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Michael J. Mauro, MD: Hello. I'm Dr Michael Mauro, and welcome to the Medscape InDiscussion podcast series on chronic myeloid leukemia (CML).
Today, we're going to discuss the state-of-the-art of monitoring and diagnostics in CML. We can review all things in monitoring related to the Philadelphia chromosome (Ph) and how we identify it and track it, and how it's played into the history and the current treatment of CML. We can do that from the perspective of someone that was there at the beginning, someone who's helped craft the new metric we use of an reverse transcriptase polymerase chain reaction (RT-PCR)–derived major molecular response as a milestone during the original imatinib trials, someone that's helped us get on the straight and narrow for diagnostics during this treatment revolution in CML. That is my guest, Dr Jerry Radich.
Dr Radich is a medical oncologist who specializes in the molecular genetics of leukemia. He studies genes and other molecules that signal treatment response, progression, and relapse, and this spans chronic and acute leukemias. He specializes in developing methods to improve the detection and treatment of CMLs and acute myeloid leukemias (AMLs). His team at the Fred Hutchinson Cancer Center studies how specific genetic variants influence treatment response and outcomes. Understanding these variants could help in the development of new drugs and enhance our ability to choose best treatments for individuals. He's been a huge leader in the field. He directs the Fred Hutchinson Cancer Center Molecular Oncology Lab, which provides high-quality molecular testing for clinical cancer research, at Fred Hutchinson and around the world.
Jerry, Welcome to InDiscussion.
Jerald P. Radich, MD: Happy to be here.
Mauro: I was going to say you need no introduction, but that was an introduction.
Radich: My mom would appreciate it. Thanks.
Mauro: Here is the inevitable icebreaker. I like to ask people an opening question. It is a pretty open-ended question, but give it a whirl. What would you say is the best thing that's happened or the best thing that maybe needs to happen for patients with CML?
Radich: In CML, we've really got an embarrassment of riches. The best thing that's happened is we now have multiple drugs to give patients, and they're all effective. They all have different side effects. For the vast majority of patients, we can find them a drug that should be effective in them. That's why for patients with CML in chronic phase, they have a lifespan that is pretty much close to the normal lifespan of the matched population.
We have an embarrassment of riches, and I think the global picture outside of diagnostics and testing is the fantastic news. We are lucky to be the model of precision medicine, personalized medicine, or whatever term you want to use. We really are the benchmark and the poster child for how the whole oncology world wants to be. That's absolutely the best news.
The flip side of that, the worst news, is that there are still patients out there in this country and in the whole world who don't have access to these medicines, which is kind of criminal. The good news is we have fantastic access to the drugs. We're getting more and more access to the testing, which is important as we'll talk about. The flip side of that is that there's still a huge unmet need in our country and in the world about having access to these drugs and access to these diagnostics.
Mauro: Well said. That was a two-pronged answer. I could synopsize that by saying that the embarrassment is that the riches aren't necessarily available to everyone. I appreciate that perspective. However, it is really a revolution, and it started with the underpinnings of a cancer driven by a sole genetic abnormality. You are the guru of the Philadelphia chromosome in my mind. How do you describe that to people?
Radich: I start by saying, this was unique and really the first example of a cancer having a specific genetic abnormality. The Philadelphia chromosome is so called because it was discovered by Peter Nowell at the Wistar Institute in Philadelphia. If it had been discovered at Roswell Park, it would have been the Buffalo chromosome. But it is the Philadelphia chromosome, and it's taking a piece from two different chromosomes, one on 9 and one on 22, and fusing them together to become a unique genetic structure that is only in the patient's CML cells. That has two implications. One is that it gives us a target to develop drugs that will interrupt the biology of disease. The other is that it gives us a target for monitoring, not like in some other weird diseases with some biomarkers where you study a serum porcelain as an indication of disease status. With the Philadelphia chromosome, you can target the thing that is driving the disease and you can monitor the thing that is linked to the disease. It's a unique situation that we have in this disease that has given us flexibility to dramatically improve patient outcomes.
Mauro: That's a great description. My favorite cheap and easy analogy in my clinic is that it's chocolate on my peanut butter and peanut butter on my chocolate. I'm not sure which is the devil there, the chocolate or the peanut butter, or the fusion gene on chromosome 22. Your answer was much more sophisticated.
Radich: Since I don't like peanut butter, you've lost me there.
Mauro: Going with that theme of things that begin with letter P, I know PCR is really the workhorse here and you've pioneered and optimized this assay. Bring us back to the beginning, when that wasn't really the classic way we were monitoring CML and we derived a new scale to which we all are beholden now to gauge responses, especially with our newer agents.
