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The Treatment of Chronic Myeloid Leukaemia in the Era of Tyrosine Kinase Inhibitors the patients play an important role in choosing the optimal treatment option in each individual patient. As was the case with nilotinib and dasatinib, bosutinib first proved its clinical efficacy in relapsing patients, and then this drug was tested in the Bosutinib Efficacy and Safety in Newly Diagnosed CML (BELA) trial, in which the efficacy of bosutinib has been evaluated in the frontline setting. 11 However the primary end point (which was complete cytogenetic response [CCyR] at 12 months) was not different for bosutinib versus imatinib and the gastrointestinal side effects (mainly diarrhoea) were more common with bosutinib – as a result bosutinib was not approved in the frontline setting, but it remains a reasonable option in the salvage setting. Ponatinib is a pan-BCR-ABL1 inhibitor retaining potency against all ABL mutations including T315I. This extremely active drug was first used in resistant cases, and then in the Ponatinib in Newly Diagnosed Chronic Myeloid Leukemia (EPIC) trial. 12 But this phase III trial was terminated early due to observation of arterial thrombotic events. If we ask ‘What is the best first-line treatment option for patients with CML-CP?’ the answer for the time being is that the best first option is between all three currently available TKIs (imatinib, nilotinib and dasatinib). But the most important concern is balancing TKI toxicity profiles and the patient comorbidities, as well as the cost of treatment. European LeukemiaNet (ELN) suggests that if the level of BCR-ABL1 IS is still >10 % by 6 months, switching the TKI might be needed, and in patients who failed to achieve a CCyR by 12 months, an alternative TKI treatment should be initiated. 13 From the DASISION and ENESTnd trials, we know that both dasatinib and nilotinib could induce molecular responses deeper and faster than imatinib, and achieving an early molecular response (EMR) might translate into less disease progression and a favourable outcome. So in patients who do not meet the criteria for gaining an EMR (i.e. BCR-ABL1 IS ≤10 % at 3 months) under any TKI, but particularly imatinib, although the current data on switching TKI at 3 months is still controversial and not excepted by all, switching to 2GTKIs can be a treatment option. Also knowing that the clinical 1. Sasaki K, Strom SS, O’Brien S, et al., Chronic myeloid leukemia in chronic phase: Survival in the era of tyrosine kinase inhibitors is similar to that of the general population in all age groups, Blood, 2014;124:1801. 2. Experts in Chronic Myeloid Leukemia, The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts, Blood, 2013;121:4439–42. 3. Soysal T, Eskazan AE, Ar MC, Generics in chronic myeloid leukemia: current arguments for and against and the established evidence, Expert Rev Hematol, 2014;7:697–9. 4. Carella AM, Dellepiane C, Lovera, et al., Chronic Myeloid Leukaemia – The Choice of Therapy and Future Perspectives, Eur Oncol Haematol, 2015;11(1):25–9. 5. 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. E u rop ean O n col ogy & Ha em atol og y outcomes with imatinib are worse in high-risk patients, someone might find it rational to use nilotinib or dasatinib among these patients in the upfront setting. But still there is no solid data about this hypothetically favourable treatment approach. Continuous TKI treatment can attenuate an individual’s quality of life. There are studies showing durable molecular responses after discontinuation of imatinib and even 2GTKIs 4 and this can be an option in a minority of the patients. But it should also be kept in mind that for the time being, optimal responders to any TKI should continue therapy indefinitely, with careful surveillance, and they can only be enrolled in studies of treatment discontinuation. 12 The current prices of TKIs are high, and the launch of generics might reduce healthcare costs. Generic imatinibs has been approved for CML treatment in some countries, and after the original imatinib loses its patent, generic imatinib will be used in many countries. Although there are conflicting results, 3 our observations show that generics were at least non-inferior to the original molecule regarding efficacy and tolerability when used in the upfront setting, as well as when used subsequently in the short run. 14,15 However, further monitoring is still warranted, and more reliable and solid long-term data should be accumulated before making any definitive conclusions about the efficacy and safety of generics. Although TKIs are effective treatment options for CML, there is a group of patients who will be resistant to these therapies and eventually fail. There are many efforts targeting mainly the CML stem cell as overviewed by Carella et al. 4 The results are promising but none of these treatment approaches are used in the daily clinical practice. In conclusion, TKIs are the mainstay of CML treatment, but some patients are intolerant and resistant to them. Among these patients alternative treatments including combining TKIs with immunotherapy and targeting the stem-cell niche are explored offering new possibilities maybe for ‘curing’ this disease in the future. n 6. Huang X, Cortes J, Kantarjian H, Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy, Cancer, 2012;118:3123–7. 7. Deininger M, International randomized study of interferon Vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib, ASH 2009;Abstract 1126. 8. Yilmaz M, Abaza Y, Jabbour E, Selecting the best frontline treatment in chronic myeloid leukemia, Curr Hematol Malig Rep, 2015 [Epub ahead of print] 9. Saglio G, Kim DW, Issaragrisil S, et al., Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia, N Engl J Med, 2010;362:2251–9. 10. Kantarjian H, Shah NP, Hochhaus A, et al., Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia, N Engl J Med, 2010;362:2260–70. 11. Cortes JE, Kim DW, Kantarjian HM, et al., Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial, J Clin Oncol, 2012;30:3486–92. 12. Baccarani M, Deininger MW, Rosti G, et al., European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013, Blood, 2013;122:872–84. 13. Lipton JH, Epic: a phase 3 trial of ponatinib compared with imatinib in patients with newly diagnosed Chronic Myeloid Leukemia in Chronic Phase (CP-CML), ASH 2014 Abstract 519. 2014. 14. Eskazan AE, Ayer M, Kantarcioglu B, et al., First line treatment of chronic phase chronic myeloid leukaemia patients with the generic formulations of imatinib mesylate, Br J Haematol, 2014;167:139–41. 15. Eskazan AE, Elverdi T, Yalniz FF, et al., The efficacy of generic formulations of imatinib mesylate in the treatment of chronic myeloid leukemia, Leuk Lymphoma, 2014;55:2935–7. 31