just pills and people live to their normal life expectancy. Some types of leukemias, particularly AML, have historically been essentially death sentences. In many types of cancers, there are stem cell populations, which are small populations of cells that are the root cause of the disease. They are the cells that survive chemotherapy and cause relapse when that happens. So, this is very well recognized in the acute leukemia world. We’ve been studying and trying to understand the leukemia stem cell population for many years. In other types of cancers there are also cancer stem cells and varying degrees of knowledge about each of these stem cell populations and each type of cancer. But we think that many, if not most, types of cancers do have a similar stem cell population that serves as the root cause of the disease.
How would you normally treat AML?
POLLYEA: Historically, the treatment of AML would require very intensive chemotherapy regimens that require a month long stay in the hospital. There is high complication rates and high death rates. Up to 20 percent of people die from these treatments, not from their disease. That’s been the standard of care for AML for decades.
You’re talking about an elderly population and then chemo, which is incredibly hard for anybody.
POLLYEA: Exactly. That’s why outcomes have been so poor for so long. The standard of care in this treatment is among the most aggressive types of chemotherapy in oncology. You add that to an older patient population and you have historically very poor outcomes.
With just the chemo treatment for AML, what would be the life expectancy?
POLLYEA: When we apply intensive chemotherapy to older patients, the long-term outcomes are extraordinarily poor. The number of patients who have a good successful long-term outcome cure is low, probably less than 10 percent of people.
But now there’s a new treatment. Can you explain this?
POLLYEA: This new therapy involves a drug called venetoclax. This drug targets a protein called BCL-2. Almost 10 years ago, Craig Jordan, my Division Chief, discovered that BCL-2 was very important for the leukemia stem cell population, the small population of cells that causes the relapse of the disease and is not effectively treated with chemotherapy in almost all cases. This discovery began the opportunity to think of ways to eradicate the stem cell population, which could lead to deep responses and maybe even cures for the disease by targeting BCL-2. It took many years to get to that point, but over the years since that discovery, we’ve made unbelievably fast progress to the point where we are now. This is an FDA approved therapy for older patients with AML.
It is FDA approved?
POLLYEA: Yes. As of November 2018, the FDA gave approval. That’s extraordinarily fast in terms of when the first clinical trial with venetoclax in AML was introduced just a few years before that. That just speaks to the unbelievable outcomes and efficacy that we’re seeing with this.
Tell me about your clinical trial.
POLLYEA: One of the first clinical trials with venetoclax was for newly diagnosed older AML patients. This was a clinical trial that we did here at the University of Colorado, and it was also done at multiple other centers across the United States. After starting the trial, we very quickly recognized that something extraordinary was happening. We were getting responses in patients who we would never expect to respond to any conventional therapy. The responses were lasting a very long time and the responses were very deep in every way that we were measuring them. This regimen was well tolerated compared to any other treatments that we had used in clinical trials, with a side effect profile that was incredibly limited. So, we knew that we were really onto something. And, our collaborators and colleagues across the country had similar experiences. Based on all of this, that has led to two large pilot studies as an extension of that original clinical trial that is just happening here at the University of Colorado.
How does this treatment work? David said he was told he was going to die within two weeks to two months and you put him right in the hospital when you saw him. Eight days later, he’s told you can’t find any leukemia.
POLLYEA: Everybody has a different course. We’re learning so much so fast about the variations in responses. In the best cases, these responses happen incredibly quick. Because it doesn’t involve intensive chemotherapy, the side effect profile is limited. The amount of time spent in the hospital compared to intensive chemotherapy is minimal. In people like David, we’re not only seeing very fast responses, but very durable responses that are going on for a year or more. It’s incredible.
What was the treatment for David? Was it a pill? Was it an infusion?
POLLYEA: David’s regimen consisted of two therapies. One was a low dose chemotherapy treatment that we’ve been using for many years for this disease. When used alone it can get the disease under some control about 20-30% of the time, and that control can last a matter of months. That’s still part of our regimen, but we pair it with this pill, venetoclax, the BCL-2 inhibitor. This combination is magical. And with both therapies together, we get very high response rates, somewhere between 70 to 90 percent. Compared to the 20 or 30 percent you might expect with a low dose chemotherapy alone, the responses occur really quickly, and they seem to be lasting a very long time for most patients.
Have you ever seen anything like this?
POLLYEA: Never. I speak for myself but a lot of my colleagues who have been doing this for much longer than I have would also agree with this.
Would you call it a cure?
POLLYEA: I think that’s a tough question because we need a lot of time before we can say a person has been cured. Also to declare someone cured they would have ideally be off all therapy, and we typically recommend that people remain on this treatment indefinitely. Despite those caveats I do think there are some people that can be cured with this treatment. We’re working very hard to figure out who those people might be. I also know that it’s not a cure for a lot of people. A lot of people get a response or remission and then they relapse. That can happen a year later or even more. So, we’re working hard to try to figure out all those things, but ultimately the goal is to cure people with a treatment like this that targets leukemia stem cells.
Can this cross the border into other cancers?
POLLYEA: I think the principle we’ve sort of helped to discover is that leukemia stem cells can be targeted in this way. The way that the venetoclax targets leukemia stem cells is completely novel. We’ve never seen a drug work like this to target any type of cancer cell, let alone a stem cell. The principle for how this works in leukemia and leukemia stem cells could potentially be applied to other cancers and other cancer stem cells. They very well could share this weakness that the leukemia stem cells have.
How does it target the leukemia stem cells?
POLLYEA: It takes advantage of a weakness that we’ve discovered inherent in the stem cell population in the way leukemia stem cells use energy. We call that metabolism. What we’ve found is, unlike any other cell in the body, leukemia stem cells are completely dependent on using energy in only one way. In other cells in the body, they have ways to compensate. Your cells have many ways to use energy. They can use proteins. They can use sugars. They can use a variety of other resources. But leukemia stem cells are completely dependent, in most cases, on doing metabolism or using energy in one way. This treatment takes that one option off the table. So other cells in the body compensate by using energy in other ways. That’s why the side effect profile is so limited. But the leukemia stem cells can’t compensate, so they die. This is a completely new way to kill cancer cells. There’s never been another therapy or mechanism that exploits this weakness.
Are the stem cells inside the cancer cells?
POLLYEA: Leukemia stem cells are their own cells. They are independent cells floating around in the mix. They are just as tiny percentage of the overall cancer cell population. If you were to look at the overall cancer cell population, that’s maybe 99.9% what we would call the bulk disease, but it’s being fueled or repopulated by this teeny tiny trace population of the disease.
So, you’re basically killing cancer?
POLLYEA: The idea that I like to give is that cancer is like a weed. You have a lawn full of weeds and if you just mowed your lawn, it might look good for a couple days. But those weeds are just going to come right back. Sometimes we know they come back worse. A leukemia stem cell directed therapy has the potential to pull the roots out of the weed, so the weed is gone. That’s the goal. That’s how a treatment like this can really differ from standard therapy.
Is venetoclax being used or tested on anything else?
POLLYEA: The incredible thing about venetoclax is that it’s FDA approved for another type of leukemia, an unrelated type of leukemia. That type of leukemia is called chronic lymphocytic leukemia. The way we think it works in AML is different. But this is an incredible drug that has the potential to really revolutionize a lot of different types of human diseases. It’s very exciting.
Tell me about your first meeting with David.
POLLYEA: When David and I first met, he was in rough shape. He’s a guy who’s been healthy his whole life, no major medical problems, has a great family, has worked hard, and was enjoying retirement with his wife. This fell on him like a ton of bricks. He became sick quickly. A realistic picture of what to expect from conventional treatment options was given to him from other oncologists and physicians and it was understandably depressing news. David was willing to jump in with both feet into a clinical trial, which is a pretty difficult thing to do. And, to do it with the enthusiasm that David had at a time when he had been given the worst news a person could ever be given in their life, was incredible. Obviously, it’s paid off well. He’s had a tremendous outcome. He quickly recognized changes and improvements in the way he felt. But, our subsequent meetings since then have been much different. My meetings with David are now like old family reunions. We talk about some of the old times and how bad things were. Mostly, we focus on all the great exciting things that he’s doing, his family, the trips he’s taking, and the different things he gets to do daily. We have a really good time.
David is just one of hundreds? I mean, they’re in a time where they’re enjoying their grandkids. This must be something that a doctor would dream to be able to be a part of?
POLLYEA: There’s no doubt about that. This has exceeded my expectations. As an oncologist, especially a leukemia doctor, our training involves how to give bad news, and even how to help a person die. Those things are still important principles of what we do. But to have this opportunity to be able to give so much hope and to be so optimistic about this disease, when for so many years it was just extremely negative, that’s the dream of a lifetime. I couldn’t ask for any more rewarding experience in my whole life.
If someone wants to apply for this this trial, can they?
POLLYEA: Yes. This trial is open here at the University of Colorado. We think we know how to make this therapy even better. We’ve made some adjustments to the regimen and that is the basis of the clinical trial that we have now because this is an FDA approved therapy, if you meet the criteria, you can just have your local doctor write a prescription. We’re trying to make it better and that’s the impetus for the current clinical trial that we’re running. Then, we have a second clinical trial where we’re expanding this therapy for younger patients. This has only to date really been tried in older AML patients that make up the bulk of the disease. There are lots of people that are younger than 60 who we think could benefit from this as well. So, we now have the only clinical trial in the whole world where a person younger than 60 can have a reasonable clinical trial option to not get intensive chemotherapy and to receive this regimen instead. We’re excited about that.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Julia Milzer, Media Relations Manager
303-725-0733
Sign up for a free weekly e-mail on Medical Breakthroughs called First to Know by clicking here