Radich: If you go back in ancient time, when we did our medical notes on clay tablets, how you monitored CML was by looking at the actual Philadelphia chromosome, and that had to be done in cytogenetic preparations. For cytogenetic abnormalities, what you have to do is grow cells and then stain them. When Janet Davison Rowley first started doing that, she was taking pictures and then piecing together chromosomes on her kitchen table. So when you talk about the fact that you can only look for 20 metaphases, that's because in the old days before automation, that was literally as many chromosome films you could go through. You had to cut up the chromosomes into bite-sized pieces, then put them together like a puzzle and figure out what the abnormalities were. That was the limitation of doing monitoring. We basically had to get bone marrow samples because it's hard to grow cells out of peripheral blood. and we were limited in detection because we were only looking at 20 events.
When PCR evolved, that was a life-changing deal as far as monitoring, because now we had a test where the dynamic range with cytogenetics was from 100% down to 1 out of 20 chromosomes, or roughly 5%, to a test that had a dynamic range of five orders of magnitude. This made everything so much easier for monitoring burden of disease and more accurately predicting outcomes.
Mauro: How do you explain PCR to people?
Radich: Everyone watches crime shows these days, right? There are CSI shows for every zip code in the world now.
Mauro: Unfortunately.
Radich: In those shows, they're always doing forensics to try to find the criminal. How they're doing that is by finding little scrapes of evidence of DNA on crime scenes and amplifying it to a level where they can actually do a test so that they can look at the perpetrators vs the innocents. What we're doing is a similar thing. We're using a test that will amplify the culprit's DNA. In this case, it's the CML. It's basically a chain reaction — sort of what your cells do. When your cells divide, they have to make twice as much DNA before they divide. We can do that in a test tube. We can basically amplify it and make twice as much DNA. Then we can repeat the process and make twice as much of that, and then twice as much of that, and then twice as much of that again. If we do that in a machine for 30 cycles, we have a million-fold amplification. We can go into a situation where it's a needle in the haystack, and we're selectively amplifying the needle so that we can finally see it in the haystack.
Mauro: I use that same analogy. I'm so glad to hear you use the words "needle in a haystack." I've got to validate my analogies, and that's perfect. I know it's quite sensitive, and we're going to talk a little bit more about that in a moment.
Before we turn to that, I wanted to ask you a little bit about something else in CML, which has probably become a little bit of a hot topic: defining the phases of CML. We're at the beginning; the World Health Organization has realigned the phases of CML. I wanted to get your take on flow cytometry and the possibility of a patient having a very small amount of immaturity, perhaps lymphoid blast clones by flow cytometry, and your take on that. I'm sorry to put you on the spot.
Radich: As you know, for most of our diseases in the hematologic malignancies, developing different classification systems is a bit of a cottage industry. Every few years, people kind of redefine these things. It's always been difficult for CML because there's always been multiple different classification schemes. It's a problem because they're based on different cytogenetic abnormalities and presence or absence of those on blast counts. Clinically, it's useful, but biologically it's a bit silly to think that one person could have a blast count of 19% and be called one thing and then someone else could have a blast count of 21% and be called another thing, with different clinical implications. Biologically, that doesn't make a lot of sense.
The whole issue you are getting at is, it's important for us to know, especially when people are on treatment, if there's any signs of them evolving from a chronic phase to a more advanced phase, whether you call it accelerated phase or blast crisis. Essentially, the critical thing there is the evolution of seeing new immature cells, be those myeloid or lymphoid.
Flow cytometry can help with that. Flow cytometry can be very sensitive in detecting aberrant cells. There's some evidence in the literature that seeing small populations of lymphoid blasts in otherwise normal people might put you on a more worrisome stream toward advanced-phase disease, meaning evolution to a lymphoid blast crisis.
The caveat there is that flow cytometry is a bit of an art form. There are various ways to use flow cytometry. It all depends on what markers you use. It depends on whether or not your model for defining an aberrant cell requires the initial diagnostic profile to look for patterns of cells afterward or whether you take the dogma that anything different from normal is abnormal. I can tell you that from work we've done with the NIH, trying to standardize flow cytometry in the leukemia setting across different well-known labs is really problematic.
