Background
Phase 2, prospective, multicenter single-arm study (STIM, STop IMatinib). N=100 CML patients in complete molecular remission (CMR; BCR-ABL1 undetectable by RQ-PCR at sensitivity ≥4.5-log reduction) for ≥2 consecutive years on imatinib. This landmark proof-of-concept trial demonstrated that CML can remain in treatment-free remission (TFR) after stopping imatinib in select patients. Published Lancet Oncology 2010.
Interventions and follow up
Regimen: Imatinib 400 mg PO once daily until sustained CMR ≥2 years, then discontinuation (treatment-free remission) in chronic-phase CML
Monitoring: Monthly RQ-PCR; restart imatinib on molecular relapse (loss of CMR/MMR)
Primary endpoint: CMR at 12 months after imatinib discontinuation (TFR)
Median follow-up: 17 months
Monitoring: Monthly RQ-PCR; restart imatinib on molecular relapse (loss of CMR/MMR)
Primary endpoint: CMR at 12 months after imatinib discontinuation (TFR)
Median follow-up: 17 months
Results
TFR (CMR maintained at 12 months): 38% (38/100)
Molecular relapse at any point: 61% (61/100)
Median time to molecular relapse: 2.5 months (nearly all within 6 months)
Re-achievement of CMR after imatinib restart: 100% (all 61 relapsers regained CMR)
TFR at 24 months: 40%
TFR by Sokal risk: low risk 52% vs high risk 22%
Molecular relapse at any point: 61% (61/100)
Median time to molecular relapse: 2.5 months (nearly all within 6 months)
Re-achievement of CMR after imatinib restart: 100% (all 61 relapsers regained CMR)
TFR at 24 months: 40%
TFR by Sokal risk: low risk 52% vs high risk 22%
Adverse events
Disease-related: No hematologic relapses (blast crisis) occurred; no long-term sequelae from relapse or reinduction
Withdrawal syndrome: Musculoskeletal pain, myalgia/arthralgia resembling imatinib withdrawal in ~30% of patients on stopping, a novel and previously unrecognized phenomenon, often self-limited within 4–8 weeks
Withdrawal syndrome: Musculoskeletal pain, myalgia/arthralgia resembling imatinib withdrawal in ~30% of patients on stopping, a novel and previously unrecognized phenomenon, often self-limited within 4–8 weeks
Conclusions
STIM demonstrated for the first time that approximately 40% of CML patients with ≥2 years of PCR-undetectable remission on imatinib can successfully stop therapy and maintain CMR long-term, without progression to accelerated or blast phase. All molecular relapsers safely regained CMR upon reinduction, establishing TFR as a safe, achievable goal in CML.
Key Limitations
Single-arm phase 2 with modest N=100 and short initial follow-up (median 17 months) limit precision of long-term TFR estimates. Eligibility required deep, sustained CMR for ≥2 years on imatinib, so results apply only to a highly selected minority of CML patients. The 4.5-log RQ-PCR sensitivity threshold and monthly monitoring frequency are more rigorous than routine practice and are integral to safe discontinuation. Predictors (Sokal score, treatment duration) were exploratory. The trial used imatinib only; generalizability to 2nd-generation TKI discontinuation was addressed later by EURO-SKI.
Clinical Context
STIM is the foundational trial establishing treatment-free remission as a legitimate goal in CML, transforming long-term management and patient counseling. It directly informed subsequent larger studies (EURO-SKI, A-STIM, TWISTER) and TKI labels that now permit discontinuation in deep, durable molecular response. ELN and iwCLL-equivalent CML guidance (ELN) endorse a TFR attempt in eligible patients with sustained deep molecular response, mandatory frequent molecular monitoring, and prompt restart on loss of MMR. ESMO-MCBS: not assigned.