- Email: [email protected]
The DESTINY of chronic myeloid leukeamia
Comment
The new century brought a new future for patients affected by chronic myeloid leukaemia as it moved from a fatal disease to a treatable illness with a life expectancy similar to the general population after the introduction of the tyrosine kinase inhibitor (TKI) therapy.1 The management of this illness was progressively modified to newer standards in continuous evolution, including treatment discontinuation in cases of deep molecular responses.2 Within 10 years, we moved from one to five TKIs with increasing potency to choose from. However, all TKIs have adverse effects (BCR-ABL is not the only target), and the more powerful the drug, the longer it is used, and the more important adverse events can develop. In October, 2013, the US Food and Drug Administration raised concerns regarding the increased frequency of ponatinib-linked arterial thrombotic events, and it was suggested that the dose should be reduced for responding patients. Similar vascular problems were previously evidenced for nilotinib,3 and other TKIs have shown pulmonary, metabolic, gastrointestinal, musculoskeletal, and cutaneous adverse events affecting safety and compliance.4 Thus, the treatment with TKIs is now changing in the attempt to address these issues. Most patients (>90%) who are optimally managed, with a strict follow-up and accurate and timely treatment adjustment, will regain a normal haematopoiesis within the first year of treatment.5 With time, approximately 50% of patients achieving a deep molecular response (>MR4; BCR-ABL1:ABL1 transcript ratio <0·01%) could attempt discontinuation of the treatment; however, half of these patients will require treatment again and will resume therapy.6 Thus, a large cohort of patients will have a normal life expectancy, but will also face lifelong therapy. The DESTINY study, reported by Richard E Clark and colleagues, is focused on this optimal larger group.7 The study was designed to test the optimal deescalation treatment of patients with chronic myeloid leukeamia with stable major molecular response (MMR; BCR-ABL1:ABL1 transcript ratio <0·1%) or MR4, assessed by at least three tests in the past 12 months, after a minimum of 3 years’ treatment with standard doses of imatinib, nilotinib, or dasatinib. It is a simple www.thelancet.com/haematology Vol 4 July 2017
and practical study that shows the effectiveness and the safety of the TKI dose reduction in optimal, but not deeper, responders, who represent the grey zone of chronic myeloid leukeamia. The first attempt to reduce the median dose of TKI without affecting the prognosis (overall survival and progression) was done in 2008, by Russo and colleagues.8 The investigators analysed an intermittent administration of imatinib (1 month on followed by 1 month off) in patients older than 65 years with at least 2 years stable complete cytogenetic remission (CCyR). A 50% dose reduction resulted in loss of CCyR in 17% of patients, regained after resuming continuous therapy; all patients had improvement in their quality of life (QoL), and none presented new side-effects (eg, the TKI withdrawal syndrome).9 Another step forward in dose modulation was the OPTIM study,10 investigating the optimisation of dasatinib dose according to plasma concentrations to improve the tolerance, side-effects, and efficacy of treatment. Patients treated with the 50% reduced dose had a lower cumulative incidence of pleural effusions and a lower rate of drug discontinuation. Clark and colleagues7 provide further insight into this research. In all 174 patients enrolled, no progression or cytogenetic relapse was reported, and the monthly monitoring quickly identified the 12 patients who lost MMR, resumed full-dose therapy, and regained MMR within 4 months. None of these patients developed point mutations as a consequence of the reduced therapy. Chronic adverse events improved in many patients, although TKI withdrawal syndrome (present here with no withdrawal, but just reduction) was reported in 36 of them. A systematic economic study was also done. Considering the real costs, 46·7% (£1 943 364) from the expected 1-year TKI budget was saved, including costs for patients already treated with an adjusted dose and the time and the number of patients that had to restart full dose. The key findings of the DESTINY study indicate the feasibility of using a dose reduction approach in future routine practice to minimise adverse events from treatment and improve QoL. In the first 12 months of the study, the costs saved from the TKI budget certainly encompass the £31 000 extra costs that will be due to the nine additional
Secchi-Lecaque/Roussel-UCLA/CNRI/FScience Photo Library
The DESTINY of chronic myeloid leukeamia
Published Online May 26, 2017 http://dx.doi.org/10.1016/ S2352-3026(17)30087-X See Articles page e310
e303
Comment
monitoring QPCR requested to monitor patients with reduced dose. These rough calculations pertain only to hospital-based expenses, and cost use analysis, including more broadly defined benefits, should be added and would probably shift the balance in favour of this health-related intervention. For patients who are unable to stop therapy, adjustment of the treatment doses without jeopardising the clinical outcome has important clinical implications. Combination of reduced dosage TKIs with newer (ABL001) or older approaches (immunomodulation) might represent a future answer to that. “In few areas has the progress been quite as remarkable as in the management of chronic myeloid leukemia”, commented John M Goldmann in 2006, and since then, the specialty is still moving. Elisabetta Abruzzese Department of Hematology, S Eugenio Hospital, Tor Vergata University, Rome, Italy [email protected] EA reports personal fees from Ariad/Incyte, is on the advisory board for Novartis, Pfizer, and Ariad/Incyte, and is a consultant for Bristol–Myers Squibb, outside the submitted work.