Obviously, if someone were to show up and you did flow cytometry and they showed some low-level leukemic blasts, myeloid or lymphoid, that would give you pause. It would probably suggest that you had to do increased monitoring, especially in the setting where right now, we usually do peripheral blood monitoring. It would be one of those things where if you did peripheral blood monitoring and did flow cytometry, maybe that's the type of patient for whom you'd go back and get a bone marrow sample to see what's really going on. I probably wouldn't panic if I had one flow cytometry result on peripheral blood that showed 0.1% lymphoid blast.
Mauro: This is very sound advice and very illuminating. It's very hard. We see black-and-white changes in guidelines and language, and then hearing from someone that can unpack the details and highlight some of the uncertainties is really helpful. I think we should all take that advice, to not panic and to do what we used to do, which is be cautious and conservative and think about running the scope of monitoring, like marrow testing.
Back to PCR. What's the deal with patients who are PCR-positive but still in treatment-free remission (TFR)? That is probably a conundrum for those that don't treat or manage CML as much as you and I. How do we understand that, and what is your take on that story?
Radich: That's a really interesting phenomenon. The original studies with TFR by François Mahon and then others took patients with undetectable disease by PCR and showed that about 50% of those patients would have relapse once you discontinued their drug, and 50% wouldn't. Now it looks like if you use a more sensitive way of doing PCR, so-called digital PCR. you'll pick up some patients who are positive by that assay, and that helps predict who is going to have relapse. No matter how you cut it, there are some patients out there who appear to have persistent disease, and you can take them off drug and they don't have relapse. There are some patients who have persistent disease, and when you take them off drug and their disease goes up a little bit, but they don't get to the period of where they have frank relapse — they either lose major molecular response or cytogenetic response.
I think there are probably two phenomena going on. One is that CML is a stem cell disease, and like all stem cell diseases, you can often find the marker in other lineages. One thing I think you're doing, and the University of Adelaide has shown this in a couple of preliminary papers, is when you're picking up a signal, you may in some cases be picking up on lymphoid cells, which aren't necessarily going to contribute toward your relapse.
Mauro: Is it fair to call them background?
Radich: Yes. Or a false-positive. I think that's one thing that's going on.
That doesn't explain the other thing that happens about 10%-20% of the time, where the disease starts going up but then it hits kind of a plateau. There, I think you're having activation of the immune system. We have evidence now that if you look at patients who, when they're first diagnosed, are really great responders and have activation of their immune system. It's sort of like once you start debulking them, it takes over and wipes out everything else. I think probably the same thing goes on with TFR. There are some patients who, once that clone starts expanding, their immune system becomes activated again and essentially rides herd on that clone. I think there's two things going on there.
Mauro: That is really helpful. I think it's hard for patients, actually, because —
Radich: Oh, absolutely.
Mauro: They're expecting a black-and-white answer, like when a surgeon says, I've removed your tumor. It's in a bowl, it's in the lab. It's not in you anymore, you're cured. In CML, your PCR has got be negative or bust. That's not the story. I think we've just heard that there could be other explanations. That's great.
Radich: Another thing to think about is that there's this old literature, and it's absolutely fascinating. Before interferon, before tyrosine kinase inhibitors (TKIs), in some patients there's a natural oscillation in their white blood cell counts with CML before they're treated. These can be 50-fold, 100-fold — massive oscillations up and down in their white blood cell count. If you can imagine that that oscillation is always going on in your stem cell pool, and you've reduced the total amount of drug burden, you might be moving that oscillation down to a point where most of the time it's negative, but then it pops up and then it goes down again, and it pops up and it goes down again, and that's just what's going on and it has no major implications for anything except really interesting biology that mathematicians go wild about.
Mauro: This was the basis of our study we added, where we're going to have patients get PCR once a week or once a month. That turned out to be too much trouble, too expensive, and too inconvenient, right?
Radich: Yes.
Mauro: I thought you were going to mention some of the very distant, but I think important, research about the fact that the Philadelphia chromosome can be detected in non-CML patients.
Radich: Yes. If you look hard enough in people my age, unfortunately, about 10%, maybe even 20%, of us will have evidence of the Philadelphia positive chromosome by PCR. That's not an entirely new finding. It was found before that older patients could have the t(14;18) translocation.
Mauro: This is not CML though. This is just sort of a very transient evidence of genetic damage.
Radich: We don't think it's CML. Most of those patients, unfortunately, have not been followed to find out what happens. We know that clonal hematopoiesis of indeterminate potential (CHIP) happens. We know that telomeres get shorter. You are accumulating mutations all the time. I guess the point is, take your vacation time. The clock is ticking.
