First-line therapy for chronic phase CML: selecting
the optimal BCR-ABL1-targeted TKI
Giuseppe Saglio & Elias Jabbour
Patients diagnosed with chronic myeloid leukemia (CML) and treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs) have long life spans. Selection of an appropriate first-line therapy can be difficult as both the unique characteristics of each TKI and patient need to be taken into account to find the optimal match. Patient characteristics include comorbidities, concomitant medications, lifestyle, risk factors, BCR-ABL1 transcript type (e.g. b2a2 or b3a2) and additional chromosomal abnormalities. Just as patients differ, side effects, drug-drug interactions, administration plans, dosing schedules and treatment-related expenses across TKIs also vary. Alignment of these charac- teristics with the appropriate TKI is key to successfully initiating CML treatment. Continued success relies on communication between the patient and the healthcare team, adherence and optimiza- tion of therapy once it is initiated. In this review, we discuss these factors, in addition to TKI efficacy and safety, the cost of therapy, the future of treating CML and treatment-free remission.
Introduction
Before targeted therapy, patients with chronic myeloid leukemia (CML) were commonly treated with inter- feron-a (IFN-a) plus cytarabine, providing patients three- to five-year overall survival (OS) rates ranging from 86% to 68% [1–3]. Response rates were improved with this
combination over IFN-a; however, the add- ition of cytarabine was believed to cause an increase in adverse events (AEs) [2]. Therapy for CML radically changed with the introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs) [4]. At the moment, three TKIs (imatinib, dasatinib and nilotinib) are approved for the first-line treatment of CML in chronic phase (CP) [5–7]. Patients with CML and treated with BCR-ABL1 TKIs can experience a life span comparable to the non-CML population, with TKIs having substantially increased the OS of patients from that with combination chemo- therapy [8–10].
The variety of options available for the treatment of CML-CP can make the selection of an appropriate first- line therapy difficult. Individual patient characteristics, such as preexisting comorbidities, concomitant medi- cations, patient age and risk factors for disease pro- gression, all influence selection of an effective therapy that also allows for a high quality of life.
ARTICLE HISTORY
Received 3 May 2017 Revised 1 September 2017 Accepted 5 September 2017
KEYWORDS
Myeloid leukemias and dysplasias; myeloprolifera- tive disorders; signaling therapies
Efficacy of TKIs in first-line clinical trials
Imatinib
The first BCR-ABL1 TKI to receive approval for first-line treatment of CML-CP was imatinib in 2002 [5], after improved efficacy was observed in the IRIS trial com- paring imatinib with IFN-a plus cytarabine [4]. From the 80% of patients on study at 10 years with known survival status, the imatinib arm had a best estimated 10-year OS rate of 83% and a best observed major molecular response (MMR; BCR-ABL1 .1% International Scale [IS]) rate of 93% [9,11]. Efficacy outcomes from additional first-line trials with imatinib and other BCR- ABL1 TKIs are described in Table 1 [1–3,8,10–24] and report superior OS rates compared to IFN-a plus cytar- abine (68%–86%) [1–3].
Dasatinib
The second-generation TKI, dasatinib, was initially approved in 2006 for treatment of patients with CML- CP or CML in accelerated or blast phase (AP/BP) who are resistant/intolerant to prior therapy (that included imatinib), followed by first-line approval in 2010 [6]. Results from the phase-3 DASISION study demon- strated high efficacy and tolerability of dasatinib in
