A multicenter prospective study on efficacy and safety of imatinib generics: A report from Polish Adult Leukemia Group imatinib generics registry
Authors: Tomasz Sacha, Joanna Góra‐Tybor, Monika Szarejko, Grażyna Bober, Olga Grzybowska‐Izydorczyk, Joanna Niesiobędzka‐Krężel, Marek Dudziński, Ewa Wasilewska, Krzysztof Myśliwiec, Justyna Gil, Michał Gniot, Iwona Pietkun, Ewa Mędraś, Jadwiga Hołojda, Joanna Wącław, Krzysztof Giannopoulos
Journal: American Journal of Hematology (2017)

Imatinib generics entered the Polish market after the Novartis' patent for Glivec expired on December 31, 2013 and reimbursement of branded imatinib was stopped on July 1, 2014. The Polish Adult Leukemia Group (PALG) Imatinib Generics Registry was established to provide clinical data on efficacy and safety of imatinib generics in a large cohort of patients with CML. A web page-based registry was established early in the 2014. The patients who commenced a therapy with imatinib generics right after the diagnosis of CML in chronic phase (group A) or were switched to generic from branded imatinib (group B) were observed during 1 year of treatment. Here, we report on patients who have completed a 12 month observation of therapy with a single imatinib generic. In the group A we evaluated the rate of optimal response to imatinib generics as well as the rate of treatment failure according to European LeukaemiaNet (ELN) criteria.1 The rate of early molecular response (EMR), complete cytogenetic response (CCyR) achieved at 6 months, the rate of major molecular response (MMR) and deep molecular responses (MR4 and MR4, 5) achieved at 12 months were assessed. In the group B (we report on patients with MMR switched to generics) the rate of sustained/improved or worsened molecular response, and the rate of CCyR/MMR/MR4/MR4, 5 loss were assessed. In both groups we evaluated the rate of hematologic adverse events (AEs) (3rd or 4th grade) and the rate of nonhematologic AEs (all grades) according to the CTCAE criteria. Additionally, the rate of patients switched to the second generation tyrosine kinase inhibitors (2GTKI) was assessed. Molecular response was evaluated in 15 standardized laboratories. EMR at 3 and 6 months of therapy, MMR, MR4, and MR4, 5 were defined as ratios ≤10%, ≤1%, ≤0.1%, ≤0.01%, and ≤0.0032%, respectively. Improvement or worsening of molecular response was defined as a reduction or increase of BCR/ABL1 to control gene ratio by ≥ 0.5 log. CML phases were defined as described elsewhere. Fifteen Hematology Centers were participating in the observation. A total of 892 records were completed, the criteria for current report were met in case of 726 records regarding 99 patients in group A, and 627 patients in group B. Among 99 patients from group A, 62 (62.6%) were treated with Nibix (Adamed), and 24 (24.2%) with Meaxin (Krka), other generics were used to treat 13 (13.1%) patients. In the group B Nibix, Meaxin, and Imatinib Teva were used in 445 (70.9%), 146 (23.3%), and 31 (4.3%) patients, respectively, and other generics in remaining 5 patients. Molecular response at 3, 6, and 12 months was assessed in 89 (89.9%), 74 (74.7%), and 89 (89.9%) patients in the group A and in 547 (87.2%), 516 (82.3%), and 550 (87.7%) patients in the group B, respectively. Efficacy and safety of imatinib generics in both groups of patients are shown in Table 1. The rates of EMR at 3 (Fig. 1) and 6 months (Fig. 2) and MMR at 12 months (Fig. 3) are shown in Table 1. CCyR at 6 months and at 12 months were achieved in 56 out of 99 (55.4%) and in 66 out of 99 (66.7%) patients, respectively. The rates of EMR and optimal response did not differ significantly between different generics. Molecular response in group B (n = 627) was sustained in 406 (64.8%), improved in 119 (19%), and worsened in 94 (15%) patients. In 53.3% of patients with worsened response a 0.5 log increase of BCR/ABL level was noted, and was simply represented by loss of sustained MR4.5. The mean duration of MR4.5 before switch to generic imatinib in those patients was 9 months (3–21 months). The hematologic and nonhematologic toxicity, and switching rate to 2GTKI in both groups A and B are shown in Table 1. Early molecular response (RQ < 10% at 3 months) was achieved in 65 out of 99 (65.7%) all previously untreated patients who received imatinib generics. EMR was achieved in 79% and 63% of patients treated with Meaxin and Nibix, respectively Reduction of BCR/ABL1 to < 10% at 6 months was achieved in 54 out of 99 patients (53.4%) of all patients switched from branded imatinib to generics and in 58% and 53% of patients switched to Meaxin and Nibix, respectively Optimal response to imatinib generics (RQ < 0.1% at 12 months) was achieved in 49 out of 99 (49.5%) of all previously untreated patients and in 16 out of 24 (66%) and 35 out of 62 (56.5%) of patients treated with Meaxin and Nibix, respectively Some early reports from Non-Western countries suggested loss of