Late molecular recurrences in patients with chronic myeloid leukemia experiencing treatment-free remission

Abstract

Treatment-free remission (TFR) is an opportunity for patients with chronic myeloid leukemia (CML). Reported cumulative incidence curves of molecular recurrence (MRec) arbor a 2-phase shape with mainly early events, but also some late events (late MRec [LMRec]). Having discontinued our first patient in 2004, we have access to a prolonged follow-up, enabling us to characterize these late events. Over 15 years, 128 patients from our institution were registered in the Stop Imatinib (STIM; A Study for Tyrosine Kinase Inhibitors Discontinuation [A-STIM]) trial. MRec was defined by the loss of major molecular response (BCR-ABL1IS >0.1%). At the first TFR attempt, patients had been taking a tyrosine kinase inhibitor for a median of 7.1 years and in BCR-ABL1IS ≤0.01% (MR4) for a median of 4 years. The median follow-up of patients in TFR was 6.5 years. The TFR rate was estimated to be 45.6% after 7 years. For 9/65 (14%) patients experiencing MRec, recurrence occurred after 2 years in TFR (median, 3.6 years). The residual rate of MRec after 2 years was estimated to be 18%. The probability of remaining in TFR was 65.4% for patients having experienced fluctuations of their minimal residual disease (MRD) (at least 2 consecutive measurements BCR-ABL1IS >0.0032% or loss of MR4), whereas it was 100% for those with stable MRD (P = .003). After 2 years in TFR, we observed an 18% residual rate of LMRec. These late events represent 14% of all MRec and occur in patients with fluctuating MRD measurements. A long-term molecular follow-up therefore remains mandatory for CML patients in TFR. The A-STIM study was registered at www.clinicaltrials.gov as #NCT02897245.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Molecular recurrence and treatment-free remission (TFR) after TKI discontinuation. (A) TFR after the first discontinuation attempt (TFR1) in 128 patients. (B) TFR after the second discontinuation attempt (TFR2) in 32 patients. The dotted lines indicate the upper and lower limits of the 95% CI for the estimated probability.

Figure 2.

Landmark analysis at 2 years. (A) Treatment-free remission probabilities for the 66 patients in TFR1 for >2 years. (B) Treatment-free remission probabilities for the patients in TFR1 for >2 years and with a stable MR4.5 (BCR-ABL1 ≤0.0032%) (bold line) and treatment-free remission probabilities for the patients in TFR1 for >2 years and with an unstable molecular remission (dashed line).

Figure 3.

Molecular recurrence for the 9 patients experiencing a late MRec. Patient are classified based on the length of TFR1. Patients 1 and 6 started TFR 1 and 4 years before 2010, respectively. Sensitivity was fixed at 10 000 ABL1 copies to define PCR negativity in these early days (left x-segment and left y-axis). A sensitivity of 32 000 ABL1 copies to define PCR negativity was applied from 2010 (right x-segment and right y-axis). A sensitivity of 32 000 ABL1 copies was available for patients 2, 3, 4, 5, 7, 8, and 9. All patients experienced a slow kinetic of molecular recurrence. MR4, molecular response 4 log (BCR-ABL1IS ≤0.01%); MR4.5, molecular response 4.5 log (BCR-ABL1IS ≤0.0032%). Vertical dotted line: TKI resumption. Black circles indicate undetectable BCR-ABL1 transcripts.