A randomised Phase II trial of Hydroxychloroquine and Imatinib versus Imatinib alone for patients with Chronic Myeloid Leukaemia in Major Cytogenetic Response with residual disease

Abstract: 1 In chronic-phase chronic myeloid leukaemia (CP-CML), residual BCR-ABL1+ leukaemia stem cells are 2 responsible for disease persistence despite TKI. Based on in vitro data, CHOICES (CHlorOquine and 3 Imatinib Combination to Eliminate Stem cells) was an international, randomised phase II trial designed 4 to study the safety and efficacy of imatinib (IM) and hydroxychloroquine (HCQ) compared to IM alone in 5 CP-CML patients in major cytogenetic remission with residual disease detectable by qPCR. Sixty-two 6 patients were randomly assigned to either arm. Treatment ‘successes’ was the primary end-point, 7 defined as ≥0.5 log reduction in 12-month qPCR level from trial entry. Selected secondary study end-8 points were 24-month treatment ‘successes’, molecular response and progression at 12 and 24 months, 9 comparison of IM levels, and achievement of blood HCQ levels >2000ng/ml. At 12 months, there was no 10 difference in ‘success’ rate (p=0.58); MMR was achieved in 80% (IM) vs 92% (IM/HCQ) (p=0.21). At 24 11 months, the ‘success’ rate was 20.8% higher with IM/HCQ (p=0.059). No patients progressed. 12 Seventeen adverse events, including four serious adverse reactions, were reported; diarrhoea occurred 13 more frequently with combination. IM/HCQ is tolerable in CP-CML, with modest improvement in qPCR 14 levels at 12 and 24 months, suggesting autophagy inhibition maybe of clinical value in CP-CML.