Elements of Treatment Discontinuation Weighed in CML

Christopher S. Seet, MD, PhD, discusses elements of treatment discontinuation in chronic myeloid leukemia.

Christopher S. Seet, MD, PhD

The potential for treatment discontinuation among patients with chronic myeloid leukemia (CML) who achieve a sustained deep molecular response to either a first- or second-generation TKI has been well established. Now, investigators are waiting on further follow-up to assess the long-term effects of treatment cessation on patient outcomes, said Christopher S. Seet, MD, PhD.

Several trials have been conducted to evaluate the safety and feasibility of TKI cessation. Among the most notable is the ENESTop trial, which demonstrated durable treatment-free remissions (TFRs) and regainable molecular responses upon relapse. In the trial, patients in chronic phase who achieved a deep molecular response of MR4.5 on second-line nilotinib (Tasigna) after ≥2 years on nilotinib and >4 weeks on imatinib (Gleevec) discontinued treatment. Among patients who stopped nilotinib, 57.9% remained in remission at week 44, while 46.0% remained in remission at week 192. Among patients who restarted nilotinib, 93.2% were able to regain MR4.5.

Given that the ENESTop trial had very strict inclusion criteria, investigators are also evaluating the viability of treatment discontinuation among patients who don’t achieve as deep of a molecular response to TKI therapy.

“We know the duration of treatment on a TKI as well as the duration of a deep molecular response is highly predictive of maintaining a TFR,” said Seet. “However, we don't know at what level we can stop treatment.”

When it comes to deciding between first- and second-generation agents, Seet explained that the decision is largely based on toxicity. However, second-generation agents are more likely to trigger a deep molecular response.

In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Seet, a hematologist and oncologist at UCLA, discussed the elements of treatment discontinuation in CML.

OncLive: Could you discuss the potential for treatment discontinuation in patients with CML?

Seet: TKIs are extremely effective in patients with CML. The life expectancy of patients in chronic phase on TKIs is approaching that of the general population. One of the big questions now is whether patients who achieve a deep molecular response on TKIs can discontinue treatment for any length of time. This is a big question for patients, as it positively impacts quality of life, lowers their risk of adverse events, and, in some cases, the expense of these treatments. Moreover, we don’t know what the long-term toxicity profile of TKI therapy is.

Several clinical trials have been conducted in this area, and most of them are still ongoing are showing that patients who achieve deep molecular responses to either first- or second generation TKIs can maintain a TFR following discontinuation. I spoke about the ENESTop trial which evaluated second-line nilotinib following failure on or intolerance to frontline imatinib. The trial showed that even after switching from a first-generation TKI to a second-generation TKI, patients who achieve a deep molecular response can maintain a durable TFR.

What questions remain following the ENESTop trial?

ENESTop had very stringent criteria for treatment discontinuation. As such, one of the big questions is whether these treatment criteria can be somewhat relaxed. Perhaps the criteria can be relaxed so that patients who don’t achieve as deep of a response could still discontinue treatment and maintain a deep TFR.

The second thing that is unknown is the long-term survival outcomes of patients who stop their TKI therapy, even those who can maintain a durable TFR. For example, what is the relapse rate going to be?

These studies are ongoing. ENESTop and similar ones with dasatinib (Sprycel) are still in early stages. We’re really only analyzing interim data right now at the 2-year mark. However, we will get data up to the 5-year mark, which should provide a fairly good indication of longer-term results. I'm not aware of any studies that are specifically designed to look at long-term survival in patients who either discontinue or continue long-term TKI therapy.

How are you deciding which TKI to give patients?

In terms of first-line treatment, the progression-free survival and overall survival data are comparable between a first-generation TKI, such as imatinib, versus a second-generation TKI. There's really no right or wrong answer. We do know that second-generation TKIs—such as nilotinib, dasatinib, and bosutinib (Bosulif)—have a more rapid onset to achieving a deep molecular response. The percentage of patients who achieve a deep molecular response can be high with a second-generation agent. That being said, many patients who switch from a first-generation TKI to a second-generation agent because they did not achieve a deep molecular response can go on to achieve one in the second-line setting. Much of the decision has to do with toxicity profiles, as well as patient risk. Patients with high-risk factors may steer you toward the use of a second-generation TKI over a first-generation drug.

Is there any rationale to explore more novel agents?

There's definitely room for novel agents in the treatment of patients who are refractory to first- and second-generation agents. Ponatinib (Iclusig) is a third-generation TKI that targets CML harboring a T359 mutation. However, [we would reserve that option for] one of the last lines of treatment in these patients. Can additional targeted therapies or immunotherapies come into that setting and compete with the current standard of care: allogeneic stem cell transplant? There's definitely room [to explore those options further] in CML.

Hughes TP, Boquimpani C, Takahashi N, et al. ENESTop 192-week results: Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after stopping second-line (2L) nilotinib (NIL). J Clin Oncol. 2019;37(15 suppl; abstr 7005). doi: 10.1200/JCO.2019.37.15_suppl.7005.