Insights into Treatment-Free Remission (TFR) outcomes in Chronic Myeloid Leukaemia (CML) – a tertiary centre experience in Malaysia

Abstract

Purpose

Tyrosine kinase inhibitors (TKIs) have improved the prognosis of chronic myeloid leukaemia (CML), allowing patients with favourable disease profiles and molecular responses to attempt treatment-free remission (TFR). We aim to establish the relapse-free survival (RFS) outcomes and identify prognostic factors for successful remission maintenance among those who attempt TFR.

Methods

Adult CML patients who had undergone TFR from January 1, 2016, to June 30, 2024, were included. Upon TKI discontinuation, real-time quantitative polymerase chain reaction (RQ-PCR) was monitored monthly for the first 12 months, then every 3 months, with TKI reinitiated upon a transcript level above 0.1% (IS). Data analysis was performed using SPSS version 29.0 (SPSS Inc., Chicago, IL, USA).

Results

Fifty-seven patients (27 males and 30 females) with a median age of 46 years (range 16 – 70) were analysed. The majority had a low EUTOS long-term survival (ELTS) score (61.4%, n = 35) and received imatinib (87.7%, n = 50). The median treatment duration was 8.8 years (range 4.2 – 18.8), and the median duration for sustained deep molecular remission (DMR) was 4.6 years (range 2.1 – 11.1). RFS was 70.2% at 6 months, 62.5% at 12 months and 56.8% at 2 years after a median follow-up of 34 months (range 9 – 101). The MR5 level was identified as an independent factor associated with sustained remission. All relapsed patients achieved DMR upon treatment reinitiation.

Conclusion

Treatment discontinuation can be safely performed, with many achieving long-term treatment-free remission. A deeper molecular response (MR5) is associated with an improved likelihood of remission maintenance.

Introduction

Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm characterised by the expression of breakpoint cluster region/Abelson murine leukaemia viral oncogene 1 (BCR-ABL1) [1]. The availability of tyrosine kinase inhibitors (TKIs), starting with the first-generation imatinib, has demonstrated significant efficacy by achieving good cytogenetic responses and preventing progression to advanced phases of CML [2, 3]. Second-generation TKIs, such as nilotinib, dasatinib, and bosutinib, have shown faster and deeper molecular responses, with a higher proportion of major molecular response (MMR) rates [4–6]. Third-generation TKIs, including ponatinib and asciminib, which specifically target the ABL Myristoyl Pocket (STAMP), are effective for patients resistant to or intolerant of frontline therapies [7, 8]. As a result, the prognosis for CML patients has greatly improved, with survival outcomes comparable to those of the age-matched general population.

The focus of CML management has thus shifted from solely improving survival to reducing adverse effects from long-term TKI use and alleviating the financial burden of continuous treatment [9]. This has led to the identification of patients with favourable disease features and excellent molecular responses as potential candidates for treatment discontinuation. Patients treated with imatinib were the first to be assessed in the STIM1 trial, which included those on treatment for over three years and who achieved a complete molecular response (CMR) for at least two years [10]. About 40% of these patients were in molecular remission at 12 and 24 months, and a long-term follow-up revealed sustained remission. The trial demonstrated that, following optimal TKI therapy, selected patients could be considered effectively cured. Subsequent trials involving second-generation TKIs have aimed to refine criteria for eligibility and identify predictors of long-term remission [11–14]. Collectively, these studies showed a common pattern: roughly half of the patients achieved long-term treatment-free remission (TFR) (38% to 60.8% at 24 months), with most relapses occurring within the first six to twelve months. Among those who relapsed, reinitiating TKI therapy and achieving deep molecular remission (DMR) confirmed that discontinuation is safe in appropriate cases.

As such, the European Leukaemia Net (ELN) and the European Society of Medical Oncology (ESMO) guidelines recommend discontinuing TKI and suggest careful selection and monitoring for suitable patients [15, 16]. In Malaysia, treatment discontinuation has been feasible since 2015, initially within clinical trials of the Malaysia Stop Tyrosine Kinase Inhibitor Trial (MSIT) (NCT02381379) and End Tyrosine Kinase Inhibitor in Chronic Myeloid Leukaemia (EnTIC) studies [17]. With the favourable outcomes from these studies, it was later adopted as a routine standard of care in our centre. This study aims to evaluate the clinical outcomes and identify factors that could predict long-term remission in future patients.

