Chronic myeloid leukemia: sequencing of TKI therapies

Abstract

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 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-ye...

Dasatinib cessation after deep molecular response exceeding 2 years and natural killer cell transition during dasatinib consolidation

“…Recent data have revealed that an increasing number of patients may gradually achieve a deep molecular response (DMR) if they continue to use second‐generation TKI for several years . However, increasing concern surrounds the long‐term adverse effects and financial burden associated with TKI …”

Long-Term Outcomes of Tyrosine Kinase Inhibitors Treatment for Chronic Myeloid Leukemia

“…The sequential indication of the three available TKIs, in our universe, do not differ from the ones suggested in different spheres [18,19]. The causes for changes to second or third line were the lack of response and in only one case, toxicity.…”

“…In prospective studies, however, greater efficacy has been shown with nilotinib or dasatinib [8,19]. The practice of using TKIs sequentially, in relation to the response to the first or second line, has become more widespread, and is frequently recommended [18,19]. In our case, the lack of response was the most frequent condition.…”

“…The comparison, however, is biased because most of the initial patients received imatinib, and already in the second line, they were treated with nilotinib or dasatinib. In prospective studies, however, greater efficacy has been shown with nilotinib or dasatinib [8,19]. The practice of using TKIs sequentially, in relation to the response to the first or second line, has become more widespread, and is frequently recommended [18,19].…”

Long‐term results of frontline dasatinib in chronic myeloid leukemia

“…Dasatinib is a highly potent, second‐generation BCR‐ABL1 tyrosine kinase inhibitor (TKI) that also inhibits other kinases in addition to ABL. Dasatinib and other second‐generation TKIs have all demonstrated efficacy after imatinib failure in all stages of chronic myeloid leukemia (CML) . A long‐term follow‐up of dasatinib after imatinib failure showed a major cytogenetic response (MCyR) in 59% of patients, with 7‐year and overall survival (OS) rates of 65% …”