- Email: [email protected]
First-line therapy for CML: decisions, decisions
Comment
Chronic myeloid leukaemia (CML) results from a balanced translocation between the long arms of chromosomes 9 and 22. This translocation brings together two genes that produce the novel BCR-ABL1 oncoprotein, a constitutively active tyrosine kinase. Less than two decades ago medical treatment for CML was ineffective and the disease could only be cured by allogeneic haematopoietic stem-cell transplantation. Since then, the introduction of imatinib (the first targeted tyrosine kinase inhibitor [TKI]) has dramatically changed the prognosis for patients with CML; many now achieve long-term disease suppression with oral drugs.1 Development of second-generation TKIs followed rapidly, with more sensitive and selective inhibition of tyrosine kinase and different toxicity profiles. Two such drugs, nilotinib and dasatinib, have been shown to result in faster and deeper molecular responses than can be achieved with standard-dose imatinib in large comparative trials.2,3 As a result, current US and European treatment guidelines recommend the use of standard-dose imatinib, nilotinib, and dasatinib as first-line therapy for chronic-phase CML.4,5 However, some key questions remain. Do the improved responses with second-generation TKIs translate into better overall survival, justifying their use as first-line therapies? Is one second-generation TKI better than another in this setting? In The Lancet Haematology, Preetesh Jain and colleagues compare the responses and outcomes of 482 patients with chronic-phase CML receiving firstline therapy with imatinib, dasatinib, or nilotinib from five clinical trials at a single US centre.6 This study sheds some valuable light on issues left unanswered by multicentre comparative studies. Reporting the outcomes of similarly structured trials in similar patient groups (albeit in fairly young patients and with good risk profiles) allowed the investigators to make comparisons that have not, and probably will not, be made in randomised trials. Importantly, the findings showed equivalent responses and patient outcomes after first-line treatment with either nilotinib or dasatinib. This information is valuable for the practising haematologist, supporting a pragmatic strategy of selection between these drugs on the basis of individual patient comorbidities and differing toxicity profiles. www.thelancet.com/haematology Vol 2 March 2015
However, this choice is not always available to patients or physicians; in the UK, the National Institute for Health and Care Excellence at present approves the use of nilotinib but not dasatinib for first-line therapy in chronic phase CML on the basis of cost alone. The investigators also reported that response speed and depth was worse, more patients discontinued therapy, and more patients had their disease transform to a more aggressive form with standard-dose imatinib than with second generation TKIs, corroborating the findings of the key comparative studies. Intriguingly, despite longer follow-up than reported in published randomised comparative trials, the study still did not show worse overall survival in patients treated with standard-dose imatinib. Although this finding might just be a time-dependent effect, another likely explanation is successful subsequent therapy with second generation TKIs. This observation might therefore support adoption of a two-stage treatment strategy starting with standard-dose imatinib and proceeding to a secondgeneration TKI in patients intolerant of or insensitive to imatinib. This strategy has recently been prospectively tested by the TIDEL investigators.7 Although there is currently little price difference between imatinib, nilotinib, and dasatinib in the USA and Europe, imatinib comes off patent within the next year in the UK and perhaps as early as 2016 in the USA, which will probably make this two-step strategy financially advantageous. As always, there are several questions relevant to current clinical practice that the investigators could not address in their study, including the effects of deep molecular remission at very early timepoints on patient outcomes and the feasibility of discontinuation of TKI therapy in patients who achieved deep and sustained remission. That said, the study does give important insight, suggesting efficacy of second generation TKIs similar to that of imatinib for first-line therapy in patients with chronic-phase CML and that survival might not be compromised by adoption of a policy of first-line imatinib therapy with a switch to second-line TKIs when necessary. In a market of first-generation, second-generation, and third-generation TKIs, which all have substantial costs, this valuable guidance could help to identify the best strategy for first-line therapy in chronic-phase CML.
Aaron Polliack/Science Photo Library
First-line therapy for CML: decisions, decisions
See Articles page e118 For the NICE recommendations for first-line treatment of chronic myeloid leukaemia with tyrosine-kinase inhibitors see https://www.nice.org.uk/ Guidance/TA251
e89
Comment
Jeff Davies Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London EC1M 6BQ, UK [email protected]
4 5
6
I declare no competing interests 1
2
3
e90
O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012; 119: 1123–29. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 2011; 12: 841–51.