Materials and methods

Study design and population

This retrospective observational study included patients aged 18 and above who attempted treatment discontinuation from January 1, 2016, to June 30, 2024, at our centre. Patients with CML in chronic phase (CP) were eligible after receiving first-line TKI for at least 4 years and achieving DMR (BCR: ABL1 (IS) < 0.01%) for at least 2 years. High-risk patients with ABL kinase domain mutations, additional cytogenetic abnormalities, or treatment failure, as defined by the ELN treatment milestones, were excluded. A detailed description of the inclusion and exclusion criteria is provided (Table 1).

Table 1.

Eligibility assessment for patient selection

No.	Inclusion Criteria	No.	Exclusion Criteria
1	Age ≥ 18 years old	1	ABL kinase domain mutation or adverse cytogenetic abnormalities.
2	Males and females (contraception for women of childbearing age)	2	History of accelerated phase (AP) or blast crisis (BC)
3	CML in chronic phase (CP) only	3	TKI failure as defined by the European Leukaemia Network (ELN) criteria
4	Major BCR-ABL transcripts b3a2 (e14a2) and/or b2a2 (e13a2)	4	Active cancers and/or ongoing treatment
5	First-line tyrosine kinase inhibitors (TKI) for ≥ 3 years (switch due to intolerance permitted)	5	History of or planned for hematopoietic stem cell transplantation (HSCT)
6	Deep molecular remission (DMR) of MR 4.0 (<0.01% IS) for ≥ 2 years	6	Renal impairment (CrCl < 50ml/min) or initiated regular dialysis
		7	Liver impairment (ALT > 2x ULN) or active viral infection (Hepatitis B/C and HIV)
		8	Severe comorbidities, including psychiatric illness.
		9	Poor adherence to treatment/defaulted routine follow-up.

CML Chronic Myeloid Leukaemia, CrCl Creatinine Clearance, ALT Alanine transferase, ULN Upper Limit of Normal, HIV Human Immunodeficiency Virus

Real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) using TRUPCR® BCR-ABL1 quantitative kit was monitored monthly for the first 12 months after discontinuation of treatment and every 3 months thereafter in a central laboratory (Clinical Reference Laboratory, Ampang Hospital). A loss of MMR (BCR: ABL1 (IS) > 0.1%) was defined as the criterion for treatment reinitiation (Fig. 1). Following treatment reinitiation, the molecular transcript was monitored every 8 to 12 weeks until the re-achievement of DMR and ABL kinase domain mutations were performed for those who failed to achieve DMR or progressed while on treatment.

Fig. 1.

Patient selection and monitoring algorithm

We collected demographic and disease-related data (European Long-Term Survival (ELTS) score, type of TKI, duration of TKI prior discontinuation, depth and duration of DMR) to identify predictors for long-term remission. Time to the loss of MMR and response to re-initiation of TKI therapy were obtained for relapse-free survival (RFS) analysis and safety evaluation, respectively.

The molecular responses in this study were defined as follows:

• MR4: ≤ 0.01% (IS)

• MR4.5: ≤ 0.0032% (IS)

• MR5: ≤ 0.001% (IS)

• CMR: undetectable BCR: ABL1 with ABL1 control > 100,000 copies in consecutive samples.

Statistical analysis

Data analysis was performed using SPSS version 29.0 (SPSS Inc., Chicago, IL, USA). Clinical characteristics and demographic data were analysed using descriptive statistics. Continuous variables are summarised as median and range. Categorical variables are expressed as absolute and percentage frequencies.

Survival curves were estimated using the Kaplan-Meier method. The potential prognostic effect of covariates for RFS is estimated using univariate and multivariate Cox proportional hazard models and reported by applying the two-sided log-rank test, and P-values < 0.05 are considered statistically significant.

Results

Demographics and treatment characteristics

Fifty-seven patients were recruited, with an equal gender distribution (27 males and 30 females) and a median age of 46 years (range 16–70). Risk stratification was performed using the ELTS score, and the majority of the patients were classified as low risk (61.4%, n = 35), while only 3 patients were categorised as high risk. All patients had major BCR-ABL (p210) transcript. Less than half (n = 28) had a subtype discerning qualitative BCR-ABL transcript performed. Among these patients, 17 expressed e14a2 (b3a2), 10 had e13a2 (b2a2), and 1 patient had both subtypes.

The vast majority received imatinib (87.7%, n = 50) as first-line therapy, while the remainder received nilotinib. This was largely due to the earlier approval of imatinib and its availability through the patient assistance programme. The median duration of treatment was 8.8 years (range 4.2–18.8).

Prior to treatment discontinuation, 18 patients had achieved MR5, and among them, half (n = 9) maintained complete molecular remission (CMR) for at least 12 months. Twenty-one patients (36.8%) achieved MR4.5, while the remainder were MR4. The median duration of treatment for sustained DMR was 4.6 years (range 2.1–11.1). Clinical and treatment characteristics are listed in Table 2.

