Chronic Myeloid Leukemia: A Review
17:21 Share

From the JAMA Network, this is JAMA Clinical Reviews, interviews and ideas about innovations in medicine, science, and clinical practice.

Welcome to listeners from around the world, and thank you for tuning in to this JAMA Clinical Review Podcast. I am your host, Mary McDermott, Deputy Editor of JAMA, and I'm here today with Dr. Eli Jabbour, Professor of Medicine at the MD Anderson Cancer Center, who is author of a JAMA review on the topic of chronic myeloid leukemia. Welcome, Dr. Jabbour. Thank you so much for hosting me, Dr. Jabbour.

So let us start by having you tell us about chronic myelogenous leukemia. What is it and how does it develop?

Of course, chronic myeloid leukemia, or CML, I use CML during my podcast today. It's a chronic myeloprotiferative neoplasm. So essentially, it's arising from the bone marrow, from the myeloid cells. Bird deficiency is chronic, defined by what we call left shift, means immature cells moving into the blood with hyperleukocytosis, including the white count. This increase can come either alone or in an increase in the platelets count.

as well as red blood cells. And therefore, whenever we think of what they call myeloproliferative neoplasm, we should always rule out CML because it can come on its own or in a setting of increase of other blood components, be it the red blood cells and the platelets.

This disease is characterized by a hallmark called pediatric chromosome, the 922 translocation, where two chromosomes exchange segments together to create this 922 translocation, resulting into an activation of the kinase protein that gives the signal for the cancer cell to live forever. That's why it's very important when we have increase of the white count throughout CML, because today we have a target therapy very effective to

toward this fusion gene that can control the disease and eventually allowing patients to live a normal lifespan. How common this disease is, it's not common, it's rare. In the USA, we see around 8,000 to 9,000 cases per year. Most of them are discovered coincidentally for blood tests done for whatever reason. Then we discover hyperleukocytosis with immature cells in the blood that trigger additional testing that we can discuss today.

Otherwise, sometimes patients can have symptoms such as fever, fatigue, night sweats, or big spleens, panomegaly, where a patient can feel having fullness and bloating sensation. That is rare in the USA, although outside the Western world where medical care is not provided to the patients rapidly, a patient can have these symptoms, and often these symptoms are a signature of chronic disease that has been ignored for a longer time. Who is at risk for CML?

There's no specific risk factor for CML, although we've reported higher incidence of CML in patients who are exposed to benzene or nuclear radiation in old days. But nowadays, these are really rare, and as such, there is no predisposition. Furthermore, we have not identified any genetic predisposition for CML. Therefore, it's sporadic, and there's no link to any genetic risk factors.

Earlier, you mentioned that people with a high white blood count should be tested for CML because we've got good treatment. So for the primary care clinician, what unexplained threshold of elevated white blood count would you recommend testing for?

There is no threshold per se, however, if you have a hyperleukocytosis, meaning increasing the weight count, one should look at immature cells in the blood, such as promyelocytes, myelocytes, basal fin increase, because usually in a study of infection where you have hyperleukocytosis, we do not see immature cells in the blood. So having immature cells in the blood, that is something suspicious.

for CML. Often in a community, a patient will receive antibiotic throughout infection, and they get the CBC done within a week or two. And if the count is still increasing with time, one should consider workup for CML. So to summarize, persistent white count despite lack of infection,

Second, immature cells in the blood are signs suspicious for CML, and that should trigger a workup for CML. And specifically, what immature cells are you referring to? Usually, if you look at the CBCs, we have neutrophils, lymphocytes, monocytes, rare AOs, and basophils. When we see, we never see blasts in the blood. We never see myelocytes or metamyelocytes or promyelocytes. When we see these cells that usually we see them in a bone marrow space in the blood,

that is an abnormal sign. And that should trigger a workup for CML. And how do patients typically present? So often the patient do present to us because they did run a blood test for a routine, let's say HMP, let's say physical, annual physical exam or insurance of whatever reason that they need a blood test or before surgery. So often our patients are asymptomatic and running a blood test for non-specific reason, they see the white count increase.

Some other patients, really, if they have trained a long time with pain, fever, night sweats, we usually see what you call the chronic phase in more advanced time, means the CML has been ongoing for a year or two. We see increased weight count, but sometimes we see weight loss, or we can see fever, or we can see abdominal bloating and sensation of fullness because of a big spleen.

