Treatment Discontinuation Achievable in Select Patients With CML

Ehab Atallah, MD

The majority of patients with chronic myeloid leukemia (CML) can expect a similar lifespan as the general population due to the advancements in therapy over the last few years. Now, the concern in the CML space is selecting optimal patients for treatment discontinuation, said Ehab Atallah, MD.

“The field is really changing; CML was a pioneer in getting patients to a deep response and improving overall survival,” said Atallah, an associate professor of medicine at the Medical College of Wisconsin Division of Hematology and Oncology. “Now, we are moving into getting these patients off-drug.”

Moreover, research has been and continues to be conducted to determine which patients will benefit from discontinuation from tyrosine kinase inhibitors (TKIs). Previous trials showing the feasibility of TKI discontinuation include the STIM1, ENESTop, and EURO-SKI studies.

OncLive: What is the current state of CML care?

What studies have evaluated TKI discontinuation for patients with CML?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Atallah, associate professor of medicine, Division of Hematology and Oncology, Medical College of Wisconsin, discussed the discontinuation of treatment for patients with CML.Atallah: CML has gone from a disease requiring transplant to now just needing a pill every day. Survival is similar to the general population, and the new paradigm is trying to get patients to stop therapy. The concept is called treatment-free remission. Now that patients are doing well, we want to get them off the drug, improve their quality of life, and reduce cost.Going back to 2010, the first study [STIM1] had a carefully selected group of patients who were doing very well and in a deep remission stop their drug, and only half of them needed to restart. Based on that study, there have been multiple studies across the world that have enrolled more than 2000 patients. Now we know that this approach is safe for a select group of patients.

How do you decide whether therapy should be stopped in a given patient?

One of the studies that was done recently was the ENESTop trial. How this is different than all the other trials is it enrolled patients who were resistant to imatinib (Gleevec) or were on imatinib first and then switched to nilotinib (Tasigna). Not all patients were resistant to imatinib; some of them were physician-choice [switches] or were intolerant to imatinib and switched to nilotinib. Once these patients who received nilotinib were in a sustained deep molecular response, they stopped nilotinib. The rates of successful treatment-free remission are about 50%—so very similar to other studies for stopping TKIs in the frontline setting.That is a very important question. The criteria for [discontinuation] are very clear in the NCCN guidelines. Patients have to be in a chronic-phase CML, not an advanced phase. They must be on-drug for at least 3 years and have a sustained deep molecular response. They also have to be compliant patients; they have to be willing to come in every month to get their lab checked for at least 6 months, and then every 2 months for 18 months. These are the patients who you would consider stopping therapy for.

Considering the success in the CML treatment landscape, is there rationale to continue to explore novel agents? Or, are you content with what is available?

Having said that, there are also physician criteria. The physician should be ready to take care of those patients. It sounds simple, but those who stop therapy need to be monitored closely, and results have to be followed. You need a good group of healthcare providers who are willing to care for these patients.Thank you for asking this—we are not happy with what we have. We [administered] a patient survey asking the question, "Are you happy with what you have?" Patients clearly expressed that they are very grateful for where they are, but they are not happy with it. You look at a survival curve, and you see that the survival for patients with CML is similar to the general population, which is great. However, for patients, they have to take a drug every day for the rest of their lives. They don't want that. We need to do better than where we are right now.

If you have 100 patients with newly diagnosed CML, only half of them will get to that sustained deep molecular response that we can consider stopping for. Of that half who are eligible for discontinuation, only half of them will be able to stop. Therefore, looking at the big picture, you end up having 70% to 80% of patients with CML who have to stay on treatment forever. There are many reasons [a patient] does not want this, such as quality of life and cost.

Are these agents still in early phases of evaluation?

Opinions on immunotherapy in hematologic malignancies have been mixed. What is the potential in CML?

We are trying to move the field forward and get patients off these drugs by adding other active agents in CML for a limited period of time, and then trying to get them to stop again. These efforts in the United States are being done through the H. Jean Khoury CML Consortium, which is a group of physicians interested in the treatment of patients with CML who want to move the field forward.In the United States, there are multiple studies. The study that will hopefully be going through the consortium very soon is ruxolitinib (Jakafi). Dr Kendra Sweet from Moffitt Cancer Center is the principal investigator on that study. There is also a study looking at adding immunotherapy to patients receiving a TKI who have not achieved sustained deep molecular response. At The University of Texas MD Anderson Cancer Center, researchers are looking at adding venetoclax (Venclexta) to TKI therapy earlier on in the treatment course to see whether that leads to better responses.There is very good preclinical rationale, but only a clinical study will tell. As I mentioned, the issue that we are facing in CML is that the survival is similar to the general population. If you have someone who has a similar survival to the general population, we don't think that it is ethically right to give them a lot of adverse events (AEs) just to do clinical trials as opposed to a disease where the survival is shorter. You have a larger margin for accepting AEs in those diseases.

Is there anything else about CML that you would like to add?

Immunotherapy was the very first treatment for patients with CML [in the form of] bone marrow transplant or stem cell transplant. We think there is role, but how is it balanced with the AEs of immunotherapy? We don't know.The main take-home message is that treatment-free remission, or getting patients off-drug, is a feasible option, but we must follow the guidelines. And, it is only for a select group of patients.