Table 2.

Baseline clinical and treatment characteristics

Characteristics
Median age (range)	46 years (16–70)
	N = 57 n(%)
Gender
- Male  - Female	27 (47.4) 30 (52.6)
EUTOS long-term survival (ELTS) score
- Low Risk  - Intermediate Risk  - High Risk  - Unknown	35 (61.4) 16 (28.0) 3 (5.3) 3 (5.3)
Tyrosine Kinase Inhibitor
- Imatinib  - Nilotinib	50 (87.7) 7 (12.3)
Median duration of TKI (range)	8.8 years (4.2–18.8)
Median duration of DMR (range)	4.6 years (2.1–11.1)
Depth of Deep Molecular Remission (DMR)
- MR 5.0  - MR 4.5  - MR 4.0	18 (31.6) 21 (36.8) 18 (31.6)

Treatment discontinuation success and safety

With a median follow-up of 34 months (range 9–101), 31 patients (54.4%) achieved long-term TFR. The RFS was 70.2% at 6 months, 62.5% at 12 months, and 56.8% at 2 years (Fig. 2). Twenty-six patients had molecular relapse and required treatment reinitiation. All patients re-achieved DMR at a median time of 5 months (range 2–34 months). Univariate and multivariate analyses identified the MR5 prior to treatment discontinuation as an independent factor significantly associated with sustained remission (Table 3).

Fig. 2.

Kaplan Meier Survival Analysis for Treatment-Free Remission (TFR)

Table 3.

Univariate and multivariate analysis of factors associated with Treatment Free Remission (TFR)

No	Variable	N (% in TFR)	P-value
1	Age < 60 years ≥ 60 years	48 (59.8%) 9 (37.0%)	0.138
2	Gender Male Female	27 (69.5%) 30 (45.0%)	0.103
3	ELTS Risk Stratification Low High and Intermediate	35 (58.2%) 19 (52.6%)	0.801
4	TKI treatment Nilotinib Imatinib	7 (85.7%) 50 (53.3%)	0.181
5	Duration of DMR ≥ 5 years < 5 years	26 (65.2%) 31 (48.4%)	0.280
6	Duration of treatment ≥ 8 years < 8 years	33 (57.9%) 24 (42.1%)	0.106
7	Depth of DMR MR 5 MR 4.5/MR 4	18 (87.2%) 39 (42.9%)	< 0.001

ELTS European Long-Term Survival, TKI Tyrosine Kinase Inhibitors, DMR Deep Molecular Remission

Of the 26 patients who experienced molecular relapse, one was found to harbour a BCR-ABL1 kinase domain mutation—specifically, a phenylalanine-to-cysteine substitution at codon 359 (F359C). She had initially achieved a deep molecular response (DMR) following reinitiation of imatinib. However, molecular progression occurred after a four-month interruption in therapy due to SARS-CoV-2 infection. Upon identification of the F359C mutation, her treatment was switched to dasatinib at 100 mg daily, resulting in achievement of a major molecular response (MMR) with ongoing therapy.

TKI withdrawal symptoms were reported in eight patients (14%), all presenting with musculoskeletal complaints, including arthralgia and myalgia. The severity was predominantly grade 1 or 2 and was effectively managed with analgesics. No patients required reinitiation of TKI therapy.

Discussion

This real-world analysis confirms that TFR is both feasible and effective in a Malaysian tertiary centre. In our study, most molecular relapses occurred within the first 6 to 12 months, with 56.8% of patients remaining in remission at two years. This outcome aligns with findings from other first-line treatment discontinuation trials involving imatinib and nilotinib, despite heterogeneity in eligibility criteria and BCR-ABL1 transcript thresholds for molecular relapse (Table 4) [10, 11, 13, 14, 18–20]. Unfortunately, attaining long-term remission does not eliminate the risk of late relapse. Two patients in our cohort experienced late relapses at 45 and 69 months, underscoring the importance of extended molecular surveillance.

Table 4.