Mauro: This is turning pessimistic. Let's regroup. I think that kind of alludes to better technologies. Our tests are even more powerful than our knowledge.
Radich: Absolutely.
Mauro: Tell me a little bit about some of the pioneering stuff you've done to move the needle for PCR testing, including some really innovative work you've done to try to get better access for PCR testing. I just want a shameless plug here, please.
Radich: Well, thank you. We do work with The Max Foundation, which is a fantastic group that if people don't know about, they should look at. They are a group that finds patients from around the globe that don't have access to TKIs. If The Max Foundation can diagnose them, which is where I come in. the patient will get free drug for life from a number of pharmacy companies. The Max Foundation now takes care of over 60,000 patients worldwide with a global staff of only about 60, which is just unbelievable. The survival of people in the program match the survival of patients who were diagnosed with CML in Seattle or New York. It just proves that you just need to get drugs to these people. To do that, we've developed technologies with partners such as Cepheid to develop an assay that you can basically do in a cartridge so it doesn't take a lot of technical training. It basically takes peripheral blood via a one-step extraction and puts it into the cartridge, and it gives you the result. That's made a huge difference. A lot of patients don't have access to electricity, so we've developed ways that you can put blood on cards and send it by snail mail for up to 3-4 months to our lab. To get BCR-ABL testing to be quite accurate, we've now developed this so you can do a whole myeloid panel on this. For patients in whom you want to look for other mutations, we can do all of it off of one card with a couple of dried blood spots. It also allows our collaborators at these institutions not have to spend amazing amount of money for refrigeration units and stuff at their hospitals. A shoebox will work.
Mauro: Amazing.
Radich: We think that we'll soon have a way to do home PCR testing, getting ready for the next pandemic, frankly.
Mauro: Wow. Thinking outside the box and thinking about what is best for patients and for a global perspective. I applaud your work.
Maybe share some parting thoughts. What do you think the future might look like with regard to molecular diagnostics and work in CML?
Radich: I actually think this is massive, that we only do bone marrow testing at diagnosis. I think that pretty soon, we may have the technology to even get away without doing that because there's going to be sequencing techniques that will enable us to look at most mutations and chromosomal abnormalities in one fell swoop. You might be able to do that off the peripheral blood sample and look for the Philadelphia chromosome and other cytogenetic abnormalities while you're looking for BCR-ABL. That's an important thing.
I think that we will soon be developing better strategies for monitoring. Right now, every patient gets the same type of every-3-months monitoring. It's clear that what makes sense is building a strategy based on how fast people respond and how long they've been on therapy, doctoring it to the patient's individual disease. I think we will be able to soon have systems where the patients will be able to contact Amazon or whatever and have kits delivered where they can access their own blood peripherally and send that into labs so they really don't have to come to clinics anymore. That's the kind of stuff I think that's going to be rolling out in the next few years.
Mauro: The future of CML. You heard it here first.
Radich: Don't put any money on it.
Mauro: I wouldn't be so sure. These are really things that are going to happen, so stay tuned. This has been fantastic. Thank you, Jerry.
Radich: Thank you.
Mauro: To recap this, we've talked about the old-school story of molecular monitoring and CML, the details of flow cytometry, PCR, molecular remission, what the deal is with PCR persistence, and some visionary takes on what we are doing now and what we might be doing soon to help better monitor patients who are Ph-positive for CML via the technologies we have and some technologies to come.
Thank you for tuning in. Please take a moment to download the Medscape app and listen and subscribe to this podcast series on CML.
Thank you, Jerry. This is Dr Michael Mauro for Medscape InDiscussion.
Resources
Chronic Myelogenous Leukemia (CML)
Genetics, Philadelphia Chromosome
Reverse Transcriptase-Polymerase Chain Reaction
Why Is It Critical to Achieve a Deep Molecular Response in Chronic Myeloid Leukemia?
Precision Oncology: Who, How, What, When, and When Not?
Discovery of the Philadelphia Chromosome: A Personal Perspective
WHO 2016 Definition of Chronic Myeloid Leukemia and Tyrosine Kinase Inhibitors
Accelerated Phase Chronic Myelogenous Leukemia
Treatment-Free Remission in CML: Who, How, and Why?
Digital PCR for BCR-ABL1 Quantification in CML: Current Applications in Clinical Practice
t(14;18) Translocations and Risk of Follicular Lymphoma
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Cite this: State of the Art Monitoring and Diagnostics in Chronic Myeloid Leukemia: the Philadelphia Chromosome and Future of CML - Medscape - Sep 28, 2023.
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