A generation ago, a CML diagnosis came with one drug and very little room to adjust if it wasn’t working. Today, patients and their doctors have six therapies to choose from, with treatment decisions shaped by tolerability, disease risk and long-term goals.
At Princess Margaret Cancer Centre in Toronto, Ontario, Canada, Dr. Dennis Kim oversees a registry of roughly 1,500 CML patients and works across both clinical care and research. Over more than 25 years in the field, he has seen how much the disease and its treatment have changed. For all the progress that has been made, Dr. Kim says the work is far from finished. “Some people may say that CML has already been overcome, but that’s just not true,” he says. “There is still significant unmet demand and an urgent need to improve existing therapies.”
Here’s what Dr. Kim had to say about how treatment has evolved, what newer therapies offer patients and what his team at Princess Margaret is working on next.
Can you briefly describe your history with CML?
When I started my transplant practice in 1997, CML was one of the most common reasons for a transplant. Then in 2000, a magic drug called Gleevec came into CML practice and changed everything. When I came to Princess Margaret Hospital in Toronto, I found we had a huge clinic but we were not really looking at how to improve our research around it. So I started a CML database, began collecting samples and tried to build something from there. I returned to South Korea in 2008 and continued my CML research — including international collaborations — and I could not escape after that. I was hooked.
From your perspective, what has changed most in how CML is treated over time?
When Gleevec arrived in 2000, we had only one treatment option. It did not matter whether patients could tolerate it or not. If they were not responding, the only solution was to increase the dose, which meant more toxicity. As we began to understand why patients were becoming resistant to treatment, ABL1 kinase domain mutations emerged as a common cause. Once we had more options available, we could switch medications instead of just increasing the dose.
Then the focus shifted again. The question became whether we could stop treatment altogether. I was the principal investigator on a Canadian tyrosine kinase inhibitor (TKI) discontinuation trial called the TROT study, and it was successful. Now the focus is on tolerability and finding treatments that patients can live with long-term. But about 30% to 40% of CML patients also carry somatic mutations beyond BCR-ABL that we still do not fully understand. Tolerability and genomics are the main themes in CML research today.
How many treatment options are currently available, and how do you typically think about them when treating patients?
We have six commercially available options right now. Five TKIs can be used as frontline therapy, with asciminib emerging as another option. The decision depends on the patient’s disease risk, overall health, access and cost, as well as their treatment goals. If someone has high-risk
disease versus low-risk disease, we may choose a different option. Comorbidities matter too. Cardiovascular issues versus problems affecting the lungs, gastrointestinal tract or liver can all influence the decision. And if a patient is aiming for treatment-free remission (TFR), rather than just long-term disease control, we may choose a different approach.
For someone newly diagnosed, what does treatment actually look like day to day?
When patients hear they have CML, they often worry about being admitted for chemotherapy. But treatment typically does not require hospitalization. In 99.9% of cases, patients are not admitted unless there is another issue. What I do recommend is taking about three months away from work at the start. This is the first time patients are going through this kind of treatment, and we do not know what side effects they might experience. There could be cytopenia, muscle cramps, significant fatigue or other issues that affect their ability to work. You do not want to be operating at 50% capacity while adjusting to therapy.
After those first few months, most patients get used to their treatment and catch up. They continue taking their medication daily, but still need close follow-up with their practitioner to manage side effects and tolerability as they come up.
What are the most common reasons patients end up switching from one treatment to another?
Around 20 to 30% of patients have to switch medications after frontline therapy. Two-thirds of the time it is because of resistance, and the other third is due to intolerance or toxicity. So resistance is the most common cause, but intolerance still affects a significant number of patients, with about 10% to 15% switching because they cannot tolerate the side effects. After the second line, that ratio flips, and patients are more likely to switch due to intolerance than resistance.
Asciminib works differently from other CML therapies. Where does it currently fit in the treatment approach and what has stood out about how patients respond to it?
All five drugs that were approved before asciminib block what is called the ATP binding pocket. But that pocket exists in multiple other proteins in the human body, which means those drugs are not just inhibiting the target protein. They are inhibiting other proteins as well, and that is where many of the side effects come from.
Asciminib works differently. It targets the myristoyl pocket, which is very unique. You do not find it in other proteins in the body. Think of it like a keyhole. Once you put a key in and lock it, the whole protein is locked. Because it is so specific, patients may not experience the same level of toxicity compared to the other TKIs. In some data, it has reduced treatment discontinuation due to side effects by about half.
In terms of where it fits, the drug has been approved as a third-line option. It was approved by Health Canada as a second-line treatment, but it has not gained reimbursement approval, so it is used second-line on a case-by-case basis. In my own practice, I have started to incorporate it as early as I can. Some patients want the newest option available, while others are more conservative and prefer treatments with a longer track record. I discuss those options with my patients and leave the decision to them.
How realistic is treatment-free remission (TFR) and what determines whether someone is a good candidate?
It is doable. In our Canadian trial, the TFR rate was about 65%. More recently, outside of a clinical trial, about 65 to 75 patients have tried TFR as part of standard care, and about 75% of those patients have been successful. The monitoring side has improved as well. We used to think patients needed monthly PCR testing in the first 12 months, which was a barrier. Now we are able to test every six weeks in the first six months, then every three months after that.
To be eligible, a patient needs to have been in chronic phase only, with no history of advanced disease. They need at least three years of treatment, at least two years of a deep molecular response at MR4 or better, and they have to be willing to stop. If they are not willing, we do not push them.
That willingness is one of the biggest hurdles. When we ran the clinical trial, about half the patients I approached were willing and half were not. Of those who said no, about 50% were afraid of relapse, even a molecular one, and another 30% did not want more frequent monitoring. But if patients understand that more than 90% who relapse respond quickly when they restart treatment, acceptance may change. We have not had a single case where a patient lost control of their CML completely.
Is there anything in the current research pipeline that you find particularly promising?
We have two studies running at Princess Margaret right now. The first is called ASK for NGS. We are trying to recruit newly diagnosed CML patients so we can run next-generation sequencing at diagnosis and better understand their mutation profiles. Patients do not have to transfer their care to us. We work with their community practitioner in a shared care model.
The second study is ASK to Advance. It targets patients who have failed frontline therapy. Based on their mutation profile, we provide asciminib with or without dasatinib, free of charge, as part of the clinical trial. Asciminib is not currently reimbursed as a second-line option in Ontario, but patients enrolled in this study receive the drug at no cost.
When patients ask whether CML will ever be cured, what do you tell them?
CML is not an incurable disease. Patients today have about a 98% chance of a normal life expectancy. But I always tell my patients two things: You have to listen to my medical advice and you have to take the pill. If you do not do both, nothing is going to happen. I cannot help you if you are not willing to help yourself.
As for a full cure, not everyone will get there, but the number is going to go up. Right now, it may be less than 10%, but we hope to keep pushing that higher. The goal is 100%.