Extended long-term follow-up and the survival of Stop Imatinib study

Abstract

The French Stop Imatinib study (STIM1) was one of the first trials to explore the possibility of discontinuing imatinib in patients with chronic myeloid leukemia (CML) who had achieved a sustained molecular response (at least a 4.5-log reduction). The stringent criteria for molecular recurrence (MRec) were defined as BCR::ABL1 transcript positivity confirmed by a second test showing either a 1-log increase or loss of major molecular response across consecutive assessments. This comprehensive update presents long-term follow-up data from the STIM1 study, with a median molecular follow-up of 12.8 years (range, 0.8-15). Results showed a molecular recurrence-free survival rate of 37% (95% confidence interval [CI], 28-48) at 120 months, and 35% (95% CI, 26-46) at 156 months after imatinib discontinuation. Importantly, no patients experienced CML progression during the follow-up. Overall survival rates were 97% (95% CI, 94-100) at 10 years and 88% (95% CI, 81-96) at 20 years. A case of late MRec, confirmed through DNA BCR::ABL1 breakpoint analysis and comparison at diagnosis and recurrence, indicated the persistence of the original disease rather than the onset of new CML. This study offers valuable insights into the safety and feasibility of imatinib discontinuation for patients with CML, supporting long-term remission while maintaining survival. This study was registered at ClinicalTrials.gov as #NCT00478985.

Graphical abstract

Figure 1.

Follow-up after imatinib discontinuation (median 12.8 [0.8-15] years). (A) MRFS: 37% (95% CI, 28-48) at 120 months and 35% (95% CI, 26-46) at 156 months. (B) Cumulative incidence of MRec. One additional MRec appeared at 90 months of follow-up. (C) The OS rate was 97% (95% CI, 94-100) at 10 years, and 88% (95% CI, 81-96) at 20 years. IMA, imatinib

Figure 2.

The CONSORT diagram of the 100 patients included in the STIM study. Pt, patient.

Figure 3.

Late MRec. For the patient with the MRec at month 90, BCR::ABL1 breakpoints were sequenced at both diagnosis and MRec to check if it was the same disease. DNA was sent to the Institute of Hematology and Blood Transfusion, Department of Molecular Genetics, Prague, Czech Republic. The library was prepared using the Illumina Nextera Rapid Capture Custom Enrichment protocol. For the enrichment of sequences covering the BCR::ABL1 breakpoint, a custom probe set developed by Thomas Ernst and colleagues from Jena was used. This panel consists of 4608 probes, targeting both the BCR gene region (23522352-23660424) and the ABL gene region (133589068-133763262). The cumulative target length in this setting is 312 268 bp. The library was quantified using Quant-iT PicoGreen, and its quality was controlled using an Agilent Technologies 2100 Bioanalyzer with a DNA 1000 chip. The library was then sequenced on a MiSeq system using the MiSeq reagent kit v3 with 2 × 250 cycles. The BCR::ABL1 breakpoints were determined by bioinformatics processing using NextGene Software in a structural variant detection workflow. The sequence of the breakpoint from the diagnostic sample was strictly similar as compared with the sample from the MRec sample.