A MULTICENTER NON-INFERIORITY STUDY OF EFFICACY AND SAFETY OF GENERIC IMATINIB IN CHRONIC MYELOID LEUKEMIA – FINAL ANALYSIS

Abstract

Aim: This study aimed to evaluate efficacy and safety of generic imatinib (IM) compared to branded imatinib (Glivec) in chronic myeloid leukemia. The primary end-point was the achievement of a major molecular response (MMR) at 12 months and safety. Secondary end-points included response evaluation, overall (OS), event-free survival (EFS) progression-free survival (PFS) and toxicity. Methods: Ambispective, multicenter, observational, non-inferiority study, in newly diagnosed Brazilian patients with chronic phase CML patients treated with IM in first line. The historic cohort consisted of CML patients treated with branded IM (Glivec) from January 2010 to December 2011 and the prospective cohort was treated with generics between January 2015 and December 2018. A total of 493 cases (214 Glivec and 279 Generic) from 10 centers were enrolled, and 393 (80%) patients were eligible for analysis (Glivec = 163; Generics = 230). EFS was measured from the start of treatment until loss of complete hematologic response, loss of major cytogenetic response, progression to accelerated or blast crisis, no response or insufficient response to study therapy, after a predefined period of time or death from any cause at any time during initial therapy or permanent discontinuation of IM by adverse events. Results: The median age was 45 and 49 years in Glivec and Generics groups, respectively (p = 0.056). Sokal score stratification in Glivec and generic groups, was respectively: low risk 50/50%; intermediate risk 49/38% and high risk 12/22% (p = 0.05). E14a2 (b3a2) frequency was 63% vs. 52% in Glivec and Generic group, respectively, and e13a2 (b2a2) 36% in both groups, e14a2+e13a2 were 1% vs. 12% (p = 0.005). There was no significant difference in gender, Eutos score and ECOG. The median time between diagnosis and treatment starting was 40 (0-169) and 28 (0-168) days (Glivec vs. Generics, respectively), p = 0.17. MMR rate at 12 months was 77/142 (54%) and 88/145 (61%) in Glivec and generics groups, respectively (p = 0.26). There were more failures in the generics group at 6 months (21% vs. 14%) (p = 0.03, respectively). There was no difference in grade 3-4 hematological and non-hematological toxicity in in the first 12 months. EFS at 24 months were higher in Glivec cohort and 76% vs. 53%, p < 0.0001, respectively), PFS and OS was not significantly different (respectively: 96% vs. 93%, p = 0.09 and 97% vs 96%, p = 0.41). The independent risk factors associated with inferior EFS were: generics use (HR = 1.78; 95%CI 1.06-2.99; p = 0.02) and High Sokal index (HR 2.25; 95%CI 1.38-3.67; p = 0.001). Conclusion: In the intention to treat analysis there was no significant difference in the primary end-point (MMR and safety at 12 months). The generics cohort presented more failures at 6 months compared to branded imatinib and inferior 24 month-EFS. There was no difference in the 24-month OS and PFS. The interpretation of the results should take into consideration the differences in CML management over the years.