TKI dose reduction can effectively maintain major molecular remission in patients with chronic myeloid leukaemia

Abstract

Targeted therapy for chronic myeloid leukaemia (CML) has allowed for a near-normal patient life-expectancy; however, quality of life and aggravation of existing co-morbidities have posed new treatment challenges. In clinical practice, TKI dose reduction occurs frequently, often on multiple occasions, because of intolerance. We conducted a retrospective 'real-world practice' review of 246 patients receiving lower than standard dose (LD) TKI after the achievement of major molecular response (MR3), because of intolerable adverse events. In 274 of 298 cases of dose reduction (91Á9%), MR3 was maintained at median follow-up of 27Á3 months. One patient progressed to blast crisis while on LD TKI. Two patients developed two new ABL kinase domain mutations (T315I and V299L), of whom one had achieved deep molecular response on an alternative LD TKI at last followup. Seventy-six patients eventually discontinued LD TKI and the two-year treatment-free remission (TFR) rate in these patients was 74Á1%. The majority of patients with CML in at least MR3 appear to be safely managed with LD TKI, although three of 246 patients had new events (progression and new mutation), indicating that this approach requires vigilance. TKI LD does not prevent the achievement of TFR in this patient population.

Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells

“…Interestingly, of the 94 patients in MMR, 54.2% achieved a molecular response level of MR4.0 or higher with a lowered dose. 76 patients discontinued TKI after 1.76 years of low dose treatment, and the 2-year TFR rate in these patients was 74.1% (61). Consistent with the DESTINY trial, a TKI step-down strategy before treatment discontinuation may be a promising strategy to improve TFR.…”

Imatinib dose optimization based on therapeutic drug monitoring in Chinese patients with chronic‐phase chronic myeloid leukemia

“…The survival rate of patients with CML has significantly improved, and an increasing number of patients pursue a dose‐optimization strategy to improve quality of life. In clinical practice, TKI dose reduction is an important strategy for reducing severe adverse reactions or to improve patient adherence 25,26 . A mathematical model suggested that a TKI dose reduction of at least 50% would not affect long‐term clinical outcomes 27 .…”

“…In clinical practice, TKI dose reduction is an important strategy for reducing severe adverse reactions or to improve patient adherence. 25,26 A mathematical model suggested that a TKI dose reduction of at least 50% would not affect long-term clinical outcomes. 27 Our results suggested that imatinib trough concentrations >1000 ng/ml in most patients administered 300 mg imatinib daily, which indicated that dose reduction to 300 mg daily could achieve MMR, from the perspective of imatinib concentration.…”

Low-dose tyrosine kinase inhibitors in patients with chronic myeloid leukemia: a retrospective study in China

“…9 97.4% (37/38) of patients remained in MMR with 50 mg dasatinib or lower, consistent with another study that reported a 3-year MRFS in MMR of 94.5%. 10 Importantly, of nine patients not in MMR, six (66.7%) achieved MMR or deeper molecular response with low dasatinib dose treatment. In our study, all patients (n=10) on half-dose nilotinib experienced maintenance of MMR.…”