Results of the Molecular Response Evaluation and TKI Dose Adjustment in Chronic Myeloid Leukemia Patients in Prospective Study of Reduction and Discontinuation Treatment of TKI (READIT)

Introduction: The feasibility of tyrosine kinase inhibitors (TKI) dose reduction before treatment-free remission (TFR) observation in chronic myeloid leukemia (CML) patients (pts) with deep molecular response (DMR) was confirmed in several trials. However, a unified step-by-step dose de-escalation and re-escalation scheme for each TKI has not been developed. Aim: To provide the data of major molecular response (MMR, BCR::ABL1≤0.1%) and deep molecular response (DMR, BCR::ABL1≤0.01%) loss and recovery in the trial READIT (NCT 04578847). Methods: The trial had 2 consecutive phases: 1) TKI 2-step dose reduction with each step lasting for at least 6 months (mo). TKI daily doses at 1st step were 300 mg for imatinib (IM), 400 mg for nilotinib (NIL), 50 mg for dasatinib (DAS) and 300 mg for bosutinib (BOS). The 2nd step TKI doses were 25 mg for DAS (50 mg every other day) and 200 mg QD for IM, NIL and BOS: 2) TFR observation. Inclusion criteria for dose reduction phase: adult CML in chronic phase, TKI therapy for >3 years (y), DMR (BCR::ABL1≤0.01%) >1y. Inclusion criteria for TFR phase: DMR ≥2y and MR4,5 (BCR::ABL1≤0.0032%) confirmation before TKI cessation. CML pts with DMR already receiving reduced doses of TKI in clinical practice could join the study at any phase/step if they met the corresponding eligibility criteria for treatment /DMR duration. In case of MMR loss after 1st or 2nd dose reduction step the dose was re-escalated to previous dose level. If MMR was lost in TFR TKI were restarted in the reduced dose of the 2nd step and if MMR was not restored after 3 mo the dose was increased to 1st step dose level. Results: A total of 103 CML pts were included: male 40%, median (Me) age 51 y (23-74). Me duration of TKI therapy/MMR/DMR at baseline was 6.7 y (3-20,6)/ 5.6 y (2-15.4)/ 4.1 y (1-14.7), accordingly and 98 (95%) pts had at least MR4.5. Standard TKI doses at baseline were used in 77 pts (62-IM, 10-NIL, 4-DAS, 1-BOS) while 26 pts were included with already reduced doses: 17 pts had 1st step doses (3-IM, 10-NIL, 2-DAS, 2-Bos) and 9 pts had 2nd step doses (4-IM, 3-NIL, 2-BOS). Thirty pts (29%) previously had at least one failed TKI cessation attempt. Me observation was 6 (6-29), 6 (6-43) and 11 (1-36) mo for 1st, 2nd step and TFR phase, accordingly. After the 1st dose reduction step (completed in 77 pts) MMR loss occurred in 1(1.3%) pt (IM), only DMR loss without MMR loss (BCR::ABL1>0,01-≤0,1%) was in 4(5.2%) pts (IM). After the 2nd dose reduction step (89 pts) MMR loss occurred in 4(4.5%) pts (IM), DMR loss without MMR loss - in 13(14.2%) pts (10-IM, 1-DAS, 2-NIL). TKI therapy was discontinued in 74 (71.8%) pts (46-IM, 19-NIL, 4-DAS, 5-Bos). TFR rate (survival without MMR loss) in the overall group was 60%, 53% and 46% at 6, 12 and 24 mo, respectively. Twelve mo TFR rate was 58% and 40% in pts with 1st and 2nd TKI discontinuation attempt, respectively (p=0.1). The 3 mo MMR recovery probability after TKI restart in reduced doses of the 2nd step was 70% in 37 pts who had lost MMR during TFR observation. In 11(30%)/37 pts without MMR recovery at 3 mo a dose was increased to 1st step level. The 12 mo MMR recovery rate was 100% in the overall group. DMR recovery rate was 83% and 100% after 12 and 24 mo, respectively. The average daily TKI dose at study completion compared to baseline was 56.3%, 72.8%, 48%, and 46.7% for IM, NIL, DAS and BOS, respectively. Conclusion: A stepwise TKI dose de-escalation strategy followed by TFR observation and reverse stepwise re-escalation in case of molecular relapse is a safe and effective option in CML pts with DMR, including pts with 2nd TFR attempt. In addition to reducing drug toxicity, this approach allows for individualized TKI dosing that can maintain DMR or MMR and reduce the financial costs of long-term therapy.