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Perspective
compared to the imatinib group: MR4, 20.7% vs. 12.0% (P=0.01) and MR4.5, 8.1% vs. 3.3% (P=0.02). Such find- ings confirm the efficacy of second-generation TKIs and their ability to induce faster and deeper molecular responses relative to that observed with imatinib.11
In conclusion, imatinib has indeed changed the land- scape of CML. Subsequently developed TKIs, dasatinib, nilotinib, and bosutinib, are potential alternatives to ima- tinib as first-line therapy, mainly due to the deeper and faster molecular responses they induce. In our opinion, initial treatment with second-generation TKIs should be offered initially to patients with higher risk of progres- sion. Alternatively, imatinib could be the initial therapy for all patients, with the incorporation of early switch to second-generation TKIs if optimal response is not achieved at three months.
Cessation of treatment
Until now the recommendation for TKI therapy in CML was to continue treatment indefinitely. However, there are numerous justifiable reasons for stopping TKI therapy. Off-target effects of TKIs and severe adverse drug reactions have been increasingly reported. These side effects may not only impair the quality of life, but some of them, such as pulmonary arterial hypertension, pleural effusion, or vascular occlusive events may poten- tially modify life expectancy. In addition, it is forbidden to administer TKIs to pregnant women, and experience in pediatric CML cases reveals growth disruption resulting from TKI therapy. The patients’ requests are also impor- tant; the question of whether TKI therapy is necessary lifelong is frequently asked.
Clinical trials have demonstrated the feasibility of stop- ping TKIs in patients with durable and deep MR beyond MMR.12-15 The convincing results of all of these studies have validated the concept of TFR, which has increasing- ly become the main focus of clinical trials in CML.16 The sine qua non condition for proposing TKI cessation is the achievement of a sustained DMR. A certified laboratory is necessary to perform and validate the robust molecular monitoring needed for safety during TFR studies. Great reassurance is to be found in the reproducibility of TFR studies over time, and with the adaption of more prag- matic and applicable criteria for patient consideration.17
Half of the patients who are eligible for TKI discontin- uation remain treatment-free, while the other 50% recov- er optimal response upon therapy re-introduction. Most of the molecular recurrence occurs in the first six months following TKI cessation. One cannot overstate the impor- tance of the safety observed to date in TFR trials, evi- denced by preserved TKI sensitivity and prompt re-induc- tion of molecular response in patients rechallenged after molecular recurrence. Of interest is a peculiar transitory TKI withdrawal syndrome reported in a minority of patients; the mechanism is unknown.18 A key question emerging from the experience with TFR trials relates to the evidence of persisting leukemic cells (e.g., persistent BCR-ABL detection) without exhibiting true relapse, and how this status should be defined (functional cure?).
The number of patients who are stopping TKI treat- ment is increasing over time and it may be possible to re- attempt TKI cessation more than once in the same
patient. Encouraging results have emerged from a multi- center study entitled RE-STI, where eligible patients, i.e., those with a second sustained DMR, remained in TFR in one third of cases.19
Although extensive long-term experience is limited, substantial knowledge accumulated during the last years justifies moving TFR strategies from research to clinical practice.
The future of CML
The future of CML therapy must answer those ques- tions pending from the torrid pace of advance over the last 20 years. While treatment choices are many, selecting the safest and optimal path to cure still needs perfection. One point oft forgotten is the longitudinal cost of TKI therapy in varying health care systems; with movement from indefinite to, ideally, defined duration therapy, this debate will evolve. Continued development of more pre- cise prognostic information derived at diagnosis, such as BCR-ABL fusion type,20 the role of cytogenetic abnormal- ities aside from the Ph chromosome,21 and the formula- tion of an idealized risk score best able to predict out- come, including that of survival,22 is ongoing. It is possible that a more meticulous scrutiny of early response and a more individualized assessment of response will better aid decision making regarding any need for change in treatment. Particular attention must be paid to comorbid conditions, especially cardiovascular disease, both at diagnosis and with therapy change, given the available data on the increase in risk and impact of comorbidities on outcome.23
During therapy, the past had us focus on the quantita- tion of BCR-ABL ‘burden’ by conventional means (cyto- genetic) whereas the present is sharply focused on the molecular assessment of disease burden. Such assessment increasingly utilizes next-generation sequencing, allow- ing for increased sensitivity, clarity regarding ABL kinase domain mutations, and clonal hierarchy. This technique may open the door to a broader consideration of molecu- lar changes during the course of CML, including the impact of non-BCR-ABL clonal markers and clonal hematopoiesis on CML and other comorbid condition risks.
Therapy should continue to evolve, with advances including non-ATP site allosteric inhibitors with ABL001 (asciminib) showing great promise in single-agent phase I data,24 bolstered by its ability to be safely combined with available TKIs for potential synergy. In addition, later generation ABL kinase inhibitors have also moved into early clinical development, including two agents with expected activity against the T315I mutation, namely PF114 (Fusion Pharma) and K0706 (Sun Pharma Advanced Research Company [SPARC]). Unmet needs continue to consist of the treatment of advanced phase disease, with novel options emerging for lymphoid transformation, and more needed for myeloid blast phase. In addition, partic- ular focus is being concentrated on novel agents able to either deepen suboptimal molecular response to TKIs or facilitate a second TFR.
While the future is very bright for those diagnosed with CML, risks remain, and success requires informed choice, careful navigation of adverse events and response mile-
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