And really, because of the increased white count, we see what we call the viscosity. And among men, we see priapism. I have been 21 years at Anderson. I've seen two priapism, where patients are coming with the priapism and they have a high white count. And what is the prognosis of CML? In old days, the produce was very poor with a median survival of six to seven years.

Since the year 2000, with the tyrosine kinase inhibitor available to us today, somebody with CML can expect to live a normal life, meaning the lifespan is similar to normal patient population when we match for age. Now, of course, that means the patient is treated and responding well, and the responses are usually quite high in a 95% range.

What often we see among our patients, the compliance issue where patients do not take their medicine, and that makes them relapse. And of course, that can compromise their survival. How do the tyrosine kinase inhibitors work? So these drugs, these tyrosine kinase inhibitors, usually they bind to the B-cell-level fusion gene and block the pathways downstream. As such, they block the proliferation and induce cancer cell deaths.

They stop working when we've seen mutations acquired that can provide the binding of these drugs to the way they should bind. And among these mutations, something called gatekeeper mutation called TTPI mutation. We know these mutations are specific to one drug versus the other. And as such, when patient is not responding very well, again, we need to perform sequencing to look at the mutations.

And I compare this to urine infection when you have an E. coli and you can do your antibiogram to select your best antibiotic. Since we have multiple kinase inhibitors available to us, performing these tests will allow us to select the best drug based on a research profile and therefore have the best response induced against it.

Got it. So anytime there's a resistance, you repeat that process? Of course, when you look at the resistance, we have to check for mutations and decide accordingly. But when somebody is not responding, we must rule out compliance because patients may not take their medicine daily and therefore they become resistant on the road. So always go back to compliance. Do you typically stage CML?

Sensitive blood cancer, usually there's systemic disease. However, there's something called prognostic factors and advanced or early stage. Most of the scoring system we have today, they belong to the old time before the era of tyrosine case inhibitors. That being said, for the physician in a committee, what they need to know, if somebody had big spleen,

High basophils, high blast, these are usually advanced phase compared to somebody with no splenomegaly, low basophil count, and low blast percentage. These are early phase. That's why we classify them usually.

And your review talks about the first, second, and third line therapies with the tyrosine kinase inhibitors. Can you give us an overview about that, please? Correct. The first line of therapy in CML is the tyrosine kinase inhibitors, what we call the first generation imatinib. Imatinib is a treatment quite effective. However, we know that patient may relapse, may progress. Why? Because the binding to the kinase domain can change.

So we had imatibat first generation, and then we had second generation of tyrosine-cai inhibitors called dasatinib or posutibonilatinib, which are second-line therapy.

However, we know that resistance can occur, means where you don't have the kinase inhibitors to bind anymore to the protein kinase by acquisition of certain mutations, such as T315I mutation. So when we get the drug, it doesn't bind to the fusion gene. Among these mutations, one called T315I mutation, we get third generation of drugs that can overcome this mutation.

And as such, you know, when you have resistance, the kinase protein is active forever. If we can block it, then we'll put everything back in order. When the last generation of tyrosine kinase inhibitors allow us to block the BCR-able oncoprotein, regardless of the mutation we have, and that can lead to normal outcomes.

So if you start someone on a first-line TKI, at what point might you think you need to transfer them to a second generation? Patients on imatinib first-line therapy who do well, they have a normal lifespan. Now, what are the milestones that trigger me to change my therapy? Usually, I look at six months. If at six months, my PCR label is what you call PCR label transcript is above 10%.

At 12 months above 1%, that is for me a failure. That means I have to change my tyrosine case inhibitors. So if I start somebody on imatinib therapy or frontline, as long as my transcript is below 10% at six months and below 1% at one year, that is success story. I will maintain my therapy.

Otherwise, if I don't hit these milestones, I have to change. And the change will be based on a mutation profile. And then I decide on what is my next step of therapy. What are the adverse effects of these medications? Okay, these medications should be taken for a lifetime. And therefore, just before I go into the therapy, I would like to make what are the goals of therapy here. The goal of therapy are first and foremost to normalize survival.

by inducing good response where the patient can take the medicine for a lifetime. The second goal is not only to normalize survival, it's to be able to stop the treatment at a certain time and induce what we call treatment-free remission. Since these medications are taken for a lifetime, there's some adverse event that we need to be aware of.

