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

Simone Claudiani; Jane F Apperley; Richard Szydlo; Afzal Khan; George Nesr; Chloe Hayden; Andrew J Innes; Kathy Dominy; Pierre Foskett; Letizia Foroni; Jamshid Khorashad; Dragana Milojkovic

doi:10.1111/bjh.17286

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

Br J Haematol. 2021 Apr;193(2):346-355. doi: 10.1111/bjh.17286. Epub 2020 Dec 24.

Authors

Simone Claudiani^{1

2}, Jane F Apperley^{1

2}, Richard Szydlo², Afzal Khan², George Nesr¹, Chloe Hayden³, Andrew J Innes^{1

2}, Kathy Dominy³, Pierre Foskett³, Letizia Foroni², Jamshid Khorashad², Dragana Milojkovic¹

Affiliations

¹ Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.
² Centre for Haematology, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK.
³ Imperial Molecular Pathology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.

PMID: 33368155
DOI: 10.1111/bjh.17286

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 (91·9%), MR3 was maintained at median follow-up of 27·3 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 follow-up. Seventy-six patients eventually discontinued LD TKI and the two-year treatment-free remission (TFR) rate in these patients was 74·1%. 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.

Keywords: CML; TFR; TKI; dose-reduction; low dose.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Aniline Compounds / administration & dosage
Aniline Compounds / adverse effects
Aniline Compounds / therapeutic use
Comorbidity
Dasatinib / administration & dosage
Dasatinib / adverse effects
Dasatinib / therapeutic use
Drug Tapering / methods*
Female
Follow-Up Studies
Fusion Proteins, bcr-abl / genetics
Humans
Imatinib Mesylate / administration & dosage
Imatinib Mesylate / adverse effects
Imatinib Mesylate / therapeutic use
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / diagnosis
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Male
Middle Aged
Mutation
Nitriles / administration & dosage
Nitriles / adverse effects
Nitriles / therapeutic use
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / adverse effects
Protein Kinase Inhibitors / therapeutic use*
Pyrimidines / administration & dosage
Pyrimidines / adverse effects
Pyrimidines / therapeutic use
Quality of Life
Quinolines / administration & dosage
Quinolines / adverse effects
Quinolines / therapeutic use
Remission Induction / methods*
Retrospective Studies
Safety
Treatment Outcome

Substances

Aniline Compounds
Nitriles
Protein Kinase Inhibitors
Pyrimidines
Quinolines
abl-bcr fusion protein, human
bosutinib
Imatinib Mesylate
Fusion Proteins, bcr-abl
nilotinib
Dasatinib