First- and second-line strategies in chronic phase CML including hematopoietic stem cell transplantation

Abstract

The review article is dedicated to the main principles of modern therapy in chronic myeloid leukemia (CML). Current treatment options for the chronic phase (CP) CML include Imatinib at standard or high doses (400 to 800 mg/d) and second-generation tyrosine kinase inhibitors (2-G TKIs), e. g. dasatinib and nilotinib. Hematopoietic stem cell transplantation (HSCT) is generally considered second or third line. Early SCT may be an option for non-high risk patients with low transplantation risks. According to the German CML Study Group the 10-year survival in CML has continuously improved,up to 85% with imatinib introduction. Previously, the survivors after busulfan and hydroxyurea were mostly transplant recipients. CML-Study III and IIIA compared allo- SCT with the best available drug treatment. Most authors who applied TKIs in CML, used imatinib, and HSCT (in some clinical situations). According to CML- Study IV the molecular responses (MR) achieved with imatinib in MR2 situations (an analogue of complete cytogenetic remission) may reach 92% after 10 years of observations. Introduction of the 2G-TKI (dasatinib and nilotinib) is associated with more rapidly occurring and more frequent molecular responses than with imatinib at standard dose (DASISION 5-year final study results, ENESTnd 5-year update). Increased imatinib dosage to 800 mg daily provides more rapid and deep molecular responses, as shown by appropriate meta-analysis of randomized trials, being associated with a 45% higher probability of achieving MMR after 12 months with IM 800 mg or 2G-TKIs, compared to IM 400 mg (p=0,0088). Second-line strategies Switching to second-line TKI treatment and/or allogeneic HSCT is recommended in cases of intolerance or drug resistance. E. g., it was concluded in the ENESTcmr Study (Hughes et al., 2014) that such transition caused more molecular responses in terms of BCR-ABL than with permanent imatinib treatment (p=0,009). The best approaches with drug treatment and HSCT at different phases of CML are described in some recent works (Jiang et al., 2011; Jabbour et al., 2011, Khoury et al., 2012). A good efficacy of allo-HSCT was shown in an update of the study by Saussele et al. (2014), with a median follow-up of 78,5 months (Fig. 1). The patients were stratified by risk. In 50-70% of cases unrelated donors served as a source of transplant. The patients transplanted in 1st chronic phase electively or after resistance to TKI therapy have shown a good 5-year survival (80%). Interestingly, the survival probability of the patients transplanted early in chronic phase was similar to that of patients’ treatment with imatinib only. Conclusion – Current first-line treatment includes imatinib, dasatinib and nilotinib. – The proportion of patients reaching MMR by 12 months is similar with optimized imatinib and second- generation TKIs. – SCT is an option for the 2nd-line treatment. – Long-term outcomes after early SCT in chronic phase is similar to the results obtained with imatinib. – Early HSCT may be considered in non-high risk CP CML patients with low transplantation risk.