What the experts say: World-renowned researcher calls treatment-free remission CML’s ‘Holy Grail’  

Female patient getting medical advice from a male physician

It wasn’t long ago that chronic myelogenous leukemia was considered a death sentence for the vast majority of patients unfortunate enough to receive a diagnosis. We’ve come a long way since then, with a number of medical breakthroughs — including stem-cell transplants and tyrosine kinase inhibitors (TKIs) — gradually extending the lifespan of patients to near normal levels.  

A little over a decade ago, the ground shifted again when it was discovered that the deep molecular response produced by TKIs continued long after some patients stopped taking them. The disease became virtually undetectable despite the fact these patients were no longer receiving therapy. 

Treatment-free remission (TFR), as it has come to be known, has been found to be effective in roughly 50% of patients who meet certain criteria, according to Dr. Jeff Lipton, a recently retired clinical investigator. We caught up with Dr. Lipton — who was just awarded the 2024 Goldman Prize for extraordinary dedication and achievement in the management and treatment of CML — as he visited family in Israel.  

Dr. Lipton’s remarkable commitment to the cause was on full display as the interview was briefly interrupted by an Iranian missile strike near his location. After being forced to seek shelter in a bomb shelter, Dr. Lipton was eager to keep talking about his long fight with the disease, the game-changing benefits of TFR and the future of CML research. 

Can you tell me a little about your history with chronic myelogenous leukemia? 

I’ve been working with CML for 35 years. I started with transplants before there were any of the current medications now being used. I’ve been through the whole evolution of the disease to where we are now.  

That’s incredible. Maybe you could talk briefly about CML, what it is and what it does. 

CML is a chronic myeloproliferative disorder associated with the overproduction of white blood cells related to a genetic mutation called the Philadelphia chromosome in the molecular rearrangement called BCR-ABL. It occurs in roughly two to three per 100,000 population. The average age of diagnoses is about 65 in the Western world but, interestingly enough, under 40 in the Third World. There are three phases of disease: chronic, accelerated and blast. The last phase is extremely difficult to control. Transplants used to be the treatment of choice, but now we have drugs called tyrosine kinase inhibitors, and an additional drug called the STAMP inhibitor, which seem to put people into appropriate remissions of various levels so their overall survival is equivalent to other people at the same age. 

What is treatment-free remission? 

Over the past 10 years or so, it was discovered that if you stop the tyrosine kinase, about 50% of eligible individuals will actually be able to stay off their medication. Unfortunately, TFR is probably only available for, at best, a third of all newly diagnosed patients and only those in the chronic phase. The rest either won’t meet the starting point, don’t want to come off their medication or have a recurrence of the disease when they do come off of it.  

 When was TFR discovered? 

The work started in Bordeaux, France, with a fellow named Francois-Xavier Mahon. It was discovered by accident, as there are some people who have to come off treatment for medical reasons or other problems with the drugs. They discovered that the response rate was sustained even after the medication was stopped. There are now at least 40 TFR trials out there on three of the drugs used to treat CML. The other drugs have not been formally tested but the three that have show a success rate of around a 50 to 60%. 

What are the benefits of TFR? 

The biggest benefit, of course, is that someone is off treatment. That means there’s no side effects from medication and patients get the psychological benefits of not having to take pills every day. There are also the cost implications, of course, because some of these drugs are damned expensive. 

What are the risks of attempting TFR?  

Well, I think the biggest risk is if it’s done in inexperienced hands and you have a non-compliant patient. You have to meet a certain standard for a certain period of time to be eligible. That doesn’t always happen. Some patients, they hit that standard and the physician attempts it, not knowing it has to be stable for a couple of years. The second thing is monitoring. People have to be monitored at least every one to two months in the first year and then every three months after that. The majority of people who fail at TFR do so during the first six to seven months. If you restart treatment immediately, the capture rate is virtually 100%. If you delay, then you may not capture as quickly. There appears to be only one case that I’ve seen recorded of someone whose disease progressed into something bad and that’s because they didn’t restart treatment.  

