Emerging Agents, TKI Discontinuation Focal Points of CML Research

Neil P. Shah, MD, PhD

Patients with chronic myeloid leukemia(CML) who discontinue treatment on a tyrosine kinase inhibitor (TKI) may potentially achieve a durable treatment-free remission (TFR), according to long-term findings of clinical trials, including the ENESTop study.

In the study, patients with CML who sustained a deep molecular response for at least 2 years on second-line nilotinib (Tasigna) were taken off treatment. MR^4.5 was determined as the response criteria to be eligible for TKI discontinuation. At a follow-up of 48 weeks, 57.9% of patients remained in TFR; after 96 weeks, 53.2% remained in TFR.

Nilotinib was restarted upon loss of major molecular response or confirmed loss of MR4.

In December 2017, the FDA updated the label for nilotinib with a provision stipulating that patients with Philadelphia chromosome-positive CML in the chronic phase who received nilotinib for at least 3 years and have achieved specific predetermined criteria may be eligible to stop treatment.

Neil P. Shah, MD, PhD, said that TKI discontinuation is feasible, as long as clinicians follow National Comprehensive Cancer Network (NCCN) guidelines.

OncLive: Please provide an overview of your presentation.

What are some of those frontline therapy considerations?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Shah, a professor of medicine and leader of the Hematopoietic Malignancies Program at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed emerging agents and the TKI discontinuation approach in the landscape of CML.Shah: I covered 3 general topics. One was frontline agents that we have for CML and updates on bosutinib (Bosulif). We also discussed the status of TKI discontinuation studies. Lastly, I spoke about some investigational agents that have promise for a mutation that is resistant to all TKIs except for ponatinib (Iclusig).For a number of years, we have had 3 frontline options. Recently, bosutinib joined the mix as our fourth option. It was the result of the head-to-head study comparing 400 mg of bosutinib to 400 mg of imatinib (Gleevec). It showed that after 12 months, there was an improvement of the genetic and molecular response rates.

Could you elaborate on the findings from ENESTop?

Is TKI discontinuation viable, and what are the criteria in place for this approach?

This was an update of 2 years of follow-up, which more or less confirmed these data. It provided a sense of how tolerable the drug is compared with imatinib. There are some toxicities that are more common with bosutinib, like gastrointestinal toxicities, but we will figure these out. It’s still early, and it’s looking favorable.The 144-week results of ENESTop showed that patients who achieve a 4.5 log reduction with nilotinib have approximately a 50% chance of maintaining that remission. Encouragingly, there have been no patients getting blast-phase disease. The majority of patients who had to restart therapy were able to regain their deep molecular response. There is TKI withdrawal syndrome reported in some patients, so it is something clinicians should be aware of.Outside the context of a clinical trial, TKI discontinuation is something the NCCN thinks is a reasonable thing to do under very select circumstances. I would refer people to the NCCN website to review the criteria. They require no history of accelerated disease, and it should be only done in adults; patients obviously have to consent to it. We would also like to see a deep response for at least 2 years.

Is a second-generation TKI best to get patients into the discontinuation strategy?

What are some of the investigational agents you mentioned?

Generally speaking, how would you describe the treatment of patients with CML as it stands today?

If patients decide they want to discontinue [treatment], they have to first be counseled about the potential risks. The primary risk we see is muscular pain associated with this; they should know there’s a possibility that may develop. We haven’t seen a result of advanced disease based on TKI discontinuation. To date, the experience is still relatively limited in the grand scheme of things.Studies have shown that second-generation agents get more patients into the deep molecular response required for TKI discontinuation. Once they get to that level of response, it appears they have pretty much the same level of response to [the first-generation TKI] imatinib. It has about a 50% chance of being successful.Two of the more mature investigational agents are ABL001, also known as asciminib. The other is PF-114. Both of these have promise. PF-114 is a little more traditional and binds where the other TKIs bind, whereas ABL001 is a little more of a novel agent. Ideally, with a cleaner safety profile, we can get these agents moving forward.We have, of course, 4 great options for frontline treatment. The majority of patients will be able to identify 1 agent that is effective and tolerable. We anticipate the majority of patients to die from causes completely unrelated to CML and its therapies. It’s great news. The prognosis of the disease is great.

Mahon F, Boquimpani C, Takahashi N, et al. Long-term treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after stopping second-line (2L) nilotinib: ENESTop 144-wk results. J Clin Oncol. 2018;36(suppl; abstr 7003). meetinglibrary.asco.org/record/161736/abstract.