As 2GTKIs are more potent than imatinib, many physicians tend to use these agents in the upfront setting among patients with CML-CP, since these newer TKIs have the ability to induce faster [early molecular response (EMR)] and deeper (DMR) responses . Three 2GTKIs (bosutinib, dasatinib, and nilotinib) have demonstrated significant clinical benefit compared with imatinib in randomized clinical trials [17,18,19], and although not always available worldwide, these agents are approved in the management of newly diagnosed patients with CML in some countries.
The choice of selecting any 2GTKI over imatinib as an upfront treatment option depends on various factors, mainly the disease risk factors, comorbidities, and the willingness of the patient for a treatment-free remission (TFR) attempt, especially if the patient is young, since the probability of achieving a sustained DMR is higher with 2GTKIs than with imatinib.
When a patient with CML-CP has started any 2GTKI as upfront treatment, there are three possible scenarios: (1) the patient may do perfectly well under the particular 2GTKI both in terms of efficacy and toxicity, so he/she will continue receiving the same TKI; (2) the patient needs to quit the 2GTKI due to toxicity, regardless of response situation under the same TKI (optimal or suboptimal); (3) the patient might discontinue the currently administered 2GTKI due to suboptimal response (both primary and secondary resistance) or progression (e.g. from CP to advanced phases) (Fig. 1).
In the first scenario, the optimal responder could continue the current 2GTKI, unless there would be a TFR attempt, as in case of sustained DMR . There are discontinuation studies with dasatinib and nilotinib but not yet with bosutinib . Moreover, nilotinib was recently licensed in the context of TFR in the United States, when used either in the upfront or salvage settings for at least 3 years with a durable (for at least 24 months) DMR (defined as MR4.5) status . Although percentages may vary from study to study, approximately 40–50% of the cases who attempted a TFR will lose their molecular responses, and reinitiation of the former TKI could be necessary. After restarting the same TKI, nearly all patients regain at least optimal molecular response (MR3) or even DMR .
The second scenario, which is the permanent discontinuation of the 2GTKI due to adverse events (AEs), may result in two different outcomes. First, the patient might have an optimal response prior to quitting the TKI, then there would be no need of an immediate TKI therapy or, if a subsequent TKI therapy is planned, the patient may receive either imatinib or an alternative 2GTKI. Second, if the patient stopped the first-line 2GTKI treatment due to toxicity prior to achieving an optimal response, the remaining 2GTKIs can be the treatment of choice and, in addition to that, imatinib can still be an option. However, in this particular case, where a 2GTKI was preferred over imatinib at diagnosis, most probably the patient would want to attempt TFR in the future, and/or the patient might have a high-risk disease, so continuing with another 2GTKI would be more logical.
In the third scenario, where the patient has stopped the 2GTKI therapy due to resistance, the remaining two 2GTKIs can be chosen according to the ABL kinase domain mutational status of the patient and/or the comorbidities should also be taken into consideration. In the case of a T315I mutation, ponatinib should be the treatment of choice. If a patient progresses to blast crisis, the patient should be checked for mutations, and appropriate induction chemotherapy together with a TKI should be initiated. If this therapy can induce a second CP, allogeneic hematopoietic stem cell transplantation (AlloHSCT) should also be kept in mind for the available patients, and patients who have failed two lines of TKI therapy should also be evaluated for AlloHSCT as well .
The availability of five different TKIs, of which four are approved for the newly diagnosed patient, can make the selection of an appropriate frontline therapy challenging. Individual disease and patient characteristics, such as risk of CML progression, age, concomitant disease or medications and patient’s expectations may guide physicians in the choice. However, besides the TKI chosen for first-line (either imatinib or a 2GTKI), a careful and timely monitoring, with prompt switch to alternative therapy in case of non-optimal response or intolerance, may grant CML patients a nearly normal life expectancy and excellent quality of life.