7
O’Brien S, Radich JP, Abboud CN, et al. Chronic myelogenous leukemia, version 1. 2014. J Natl Compr Canc Netw 2013; 11: 1327–40. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122: 872–84. 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; 2: e118–28 Yeung DT, Osborn MP, White DL, et al. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood 2015; 125: 915–23.
www.thelancet.com/haematology Vol 2 March 2015
Chronic myeloid leukaemia (CML) results from a balanced translocation between the long arms of chromosomes 9 and 22. This translocation brings together two genes that produce the novel BCR-ABL1 oncoprotein, a constitutively active tyrosine kinase. Less than two decades ago medical treatment for CML was ineffective and the disease could only be cured by allogeneic haematopoietic stem-cell transplantation. Since then, the introduction of imatinib (the first targeted tyrosine kinase inhibitor [TKI]) has dramatically changed the prognosis for patients with CML; many now achieve long-term disease suppression with oral drugs.1 Development of second-generation TKIs followed rapidly, with more sensitive and selective inhibition of tyrosine kinase and different toxicity profiles. Two such drugs, nilotinib and dasatinib, have been shown to result in faster and deeper molecular responses than can be achieved with standard-dose imatinib in large comparative trials.2,3 As a result, current US and European treatment guidelines recommend the use of standard-dose imatinib, nilotinib, and dasatinib as first-line therapy for chronic-phase CML.4,5 However, some key questions remain. Do the improved responses with second-generation TKIs translate into better overall survival, justifying their use as first-line therapies? Is one second-generation TKI better than another in this setting? In The Lancet Haematology, Preetesh Jain and colleagues compare the responses and outcomes of 482 patients with chronic-phase CML receiving firstline therapy with imatinib, dasatinib, or nilotinib from five clinical trials at a single US centre.6 This study sheds some valuable light on issues left unanswered by multicentre comparative studies. Reporting the outcomes of similarly structured trials in similar patient groups (albeit in fairly young patients and with good risk profiles) allowed the investigators to make comparisons that have not, and probably will not, be made in randomised trials. Importantly, the findings showed equivalent responses and patient outcomes after first-line treatment with either nilotinib or dasatinib. This information is valuable for the practising haematologist, supporting a pragmatic strategy of selection between these drugs on the basis of individual patient comorbidities and differing toxicity profiles. www.thelancet.com/haematology Vol 2 March 2015
However, this choice is not always available to patients or physicians; in the UK, the National Institute for Health and Care Excellence at present approves the use of nilotinib but not dasatinib for first-line therapy in chronic phase CML on the basis of cost alone. The investigators also reported that response speed and depth was worse, more patients discontinued therapy, and more patients had their disease transform to a more aggressive form with standard-dose imatinib than with second generation TKIs, corroborating the findings of the key comparative studies. Intriguingly, despite longer follow-up than reported in published randomised comparative trials, the study still did not show worse overall survival in patients treated with standard-dose imatinib. Although this finding might just be a time-dependent effect, another likely explanation is successful subsequent therapy with second generation TKIs. This observation might therefore support adoption of a two-stage treatment strategy starting with standard-dose imatinib and proceeding to a secondgeneration TKI in patients intolerant of or insensitive to imatinib. This strategy has recently been prospectively tested by the TIDEL investigators.7 Although there is currently little price difference between imatinib, nilotinib, and dasatinib in the USA and Europe, imatinib comes off patent within the next year in the UK and perhaps as early as 2016 in the USA, which will probably make this two-step strategy financially advantageous. As always, there are several questions relevant to current clinical practice that the investigators could not address in their study, including the effects of deep molecular remission at very early timepoints on patient outcomes and the feasibility of discontinuation of TKI therapy in patients who achieved deep and sustained remission. That said, the study does give important insight, suggesting efficacy of second generation TKIs similar to that of imatinib for first-line therapy in patients with chronic-phase CML and that survival might not be compromised by adoption of a policy of first-line imatinib therapy with a switch to second-line TKIs when necessary. In a market of first-generation, second-generation, and third-generation TKIs, which all have substantial costs, this valuable guidance could help to identify the best strategy for first-line therapy in chronic-phase CML.
Aaron Polliack/Science Photo Library
First-line therapy for CML: decisions, decisions
See Articles page e118 For the NICE recommendations for first-line treatment of chronic myeloid leukaemia with tyrosine-kinase inhibitors see https://www.nice.org.uk/ Guidance/TA251
e89
Comment
Jeff Davies Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London EC1M 6BQ, UK [email protected]
4 5
6
I declare no competing interests 1
2
3
e90
O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012; 119: 1123–29. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 2011; 12: 841–51.
7
O’Brien S, Radich JP, Abboud CN, et al. Chronic myelogenous leukemia, version 1. 2014. J Natl Compr Canc Netw 2013; 11: 1327–40. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122: 872–84. 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; 2: e118–28 Yeung DT, Osborn MP, White DL, et al. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood 2015; 125: 915–23.
www.thelancet.com/haematology Vol 2 March 2015