title: Responses to second-line tyrosine kinase inhibitors are durable: an intention-to-treat analysis in chronic myeloid leukemia patients.
abstract: Second-generation tyrosine kinase inhibitors (2G-TKIs) are effective at inducing complete cytogenetic responses (CCyRs) in approximately half of chronic myeloid leukemia patients treated while still in the chronic phase and after failing imatinib. It is less clear whether these responses are durable. In the present study, we report the clinical outcome of 119 patients who received a 2G-TKI as second-line treatment while still in the chronic phase. In an intention-to-treat analysis, the 4-year probabilities of overall and event-free survival were 81.9% and 35.3%, respectively. Sixty-two patients discontinued the initial 2G-TKI because of resistance or intolerance. To further explore the durability of cytogenetic responses, irrespective of the need for a third-line TKI, we used the concept of "current CCyR-survival" (c-CCyRS). The c-CCyRS at 4 years was 54.4%. After introduction of a 2G-TKI, 77 patients had a 3-month BCR-ABL1/ABL1 transcript ratio of ≤ 10% and had significantly superior overall survival (91.3% vs 72.1%, P = .02), event-free survival (49.3% vs 13.0%, P < .001), and c-CCyRS (67.2% vs 11.2%, P = .0001) compared with the 33 patients with ratios > 10%. The 3-month molecular response was the only independent predictor for overall survival. Using an intention-to-treat analysis, we have shown that the responses to second-line therapies are durable. Patients destined to fare poorly can be identified early during therapy.
authors.affiliation: Department of Haematology, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Dragana
authors.initials: D
authors.lastname: Milojkovic
authors.forename: Jane F
authors.initials: JF
authors.lastname: Apperley
authors.forename: Gareth
authors.initials: G
authors.lastname: Gerrard
authors.forename: Amr R
authors.initials: AR
authors.lastname: Ibrahim
authors.forename: Richard
authors.initials: R
authors.lastname: Szydlo
authors.forename: Marco
authors.initials: M
authors.lastname: Bua
authors.forename: Alistair
authors.initials: A
authors.lastname: Reid
authors.forename: Katayoun
authors.initials: K
authors.lastname: Rezvani
authors.forename: Letizia
authors.initials: L
authors.lastname: Foroni
authors.forename: John
authors.initials: J
authors.lastname: Goldman
authors.forename: David
authors.initials: D
authors.lastname: Marin
mesh_terms: D000814:Aniline Compounds / Q000627:therapeutic use; D001549:Benzamides; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D013844:Thiazoles / Q000627:therapeutic use; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000814:Aniline Compounds; D001549:Benzamides; D009570:Nitriles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D013844:Thiazoles; C471992:bosutinib; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib