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Chronic myelogenous leukemia

Is it beneficial to use hydroxychloroquine and imatinib combination in order to achieve deeper molecular responses in patients with chronic myeloid leukemia?

Leukemia volume 34, pages 3426–3427 (2020)Cite this article

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I have read with great interest the paper by Horne et al. [1], in which the authors randomly assigned 62 patients with chronic myeloid leukemia in chronic phase (CML-CP) into two groups as one group consisting of cases continuing imatinib alone (n = 30) and the other group containing patients who received imatinib in combination with hydroxychloroquine (n = 32). All patients received imatinib for more than 12 months and achieved at least major cytogenetic response with molecular detectable disease. The authors showed that at 12 and 24 months, major molecular response (MMR) rates were higher in the combination arm (71.9 and 68.8%) than those of the imatinib arm (66.7 and 63.3%), although the differences were not significant [1].

Although the study displays some interesting and encouraging results regarding the autophagy inhibition and its potential clinical impact in the management of patients with CML-CP, there are some points that need further clarification.

  • Patients in the combination arm had superior molecular responses than cases receiving imatinib alone. However, the distribution of disease risk scores between the two study arms were not displayed, and maybe there were more patients with high risk scores in the imatinib alone arm and at least this could be one of the reasons for the superior outcomes observed in the combination arm.

  • Most of the patients in both arms received 400 mg imatinib, and only 10% and 15.6% percentage of patients had 600–800 mg daily imatinib in the imatinib alone and combination arms, respectively. In CML-CP patients achieving suboptimal responses under 400 mg imatinib, increasing the dose to 600 mg may be beneficial. In the LASOR trial, increasing daily imatinib dose from 400 to 600 mg induced MMR at 12 and 24 months in 25% and 36% of the patients, respectively, who had suboptimal cytogenetic responses according to 2009 European LeukemiaNet recommendations [2]. In the TIDEL trial, where CML-CP patients received upfront 600 mg/day imatinib, the MMR rates at 12 and 24 months were 47% and 73%, respectively [3]. In a more recent study, where two different dose intensifications (400→600 mg imatinib) were compared, the MMR rates were 52.1% and 58.7% at 12 months and 70% and 68.3% at 24 months for the two different dose escalation strategies [4]. Having said that, since in the present study the MMR rates of the combination arm at 12 months and 24 months were 71.9% and 68.8%, respectively [1], for my point of view, increasing the daily dose of imatinib from 400 to 600 mg would most probably induce similar molecular response rates when compared to the imatinib and hydroxychloroquine combination arm of the present study. So, I think adding a third study arm consisting of patients with a dose escalation to 600 mg imatinib and comparing this group with the combination arm both in terms of efficacy and toxicity would be more interesting and informative.

  • Higher doses (600 or 800 mg) of imatinib are more toxic than the standard-dose imatinib and not all patients can tolerate these doses. In this study, although generally well-tolerated, imatinib, and hydroxychloroquine combination was also associated with some significant toxicities. Hematologic adverse events were more prominent in the combination arm both in the treatment and follow-up periods and especially diarrhea, nausea, and abdominal pain were more frequent in the combination arm especially within the treatment period [1]. For example, in the TIDEL trial, the grade III–IV neutropenia was observed in 20.4% of the patients [3], and grade II–IV neutropenia was seen in 19% of the patients receiving imatinib and hydroxychloroquine combination in the present study [1]. Grade III–IV diarrhea and nausea were observed in 1.9% and 1.9% of the patients in TIDEL trial [3], whereas in the present study, grade ≥ II diarrhea and nausea were seen in 34% and 9% of the patients [1], respectively. So, although can be more toxic than 400 mg/day imatinib, 600 mg imatinib may be more tolerable than the imatinib and hydroxychloroquine combination with comparable response rates in this patient population.

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References

  1. Horne GA, Stobo J, Kelly C, Mukhopadhyay A, Latif AL, Dixon-Hughes J, et al. 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. Leukemia. 2020. https://doi.org/10.1038/s41375-019-0700-9.

  2. Cortes JE, De Souza CA, Ayala M, Lopez JL, Bullorsky E, Shah S, et al. Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial. Lancet Haematol. 2016;3:e581–91.

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  3. Hughes TP, Branford S, White DL, Reynolds J, Koelmeyer R, Seymour JF, et al. Impact of early dose intensity on cytogenetic and molecular responses in chronic-phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood. 2008;112:3965–73.

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Acknowledgements

AEE would like to thank his mentor retired Prof. Teoman Soysal for his continuous support and guidance and he wishes him a long, happy, and healthy retirement.

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  1. Division of Hematology, Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey

    Ahmet Emre Eşkazan

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Correspondence to Ahmet Emre Eşkazan.

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AEE has received advisory board honorarium from Novartis, and he also received speaker bureau honoraria from Novartis, Bristol-Myers Squibb, and Pfizer outside the present study.

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Eşkazan, A.E. Is it beneficial to use hydroxychloroquine and imatinib combination in order to achieve deeper molecular responses in patients with chronic myeloid leukemia?. Leukemia 34, 3426–3427 (2020). https://doi.org/10.1038/s41375-020-0796-y

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