Do patients have trouble with the idea of stopping their medication? That must be difficult psychologically, if not physically. 

It really is. The other thing we’ve noticed is that there is a TKI withdrawal effect that a quarter to a third of patients experience and this can result in significant muscle pain and joint pain. Now, it’s usually self-limited and goes away within a couple of months, but patients can go through a bit of a hairy period where they feel very uncomfortable. Sometimes you may need to treat it with analgesics or even anti-inflammatories. 

 What makes a person a good candidate for TFR?  

The most important thing is their molecular response to medication. They must have what’s called an MR4 or 4.5. MR4 means a four-log reduction from the original baseline (this means a qPCR test has revealed the patient has achieved a deep molecular response and 1 out of every 10,000 cells, or 0.01%, are CML cells). MR4.5 means four and a half logs (or 1 out of every 32,000 cells, or 0.0032%, are CML cells). They must meet that standard very stably for a couple of years. Second, they must have a lab available that can monitor them appropriately every one or two months in the first year and every three months thereafter. Third, the patient must be motivated and compliant enough that they will get their testing done. They also have to be in the chronic phase of CML. Those are the big issues to doing it safely. 

And, as you said, if a patient does relapse, the same medication typically works for them again?  

Yes, usually pretty quickly.  

Have you helped many patients attempt TFR? 

The government reimbursements at the hospital I worked in only allowed for testing every three months — meaning I couldn’t meet the criteria of testing every month in the first year. So, I would tell patients, ‘Look, I’m not able to do the standard monitoring because it’s not reimbursed. If you choose to do it, you do it with somewhat more risk.’ If I could have met the criteria, I would have gotten a lot more patients on TFR. 

Do you have a sense of why TFR works for some patients and not others? 

That’s the big question. We know that the longer someone has had a deep response, the better the chances are of it being successful. There’s a big European study, the EURO-SKI study, which suggests that for each additional year someone has a deep molecular response, their chances are slightly increased. It does not appear that the drug they take makes a difference. A lot of people are looking at other molecular changes people may have in their blood cells that might put them at higher risk or not, but, right now, the chance of predicting a successful TFR is not absolute. 

How do patients generally react when you talk to them about TFR? 

The majority are willing to do it but some don’t even attempt it. They’re happy, they’re not having any side effects that seem to bother them on the medication they’re on and they don’t want to rock the boat. I’ve been involved with a number studies where patients have been successful and they’re quite happy. I think the biggest thing patients need to realize is that not having a successful TFR is not a failure. It just means they go back on their medication and they still have a near-normal life expectancy. Some patients get depressed because they feel like they failed but I don’t consider it a failure. On the one hand, you have the Holy Grail, which is TFR, but on the other, you have what people would call a functional overall survival, with them having no evidence of the disease and living a normal life — perhaps with some side effects. And not all of them have side effects.  

Where do you see the future of CML research going?  

Researchers are looking at drugs that might have a reduced side effect profile for people who have to be on them. They’re also trying to find out if there’s some underlying predictability as to who might be successful on TFR. They’ll also look at people who present with advanced disease — especially blast crisis, where the success of treatment is not as good as we would like. 

How has this journey as a clinical investigator been for you? It must be satisfying to see TFR helping patients live their lives without medication? 

I’ve seen how the disease has changed from when I first started. The only treatments for CML back then controlled the blood counts but not the disease. If you were 40 years of age or younger — and had a sibling who matched you — you could have a stem-cell transplant, but when you consider the average age of diagnosis is around 65, the majority of patients weren’t even eligible by age. It was a small percentage of patients who did well. Now, there’s near-normal survival for virtually everybody, so that’s been great to see. You don’t often see an evolution like that in your career. 

Are you enjoying your retirement?  

Well, I’m bored out of my tree and driving my wife nuts. She’s standing in the background now nodding her head.