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

G A Horne, J Stobo, C Kelly, A Mukhopadhyay, A L Latif, J Dixon-Hughes, L McMahon, P Cony-Makhoul, J Byrne, G Smith, S Koschmieder, T H BrÜmmendorf, P Schafhausen, P Gallipoli, F Thomson, W Cong, R E Clark, D Milojkovic, G V Helgason, L Foroni, F E Nicolini, T L Holyoake, M Copland, G A Horne, J Stobo, C Kelly, A Mukhopadhyay, A L Latif, J Dixon-Hughes, L McMahon, P Cony-Makhoul, J Byrne, G Smith, S Koschmieder, T H BrÜmmendorf, P Schafhausen, P Gallipoli, F Thomson, W Cong, R E Clark, D Milojkovic, G V Helgason, L Foroni, F E Nicolini, T L Holyoake, M Copland

Abstract

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

Conflict of interest statement

ALL: honoraria (Kite a Gilead Company), speakers bureau (Kite a Gilead Company) and consulting or advisory role (Jazz Pharmaceuticals). JB: honoraria (Novartis, Pfizer) and speakers bureau (Novartis, Pfizer, Jazz Pharmaceuticals, Alexion). GS: research funding (Novartis, Pfizer, Ariad). SK: honoraria (Novartis, BMS, Pfizer, Incyte, Roche, AOP Pharma, Janssen, Bayer) and consulting or advisory role (Pfizer, Incyte, Novartis, AOP Pharma, BMS, CTI, Roche, Bayer). SK: research funding (Novartis, BMS, Janssen). THB: consulting or advisory role (Novartis, Pfizer, Janssen, Merck, Takeda) and research funding (Novartis, Pfizer). PS: honoraria (BMS, Novartis, Alexion, MerckSerono, Pfizer, MSD, Roche, Gilead) and consulting or advisory role (BMS, Novartis, Merck Serono, Alexion, Pfizer). PG: honoraria (BMS). FT: consulting or advisory role (bionomics) and research funding (Roche, Lilly, AstraZeneca). REC: honoraria (Novartis, Pfizer, BMS), consulting or advisory role (Novartis, Pfizer, Jazz Pharmaceuticals, Abbvie) and research funding (Novarits, BMS). DM: consultancy and honoraria (ARIAD, Bristol-Myers Squibb, Novartis, Pfizer, Incyte) and speakers bureau (Incyte). FEN: consulting or advisory role (Incyte, Sun Pharma Ltd) and speakers bureau (Incyte, BMS, Novartis). TLH (sadly passed away): research funding (Novartis, BMS), advisory board member (Novartis, Incyte), and honoraria (BMS, Novartis, Incyte). MC: research funding (Novartis, BMS, Cyclacel, Incyte), advisory board member (BMS, Novartis, Incyte, Pfizer), and honoraria (Astellas, BMS, Novartis, Incyte, Pfizer, Takeda, Celgene). The other authors have no competing financial interests to disclose.

Figures

Fig. 1. Trial CONSORT diagram.
Fig. 1. Trial CONSORT diagram.
IM = Imatinib; IM/HCQ = Imatinib and Hydroxychloroquine; Rx = treatment.
Fig. 2. Plot of median BCR-ABL1:ABL1 ratio…
Fig. 2. Plot of median BCR-ABL1:ABL1 ratio (with upper and lower quartiles denoted by vertical bars) over the study period, split by treatment arm.
Separate trend lines are shown for each treatment arm, for patients with baseline BCR-ABL1:ABL1 greater than (“high” group) and less than or equal to (“low” group) the overall median value. Individual patient data (jittered) are overlaid. Values that are recorded as undetectable (zero) have been censored at 0.001%—the censored ranges are denoted by dotted lines.
Fig. 3. Butterfly plots illustrating the prevalence…
Fig. 3. Butterfly plots illustrating the prevalence of selected haematology and biochemistry toxicities and adverse events during the first 12 months of treatment and during follow-up.
The percentage of patients on each arm with toxicities and adverse events present at any grade and grade ≥2 are presented, restricted to toxicities and adverse events where at least 10% of patients on either arm experience worse grade ≥1 during the relevant period. The two-sided p value from a Mann–Whitney test comparing the distribution of grades between treatment arms is presented for each CTCAE-defined toxicity. Significant differences between arms at the two-sided 5% level are depicted (*).

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