Five Years after Frontline Tyrosine-Kinase Inhibitor (TKI) Treatment Initiation for Chronic Myeloid Leukemia: What Does It Happen in a Real-Life Setting?
Authors: De Benedittis Daniela , Breccia Massimo , Carmosino Ida , Mariggiò Elena , Molica Matteo , Mohamed Sara , Massaro Fulvio , De Luca Maria Lucia , Scalzulli Emilia , Lisi Chiara , Passucci Mauro , Colafigli Gioia , Loglisci Maria Giovanna , Diverio Daniela , Mancini Marco , Foà Robin , Latagliata Roberto 
Published: October 2019

Abstract
Current treatment with Tyrosine-Kinase Inhibitors (TKI) has profoundly changed long-term prognosis of newly diagnosed Chronic Myeloid Leukemia (CML). However, the true disease/patient status at different time-points is still based on few data from controlled clinical studies (mainly based on "cumulative incidence" more than "effective situation" of any single patient at any single time from TKI start) and is still unclear in the real-life setting without selection criteria.
In order to give an effective picture of their 5-year status, all consecutive CML patients newly diagnosed at our Institute until 6/2012 (i.e. with a minimum observation period of 5 years) and treated frontline with any TKI at any dosage in both controlled clinical trials or current clinical practice were retrospectively evaluated. On the whole, 259 patients, treated with imatinib (219) or 2nd generation TKI (2-TKI) (35 with nilotinib and 5 with dasatinib), were collected: the main features at diagnosis of the entire cohort and according to TKI are reported in the Table 1, without differences between the 2 groups. In the imatinib group, 13/219 patients (6%) received a reduced starting dose (< 400 mg/day), while all patients in the 2-TKI group started initial standard doses.
At the 5-year evaluation, 227 pazienti (87.6%) were alive, 16 died (6.2%) and 16 (6.2%) were lost to follow-up. Among the 227 patients alive, 176 (67.9% of the entire cohort) were in Complete Cytogenetic Response (CCyR), 163 (62.9% of the entire cohort) were in Major Molecular Response (MMolR) and 121 (46.7% of the entire cohort) were in Deep Molecular Response (DMR). The remaining 51 patients alive at the 5th year (19.7% of the entire cohort) were in 2nd or subsequent line of treatment, due to intolerance in 13 cases (25.5%) or primary/secondary resistance in 38 (74.5%). Among the 16 deaths, 5 (1.9% of the entire cohort) were CML-related and 11 (4.3% of the entire cohort) were CML unrelated. Among the 16 patients lost to follow-up, 8 (3.1% of the entire cohort) were in response to 1st line treatment and 8 (3.1% of the entire cohort) were in 2nd line/resistant disease at the last visit. Six patients (2.3%) evolved in blastic phase and 8 (3.1%) developped a 2nd neoplasia. In the group treated frontline with 2-TKI there was a higher rate of patients alive in MMolR (p=0.038) but not in DMolR (p=0.137), with a lower rate of primary/secondary resistance (p=0.048) but a higher incidence of intolerance (p=0.002) compared to patients treated frontline with imatinib (Table 2).
Five-year cumulative overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) of the entire cohort were 93.2% (IC 95% 90.2-96.2), 78.2% (IC95% 73.1-83.3) e 70.2% (IC95% 64.5 - 75.9), respectively. According to initial treatment, 5-year PFS was significantly better in the 2-TKI group (p=0.003), but no difference was observed between the 2 groups as to 5-year EFS (p=0.274) and 5-year OS (p=0.077).
In conclusion, results achievable at 5 years with frontline TKI treatment in the current clinical practice are excellent, with at least two thirds of patients alive in MMolR and about half of patients also in DMolR under frontline approach: deaths CML-related in the first 5 years of treatment are very rare and less than 1 out 5 patients needs to change frontline approach for intolerance/resistance. The role of frontline 2-TKI in this real-life setting deserves further examinations in larger unselected cohorts at longer time-points.

Disclosures
Breccia: BMS: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Foà:ROCHE: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; INCYTE: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD.