CML-270: Dose De-Escalation of Second-Generation Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia Patients with Major and Deep Molecular Response

Abstract

Context Chronic myeloid leukemia (CML) patients (pts) receive a long-term treatment with tyrosine kinase inhibitors (TKI) in standard doses. A new approach with reduced dose TKI use is desirable for the CML pts with adverse effects (AE) or with a high risk of AE, particularly in pts with major molecular response (MMR) and deep molecular response (DMR) receiving second generation TKI (2GTKI). Objective To evaluate the stability of MMR in CML pts after dose reduction of 2GTKI. Patients We included 36 pts taking 2GTKI, all in chronic phase, in retrospective analyses. Median (Me) age was 47 years (range 22-71). Me therapy duration was 42.5 months (mo). MMR was in 7 (19%) pts, DMR in 29 (81%) pts. Me duration of MMR was 21.5 mo at the time of dose reduction. The AEs were in 21 (58%) pts before the dose reduction. Interventions The dose reduction of nilotinib and dasatinib was done in 28 (78%) and 8 (22%) pts. Initial dose of nilotinib was 800, 600 and 400 mg in 18 (64%), 8 (28%) and 2 (7%) pts. The dose of nilotinib was reduced to 600, 400, 300, and 200 mg in 1 (4%), 21 (75%), 2 (7%) and 4 (14%) pts. The initial dose of dasatinib was 140 mg in 1 (12.5%) and 100 mg in 7 (87.5%) pts, and the reduced dose was 70 and 50 mg in 2 (25%) and 6 (75%) pts. Results Me follow-up after 2GTKI dose reduction was 13 mo. The MMR loss occurred in 3 pts with MMR duration 3, 6 and 8 mo at the time of dose reduction. Survival without MMR loss at 12 mo was 96% (CI 89% -100%) and 64% (CI 23-100%) in the DMR and MMR cohort. MMR was regained in all pts after the standard dose therapy was recommenced. The toxicity after dose reduction was resolved in 19 (90%) of 21 pts with the previously observed AE. Conclusions This option allows reduction of the drug toxicities and prevents the potential AE of TKI therapy. In January 2020 in Russia, the prospective clinical trial was started in order to evaluate a relapse-free survival after discontinuation of therapy with the previous 12-months two-stage phase of TKI dose reduction.