The Dose and the duration of frontline therapy with Imatinib does not affect response to Dasatinib in Imatinib-Resistant or -intolerant patients with chronic myeloid leukemia (CML). Results from a real Life-Based Italian Multicenter retrospective study on 124 Patients.
Authors: Visani Giuseppe , Breccia Massimo , Piccaluga Pier Paolo , Gozzini Antonella , Specchia Giorgina , Montefusco Enrico , Morra Enrica , Annunziata Mario , Luciano Luigiana , Camera Andrea , Cavazzini Francesco , Stagno Fabio , Di Raimondo Francesco , Pregno Patrizia , Pirillo Francesca , Santini Valeria , Bosi Alberto , Pacilli Matteo , Pungolino Ester , Usala Emilio , Angelucci Emanuele , Crugnola Monica , Binotto Gianni , Maino Elena , Loscocco Federica , Barulli Sara , Nicolini Giuseppina , Cuneo Antonio , Latagliata Roberto , Ferrara Felicetto , Isidori Alessandro 
Published: October 2019

Abstract
Abstract 1124
Poster Board I-146

Background
Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC with significant activity in patients with CML resistant or intolerant to front-line Imatinib (IM). However, the information so far available are to great extent limited to controlled clinical trials, which usually recruited patients with acceptable performance status, and no major organ dysfunction. Noteworthy, this fact, although essential for ethical reasons in clinical trials, may somehow determine an overestimation of the clinical benefit of new compounds. Thus, further studies based on non selected populations are indeed opportune.

Patients and Methods
A total of 124 patients (61 male and 63 females) with CML resistant or intolerant to IM received Dasatinib as second line therapy outside from clinical trials. 91 patients had a resistant disease, 19 were intolerant to IM and 14 patients were both resistant and intolerant to IM. Median age at switching to Dasatinib was 56.5 years (range 21-82). 62/124 patients escalated IM before switching from 400 to 600 mg/day and 26/62 patients received an additional dose escalation from 600 to 800 mg/day. Median time on IM prior to the switch to Dasatinib was 36 months (range 2-99), whereas median time on IM after dose escalation was 9 months (range: 1-43).
Dasatinib was given at 100 mg once daily in 54/124 patients (43%), at 70 mg twice daily in 43/124 patients (35%) and at 50 mg once daily in the remaining patients (22%).
Response (hematologic, cytogenetic and molecular), toxicities according to NCI-CTC, discontinuation/dose reduction of Dasatinib, event-free survival (EFS) and overall survival (OS) were evaluated.

Results
With a median follow-up of 12 months, 94% of patients attained a complete hematological response (CHR), whereas 69% and 51% achieved a major (MCyR) or a complete cytogenetic response and 32% attained a major molecular response (MMR). Cumulative EFS and OS at 12 months were 91 and 93% respectively. These data are in line with those of clinical trials, but the population of the present study was not selected.
The commonest grade III/IV adverse events were thrombocytopenia and neutropenia, occurring in around half of patients. Only 3% of the patients suffered from a grade III-IV pleural effusion or dyspnea.
The achievement of CHR, MCyR, CCyR and MMR significantly influenced EFS (p=0.006; 0.04; 0.008 and 0.003 respectively) and OS (p=0.002; 0.02; 0.004 and 0.001 respectively) both in univariate and in multivariate analysis.
Intriguingly, neither the dose nor the duration of prior IM affected the response to Dasatinib, neither before switching to Dasatinib (p= 0.9 and p=0.4) nor after it (p=0.4 and 0.7). Moreover, dose escalation to IM 600 or 800 mg/day did not influence negatively the subsequent response to Dasatinib (p=0.8). In addition, we did not observe any difference in the response rate (CHR, MCyR, CCyR, MMR) between patients who received prior IM for more than 3 years with respect to those patients who received it for less than 3 years (p=0.9).
Regarding Dasatinib therapy, we observed a statistically significant better outcome in term of both DFS and OS for those patients receiving lower doses continuously without interruption (p=0.05 and p=0.04) with respect to patients who received higher doses but were forced to stop the treatment due to grade III-IV toxicity. This observation clearly indicate the necessity of administer dasatinib continuously to patients in order to override possible mechanisms of resistance due to the reduction of the plasma level of the drug.

Conclusions
We confirm the safety and efficacy of Dasatinib as second line therapy for unselected patients with CML either resistant or refractory to IM even outside from clinical trials. Neither the dose nor the duration of Imatinib affects the response to Dasatinib. As well, patients receiving continuously Dasatinib, even at low doses, perform better. In conclusion, these findings show an increase possibility of cure for unselected patients resistant or intolerant to Imatinib submitted to second line therapy with Dasatinib in everyday clinical practice.

Disclosures
No relevant conflicts of interest to declare.