Published on November 6, 2018
During this Ask the Expert segment, a Patient Power community member wants to know “what is the risk of progression from myelofibrosis to acute myeloid leukemia (AML)?” Myeloproliferative neoplasm (MPN) expert Dr. Naveen Pemmaraju, from The University of Texas MD Anderson Cancer Center, explains prognostic factors, risk stratification, and symptoms of progression. Dr. Pemmaraju also discusses recent developments in treatment research for patients who do progress to AML. Watch now to find out more.
This is a Patient Empowerment Network program. We thank Incyte Corporation for their support.
Transcript | What is the Risk of Progression From Myelofibrosis to AML?
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A small percentage of us with myelofibrosis have the risk of progressing to AML. I know there been a lot of new drugs now either approved, or in development for AML. And some that help people who have secondary AML.
Right? But tell us about the risk of progression, and then what do you do about it?
Right. So, that’s a great topic, and as you know, you’ve been doing this for so long now. This has often been a very not great part of the conversation, but it’s an exciting time for our patients based on the research I’m about to share. So, the first part is progression to AML, which we touched on earlier. We do have an objective prognostics scoring system. Actually we have so many scoring systems now that many of our patients are starting to see them.
But the IPSS, or International Prognostics Scoring System, was first developed by our colleague, Cervantes at a—now, this is right before 2010, so ’07 to ’09. That one is supposed to be applied at diagnosis and based on five of these risk factors, we can prognosticate, or tell which of our patients are at a higher risk for AML. And so, a lot of our viewers ask that. So, it is true. Age—over a certain age, white count of 25,000, circulating blasts, constitutional symptoms, and anemia made up that original five.
Since that time, there are dynamic scoring systems, DIPS, DIPS PLUS and others that include, or modify as some of those risk factors. So, we can tell, at least based on a textbook impression, who has a higher likelihood of going to AML. Once our patients go to AML, there’s a lot of hope now. There have been four—count them—four new FDA approvals for AML in just the last 12-24 months. They apply to different segments of AMLs, two of them are targeted therapy, so one drug called MyTosterone hits the FLIP3 inhibitor, one drug hits the IDH1 and 2. Actually those are two separate drugs.
The drug you were referring to had a code name CPX-351, or Vyxeos, and it does have an approved label for so-called secondary, or therapy-related AML. Although I will caution our viewers that – MPN patients, specifically, we’re not included in those early data sets. They were more geared towards patients with MDS leading to AML, but the principle is there for us.
And then finally there’s another drug called gemtuzumab or Mylotarg. So, you have four FDA approvals, ongoing clinical trials with combination therapy, excitement and ongoing investigation for CAR-T cells, optimizing stem, so transplant, and then combining possibly MPN drugs with AML drugs in a clinical trial setting. So, I think this is actually a very, very important time to talk about AML in all of our MF and MPN sessions.
Okay. Just one brief question, and—if someone like me, where I’m on ruxolitinib (Jakafi) myself, but if that sort of poops out, or that, or another medicine is not working for me, and I’m developing AML, do you feel now it’s a more hopeful time than it’d had been previously?
I do, Andrew, and you know me. I used the word ‘hope’ very seriously and very carefully. Before with AML—and I mean, just five to seven years ago, it was not as hopeful of a time for us, as researchers, and for our patients. Not just because of the FDA approvals. That obviously is very encouraging and applies to a lot of our patients, but also because of the funding, the research, and the ideas for combination chemotherapies, and the emergence of these immune therapies. I think it’s a hopeful time for all of us involved with AML.
And specifically as you were mentioning this secondary, or post MPN, or post MDSAML, which is largely been an urgent unmet medical need.
Okay. And just to everybody understands, AML, acute myeloid leukemia, so it’s acute and as has been in the past a five alarm fire and now they’re developing medicines for that. All right. Let’s go on. Bonnie has a question. “I have myelofibrosis and my only symptom is that my spleen is enlarged. I’m on hydroxyurea (Hydrea), but hesitant to switch to Jakafi or Ruxolitinib. Assuming no real discomfort and just moderate weight loss and stable blood counts, does an enlarging spleen itself cause problems?” And also, I guess the bigger question, Naveen is, is there a penalty for waiting if there is a treatment that might line up with what you got?
You’re right on. Yeah. This is very, very serious, important topic. So, for the first part of the question, the spleen itself being enlarged can in fact cause some really, really big problems for a lot of our patients. It is true, as the questioner’s asking, that one can have mild splenomegaly. So, a spleen that’s slightly enlarged, not yet causing physical symptoms of early satiety, which means getting full fast, or physical discomfort, but a lot of patients do have that. So, yes, a big spleen alone can cause not only local problems, but also systemic. Because again, it’s a disease of cytokines; messengers and proteins that are being scattered all throughout the body, causing the body to feel flu-like symptoms, or fatigue.
Now, the studies for Ruxolitinib are very specific. These are two Phase III studies, they are called Comfort 1 and 2, published in the New England Journalfive six years ago now. And they did include patients with intermediate to, or high-risk disease. Or intermediate to high-risk disease, shall we say. And although the spleen itself doesn’t come out in the scoring system, some position is that it should be patients with more advanced, or higher scoring diseases than say someone with lower risk disease.
So, with the trial data that we have we know a couple of things. One, the drug got approved in those more advanced patients. Two, there was early crossover that was allowed. So, one of the comfort studies, Andrew, was as you know, randomize to placebo. So, no active therapy, and one was best available therapy. Even with the early crossover allowed to the ruxolitinib, both are not showing overall survival benefit. Translated into more layman’s terms, what that means is, it does appear, maybe, possibly, that if you got the drug at the beginning early on, there looks to have been some long-term benefit.
We won’t know that until further studies are done, and those studies are being planned. Those are called ‘early intervention’ studies, so people at a lower, earlier stage, low-risk, Intermediate 1, and I think we’ll all be eager to see how that benefits our patients.
Okay. Great. So, the penalty for waiting—right now it appears there could be a penalty. In other words, it could be better to get on it. Don’t wait. If you and your doctor agree, there’s a therapy for you.
I think that’s exactly the resource position to take, which is I think that—I believe that there are a subset of our patients who exactly fit what you said. They are symptomatic, out of proportion to the risk scores that are available. The spleen is highly enlarged, although they have lower intermediate risk by IPSS. And that’s exactly the area of investigation for myself, and our colleagues. And even in the clinic there might be some role to assessing patients as you said like that. So, it shows you the limitation of these text book scoring systems and how much research we have left to do.