Imatinib therapy, they're usually well-tolerated. They all cause lowering the count for a certain time at the beginning, what you call myelosuppression. But some adverse events are specific to each one of them. Imatinib can cause what you call periorbital edema and swelling in the lower extremities, fatigue, and bone aches. Usually, they are treated with a symptomatic way, if we need diuretics at best, but nothing major. Dasatinib, for example, can cause, the whole myeloderm can cause pleural effusion.

fluid around the lungs, pericardial effusion, really, and treat with steroids. And really, we do see what you call pre-monotary hypertension. That should mean we stop therapy immediately. It's reversible. Nilotinib can cause glucose in torus and can cause pancreatitis. But the whole market as well is vascular event, occlusive events. We've seen stroke, MI, or others.

Bosutinib is a drug that can cause diarrhea, GI disturbance, liver dysfunction. Somebody with, for example, inflammatory disease should avoid this drug because it causes exacerbation of Crohn's or ulcerative colitis. Prenatib, a drug that can cause vascular events, so hypertension, stroke, vascular event peripheral and large vessels.

and pancreatitis. In a simnib, the last drug, it can cause pancreatitis and thrombocytopenias and vascular events as well. These are, in summary, the adverse events encountered. Now, I must say that the benefit of this drug outweighs their safety concerns.

But when I prescribe these drugs, if I have multiple of them, I should direct my therapy based on a patient's comorbidities and patient profile. I would like to highlight that the median age of CMN patients is 60 to 65. Therefore, these patients already have risk factors for other diseases. And as such, we should minimize drug interactions and offer the drugs that suit the patient the best. Your review talks about hematopoietic stem cell transplant. Who would be a candidate for that?

Today in the USA, we're doing less and less transplant for this patient because we have multiple line of DKI. However, I think transplant should be offered today to somebody coming or progressing to blast phase disease, the ultimate phase of CML. Somebody who failed at least two drugs or three drugs and acquire specific mutations. These are patients that we consider transplant down the road. But this is really rare.

And then your review also talks about some people who can come off of these drugs, the TKIs. Can you speak to that? Treatment-free remission, we can offer treatment discontinuation, has become something more used in routine practice. For a patient in whom I can stop therapy, they must have achieved a deep molecular response. Deep molecular response is defined by four-lock reduction of the transcript, sustained for at least three years, I will say five years.

So you need to be compliant. You take the medicine. You need to respond and have a durable response. If you can meet this goal, meet this objective, then, of course, you can stop therapy. Stopping therapy, it's feasible, but patients should be compliant. In a way, if we stop therapy, 80% of the patients will succeed in maintaining what we call treatment-free remission, where disease will not come back.

But we need to monitor very carefully. More than half of the patients, if they have to relapse, they relapse the first six months, means disease coming back. And even at the long run, we've seen this coming back after two or three years. So therefore, I will educate my patient, if you can do close monitoring, then fine to stop therapy if you already responded so well. But if patient cannot follow up closely because they live far away, they don't have the means, then these are not candidate for treatment discontinuation.

One thing that I wanted to ask earlier is, does every patient you're considering for a possible CML diagnosis require a bone marrow? Yes, it's a very important question. A bone marrow evaluation, it must be done up front. Sometimes we can do fish on a blood and we can tell somebody it's CML, but the bone marrow is important for staging, although there's no proper staging in CML. For example,

To run a karyotype, we need cells in division, in mitosis, and in the blood, you usually see mature cells. They do not divide. So when doing a bone marrow, you can have immature cells where you can look at the mitosis, see if they have translocation 922 or something additional, such as other chromosomes that put the patient at higher risk than others.

Sometimes you do blood tests and you don't see base office increase. You do a bone marrow, you have base office above 20%, that put patient in advanced stage as well. So therefore, it's very critical once you have suspicion for CML to have a bone marrow evaluation. Thanks so much for this very thorough review of CML. Is there anything you'd like to add that we didn't cover? I think, no, I think CML, it's a rare disease.

It's 9,000 cases, but highly, highly manageable. And it's a model of cure in cancer. So I advise physician and community to see CML, even though they're comfortable, they call always an expert because it's a rare disease and you can get some tips that can allow you to teach your patient the best way possible and secure the best doctor outcome for you. Great. Thank you so much. Of course. My pleasure.

I've been speaking today with Dr. Elie Javour about his JAMA review on the topic of chronic myelogenous leukemia. You can find a link to the article in this episode's description. For more of our podcasts, please visit us at jamanetworkaudio.com. You can subscribe and listen wherever you get your podcasts.

This content is protected by copyright by the American Medical Association with all rights reserved, including those for text and data mining, AI training, and similar technologies.