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Haematological Malignancies Chronic Myeloid Leukaemia Chronic Myeloid Leukaemia – The Choice of Therapy and Future Perspectives Angelo M Carella, Clara Dellepiane, Davide Lovera, Adalberto Ibatici, Chiara Ghiggi, Andrea Carella and Germana Beltrami Medical Doctor, Hematologist, Divisione di Ematologia 1, IRCCS Azienda Ospedaliera Universitaria San Martino – IST, Genoa, Italy Abstract Recently, the advent of imatinib has opened a new era in the treatment of chronic myeloid leukaemia (CML), leading to an impressive increase in overall survival rates. Today, many CML patients can expect to survive, if properly managed, likely similar to the general population. Recent progresses in CML stem cell biology have identified new leukogenetic pathways and therapeutic strategies that can be used to target the CML stem cell compartment. These studies have opened new perspectives in CML therapy and have highlighted major strategies for treating, and possibly eradicating, CML in the upcoming years. Keywords Chronic myeloid leukaemia, stem cell biology, tyrosine kinase inhibitors, new therapeutic strategies Disclosure: Angelo M Carella, Clara Dellepiane, Davide Lovera, Adalberto Ibatici, Chiara Ghiggi, Andrea Carella and Germana Beltrami have no conflicts of interest to declare. No funding was received in the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 21 April 2015 Accepted: 12 May 2015 Citation: European Oncology & Haematology, 2015;11(1):25–9 Correspondence: Angelo M Carella, Divisione di Ematologia 1, IRCCS Azienda Ospedaliera Universitaria San Martino – IST, Largo Rosanna Benzi, 10-16132 Genova, Italy. E: angelomichele.carella@hsanmartino.it. The overwhelming majority of patients diagnosed with chronic phase chronic myeloid leukaemia (CP-CML) can achieve long-term survival with a good quality of life. In a recent review, it has been suggested that CML patients responsive to tyrosine kinase inhibitors (TKIs) might become a chronic disease, such as diabetes or hypertension, requiring maintenance treatment. 1 If we accept this concept, TKI exposure could raise some problems, such as emerging resistance, chronic toxicity and, last but not least, financial costs. 2 The initial therapy of CML is based on three available TKIs. These drugs are able to inhibit the phosphorylative activity of the proteins that are coded by the BCR-ABL fusion gene. 3–6 The TKIs registered for their activity on BCR-ABL are imatinib, nilotinib and dasatinib. Another compound – bosutinib – has been recently evaluated in first–second line therapy. 7 A fifth compound – ponatinib – has been tested in advanced patients. 8 Imatinib was introduced in 1998 and changed the therapeutic landscape for patients with CML: it remains the most generally utilised first-line therapy for newly diagnosed CML patients. A complete haematological response (CHR) is typically achieved by almost all CML patients. The complete cytogenetic remission (CCyR) rate ranges between 60–80 %, the major molecular response (MMR) ranges between 40–60  % and the complete molecular response (CMR) ranges between 15–30  %. Despite this, about one-third of patients who receive imatinib become resistant or discontinue the drug because of side effects. 9–14 The progression-free survival (PFS) and overall survival (OS) at 10 years are in the order of 80–85 % 10–13 (see Figure 1). The most important side effects of imatinib are fluid retention, myalgia and fatigue. Tou ch MEdi c a l MEdia Nilotinib is a derivative of imatinib that was designed to target BCR- ABL more specifically than imatinib. It is able to inhibit also most mutated forms with the exception of T315I mutation. 15 When this inhibitor has been used as second-line therapy, the CCyR and MMR were around 50 % and 25 %, respectively; 16 when employed as first- line treatment, the achievement of CCyR and MMR were deeper, faster and superior to imatinib. 17–19 The major side effects of nilotinib are elevated bilirubin, aspartate and alanine aminotransferase, lipase and amylase and peripheral arterial obliterative disease. More recently, nilotinib has been associated with an increased risk of cardiovascular events, which tend to occur later than ponatinib. 19–21 These cardiovascular events (ischaemic heart disease, ischaemic cerebrovascular events and peripheral artery disease) occurred in between 6 and 12 % of patients when the drug is delivered at 300 and 400 mg BID doses, respectively. Dasatinib is an active BCR-ABL, which was designed as a Sarc kinase inhibitor. It is able to inhibit most mutated forms with the exception of the T315I mutation. The results of CCyR and MMR are similar to nilotinib. 22 When this inhibitor was employed as first-line treatment, the responses were deeper, faster and superior to imatinib. 22 The major side effects of this TKI inhibitor are leuco-thrombocytopenia, pleural effusion and, more rarely, pulmonary complications. The results of bosutinib are generally similar to those of the previously described three TKI inhibitors but the differences in terms of CCyR and MMR with imatinib are less significant. 7 Diarrhoea and an increase of liver enzymes are the most important side effects. 25