Dr Atallah Assesses Outcomes Following the Discontinuation of TKIs in CML

This study, the life after stopping TKI, the last study, was our NIH-funded study looking at patients with CML and seeing if they can stop their drug. We started this study back in 2014. Dr. Kathryn Flynn and I are Co-PIs and we collaborated with multiple investigators in the US.

At that point, there was some data from some trials, especially the first one that came from France and Australia that patients with chronic myeloid leukemia who are doing really well, are in a sustained remission for a couple of years are able to stop their drug. We wanted to test this in the US in a larger study. That is why we initiated the study in 2014.

There was some background back then. A little bit more background about CML. CML is chronic myeloid leukemia. Approximately 6,000 to 7,000 patients are diagnosed with this each year. Patients receive tyrosine kinase inhibitors or TKIs, which are oral pills for their treatment. There is four of them that are FDA-approved for frontline and five overall approved.

Patients with CML take these drugs. They take a pill every day and they do really well. The survival, at least from a Swedish registry, for patients with CML is similar to the general population. These are pretty awesome results for treatment of leukemia. Prior to that, patients needed a stem cell transplant to be cured.

Now, our focus in CML is to try to improve patients' quality of life and make them feel better. One of the ways to do that is to get them off-drug. This was the reason of why to try to get people off-drug is to improve their quality of life, make them feel better, they're not on medication.

The bigger picture, financial toxicity to the patient, to the nation, a win-win situation if we could get people off-drug. In this study, we enrolled 172 patients with CML.

These are a select group of patients with CML, patients who were not resistant to any tyrosine kinase inhibitor before, were in the chronic phase, were on drugs for at least three years, and were in a deep remission, what os called MR4 or less than 0.01% for at least two years. We enrolled these patients in the study, stop their drug, and monitored them closely with two things.

We did PCRs. We did a PCR monthly for the first 6 months, then a PCR every 2 months for 18 months, and then a PCR every 3 months, essentially, forever. At the same time, with these PCRs, we collected quality of life in patients' reported outcome data to show if patients feel better once they get off their drug.

Our results are pretty consistent overall with other international studies. In this, about 112 patients or 65% stayed in MMR. 60% stayed off their drug. To explain that a little more, patients stopped if their level was below 0.01% for at least two years. We would only restart if their PCR goes above 0.1%.

In other words, there are patients who could have a detectable level of PCR-able but we do not start their drug. We continue to watch them until they lose MMR. The second thing is there are some patients who, despite not losing MMR, still restarted their drug.

Some of those were because patients were nervous, the physician was nervous, they were very close to losing MMR, and also, some of the toxicity of stopping the drug, which was something that's being more and more reported which I will talk about in a little bit, the withdrawal syndrome.

We also did two types of PCR. A digital PCR, which is a sensitive PCR, and a regular PCR or a RQ-PCR. Digital PCR is FDA-approved but it is not available everywhere. It is currently FDA-approved for use. We found that patients who were negative by both the digital PCR and the PCR at the time of discontinuation had the best chance of staying in remission.

Also, patients who were negative at the time they discontinued and stayed negative at three months, those patients had a very small chance of relapse or of losing MMR with only 10% of those patients relapsing. Those results are quite significant.

In that way, if we have a patient who was negative by both RQ-PCR and digital PCR at the time they discontinued then they are negative again at three months, we can tell this patient, "You know, you have a 90% chance of staying in remission." That's a really good thing to let the patient know or a pretty good predictor.

The other thing we found is that patients did feel better. At 12 months, 80% of patients had an improvement in their fatigue. 34% had improvement in depression. Many patients also had improvement in their diarrhea.

What was also a little concerning when patients discontinued drug, the best way I describe it to patients, I tell them, "Discontinuing drug, you really have a possibility for three major side effects." First one is needing to come in to get labs frequently.

The first thing is needing to come in, get your labs checked once a month for six months and every two months increases the burden a little bit on the patient in terms of testing and coming into the institution for the first year or so.

The second thing is withdrawal syndrome. It was previously reported, and we found in our study, that about 30% of patients get some kind of joint pain that's not very clear why they get this joint pain.

Lastly, anxiety. Patients think of it as having CML all over again where before they decided to join the study or before they decided to try to stop drug, they would get their labs checked every three months. They would take a pill every day and settled into their routine.

Now, with the trial of discontinuation, things act up again where they have to think about going in to get checked. They come to see me, "Is my PCR positive? Will I need to restart the drug?" Brings back a lot of this anxiety.

In summary, the study added to the evidence that for patients with CML who are in a deep remission, sustained deep molecular response, we can discontinue their drug as long as they are monitored closely and restart their drug when they relapse. We can tell patients that when they discontinue the drug, they will feel better to some degree.

It is not like they will suddenly be running marathons again, but their symptoms will improve. We can also warn them of the muscular-skeletal side effects or the withdrawal, counsel them about the need to come in for the labs and how important that is, and also counsel them about the time to restart, that it could be a stressful time for them.

This study and the collaboration we had in the United States across all the centers has led to the formation of the H. Jean Khoury Cure CML Consortium, which is a large group of CML experts across the nation. Our goal is to improve the clinical care and outcome of patients with CML. Our main goal is to cure patients with CML where essentially all patients are off drug and in remission.

In the big picture, if we think of 100 newly diagnosed CML patients, approximately half of them will get to that deep remission that they can consider stopping. Like I talked earlier, about half of those will be able to discontinue their drug. At the end of the day, between 20 and 30 patients will have a successful treatment-free remission out of every 100 patients who are newly diagnosed CML. Thank you.