Generic Versus Branded Imatinib As Frontline Therapy in Chronic-Phase Chronic Myeloid Leukemia Patients in Italy: A Case-Control Study
Authors: Bonifacio Massimiliano , Tiribelli Mario , Binotto Gianni , Miggiano Maria Cristina , Basso Marco , Calistri Elisabetta , Scaffidi Luigi , Stella Rossella , Frison Luca , Sartori Roberto , Ruggeri Marco , Semenzato Gianpietro , Fanin Renato , Krampera Mauro 
Published: November 2019

Introduction. Imatinib is the most commonly used frontline drug in chronic phase (CP) chronic myeloid leukemia (CML) patients worldwide. In early 2017 a generic formulation of imatinib was introduced in Italy and uniformly replaced branded imatinib (Glivec®), upon requirement of regional health authorities. In the last years various groups reported on the efficacy and safety of generic imatinib with conflicting results, partly related to substandard pharmaceutical quality of some products used in developing countries. In a multicenter cohort of 294 patients treated in Italy with branded imatinib for at least 6 months and then switched to generic imatinib we observed that the majority of patients maintained or improved their molecular response. Here, we analyzed patients who received generic imatinib since diagnosis.
Aims. To analyze the rates of molecular responses at 3, 6 and 12 months and of treatment discontinuation in CML patients treated frontline with generic imatinib, compared to a case-matched historical cohort of CML patients who received frontline branded imatinib at our institutions.
Methods. We analyzed 31 newly diagnosed CP-CML patients consecutively enrolled in a prospective observational registry between January 2017 and July 2018, treated frontline with generic imatinib 400 mg/day (diverse manufacturers) and evaluable for all the ELN2013 molecular milestones (if not discontinued earlier). They were compared to a retrospective cohort of 31 patients, matched for age, gender, and Sokal risk, diagnosed between 2007 and 2014 and treated with branded imatinib 400 mg/day for at least 24 months before eventual switching to a generic formulation. Definitions of molecular responses were made according to the ELN2013 recommendations.
Results. A total of 62 patients were included in the analysis: 31 patients (21 males and 10 females) treated with generic imatinib ("cases") and 31 treated with branded imatinib ("controls"). Median age at diagnosis of the cases was 68 years (range 33-89), Sokal score was low/intermediate/high in 8 (26%), 19 (61%) and 4 (13%) patients, respectively. The controls were matched for gender, age (+/- 4 years, median age 68, range 35-85) and Sokal score. As median follow-up time for the cases was 18.6 months (range 2.2-28.5), controls were censored at 24 months after imatinib start.
Optimal molecular response at 3 months was attained in 23/30 (76.7%) cases and in 18/29 (62%) controls (p=0.35); one case died after 2 months of imatinib therapy for a CML-unrelated cause, while 2 controls were molecularly not evaluable. At 6 months, 17/29 (58.6%) cases and 17/30 (56.7%) controls achieved BCR/ABL transcript <1%, respectively (p=1). At 12 months, MMR was attained by 14/30 (46.7%) cases and by 13/29 (44.8%) controls (p=1). Twelve out of 31 patients (38.7%) permanently discontinued generic imatinib due to warning/failure response (n=6), intolerance (n=4) or death while on treatment at 2 and 13 months (meningoencephalitis of unknown origin and cardiovascular event, respectively). Among patients treated with branded imatinib, 12/31 (38.7%) stopped within the 24th month of therapy for resistance (n=8), intolerance (n=3) or death at 16 months (acute renal failure). No patient receiving generic imatinib progressed to advanced phase, while one control developed a blast crisis at 6 months of branded imatinib and deceased shortly after. Estimated overall survival at 24 months in cases and controls was 92.5% and 93.1%, respectively.
Conclusions. Our preliminary data suggest an equivalent efficacy of generic imatinib compared to a matched population of historical patients treated with the originator drug in Italy. A continue pharmacovigilance by reporting efficacy and safety outcomes of generic drugs is needed to ensure an optimal management of CML patients.

Disclosures
Bonifacio: Novartis: Honoraria, Research Funding; Amgen: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Tiribelli:Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Krampera:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.