Response-Driven Treatment Changes
During TKI treatment, the degree to which the bulk of leukemia is reduced is a key prognostic marker of PFS. Accurate quantification of residual disease is necessary to guide clinical decisions. Ideally, every patient should have access to regular molecular monitoring according to a well-defined surveillance program and reliable internationally standardized quantitative PCR methods [
38]. Assessment of molecular responses is also indispensable to identify candidates for TKI discontinuation. Optimal responses enable a near-to normal life expectancy and do not require any therapeutic modification in the absence of safety issue, unless patients qualify for stopping treatment [
20] [
39] [
40].
Identification of resistance necessitates a change in treatment strategy, primarily guided by results from
BCR-ABL mutational analyses. In the absence of a
BCR-ABL mutation, any second-generation TKI may be chosen in patients resistant to first-line imatinib although it is somewhat unfortunate that no direct comparison studies were performed [
20] [
19]. For those resisting a first-line second-generation TKI, ponatinib may be a more efficient option than another second-generation TKI but this has regrettably not been investigated in a randomized study [
41]. In case of resistance to a second-line second-generation TKI, several lines of evidence point to greater results with ponatinib than with an alternate second-generation TKI [
42]. Ponatinib at the registered dose of 45 mg QD exposes patients to a high burden of arterial occlusion events especially when atherosclerotic CVD or strong risk factors like diabetes or hypertension are already present; thus, CVD prevention is essential [
12]. Ponatinib-associated newly occurring or worsening hypertension is another matter of concern, and it must be detected early as it can be controlled with dose adjustment and anti-hypertensive drugs [
12] [
16].
In the presence of a
BCR-ABL mutation, selection of the most effective alternate TKI is possible, depending on localization within the different structural and functional domains of the kinase,
in vitro sensitivity, and clinical efficacy data. Over 100 different mutations have been discovered in imatinib-resistant patients while the spectrum of mutations resistant to second-generation TKIs is much narrower. With the exception of T315I, mutations that confer resistance to nilotinib or dasatinib hardly overlap. Nilotinib is ineffective against
BCR-ABL mutations Y253H, E255K/V, and F359V/C/I, both
in vitro and in patients [
43]. Of note, the initial recommended dose of nilotinib second line or beyond is 400 mg BID, substantially higher than what given first line. Awareness of the dose-dependency of cardiovascular toxic effects of nilotinib and vigilance is essential in order to avoid irreversible complications [
21••]. The
BCR-ABL mutations V299L, T315A, and F317L/V/I/C confer a high degree of resistance to dasatinib
in vitro and dasatinib fails to rescue harboring those [
44]. The
BCR-ABL mutations E299V, G250E, E255K are associated with high or very high resistance to bosutinib both
in vitro and in patients [
45]. The T315I mutation is sensitive to ponatinib only and the prognosis of patients carrying this mutation impressively improved since approval of ponatinib. Five-year report of phase 2 “Ponatinib Ph1 ALL and CML Evaluation” (PACE) international study indicated a 70% rate of complete cytogenetic responses, a 58% rate of MMR, and a 38% rate of MR4.5 in the T315I+ cohort and responses were sustained, thus dispelling the specter of allogeneic stem cell transplantation (ASCT) [
46] [
47]. Although exceptionally performed, ASCT remains a key option in case of multi-resistance or progression to AP/BC.
Warning corresponds to a situation where TKIs decrease
BCR-ABL transcripts below the 1% IS threshold during the first year of therapy, but MMR is not attained. Patients in the warning zone need to be carefully monitored as secondary resistance may finally emerge [
6]. Alternatively, the molecular response may remain stable overtime or even spontaneously improve with longer duration of treatment; thus, a change in TKI is not absolutely required [
20] [
19]. However, in the absence of a switch to a more potent TKI, the likelihood of a DMR for patients in the warning zone is quite poor [
48] [
49], precluding any TKI discontinuation attempt. A switch from first-line imatinib to a second-generation TKI appears as an interesting option for those aiming at TFR. The randomized phase 3 “ENEST–Complete Molecular Remission” study investigated the probability to gain a DMR upon transition to nilotinib. For patients in the warning zone on long-term imatinib, the probability to achieve a MR4.5 was 33.3% by 4 years in the nilotinib 400 mg BID arm
versus 3.6% for in the imatinib control arm [
50•]. Earlier switch based on warning at specific time points during the first year of imatinib therapy may provide even better results as suggested by results from the “Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II” study [
51]. What to do for patients in the warning zone on first-line second-generation TKI is not straightforward. In our opinion, ponatinib is not an option to address such situation as risks of switching may outweigh benefits.
Toxicity-Driven Treatment Changes
Severe, recurrent, or chronic toxicity forces discontinuation of the relevant TKI unless manageable by supportive care or dose reduction. General rule for next TKI choice includes avoidance of cross-intolerance while efficacy should remain in focus. Cross-intolerance relates to the recurrence during treatment with a new TKI of the same adverse event that led to intolerance to the prior TKI. Pooled data from several clinical trials showed that among patients with severe non-hematological intolerance to imatinib, cross-intolerance with dasatinib was observed in 4% of the cases, mainly including skin rash, myalgia, and arthralgia [
52]. Analysis of data from the pivotal phase 2 registration trial of nilotinib 400 mg BID showed that 7% of patients with severe or moderate but chronic non-hematological intolerance to imatinib developed side effects of the same nature on nilotinib, mainly including diarrhea [
53]. Of note, there are some data to support the use of 300 mg BID of nilotinib instead of 400 mg BID in patients responding well but intolerant to first-line imatinib or dasatinib [
54] [
55]. Rate of cross non-hematological intolerance between imatinib and bosutinib was considered as low during development of bosutinib at 500 mg QD beyond the first-line setting, with the notable exception of gastrointestinal disorders such as nausea and diarrhea [
45]. However, pleural effusion on bosutinib may occur at a very high frequency in patients with such a history on prior TKI, especially dasatinib [
56]. Finally, it may not be wise to choose ponatinib in patients experiencing arterial occlusion on nilotinib for obvious safety reasons, except in patients deemed at high risk of disease progression in the absence of a suitable alternative option.