Background: The feasibility of TKI dose reduction as a step before treatment-free remission (TFR) phase has been confirmed in several trials. We aimed to develop a program of the observation of CML pts with major molecular response (MMR) and deep MR (DMR) using a planned TKI stop after a period of 2-step dose reduction.
Aims: To provide the results of maintaining the MR to therapy with reduced doses of TKI, the survival without MMR (BCR::ABL1 ≤0,1%) loss after TKI stop with previous follow-up on reduced-dose TKI therapy and the probability of recovery of DMR (BCR::ABL1 ≤0.01%) and MMR after resuming TKI therapy at reduced doses in CML pts.
Methods: There were two phases in the trial: 1) TKI dose reduction phase for at least 12 months (mo), 2) TFR phase - 24 mo. TKI dose reduction consists of 2-steps each lasting for 6 mo. The inclusion criteria were: CML patients (pts) in chronic phase, age ≥18 years (y), TKI therapy duration ≥ 3 y, duration of MMR and DMR for at least 2 and 1 y. The CML pts were included in the TFR phase with a duration of DMR (at least MR4.5 at the moment of TKI stop) ≥2 y. The dose of TKI was increased in the event of MMR loss by +1 level from that at which molecular relapse developed.
A total of 103 pts were included in the trial. The baseline characteristics were: female 60%, median (Me) age at diagnosis and at inclusion in the trial was 45 y (range 11-71) and 51 y (range 23-74); ELTS 61%:17%:1%, 21% for low, intermediate, high and unknown risk group. Thirty pts (29%) had a history of at least one TKI stop. Me TKI therapy duration, duration of MMR and DMR were 7 y (range 3-20,6), 3,3 y (range 2-15,4) and 2,5 y (range 1-11) in general group.
At baseline 69 (67%) pts received IM and 34 (33%) pts - second-generation (2G) TKI (Table 1).
Results: Seventy-three pts have completed 1st dose reduction step lasting for 6 mo: IM - 58 pts, 2G-TKI – 15 pts. Five pts (9%) lost DMR on IM 300 mg. There are no MMR loss on 1st dose reduction step.
Seventy-two pts completed the 6 mo 2nd step of dose reduction: IM - 47 pts, 2G-TKI – 25 pts. Twelve pts lost DMR (without MMR loss): 9 pts (19%) on IM 200 mg, 3 pts (12%) on TKI-2G (1 - DAS 25 mg, 2 - NIL 200 mg). Three pts (6%) lost MMR on IM 200 mg.
Sixty-nine pts were included in TFR phase, 18 pts (26%) had a history of at least one TKI stop. Me follow-up after TKI stop was 18 mo (range 1-33).
The survival without MMR loss was 48% after 24 mo TKI stop in the general group of pts. The survival without MMR loss was 54% and 32% in pts with 1st and 2nd TKI stop. (Figure 1). The CML pts with molecular relapse resumed TKI therapy at reduced doses of 1st step after TKI stop: IM - 19 pts - up to 200 mg; NIL - 7 pts - up to 200 mg; DAS - 2 pts - up to 25 mg; BOS - 3 pts - up to 200 mg). The probability of recovery of MMR and DMR was 71% and 42% after 3 mo resumption of TKI therapy. The dose of TKI was increased to 2nd step in 8 patients who did not achieve MMR on TKI therapy at doses of 1st step after 3 mo. The probability of recovery of MMR and DMR was 100% and 82% after 6 mo resumption of TKI therapy at reduced doses (Figure 2).
Summary/Conclusion: The reduced-dose TKI therapy has been demonstrated to be safe in pts with stable DMR ≥1 y. The rate of MMR loss in general group and after 1st TKI stop was comparable to that observerved in TFR trials without previous TKI de-escalation phase. The survival rate without MMR loss was encouraging in CML patients with the 2nd TKI discontinuation - 32%. We observed high rate of MMR and DMR recovered on the reduced doses of TKI; only a minor of pts needed a 2nd stop dose escalation.
Keywords: Tyrosine kinase inhibitor, treatment-free remission, Chronic myeloid leukemia