List of selected first-line treatment discontinuation trials [10, 11, 13, 14, 18–20]

Study	TKI treatment (duration)	N	DMR criteria	Relapse Criteria	RFS (12 months)	RFS (24 months)	Predictors of successful TFR
HSA	Imatinib/Nilotinib (3 years)	57	MR4 (2 years)	MMR	63.2%	56.8%	MR5/CMR
KID	Imatinib (3 years)	90	MR5 (2 years)	MMR	62.2%	58.8%	Long TKI duration dPCR negative Withdrawal syndrome
STIM1	Imatinib (3 years)	100	MR5 (2 years)	MR5	41%	38%	Male Long TKI duration Low Sokal score
TWISTER	Imatinib (3 years)	40	MR4.5 (2 years)	MMR	52%	45%	Long interferon use Short time to MR4.5
EURO-SKI	Any TKI (3 years)	728	MR4 (1 year)	MMR	53.5%	50.1%	Long TKI duration PB blasts count (e14a2) transcript
ENEST Freedom	Nilotinib (2 years)	190	MR4.5 (1 year)	MMR	51.6%	48.9%	Low Sokal score
LAST	Any TKI (3 years)	171	MR4 (2 years)	MMR	66.7%	60.8%	Deep MR dPCR negative

Identifying predictors of sustained remission in TFR trials helps to refine eligibility criteria. Factors reported to influence success include a low Sokal score, longer TKI treatment duration, and deeper molecular responses. In our study, MR5 and CMR before treatment discontinuation were strong predictors of sustained remission. Notably, all patients with CMR remained relapse-free, highlighting the importance of molecular response depth, a finding supported by a recent systematic review and meta-analysis [21].

Early identification of molecular relapse and prompt treatment re-initiation were effective, with all relapsed patients in this study re-attaining DMR. Although acquired ABL1 kinase domain mutations are rare, 1 patient developed the F359C mutation, which is known to confer resistance to imatinib, necessitating a switch to dasatinib [22, 23]. While this was an isolated case, it highlights the importance of mutation analysis in all relapsed patients, particularly after failure to achieve early MMR or DMR upon TKI reinitiation.

Our study has several limitations. The small cohort size and relatively short follow-up period restrict the statistical power and the ability to perform subgroup analyses. This is particularly relevant in the nilotinib-treated subgroup, with 6 out of 7 patients remaining in remission at the time of writing, suggesting a possible trend in favour of the second-generation TKI. The retrospective nature of this study contributed to incomplete clinical data, particularly to risk stratification. The absence transcript subtype precluded analysis of the potentially favourable e14a2 as reported in the EURO-SKI study [20].

TKI withdrawal, though often underrecognized, is an important aspect of patient counselling. Lee et al. reported that the presence of withdrawal symptoms may be prognostic of a successful TFR attempt [19]. Our reported incidence of withdrawal syndrome (14%) is lower than in other studies, which may be attributed to using a self-reported symptom assessment rather than a structured questionnaire approach [19, 24]. The single-centre nature of this study also limits its generalisability within this region. Nonetheless, despite these limitations, this study contributes valuable regional data to the global TFR experience.

Conclusion

This study suggests that TFR is both feasible and safe for selected CML patients who achieved DMR within daily clinical practice. With over half of the cohort maintaining molecular remission at two years, our findings are comparable with global TFR outcomes, despite differences in geography and healthcare infrastructure. A deeper molecular response, specifically MR5, appeared to be an important factor associated with sustained remission, supporting the importance of optimizing disease control prior to TKI cessation.

Most relapses occurred within the first 12 months and were reversible, with all affected patients regaining DMR upon treatment reinitiation. Notably, two patients experienced late relapse (beyond 3 years), highlighting the need for extended molecular surveillance. One patient eventually developed a kinase domain mutation, suggesting that factors such as treatment adherence, viral infections, and mutation acquisition may contribute relapse biology. These observations suggest potential value in incorporating mutation analysis and genetic profiling into post-relapse evaluation in guiding re-treatment strategies.

As TFR becomes increasingly incorporated into routine care, our regional experience offers valuable insights into patient selection, safety considerations, and long-term outcomes. These real-world data contribute evidence towards the feasibility of TFR implementation in Asian patient populations, particularly in resource-limited settings where reducing long-term treatment costs and healthcare burden is especially valuable. Success in such contexts underscores the need for appropriate infrastructure and personalised management strategies to ensure safe and effective TFR.

Authors’ contributions

C.C.K.L. carried out the data acquisition, analysis and interpretation, wrote and revised the article content and approved the final version to be submitted. Y.L.B. carried out data acquisition, analysis and interpretation and revised the article. L.M.L., A.S., Y.S.W. and S.M.L. carried out data acquisition and approved the article. S.L.C., V.S. and S.M.T. provided the data from the reference laboratory.

Funding

The authors have not received any financial support

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This retrospective study was conducted in accordance with the Declaration of Helsinki. This trial is registered in the National Medical Research Register (NMRR) of Malaysia [NMRR ID-25-02686-NHF] with a waiver of informed consent due to the retrospective nature of the study.

Competing interest

The authors declare no competing interests.