Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: retrospective analysis of patient data from five clinical trials

Jain, Preetesh; Kantarjian, Hagop; Alattar, Mona Lisa; Jabbour, Elias; Sasaki, Koji; González, Graciela Nogueras; Dellasala, Sara; Pierce, Sherry; Verstovšek, Srđan; Wierda, William G.; Borthakur, Gautam; Ravandi, Farhad; O’Brien, Susan; Cortes, Jorge

doi:10.1016/s2352-3026(15)00021-6

Cited by 71 publications

(69 citation statements)

References 33 publications

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“…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.…”

Section: Learning Objectivesmentioning

confidence: 99%

“…4 With longer follow-up, 10-year survival rates of more than 80% with imatinib therapy have been reported. 6 The reasons for change in therapy vary. Generally, in both the DASISION and ENESTnd studies, the most common reason for change from imatinib was related to efficacy (ie, suboptimal response, treatment failure, or disease progression), whereas the most common reason for change from a second-generation TKI was the presence of adverse events.…”

Section: Long-term Survival End Pointsmentioning

confidence: 99%

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Chronic myeloid leukemia: sequencing of TKI therapies

Cortes

Kantarjian

2016

Hematology

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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...

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Section: Learning Objectivesmentioning

confidence: 99%

Section: Long-term Survival End Pointsmentioning

confidence: 99%

Chronic myeloid leukemia: sequencing of TKI therapies

Cortes

Kantarjian

2016

Hematology

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“…It blocks the BCR-ABL tyrosine kinase activity and subsequently induces apoptosis, followed by a reduction in the proliferation of BCR-ABL-expressing cells (2). Therefore, the treatment of patients with CML with imatinib significantly increased survival and improved quality of life (3).…”

Section: Introductionmentioning

confidence: 99%

Co-existence of isodicentric Ph chromosomes and the three-way Ph chromosome variant t(3;9;22)(p21;q34;q11) in a rare case of chronic myeloid leukemia

Lin

Chen

et al. 2018

Oncol Lett

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Abstract. More than 90% of patients with chronic myeloid leukemia (CML) have the chromosomal translocation t(9;22)(q34;q11), while 5-8% of patients have complex variant translocations that have previously been thought not to affect the efficacy of imatinib therapy. The present study reports a patient with CML in B-lymphoid blast crisis who had a rare three-way Philadelphia (Ph) variant t(3;9;22)(p21;q34;q11), in addition to isodicentric Ph chromosomes. The patient was initially treated with imatinib for >2 months with a very poor response. When no T315I or F317L mutations in the ABL proto-oncogene 1 region were detected, the patient received dasatinib treatment (140 mg daily) and achieved a complete hematologic response. Following allo-hematopoietic stem cell transplantation, the patient displayed clinical, hematological and cytogenetic remission, with complete molecular response and complete donor chimerism, and stopped taking dasatinib at the last follow-up. The present data suggest that BCR-ABL gene amplification may be associated with imatinib resistance, which can be overcome with dasatinib. The present analysis suggests an alternative therapy strategy for CML involving isodicentric Ph chromosomes.

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“…1 Although the number of studies is limited, and the follow up is short and sometimes defective, survival data are substantial; around 90% at 5 years, 89% at 6 years, 86% at 8 years, and 83-84% at 10 years [2][3][4][5][6][7][8][9][10] (Table 1). Only 50% of deaths are due to the progression of leukemia, while 50% occur in remission and are due to other causes which occasionally include treatment-related toxicity and related complications.…”

mentioning

confidence: 99%

“…The dynamics and stability of tumor shrinkage after treatment can currently be precisely tracked by MRD kinetics; these data might be useful as an early in vivo predictor of the anti-lymphoma effect of a new compound. 6,9,10 Moreover, MRD can be used as a surrogate end point for progression-free survival (PFS) comparing the efficacy of different treatments in randomized trials, thus accelerating the development, and eventually the approval, of new drugs. For example, the superior outcome of the cytarabine-containing experimental arm of the "MCL Younger" phase III trial of the European MCL Network was heralded by a higher rate of MRD clearance many years before publication of the final results.…”

mentioning

confidence: 99%