Treatment-Free Remission in Chronic Myeloid Leukemia

Patient Selection and Monitoring

The National Comprehensive Cancer Network recommends that approximately 40-50% of eligible patients can successfully discontinue TKI therapy without experiencing molecular relapse, for carefully selected CML-CP patients who have maintained a deep molecular response for at least 2 years on TKI therapy 1, 2
High-quality internationally standardized, accurate, sensitive qRT-PCR laboratory is required for patient selection 3, 4
Patients with non-high Sokal score at diagnosis, typical b2a2 or b3a2 BCR-ABL1 transcripts, and chronic phase disease are eligible for TFR 4
Optimal response to first-line therapy, duration of TKI therapy > 5 years, and achievement of MR4.5 are also required for TFR eligibility 4
Duration of deep molecular response (MR4 or MR4.5) > 2 years is necessary for TFR 4, 2

Monthly molecular monitoring during the first 6 months, every 2 months for the subsequent 6 months, and every 3 months indefinitely thereafter is essential after TKI discontinuation 5, 2
Molecular relapse is defined as loss of major molecular response (MMR; BCR-ABL1 >0.1%) 5, 2
Most relapses occur within the first 6 months after discontinuation 5, 2
Resumption of TKI therapy immediately after relapse results in regaining deep molecular response in almost all patients 2

Approximately 40-60% of patients maintain TFR after discontinuation 2
The STIM1 study showed 38% TFR rate at 60 months with imatinib 2
Second-generation TKIs (dasatinib, nilotinib) may achieve higher rates of deep molecular response, potentially increasing TFR eligibility 3
High-risk Sokal score and stable deep molecular response duration before TKI suspension < 5 years are associated with higher risk of molecular relapse 4, 3

About 50% of children treated with at least 3 years of imatinib who maintain stable deep molecular response for at least 2 years can discontinue TKI permanently without molecular relapse 5
TFR attempts should be limited to children in CML-CP who have not experienced previous progression, treatment failure, or warning signs 5
The approach to TFR should be individualized and carefully addressed after discussion with parents/caregivers 5

Successful TFR reduces healthcare costs 5
All patients should be informed that TFR is a treatment goal but not a cure, and lifelong monitoring is required 6

Chronic‑phase CML patients may consider TFR only when they achieve a deep molecular response (MR4.5, defined as BCR‑ABL1 ≤ 0.0032 % on the International Scale) and meet defined duration thresholds [7][8].
The deep molecular response (MR4 or MR4.5) must be sustained for at least 2 years as measured by a standardized laboratory [7][8].
Patients must have received a tyrosine‑kinase inhibitor (TKI) for > 5 years before attempting discontinuation [7][8].
An optimal response to first‑line TKI therapy is required (i.e., achievement of at least MR4) [7][8].
Only patients who are in the chronic phase of CML are eligible for TFR [7][8].
At diagnosis, a low or intermediate Sokal risk score (non‑high) is a prerequisite for TFR eligibility [7][8].
The presence of typical BCR‑ABL1 transcripts (b2a2 or b3a2) or atypical transcripts does not preclude TFR, provided other criteria are met [7][8].

The treating centre must have access to a high‑quality, internationally standardized quantitative RT‑PCR assay that is both precise and sensitive [7][8].
PCR results must be returned within 4 weeks to allow timely clinical decisions [7][8].
The laboratory should be capable of providing PCR testing at intervals of 4–6 weeks when clinically indicated [7][8].
A structured clinical follow‑up system must be in place to enable rapid intervention if molecular relapse occurs [7][8].

Molecular relapse is defined as loss of major molecular response (BCR‑ABL1 > 0.1 % IS) 9.
Upon detection of molecular relapse, immediate reinstatement of TKI therapy is mandated 9.

Prior to any TFR attempt, strict adherence to the current TKI regimen must be confirmed, especially in adolescent patients 10.
Patients with a history of disease progression, prior treatment failure, or any warning signs (e.g., rising BCR‑ABL1 levels) are contraindicated for TFR 10.