Conclusion – current place in CML therapy
Modern therapy which radically changed the prognosis of CML started in June 1998 with the first administration of imatinib, a first-generation TKI. The expectations of patients and physicians regarding the results of therapy have been substantially changed over the last decade of experience with TKIs.
The treatment goal for CML is no longer a prolongation of survival, but discontinuation of therapy and cure. Deep molecular responses are achieved by the majority of imatinib-treated patients; however, the results of clinical trials suggest that patients treated up-front with 2G-TKIs have a better chance to achieve faster and deeper molecular responses (MR4.0 or MR4,5), which are the key criteria for discontinuation studies.
Nevertheless, until recently, all the 2G-TKIs compared to imatinib studies have shown no difference in OS. During the 2014 ASH Annual Meeting, Larson et al presented the latest follow-up of ENEST study in which, after 6 years, there were significantly fewer deaths among patients in the nilotinib 400 mg twice daily arm than in the imatinib 400 mg once daily arm.39
Most patients diagnosed with CML will receive prolonged therapy; therefore, individual patient’s comorbidities, disease characteristics, ability to follow doctor’s orders, and treatment schedule and preferences regarding a goal of therapy should guide the decision of choice of initial treatment.
Patients with CML-CP could be stratified with the use of risk stratification scores, such as Sokal,40 Hasford,41 and EUTOS,42 to help predict the outcomes of therapy. Low-risk category patients are expected to have optimal responses on imatinib, dasatinib, or nilotinib used in the first-line setting.
However, patients with intermediate- or high-risk disease may benefit more when 2G-TKIs are chosen as a frontline treatment.43,44
Another factor that could influence the choice of optimal initial treatment is human organic cation transporter-1 (OCT-1) expression. Low OCT-1 expression and activity could affect the concentrations of imatinib in CML cells45–47 and is associated with lower OS (87% vs 96%) and EFS (48% vs 74%) when compared to patients with high OCT-1 activity.
Therefore, it was suggested that patients with low activity of OCT-1 may benefit from dasatinib or nilotinib since they are not transported into CML cells by OCT-1. The role of innate immunity in the achievement of optimal response to therapy was underlined by observation by Yeung.
Killer immunoglobulin-like receptors – specifically, the KIR2DS1 allele has been associated with lower probabilities of achieving CCyR at 2 years, reduced probabilities of OS and PFS, and lower rates of MMR in patients treated with frontline imatinib therapy.48,49
Since the results of clinical trials do not support sufficiently the routine use of HD imatinib as frontline treatment for CML-CP all the aforementioned factors could favor a choice of 2G-TKIs in the first-line setting.
A number of analyses have been conducted to determine the response rates of patients resistant to standard dose of imatinib including those with various BCR-ABL1 mutations to HD imatinib and 2G-TKIs.
Based on the critical analysis of those studies, the recent ELN recommendation does not support imatinib dose escalation in such cases since the 2G-TKIs and 3G-TKIs appeared to be more effective.24,25 HD imatinib is recommended as one of the possible treatment option for AP and BP of CML.
Taking into consideration that clonal evolution with new additional cytogenetic aberrations and newly emerging ABL kinase domain mutations contribute largely to CML progression, the therapy of AP/BP with TKI according to mutational tests, and possibly combination with chemotherapy should be considered.
TS was supported by EU program: FP7-REGPOT-2012-CT2012-316254-BASTION.
The authors report no conflicts of interest in this work.