Efficacy and Safety of Generic Imatinib Compared to Glivec in Chronic Phase - Chronic Myeloid Leukemia - a Multicenter, Observational Study
Authors: Pagnano Katia B , Fava Carmen , Miranda Eliana C , Bendit Israel , Seguro Fernanda S , Magalhaes Gustavo HR , Clementino Nelma D , Conchon Monika , Gonçalves Natália N , Gaidano Gianluca , Lunghi Monia , Moellmann-Coelho Arthur , Luise Ingrid , Bergamaschi Micaela , Ferrero Dario , Centrone Renato , Pregno Patrizia , Fogliatto Laura , Giai Valentina , Dragani Matteo Emidio , Moiraghi Elena , Bortolini Jaisson , Castelli Andrea , Cuttica Alessandra , Bortolheiro Teresa Cristina , Pinna Cristiane , De Souza Carmino Antonio , Saglio Giuseppe 
Published: October 2019

Abstract
Glivec was the first tyrosine kinase inhibitor (TKI) approved for chronic myeloid leukemia (CML) treatment and its efficacy has been demonstrated in a large number of trials. Generic formulations have been used recently as a more cost effective treatment, but there are few studies that have prospectively evaluated the efficacy and safety of these drugs.Aims: The present study aimed to evaluate the efficacy and safety of generic imatinib in CP-CML in first line therapy. Methods: This is a multicenter, observational, cohort-type study. The prospective cohort consisted of patients who initiated treatment with generic imatinib between January 2015 and September 2017; whereas the retrospective cohort was treated with Glivec between January 2010 and December 2011. All patients started imatinib in CP, less than six months from diagnosis. Patients were managed according to European Leukemia Net (ELN) 2009 and 2013 recommendations. The definition of the responses followed the ELN 2013 criteria. Adverse events were assessed based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.3, 2010. Event-free survival (EFS) was measured from starting date of treatment until loss of complete hematologic response, loss of major cytogenetic response, progression to accelerated (AP) or blast crisis (BC) or death from any cause at any time during initial therapy or discontinuation of imatinib by any cause. Patients that switched from Glivec to generic where censored. Overall survival (OS) was measured from starting date of imatinib until to the date of death from any cause while on therapy or last seen. Progression-free survival (PFS) was measured from starting date of imatinib to transformation to AP or BC or deaths while on therapy. Survival curves were calculated by the Kaplan-Meier method and compared with the log-rank test. Cox regression was used with Backward Wald Method. SPSS version 21.0 was used applying the chi-square and t-test, when adequate. All analysis considered p-value <0.05 as significant.
Results: A total of 445 patients were analyzed (Glivec=285; Generic=160). The median age was 54 years (18-87) in Glivec and 50 (18-89) in the Generic group (P=0.027). Sokal score stratification in Glivec and generic groups, was respectively: low risk 14.4%/25.7%; intermediate risk 42.3%/38.2% and high risk 43.3%/36.1% (P=0.02). B3a2 frequency was 51.5% vs. 37.7% in Glivec and Generic group, respectively, and b2a2 41.4% vs. 53.8% (P=0.017). There was no significant difference in gender, Hasford, EUTOS scores and ECOG. The median follow-up was 25 months (0-71) and 11 months (0-31) for Glivec and Generic groups, respectively (P<0.0001). The median time between diagnosis and imatinib starting was 18 days (0-119) in Glivec and 27 days (0-168) in the Generic group (P= 0.015). The rate of treatment failure at 3 months according to the ELN 2013 criteria was 6.6% and 14.7% in Glivec vs. Generic (P=0.04); whereas at 6 months there were no significant differences (12.3% vs. 18.9%; P=0.09). There was no significant difference in grade 3 and 4 hematological and non-hematological toxicity during the follow-up. There were 5 and 3 cases of progression in the Glivec and Generic group, respectively. In the Cox regression multivariate analysis, the independent factors for EFS were age at diagnosis (HR=1.03; CI95% 1.00-1.07; P=0.039) and toxicity grade 3-4 (HR 3.37; CI95% 1.08-10.4; P=0.036). The initial therapy was discontinued for the following reasons, in Glivec and generic group respectively: resistance (19.7% vs. 47.5%), intolerance (15.3% vs. 23.7%), non-adherence (4.4% vs. 3.4%), death (2.0% vs. 6.8%), clinical trial (0.5% vs. 10.2%), progression (2.0% vs. 5.0%), pregnancy (0 vs. 3.4%), switch from Glivec to generic (56.1%). OS, PFS and EFS at 24 months were higher in Glivec group in comparison to Generic (99% vs. 96%, P=0.016), (98% vs. 95%, P= 0.026) and (73% vs. 58%; P<0.0001 respectively.
Conclusion: The group treated with generic imatinib presented higher rate of failure at 3 months and lower OS, PFS and EFS at 24 months. Differences between the groups included a longer time to initiate treatment in the Generic group, a higher proportion of patients with b2a2 transcripts, which were related to an inferior rate of molecular responses and survival in other studies. There was no difference in the safety profile. The long-term impact in prognosis will be evaluated after a longer follow-up.

Disclosures
Pagnano: Shire: Other: Lecture; Abbvie: Consultancy; EMS: Other: Financial support for participation in congress; Novartis: Consultancy. Magalhaes:Novartis: Consultancy, Other: Lecture. Clementino:EMS: Other: Financial support for congress. Gaidano:AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Morphosys: Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Centrone:EMS: Other: Financial support for congress, Speakers Bureau; Bristol Meiers-Squibb: Other: Financial support for congress, Speakers Bureau; Novartis: Other: Financial support for congress, Speakers Bureau; Astra Zeneca: Speakers Bureau; Janssen: Other: Financial support for congress, Speakers Bureau. Fogliatto:Novartis: Consultancy; Roche: Consultancy, Speakers Bureau; Janssen: Honoraria, Research Funding. Giai:Pfizer: Consultancy; Novartis: Consultancy. Bortolheiro:Abbvie: Consultancy, Speakers Bureau; Sanoffi: Speakers Bureau; Novartis: Consultancy, Speakers Bureau.