doi:10.1111/ejh.12440
European Journal of Haematology 94 (189–190)
EDITORIAL
Another piece of the puzzle – optimal TKI selection before treatment discontinuation in CML Dominik Wolf Medical Clinic 3, University Hospital Bonn (UKB), Bonn, Germany
The incredible advances made in the field of CML management during the last 20 years are currently in the phase of bringing as much patients as possible to treatment concepts allowing TKI discontinuation and potential cure (1, 2). Cure is clinically reflected by continuous treatment discontinuation without subsequent disease relapse. Data from the French STIM (3) and the Australasian TWISTER (4) studies are encouraging; however, only less than 20% of patients in the imatinib era indeed finally fulfil the requirements for treatment discontinuation. Therefore, the introduction of the 2ndgeneration TKIs is an important step to allow in the future a higher percentage of patients to discontinue therapy and to be potentially cured. Thus, data from randomized trials showing the superiority of 2nd-generation TKIs vs. imatinib are still important as positive data help patients and physicians to tolerate the clinically more relevant side effects of 2nd generation TKIs for the achievement of continuous deep molecular remission. The here presented paper by the Nordic CML group (NCMLSG) helps us further to believe that starting with a 2nd-generation TKI is probably the optimal strategy to get as much patients as possible in deep molecular remission (5). Henrik Hjorth-Hansen and his Nordic co-workers performed an interesting randomized trial comparing dasatinib versus imatinib in the front-line setting in CP-CML. The study was rather small, but the adjunct research programme aiming at quantifying CML stem cell dynamics with respect to their prognostic relevance is highly innovative (6). The scientific programme demonstrated that at diagnosis, the proportion of leukaemic stem cells (LSC) markedly varied between different individuals but correlated with various clinical variables (i.e. LSC burden at diagnosis was associated with less therapy-related haematological toxicity and superior cytogenetic and molecular responses). Most importantly and in contrast to in vitro findings, TKI therapy very rapidly depleted most of the detectable LSC in vivo. The authors now show in this issue of the European Journal of Haematology that especially the molecular data of their NCMLSG study compare favourable to the Correspondence Dominik Wolf, MD, Department of Internal Medicine III, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. Tel: 49 228 287 17233; Fax: 49 228 287 51729; e-mail: [email protected]
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
DASISION trial (7) or another randomized US trial from G. Radich and co-workers (8). Of note, even though the Nordic population was even older and had a comparable distribution of risk scores, the Nordic molecular response rates were almost doubled as compared to the two mentioned reference studies. At 24 months, for example, 52% in the NCMLSG trial had MR4.5 as opposed to 17% of patients in the DASISION study. It remains elusive whether the Nordic patients have a higher level of compliance due to the excellent healthcare system, or whether there are specific genetic polymorphisms regulating different TKI sensitivities [e.g. MRD1 polymorphisms or expression levels (9, 10)] or whether these observations are just due to the smaller patient population and thus do not reflect biological and potentially modifiable variables. The data are, however, of importance, especially with respect to possible cessation scenarios, as it suggests that dasatinib is clearly superior to imatinib in the induction of deep molecular responses, which is a prerequisite for TKI discontinuation. References 1. Druker BJ. Translation of the Philadelphia chromosome into therapy for CML. Blood 2008;112:4808–17. 2. Mahon FX. Is going for cure in chronic myeloid leukemia possible and justifiable? Hematology Am Soc Hematol Educ Program 2012;2012:122–8. 3. Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010;11:1029–35. 4. Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 2013;122:515–22. 5. Hjorth-Hansen H, Stenke L, Soderlund S, et al. Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukemia (CML) patients in chronic phase: clinical results from a randomized phase 2 study (NordCML006). Eur J Haematol 2014. 6. Mustjoki S, Richter J, Barbany G, et al. Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients. Leukemia 2013; 27:1520–6.