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1
Gambacorti-Passerini C, Antolini L, Mahon FX, et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst 2011; 103: 553–61. 2 Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia. Blood 2013; 122: 872–84. 3 Le Coutre P, Rea D, Abruzzese E, et al. Severe peripheral arterial disease during nilotinib therapy. J Natl Cancer Inst 2011; 103: 1347–48. 4 Steegmann JL, Baccarani M, Breccia M, et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia 2016; 8: 1648–71. 5 Jain P, Kantarjian H, Alattar ML, et al. Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: retrospective analysis of patient data from five clinical trials. Lancet Haematol 2015; 3: e118–28. 6 Hughes TP, Ross DM. Moving treatment-free remission into mainstream clinical practice in CML. Blood 2016; 128: 17–23. 7 Clark RE, Polydoros F, Apperley JF, et al. De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): a non-randomised, phase 2 trial. Lancet Haematol 2017; published online May 26. http://dx.doi. org/10.1016/S2352-3026(17)30066-2. 8 Russo D, Martinelli G, Malagola M, et al. Effects and outcome of a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia. Blood 2013; 121: 5138−44. 9 Richter J, Söderlund S, Lübking A, et al. Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome? J Clin Oncol 2014; 32: 2821–23. 10 Rousselot P, Mollica L, Guerci-Bresler A, et al. Dasatinib daily dose optimization based on residual drug levels resulted in reduced risk of pleural effusion and high molecular response rates: final results of the randomized OPTIM dasatinib trial. Haematologica 2014; 99 (s1): P678 (abstr).
www.thelancet.com/haematology Vol 4 July 2017
The new century brought a new future for patients affected by chronic myeloid leukaemia as it moved from a fatal disease to a treatable illness with a life expectancy similar to the general population after the introduction of the tyrosine kinase inhibitor (TKI) therapy.1 The management of this illness was progressively modified to newer standards in continuous evolution, including treatment discontinuation in cases of deep molecular responses.2 Within 10 years, we moved from one to five TKIs with increasing potency to choose from. However, all TKIs have adverse effects (BCR-ABL is not the only target), and the more powerful the drug, the longer it is used, and the more important adverse events can develop. In October, 2013, the US Food and Drug Administration raised concerns regarding the increased frequency of ponatinib-linked arterial thrombotic events, and it was suggested that the dose should be reduced for responding patients. Similar vascular problems were previously evidenced for nilotinib,3 and other TKIs have shown pulmonary, metabolic, gastrointestinal, musculoskeletal, and cutaneous adverse events affecting safety and compliance.4 Thus, the treatment with TKIs is now changing in the attempt to address these issues. Most patients (>90%) who are optimally managed, with a strict follow-up and accurate and timely treatment adjustment, will regain a normal haematopoiesis within the first year of treatment.5 With time, approximately 50% of patients achieving a deep molecular response (>MR4; BCR-ABL1:ABL1 transcript ratio <0·01%) could attempt discontinuation of the treatment; however, half of these patients will require treatment again and will resume therapy.6 Thus, a large cohort of patients will have a normal life expectancy, but will also face lifelong therapy. The DESTINY study, reported by Richard E Clark and colleagues, is focused on this optimal larger group.7 The study was designed to test the optimal deescalation treatment of patients with chronic myeloid leukeamia with stable major molecular response (MMR; BCR-ABL1:ABL1 transcript ratio <0·1%) or MR4, assessed by at least three tests in the past 12 months, after a minimum of 3 years’ treatment with standard doses of imatinib, nilotinib, or dasatinib. It is a simple www.thelancet.com/haematology Vol 4 July 2017
