Chronic myeloid leukemia: sequencing of TKI therapies

J. Cortes, H. Kantarjian
2016 Hematology ASH Education Program  
Multiple tyrosine kinase inhibitors (TKIs) are available for managing patients with chronic myeloid leukemia. Although most patients have a favorable outcome with their initial therapy, whether imatinib or a second-generation TKI was used, some will require subsequent use of one or more different TKIs. Such sequencing might be indicated in a reactive way (ie, for patients who have experienced resistance or intolerance to their initial therapy) or in a proactive way (ie, for patients with a
more » ... atients with a somewhat favorable outcome who have not reached an "optimal" outcome). Sequencing of TKIs has become standard practice, and the proper use of sequenced TKIs is likely to optimize outcomes and resource utilization. Learning Objectives • Assess the different scenarios in which TKI sequencing can be used in patients with chronic myeloid leukemia • Critically review the outcomes associated with sequencing of TKI in patients with chronic myeloid leukemia Tyrosine kinase inhibitors (TKIs) became standard therapy for patients with chronic myeloid leukemia (CML) not long after the first patient received STI571 (later known as imatinib mesylate) on a phase I clinical trial. 1 The initial approved indication was for patients with resistance to or intolerance of interferon alpha-based therapy, the standard at the time. By 2003, imatinib was approved as frontline therapy for CML, 2 and since then, nearly all patients with access to TKIs have received them as initial therapy. Shortly thereafter, secondgeneration agents, including dasatinib, nilotinib, and bosutinib, with increased potency, different structures that allowed them to overcome most mutations leading to resistance to TKIs, and different toxicity profiles, were introduced and eventually received regulatory approval. Later, ponatinib, a drug with activity against T315I and all mutations tested, proved effective in overcoming resistance in most patients, even those who had received 3 or more prior TKIs. All TKIs were eventually compared with imatinib in the first-line setting, and they generally demonstrated higher response rates, with deeper and faster responses which, in the case of dasatinib and nilotinib, were sufficient to lead to their approval as initial therapy for patients with chronic phase CML (CML-CP). This rapid development has resulted in the availability of multiple TKIs, and along with this, the sequential use of various TKIs in patients with CML-CP (Figure 1 ). The use of sequential TKI therapy, regardless of the choice of initial therapy, is perhaps more common than is usually appreciated. Despite the professed efficacy of initial therapy with TKIs, at least onethird of all patients initially treated in clinical trials with any TKI for newly diagnosed CML, whether imatinib or a second-generation TKI, have received at least one additional TKI. After 5 years of follow-up in the DASISION trial (in the final report), 39% of patients initially treated with dasatinib and 37% of those treated with imatinib are no longer receiving their initial therapy. 3 Similarly, the 5-year follow-up of the ENESTnd study showed that 40% of patients treated with nilotinib 300 mg twice per day (the standard dose for first-line therapy), 38% of those treated with 400 mg twice per day, and 50% of those treated with imatinib had discontinued therapy. 4 With a shorter follow-up (24 months), the BELA trial reported that 37% and 29% of patients treated with bosutinib (not currently approved as first-line therapy) or imatinib, respectively, discontinued therapy. 5 Studies with longer follow-up suggest that fewer patients discontinue therapy beyond the first 3 to 5 years. After 10 to 12 years of follow-up, 41% of patients treated with standard-dose (400 mg) imatinib and 43% of patients treated with high-dose (800 mg) imatinib had discontinued therapy. 6 Unfortunately, the contribution of sequential therapy to the overall outcome of patients has received less attention than would be expected considering the frequency of its use. Most of the literature reports on the results of intervention with a given TKI for as long as it is used. Studies are frequently terminated prematurely (eg, IRIS after 8 years, DASISION after 5 years). The contribution of prior and subsequent therapy is infrequently considered in assessing long-term outcome. Thus, the effect of sequential therapy is incompletely understood and frequently inferred only indirectly. The value of such an approach can have a significant impact on different end points of interest for patients with CML-CP. Furthermore, sequential TKI therapy can be used reactively or proactively. In the reactive approach, a TKI switch is used when a patient experiences therapy failure, whether because of resistance or intolerance. In the proactive approach, the switch is implemented to improve a response or tolerability that is perhaps acceptable but not what could be considered optimal. Long-term survival end points The ultimate end point of cancer therapy is overall survival (OS). The effect of sequential therapy for CML-CP on survival has not been specifically reported but can be extrapolated with some accuracy on the basis of the published reports. Across multiple studies, despite the high rates of treatment discontinuation summarized above, the OS has remained excellent. In the DASISION study, 5-year OS was 91% in patients treated with dasatinib and 90% in those treated with imatinib. 3 Similarly, in the ENESTnd study, the 5-year survival rate was 94% to 96% for patients treated with nilotinib and 92% for those
doi:10.1182/asheducation-2016.1.164 pmid:27913476 fatcat:bhxdzgvjojftra4ipueq2q2umi