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 1^st step were 300 mg for imatinib (IM), 400 mg for nilotinib (NIL), 50 mg for dasatinib (DAS) and 300 mg for bosutinib (BOS). The 2^nd 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 1^st or 2^nd 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 2^nd step and if MMR was not restored after 3 mo the dose was increased to 1^st 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 1^st step doses (3-IM, 10-NIL, 2-DAS, 2-Bos) and 9 pts had 2^nd 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 1^st 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 2^nd 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 1^st and 2^nd TKI discontinuation attempt, respectively (p=0.1). The 3 mo MMR recovery probability after TKI restart in reduced doses of the 2^nd 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 1^st 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 2^nd 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.