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Editorial
7. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014;123:494–500. 8. Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood 2012;120:3898–905. 9. Agrawal M, Hanfstein B, Erben P, et al. MDR1 expression predicts outcome of Ph+ chronic phase CML patients on
190
second-line nilotinib therapy after imatinib failure. Leukemia 2014;28:1478–85. 10. Dulucq S, Bouchet S, Turcq B, Lippert E, Etienne G, Reiffers J, Molimard M, Krajinovic M, Mahon FX. Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2008;112:2024–7.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
European Journal of Haematology 94 (189–190)
EDITORIAL
Another piece of the puzzle – optimal TKI selection before treatment discontinuation in CML Dominik Wolf Medical Clinic 3, University Hospital Bonn (UKB), Bonn, Germany
The incredible advances made in the field of CML management during the last 20 years are currently in the phase of bringing as much patients as possible to treatment concepts allowing TKI discontinuation and potential cure (1, 2). Cure is clinically reflected by continuous treatment discontinuation without subsequent disease relapse. Data from the French STIM (3) and the Australasian TWISTER (4) studies are encouraging; however, only less than 20% of patients in the imatinib era indeed finally fulfil the requirements for treatment discontinuation. Therefore, the introduction of the 2ndgeneration TKIs is an important step to allow in the future a higher percentage of patients to discontinue therapy and to be potentially cured. Thus, data from randomized trials showing the superiority of 2nd-generation TKIs vs. imatinib are still important as positive data help patients and physicians to tolerate the clinically more relevant side effects of 2nd generation TKIs for the achievement of continuous deep molecular remission. The here presented paper by the Nordic CML group (NCMLSG) helps us further to believe that starting with a 2nd-generation TKI is probably the optimal strategy to get as much patients as possible in deep molecular remission (5). Henrik Hjorth-Hansen and his Nordic co-workers performed an interesting randomized trial comparing dasatinib versus imatinib in the front-line setting in CP-CML. The study was rather small, but the adjunct research programme aiming at quantifying CML stem cell dynamics with respect to their prognostic relevance is highly innovative (6). The scientific programme demonstrated that at diagnosis, the proportion of leukaemic stem cells (LSC) markedly varied between different individuals but correlated with various clinical variables (i.e. LSC burden at diagnosis was associated with less therapy-related haematological toxicity and superior cytogenetic and molecular responses). Most importantly and in contrast to in vitro findings, TKI therapy very rapidly depleted most of the detectable LSC in vivo. The authors now show in this issue of the European Journal of Haematology that especially the molecular data of their NCMLSG study compare favourable to the Correspondence Dominik Wolf, MD, Department of Internal Medicine III, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. Tel: 49 228 287 17233; Fax: 49 228 287 51729; e-mail: [email protected]
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
DASISION trial (7) or another randomized US trial from G. Radich and co-workers (8). Of note, even though the Nordic population was even older and had a comparable distribution of risk scores, the Nordic molecular response rates were almost doubled as compared to the two mentioned reference studies. At 24 months, for example, 52% in the NCMLSG trial had MR4.5 as opposed to 17% of patients in the DASISION study. It remains elusive whether the Nordic patients have a higher level of compliance due to the excellent healthcare system, or whether there are specific genetic polymorphisms regulating different TKI sensitivities [e.g. MRD1 polymorphisms or expression levels (9, 10)] or whether these observations are just due to the smaller patient population and thus do not reflect biological and potentially modifiable variables. The data are, however, of importance, especially with respect to possible cessation scenarios, as it suggests that dasatinib is clearly superior to imatinib in the induction of deep molecular responses, which is a prerequisite for TKI discontinuation. References 1. Druker BJ. Translation of the Philadelphia chromosome into therapy for CML. Blood 2008;112:4808–17. 2. Mahon FX. Is going for cure in chronic myeloid leukemia possible and justifiable? Hematology Am Soc Hematol Educ Program 2012;2012:122–8. 3. Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010;11:1029–35. 4. Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 2013;122:515–22. 5. Hjorth-Hansen H, Stenke L, Soderlund S, et al. Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukemia (CML) patients in chronic phase: clinical results from a randomized phase 2 study (NordCML006). Eur J Haematol 2014. 6. Mustjoki S, Richter J, Barbany G, et al. Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients. Leukemia 2013; 27:1520–6.
189
Editorial
7. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014;123:494–500. 8. Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood 2012;120:3898–905. 9. Agrawal M, Hanfstein B, Erben P, et al. MDR1 expression predicts outcome of Ph+ chronic phase CML patients on
190
second-line nilotinib therapy after imatinib failure. Leukemia 2014;28:1478–85. 10. Dulucq S, Bouchet S, Turcq B, Lippert E, Etienne G, Reiffers J, Molimard M, Krajinovic M, Mahon FX. Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2008;112:2024–7.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
