Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study

Abstract

T he aim of the Korean Imatinib Discontinuation Study was to identify predictors for safe and successful imatinib discontinuation. A total of 90 patients with a follow-up of ≥12 months were analyzed. After a median follow-up of 26.6 months after imatinib discontinuation, 37 patients lost the major molecular response. The probability of sustained major molecular response at 12 months and 24 months was 62.2% and 58.5%, respectively. All 37 patients who lost major molecular response were retreated with imatinib therapy for a median of 16.9 months, and all achieved major molecular response again at a median of 3.9 months after resuming imatinib therapy. We observed newly developed or worsened musculoskeletal pain and pruritus in 27 (30%) patients after imatinib discontinuation. Imatinib withdrawal syndrome was associated with a higher probability of sustained major molecular response (P=0.003) and showed a trend for a longer time to major molecular response loss (P=0.098). Positivity (defined as ≥ 17 positive chambers) of digital polymerase chain reaction at screening and longer imatinib duration before imatinib discontinuation were associated with a higher probability of sustained major molecular response. Our data demonstrated that the occurrence of imatinib withdrawal syndrome after imatinib discontinuation and longer duration of imatinib were associated with a lower rate of molecular relapse. In addition, minimal residual leukemia measured by digital polymerase chain reaction had a trend for a higher molecular relapse.

De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial

“…Secondly, this practice-changing view is reinforced by the demonstration of general improvement of adverse events in both the MMR and MR4 cohorts, with only mild (none > grade 2 severity) and transient evidence of the musculoskeletal symptoms that have recently been described on complete TKI withdrawal 9,15 . Although these and other symptoms generally improved during de-escalation as shown in Figure 3, this trend was not of sufficient strength to be detectable by the quality of life assessment tools used here, emphasising their inappropriateness for well controlled CML patients in the TKI era 16,17 .…”

“…Using this definition of recurrence, at 24 months after TKI cessation the A-STIM and KIDS studies reported that 58-64% of patients are recurrence-free 8,9 and the large EUROSKI study of 868 patients similarly recently reported a rate of 52% at the same time point 10 .…”

Rationale and motivating factors for treatment-free remission in chronic myeloid leukemia

“…[58][59][60] These findings suggest that immunogenic effects of treatment may affect the probability of TFR success. Other factors associated with successful TFR include achievement of UMRD 9 months after switching from IFN to imatinib, [7] duration of imatinib 62 months, [15] imatinib withdrawal syndrome (i.e. musculoskeletal pain and/or pruritus after stopping imatinib), [15] negative digital PCR at enrollment, [15,16] and age 45 years.…”

“…[4][5][6][7][8][9][10][11][12][13][14][15][16][17] In reports of patients who stopped imatinib without achieving deep molecular responses, rapid relapses requiring treatment reinitiation were typical. [56,57] In addition to achievement of deep molecular responses, other potential predictors of TFR success have been assessed in a number of TFR studies (Table 2).…”

“…[2] However, there is increasing evidence demonstrating that, within the context of a clinical trial and with rigorous molecular monitoring, some patients may be able to suspend TKI therapy without losing their responses, [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] a state known as treatment-free remission (TFR).…”