When should tyrosine kinase inhibitor (TKI) therapy be discontinued for chronic myelogenous leukemia (CML)?

Updated: May 23, 2021
  • Author: Emmanuel C Besa, MD; Chief Editor: Sara J Grethlein, MD, FACP  more...
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Answer

Discontinuing TKI therapy for certain patients, an approach first put forward in 2006, has the potential to reduce side effects associated with lifelong TKI therapy and to be cost-effective measure. Treatment-free remission (TFR) is achieved when a patient who has discontinued TKI therapy maintains an MMR and does not need to restart therapy.

Several guidelines provide recommendations on discontinuation of TKI treatment. European LeukemiaNet guidelines recommend that patients with CML who are responding optimally to treatment continue it indefinitely, but advise that treatment discontinuation may be considered in individual patients, especially women of childbearing age who have achieved an optimal response and are considering pregnancy. [23]

European Society for Medical Oncology (ESMO) guidelines advise that treatment discontinuation may be considered in individual patients, provided that proper, high-quality and certified monitoring can be ensured. [22]  ESMO prerequisites for safe discontinuation include the following:

  • Meeting institutional requirements for safe supervision
  • Identification of typical  BCR–ABL1 transcripts at diagnosis
  • At least 5 years of TKI therapy
  • Achievement of MR4.5 (ie, molecular response with 4.5-log reduction)
  • Stability of deep molecular remission (at least MR4) for at least 2 years 

NCCN guidelines state that discontinuation of TKI therapy appears to be safe in select CML patients, but recommend consultation with a CML specialist to review the appropriateness for TKI discontinuation and potential risks and benefits, and advise that some patients have experienced significant adverse events that are believed to be due to TKI discontinuation. [21]  NCCN criteria for discontinuation are as follows:

  • Age ≥18 years.
  • Chronic phase CML, with no prior history of accelerated or blast phase CML
  • On approved TKI therapy for at least 3 years.
  • Prior evidence of quantifiable  BCR-ABL1 transcript
  • Stable molecular response (MR4;  BCR-ABL1 ≤0.01% IS) for ≥2 years, as documented on at least 4 tests, performed at least 3 months apart.
  • Access to a reliable quantitative PCR test with a sensitivity of detection of at least MR4.5 ( BCR-ABL1 ≤0.0032% International Scale [IS])

For monitoring after TKI discontinuation, the NCCN recommends monthly molecular monitoring for 1 year, then every 2 months for the second year, and every 3 months thereafter (indefinitely) in patients who remain in MMR (MR3; BCR-ABL1 ≤0.1% IS) 

The NCCN recommends prompt resumption of TKI within 4 weeks of a loss of MMR, monthly molecular monitoring until MMR is re-established, then every 3 months thereafter, indefinitely. In patients who fail to achieve MMR after 3 months of TKI resumption, BCR-ABL1 kinase domain mutation testing should be performed, and monthly molecular monitoring should be continued for another 6 months. [21]

In general, patients in the chronic phase of CML with a stable, prolonged, and deep molecular response (DMR) for ≥2 years might be ready to discontinue TKI therapy. [70, 71, 21, 20]

Patients who have achieved an MMR/MR but have not reached a DMR and are therefore not eligible to attempt TFR should be reassured by their physicians that they have still reached a treatment goal or safe haven and can continue receiving TKI treatment and have a similar life expectancy to that of the general population. If these patients continue to adhere to treatment they may in time reach a deeper molecular response, at which point, once sustained, TFR might be an option.

If a patient wishes to stop treatment because of problems with the TKI, the physician should discuss with the patient the possibility of switching to a second-generation TKI that might enable achievement of a deeper molecular response. At this time, the patient should be advised about the adverse-effect profiles of TKI treatments. 

Before discontinuing TKI therapy, the physician needs to confirm that the patient understands the need to attend more-frequent routine clinic visits (eg, montlhly for the first year) and undergo regular and lifelong monitoring. TFR does not mean a cure, and molecular recurrence can develop at any time, requiring TKI treatment to be restarted. Clinical monitoring will also enable the identification of long-term toxicity of previous TKI therapy. 

The treating physician should discuss TKI withdrawal syndrome with patients thinking about discontinuing TKI therapy. TKI withdrawal syndrome is seen in up to 30% of patients and can last for months. The syndrome consists principally of musculoskeletal pain. Generally, the pain can be managed with over-the-counter pain medications such as acetaminophen or nonsteroidal anti-inflammatory drugs. In more severe cases, corticosteroids may be indicated.

TKI withdrawal syndrome does not appear to be dependent on the particular TKI the patient was taking, and its occurrence has been associated with a greater chance of achieving successful TFR.

Screening for potential psychological issues associated with TFR should form a part of routine monitoring, because certain patients may require professional psychological help. Physicians should also be aware that patients could experience anxiety as a result of fluctuating BCR-ABL blood levels during TFR. The main anxiety that patients have experienced is a fear of disease recurrence or progression.

About 82% of patients would be willing to stop TKI therapy if their disease were likely to remain stable and, if treatment needed to be restarted, the probability of a response to TKI therapy were high. [70] Patients were also more likely to attempt TFR if their risk of recurrence was < 30%; in fact, 40% to 60% of patients sustain TFR for longer than 1 to 2 years. Most cases of molecular recurrence will develop within the first 6 months of stopping TKI therapy, and the confirmed loss of MMR should be seen as an indication to restart therapy. Late molecular recurrences do develop; thus, patient adherence to monitoring during TFR is vital to detect recurrence and ensure protection from disease progression.  

Factors that are potentially predictive of molecular recurrence include previous TKI treatment duration and previous duration of DMR. Studies have shown that resuming TKI therapy immediately after the loss of MMR results in regaining MMR in almost all patients. No risk, to date, has been found of developing resistance to TKIs, and attempting a second TKI discontinuation after molecular recurrence is possible, once a prolonged DMR has again been achieved. Some data have shown this might be effective in ∼30% of cases after an adequate duration of the re-achieved DMR. The speed of molecular recurrence after the first attempt at TFR was the only factor associated with a poorer outcome with the second attempt.  

Worldwide, more than 2000 patients with CML have attempted TFR, and no instances of disease progression have been reported. Attempting TFR may become a standard part of CML care, and with patients’ concerns addressed in patient–physician discussions, a greater number of eligible patients will be willing to discontinue TKI therapy and attempt TFR outside a clinical trial.


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