hematologic and cytogenetic response and deleterious effects in patients switched from branded to generic imatinib.2 Additionally, the crystal form of active pharmaceutical ingredient of imatinib was suggested initially to be an important factor influencing the clinical efficacy. Loss of patent exclusivity of branded imatinib has opened the Polish market to multiple manufacturers. As a result of discounts offered by competing pharmaceutical companies, in the years 2014–2016 the cost of CML therapy with 400 mg per day of generic imatinib was not higher than 615 USD–2000 USD per year. In our observation all generics were well tolerated, we did not observed an increased discontinuation and switching to 2GTKI rates. The frequency of hematologic and nonhematologic toxicity and switching rate to 2GTKI were comparable to the historical control of 177 patients treated with branded imatinib in the first author's institution in years 2001–2010.3 Our data support the conclusion that the a and b crystal forms of imatinib do not differ in terms of clinical efficacy. The rate of EMR (65.2%) achieved in group A patients were comparable to EMR rates achieved in patients treated with branded imatinib in the ENESTnd,4 and Dasision5 trials (66 and 65%, respectively). The cumulative incidence of CCyR at 6 months and MMR at 12 months were in our observation higher (65.7 and 53.3%, respectively) than in the EUTOS registry (57% of cumulative CCyR rate after 12 months, and 41% of cumulative MMR rate after 12 months).6 CCyR and MMR loss rates were not higher than in the historical control group (Fig. 4). All patients who lost a MR4.5 remained in MR4 throughout the study. The results of our short, 1-year observation suggest that molecular and cytogenetic response rates and AEs rates on imatinib generics and branded imatinib are alike when used in the upfront setting, as well as when used subsequently. Because of the relatively short period of observation, the same conclusions cannot be made for overall survival, for treatment-free survival, and for late or unexpected side-effects. The long-term use of imatinib generics will provide more solid prospective data. Loss of responses under imatinib generics therapy in patients switched from branded to generic imatinib (group B). CCyR, MMR and MR4.5 were lost in 0.3, 1.3, and 10.3%, respectively of patients switched from branded to generic imatinib The authors thank the many patients and clinicians, who contributed samples and follow-up data to this study; Agnieszka Giannopoulos and Franciszek Czachorowski from Hematoonkologia.pl for their excellent technical support, Bogdan Ochrem for technical support and Zofia Kubala for coordination of the study. T.S. designed the registry and performed the research, analyzed data, and wrote the manuscript; J.G-T. performed research and contributed to the registry design and to manuscript preparation; M.Sz. performed research, G.B. performed research, O.G-I. performed research, J.N-K. performed research, M.D. performed research, E.W. performed research, K.M. performed research, J.G. performed research, M.G. performed research, I.P. performed research, E.M. performed research, J.H. performed research, J.W. performed research and contributed to manuscript preparation; K.G. contributed to the registry design, analyzed data and contributed to manuscript preparation. T.S. receives honoraria from Novartis, Bristol-Myers Squibb, Pfizer and Incyte; he is on the speakers' bureaus of Novartis, Bristol-Myers-Squibb Pfizer and Ariad. J.G-T. receives honoraria from Novartis, Bristol-Myers Squibb, Pfizer and Ariad; she is on the speakers' bureaus of Novartis Bristol-Myers Squibb and Ariad. M.Sz. receives honoraria from Novartis and Bristol-Myers Squibb, she is on the speakers' bureaus of Novartis and Bristol-Myers Squibb, G.B. receives honoraria from Novartis and Bristol-Myers Squibb, O.G-I receives honoraria from Novartis and Bristol-Myers Squibb, J. N-K. receives honoraria from Novartis and Bristol-Myers Squibb, M.D. receives honoraria from Novartis and Bristol-Myers Squibb, he is on the speakers' bureaus of Novartis and Bristol-Myers-Squibb, E.W. receives honoraria from Novartis and Bristol-Myers Squibb, she is on the speakers' bureaus of Novartis and Bristol-Myers Squibb, K.M. receives honoraria from Novartis and Bristol-Myers Squibb, J.G. receives honoraria from Novartis and Bristol-Myers Squibb, M.G. receives honoraria from Novartis and Bristol-Myers Squibb, he is on the speakers' bureaus of Novartis and Bristol-Myers-Squibb, I.P. receives honoraria from Novartis and Bristol-Myers Squibb, E.M. receives honoraria from Novartis and Bristol-Myers Squibb, she is on the speakers' bureaus of Novartis and Bristol-Myers Squibb, J.H. receives honoraria from Novartis and Bristol-Myers Squibb, J.W. has nothing to disclose, K.G. receives honoraria from Novartis and Bristol-Myers Squibb, he is on the speakers' bureaus of Novartis and Bristol-Myers Squibb.