The concept of treatment-free remission (TFR) emerged from small observational studies in which some patients who stopped treatment with a tyrosine kinase inhibitor (TKI) because of intolerance or by preference remained in remission for at least several months. This led to larger studies, such as the Stopping Imatinib (STIM) study, in which 100 patients who had been in complete molecular response (CMR) for at least 2 years (> 5-log reduction in BCR–ABL and ABL levels and undetectable transcripts on quantitative reverse transcriptase polymerase chain reaction [RT-qPCR]) stopped treatment. After cessation of treatment, 41% were free from molecular relapse (defined as 1-log rise in BCR–ABL1 transcripts) at 12 months. Relapses generally occurred in the first 6 months after stopping treatment, with only three late relapses (after 18 months). Importantly, those who experienced relapse responded to subsequent imatinib, with 16 of 42 (38%) going on to achieve a second CMR.
Similar results were reported in the Australasian TWISTER study, which investigated patients in molecular remission to a sensitivity of 4.5 logs (i.e. MR4.5): 47% remained in molecular remission at 24 months.
However, these studies were conducted in ‘ideal’ patients who were clearly in molecular remission, whereas in real-world practice patients often hover just below MR4.5 with persistent low levels of BCR–ABL1 transcripts following cessation of treatment. This cohort of patients were investigated in the French A-STIM trial;3 molecular relapse was defined as BCR–ABL1 transcripts above MR3. Despite this, the TFR rate was 37% at 36 months, which is highly comparable to the results from the STIM and TWISTER studies.
The EURO-SKI trial had even less stringent inclusion criteria, allowing patients to discontinue TKI treatment after 3 years with MR4. The molecular relapse-free rate was 50% at 24 months. While this allowed more patients to stop TKI treatment, subgroup analysis demonstrated that the longer the duration of treatment, the deeper the remission and the greater the probability of maintaining remission to MR3.
Thus, an attempt at TFR may be considered for patients in remission below MR4 and who have taken a TKI for at least 3 years, although some international experts, such as François-Xavier Mahon at the Institut Bergonié, Bordeaux, France, tend to be more conservative, given that longer treatment is associated with deeper and more persistent remission (Table 3.1). However, practice is informed by local guidelines, which vary widely. For example, the US National Comprehensive Cancer Network guidelines require only MR4 for 2 years.
