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TFR in CML
Treatment-Free Remission for Patients With CML: Where Are We Now

Released: September 21, 2020

Expiration: September 20, 2021

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Prior to the introduction of tyrosine kinase inhibitors (TKIs), most patients with newly diagnosed chronic myeloid leukemia (CML)  had an expected median survival of about 4 to 5 years. Today, most patients on TKI therapy may have a normal life expectancy. One of the ongoing challenges in managing patients with CML is to offer the possibility of treatment-free remission (TFR) and even potential cure to as many patients as we can. TFR is an important treatment goal and very attractive to patients, as we know that a significant proportion of patients have the chance of achieving this goal. In this commentary, I share my thoughts on TFR in the setting of initial therapy for CML.

Critical Milestones in First-Line CML
In order to determine whether patients with CML are eligible for treatment discontinuation after first-line TKI therapy, we need to define the critical milestones that patients have to achieve. These criteria have been developed by major societies around the world and are generally quite homogeneous: Patients must achieve an “optimal” response, which is defined as BCR‑ABL1 transcripts < 10% at 3 months and even lower BCR‑ABL1 transcript levels with longer TKI treatment. At any time past 12 months, an optimal response is consistently defined as BCR‑ABL1 transcripts < 0.1%.

STIM Study
The trial that piloted the concept of TFR was the French STIM study. This trial enrolled a select cohort of patients with CML in complete molecular remission on imatinib who were allowed to stop treatment if they had a sustained complete molecular remission for at least 2 years. Almost 40% of the patients who had stopped imatinib treatment did not relapse, which was a major but welcome surprise to many investigators, including myself. In the study it appeared that molecular recurrence plateaued about 18 months after stopping treatment, with no additional relapses reported from 24 months through almost 8 years of follow-up.

EuroSki Study
The STIM study was repeated in Europe in a multinational fashion as part of the EuroSki study reported by Saussele and colleagues. The good news is that this study was able to replicate the findings from the STIM trial with even higher relapse‑free survival rates. Notably, one difference between the 2 studies was that there were late relapses past 18 months in the EuroSki study, although the frequency was rather low.

Possible Criteria for TFR
The results from the STIM and EuroSki studies made it very attractive for doctors and patients to consider discontinuing treatment outside of clinical trials. Therefore, there has been a high demand for defining criteria for safely discontinuing treatment after optimal response to first-line TKI therapy. Cortes and colleagues developed the following potential criteria for choosing TFR as an option:

  • Institutional criteria met (eg, rapid, sensitive monitoring assays and structured follow-up)
  • Low or intermediate Sokal score at diagnosis
  • Typical BCR‑ABL1 transcript at diagnosis
  • A past history of chronic phase CML only
  • Optimal response to first-line TKI
  • Duration of all TKI treatment of > 8 years
  • Achieving a deep molecular response (MR4.5)
  • Duration of deep MR of > 2 years

If patients meet these criteria, it is safe to discontinue TKI treatment. There is still a chance for relapse, but the chance of achieving another deep MR once treatment has been reinitiated is high.

Select Larger Clinical Trials of TFR
The obvious question is whether we can increase the number of patients achieving TFR by using second-generation TKIs as opposed to imatinib as first-line treatment. There are a number of published studies of TFR with imatinib and second-generation TKIs. To be noted, these studies cannot be directly compared because several criteria differed across studies, including the TKIs used, the definition of a deep MR as well as its duration, and the criteria for restarting treatment after relapse.

A recent review article of several TFR studies suggested that there may be a slight correlation between TKI duration period and TFR rate, at least with imatinib as the first TKI. Interestingly, the ENESTFreedom study using nilotinib had a very short median TKI duration prior to TFR, yet a similar TFR rate was observed compared with imatinib studies with significantly longer median TKI duration. So one might conclude that with a second-generation TKI, you may, to some degree, be able to discontinue treatment after a relatively short duration of treatment. Obviously, this is mainly speculation that will require further investigation.

Patient Perspective
In a survey conducted by CML advocacy groups involving more than 1000 patients in 68 countries, important patient perspectives were identified. First, patients have different reasons for wanting to stop treatment, with the foremost being to end toxicities associated with their current treatment. Other patients not experiencing side effects are afraid of developing them in the future with ongoing long-term treatment. Some patients simply do not want to take daily medication or want to test whether they can be disease free without treatment. 

Another important issue to consider in this context is that the side effects that patients experience are often low‑grade, chronic toxicities, not the more clinically important ones such as pleural effusions. Patients actually consider these chronic, low‑grade but persistent side effects—fatigue, rash, and muscle soreness—more significant. Moreover, patients have a strong desire to become better informed about the rationale behind TFR, how to actually discontinue their therapy, and what they can expect once the drug has been stopped.

Take-Home Points
To summarize, it is clear that with the increased survival of patients with CML using TKI therapy, the prevalence of CML is expected to continue increasing. As we establish criteria for identifying good candidates for TFR, we may be able to increase the number of patients achieving TFR with second-generation TKIs, keeping in mind that each TKI has a unique spectrum of nonhematologic side effects. Finally, the patient’s perspective is essential and must be weighed when considering and undertaking TFR strategies.

Your Thoughts?
What are your questions about TFR in patients with CML who achieve deep molecular remissions with first-line TKI therapy? Please share your thoughts and questions in the discussion box below.

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In your clinical practice, do you discuss the possibility of TFR with your patients with chronic phase CML?
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