and practical study that shows the effectiveness and the safety of the TKI dose reduction in optimal, but not deeper, responders, who represent the grey zone of chronic myeloid leukeamia. The first attempt to reduce the median dose of TKI without affecting the prognosis (overall survival and progression) was done in 2008, by Russo and colleagues.8 The investigators analysed an intermittent administration of imatinib (1 month on followed by 1 month off) in patients older than 65 years with at least 2 years stable complete cytogenetic remission (CCyR). A 50% dose reduction resulted in loss of CCyR in 17% of patients, regained after resuming continuous therapy; all patients had improvement in their quality of life (QoL), and none presented new side-effects (eg, the TKI withdrawal syndrome).9 Another step forward in dose modulation was the OPTIM study,10 investigating the optimisation of dasatinib dose according to plasma concentrations to improve the tolerance, side-effects, and efficacy of treatment. Patients treated with the 50% reduced dose had a lower cumulative incidence of pleural effusions and a lower rate of drug discontinuation. Clark and colleagues7 provide further insight into this research. In all 174 patients enrolled, no progression or cytogenetic relapse was reported, and the monthly monitoring quickly identified the 12 patients who lost MMR, resumed full-dose therapy, and regained MMR within 4 months. None of these patients developed point mutations as a consequence of the reduced therapy. Chronic adverse events improved in many patients, although TKI withdrawal syndrome (present here with no withdrawal, but just reduction) was reported in 36 of them. A systematic economic study was also done. Considering the real costs, 46·7% (£1 943 364) from the expected 1-year TKI budget was saved, including costs for patients already treated with an adjusted dose and the time and the number of patients that had to restart full dose. The key findings of the DESTINY study indicate the feasibility of using a dose reduction approach in future routine practice to minimise adverse events from treatment and improve QoL. In the first 12 months of the study, the costs saved from the TKI budget certainly encompass the £31 000 extra costs that will be due to the nine additional
Secchi-Lecaque/Roussel-UCLA/CNRI/FScience Photo Library
The DESTINY of chronic myeloid leukeamia
Published Online May 26, 2017 http://dx.doi.org/10.1016/ S2352-3026(17)30087-X See Articles page e310
e303
Comment
monitoring QPCR requested to monitor patients with reduced dose. These rough calculations pertain only to hospital-based expenses, and cost use analysis, including more broadly defined benefits, should be added and would probably shift the balance in favour of this health-related intervention. For patients who are unable to stop therapy, adjustment of the treatment doses without jeopardising the clinical outcome has important clinical implications. Combination of reduced dosage TKIs with newer (ABL001) or older approaches (immunomodulation) might represent a future answer to that. “In few areas has the progress been quite as remarkable as in the management of chronic myeloid leukemia”, commented John M Goldmann in 2006, and since then, the specialty is still moving. Elisabetta Abruzzese Department of Hematology, S Eugenio Hospital, Tor Vergata University, Rome, Italy [email protected] EA reports personal fees from Ariad/Incyte, is on the advisory board for Novartis, Pfizer, and Ariad/Incyte, and is a consultant for Bristol–Myers Squibb, outside the submitted work.
e304
1
Gambacorti-Passerini C, Antolini L, Mahon FX, et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst 2011; 103: 553–61. 2 Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia. Blood 2013; 122: 872–84. 3 Le Coutre P, Rea D, Abruzzese E, et al. Severe peripheral arterial disease during nilotinib therapy. J Natl Cancer Inst 2011; 103: 1347–48. 4 Steegmann JL, Baccarani M, Breccia M, et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia 2016; 8: 1648–71. 5 Jain P, Kantarjian H, Alattar ML, et al. Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: retrospective analysis of patient data from five clinical trials. Lancet Haematol 2015; 3: e118–28. 6 Hughes TP, Ross DM. Moving treatment-free remission into mainstream clinical practice in CML. Blood 2016; 128: 17–23. 7 Clark RE, Polydoros F, Apperley JF, et al. De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): a non-randomised, phase 2 trial. Lancet Haematol 2017; published online May 26. http://dx.doi. org/10.1016/S2352-3026(17)30066-2. 8 Russo D, Martinelli G, Malagola M, et al. Effects and outcome of a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia. Blood 2013; 121: 5138−44. 9 Richter J, Söderlund S, Lübking A, et al. Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome? J Clin Oncol 2014; 32: 2821–23. 10 Rousselot P, Mollica L, Guerci-Bresler A, et al. Dasatinib daily dose optimization based on residual drug levels resulted in reduced risk of pleural effusion and high molecular response rates: final results of the randomized OPTIM dasatinib trial. Haematologica 2014; 99 (s1): P678 (abstr).
www.thelancet.com/haematology Vol 4 July 2017