Induction–maintenance approach for the chronic phase of chronic myeloid leukaemia (IMPACT-I): a prospective, single-arm, phase 2 study

Abstract

Imatinib and second-generation tyrosine-kinase inhibitors (2G-TKIs) are standard options for the first-line treatment of chronic myeloid leukaemia. Although 2G-TKIs are superior to imatinib in terms of rate and depth of molecular response, they do not bring significant improvements in survival outcomes, and concerns exist over their long-term safety. The availability of a generic formulation makes imatinib an attractive economical option. We propose a novel induction-maintenance approach that would have the advantage of inducing early molecular response with 2G-TKIs, followed by maintenance with the safer and more affordable imatinib. IMPACT-I was a prospective, single-arm, phase 2 study done at Queen Mary Hospital, a university-affiliated tertiary hospital in Hong Kong. Adult patients with chronic myeloid leukaemia in chronic phase were enrolled after providing written informed consent. Inclusion criteria were having received a 2G-TKI as a first-line treatment for at least 12 months, and to have had a sustained and good molecular response (defined as a BCR-ABL1 level of ≤0·1%) for at least 6 months. Patients who had documented mutations in the kinase domain or a history of switching tyrosine-kinase inhibitors due to unsatisfactory responses were excluded. After switching to imatinib, participants were followed up for clinical, haematological, and molecular monitoring (bimonthly in the first 6 months, quarterly in months 7-12; and every 3-6 months thereafter, with follow-up ongoing at the time of writing). Molecular response was assessed according to the International Scale as the ratio of BCR-ABL1 transcripts to ABL1 transcripts with an assay sensitivity of molecular response of at least 4·5 (MR4·5) at least. Molecular tests were repeated at 1-month intervals if BCR-ABL1 was higher than 0·1% but less than 1%. Molecular progression was defined as BCR-ABL1 of at least 1% at one timepoint, or BCR-ABL1 higher than one 0·1% but less than 1% in two consecutive tests. The primary outcome was molecular progression-free survival at 6 months after switching to imatinib. Ten patients were enrolled between Aug 9, 2017, and April 27, 2021. Six patients had had dasatinib for at least 12 months, and four patients had had nilotinib for at least 12 months. The median duration of 2G-TKI treatment before the switch was 42·5 months (IQR 32·5-52·5) and the median durations of good molecular response before the switch was 30·0 months (IQR 19·5-41·5). All except one patient (on the nilotinib group) had adverse reactions of grades 1-3 on the Common Terminology Criteria for Adverse Events (CTCAE) to 2G-TKIs, with rash (two in the nilotinib group, two in the dasatinib group) and pleural effusion (none in the nilotinib group, three in the dasatinib group) being the most common. After a median follow-up of 41·0 months (IQR 11·0-50·6), all ten patients continued to have good molecular response. Molecular progression-free survival at 6 months was 100%. One patient, who was in molecular response 3 before withdrawal, exited the trial after 9 months of imatinib therapy for personal reasons. The other nine patients remained on generic imatinib as of the last follow-up on Dec 22, 2021; eight (89%) of nine were in deep molecular response (MR4·5 or greater). Imatinib was well tolerated. Only grade 1-2 toxic effects were observed, namely peripheral oedema, diarrhoea, and dyspepsia. Our study suggests that the induction-maintenance approach is safe and efficacious. All patients remain in good molecular response after switching to imatinib, and the vast majority of them had a deep molecular response. This practical strategy not only implies substantial pecuniary savings (estimated at US$30 000 per annum per patient), but also retains the possibility of treatment-free remission, bringing important and positive health-cost implications for low-income regions. 2017 Young Investigator Research Grant from the Hong Kong College of Physicians.