Tyrosine kinase inhibitors (TKIs) have raised the bar for what chronic myeloid leukemia (CML) treatment can achieve. For most patients diagnosed in chronic phase, the immediate objective is no longer simply to control a life-threatening leukemia, but to achieve durable molecular suppression while maintaining quality of life over decades of treatment.
Treatment-free remission (TFR) describes the maintenance of molecular response after TKI discontinuation. Long-term studies have shown that a good number of eligible patients can remain off therapy, while most who lose molecular response can regain it after restarting treatment.
Achieving a deep molecular response (DMR) is important not only because it demonstrates excellent disease control. In the right patient, sustaining that response long enough may create an opportunity to live without continuous TKI therapy. The role of TFR in modern CML management will be discussed at OncoDaily’s LeukO 2026 Global Virtual Congress on Leukemias, taking place September 3-4.
Treatment-Free Remission Does Not Mean Eradication of CML
TFR should not be interpreted as proof that every leukemic cell has been eradicated. Sensitive molecular techniques can detect residual BCR::ABL1-positive cells in some patients who remain in long-term TFR.
Why disease remains controlled without continued kinase inhibition is not fully understood. Leukemic stem-cell biology and immune surveillance may contribute, but no single mechanism adequately predicts who will maintain TFR. Clinically, the definition is more practical: the patient remains off TKI therapy without losing the molecular response threshold that would require treatment to be restarted.
Who Can Consider Treatment-Free Remission?
Not every patient with a good response to a TKI is ready for discontinuation. The 2025 European LeukemiaNet (ELN) recommendations place several conditions around a TFR attempt. Patients should have:
- chronic-phase disease
- appropriate treatment history
- sustained DMR
- access to high-quality quantitative BCR::ABL1 testing
- the ability to undergo frequent molecular monitoring
The distinction between major molecular response (MMR) and DMR is particularly important. MMR corresponds to BCR::ABL1 ≤0.1% on the International Scale, while DMR is defined as MR4 or deeper.
MR4 corresponds to BCR::ABL1 ≤0.01% IS and MR4.5 to ≤0.0032% IS. TFR studies have generally required sustained MR4 or deeper responses before discontinuation. Disease history matters as well. Current recommendations focus on patients in first chronic phase and generally exclude those with previous accelerated- or blast-phase disease.
What the Major TFR Studies Have Taught Us
The early STIM studies provided proof that TKI discontinuation was possible. Patients with sustained deep responses after long-term imatinib stopped therapy, and a proportion remained in molecular remission without further treatment. Importantly, most molecular recurrences occurred relatively early, establishing the need for intensive monitoring.
EURO-SKI, one of the largest prospective TKI discontinuation studies, showed that longer TKI treatment and DMR duration were associated with a greater likelihood of maintaining molecular remission after discontinuation.
ENESTfreedom evaluated patients who achieved sustained DMR after frontline nilotinib, while ENESTop studied patients who reached sustained DMR after switching from imatinib to nilotinib. Long-term follow-up showed that TFR can remain durable in appropriately selected patients and that most who lose molecular response respond again after restarting nilotinib.
DESTINY explored a different strategy: reducing the TKI dose before complete discontinuation. Patients first underwent a period of dose de-escalation and then stopped therapy if molecular control was maintained. The study demonstrated that discontinuation does not necessarily have to be approached as an immediate transition and helped generate broader interest in dose optimization as part of long-term CML management.
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What Happens After the TKI Is Stopped?
The 2025 European LeukemiaNet recommendations call for frequent BCR::ABL1 monitoring during the first months after stopping, followed by progressively less frequent testing if molecular response remains stable. Long-term monitoring is still required because late recurrence, although less common, can occur.
The key threshold is loss of major molecular response (MMR), defined as BCR::ABL1 >0.1% on the International Scale. Current practice is to restart TKI therapy when MMR is lost. This approach allows recurrence to be detected while disease burden remains very low.
Can We Predict Who Will Remain Treatment-Free?
Longer TKI exposure and longer duration of DMR are among the most consistently associated predictors of successful TFR. EURO-SKI and subsequent studies helped establish the importance of response duration, which is reflected in contemporary ELN recommendations.
Other potential predictors have been investigated, including age, type of BCR::ABL1 transcript, depth of molecular response, immune-cell profiles, and characteristics of residual leukemic populations. None currently provides sufficient individual-level certainty. Molecular monitoring therefore remains necessary even when a patient has several favorable features.
Why Do Patients Want Treatment-Free Remission?
The value of TFR extends beyond removing a tablet from the daily routine. Long-term TKIs can produce chronic low-grade adverse effects, drug interactions, financial burden, and treatment fatigue. For younger patients, pregnancy and family planning may also make treatment discontinuation particularly relevant when it can be attempted safely.
In the LAST study, 172 patients with chronic-phase CML were followed prospectively after stopping TKI therapy. TKI discontinuation was associated with improvements in several patient-reported symptoms, including fatigue, diarrhea, depression, and sleep disturbance, although improvements in broader physical and cognitive functioning were limited.
TFR may also introduce a different burden. Patients who previously relied on daily therapy to control CML may experience anxiety when treatment stops, particularly while waiting for frequent molecular results. Studies examining quality of life after TKI discontinuation show that the experience of TFR is not defined only by fewer adverse effects, confidence in monitoring is also important.
TKI Withdrawal Syndrome
Stopping therapy can occasionally produce symptoms of its own. A proportion of patients develop musculoskeletal pain or stiffness after TKI discontinuation, commonly described as TKI withdrawal syndrome.
Symptoms most often involve the shoulders, hips, extremities, or other sites and usually appear within the first weeks or months after stopping. They are generally manageable and often improve over time, though some patients require analgesic or anti-inflammatory treatment. Reviews of TFR experience have consistently identified withdrawal syndrome as a clinically relevant consequence of discontinuation.
This is worth discussing before a TFR attempt because patients may reasonably expect stopping therapy to immediately reduce treatment-related symptoms.
TFR Is an Option, Not the Goal for Every Patient
For many patients, continuous TKI therapy will remain the appropriate strategy. Some will not achieve the sustained DMR required for discontinuation, while others may satisfy molecular criteria but prefer to remain on treatment. TFR is therefore an option for selected patients, not a universal endpoint of CML therapy.
The 2025 ELN recommendations place TFR within long-term CML management while continuing to emphasize durable disease control and individualized TKI selection. The evolving role of TFR will be discussed at LeukO 2026, including who may be eligible, when discontinuation can be considered, and how it should be managed in clinical practice.
