Chronic myeloid leukemia (CML) is a rare disease characterized by the presence of the Philadelphia chromosome (Ph+) . In 2001, the Food and Drug Administration (FDA) approved imatinib mesylate (Glivec, Novartis, Klybeckstrasse, Basel, Switzerland), a first-generation
However, owing to these contrasting results, assessing the safety and efficacy of available generic formulations is of paramount importance. Furthermore, some patient associations and clinicians are doubtful about a switch to the generic one for fear of disease worsening and higher side effects [17-19]. For these reasons, it is necessary to further assess the efficacy and safety of new generic formulations in larger and prospective trials.
This is an observational, multicenter, retro-prospective analysis of patients with CML in the CP with stable disease [defined as at least 18 months of complete cytogenetic response (CCyR) and 36 months of treatment with branded imatinib] who had their treatment switched from branded to generic imatinib since January 2017 in 12 Italian Institutes belonging to the REL (Lombardy Hematological Network). Previous treatments with interferon or oncocarbide were allowed if administered for a maximum of one month for cytoreductive purpose. Patients in the AP or BP at the time of enrollment were excluded, as well as patients the in second or subsequent lines of treatment. Five manufacturers of generic imatinib were used during this period: Accord, Sandoz, Teva, Dr. Reddy, Mylan; accord accounted for more than 50% of total usage. We analyzed the variation in quantitative PCR values, considering
The study was conducted in accordance with the Declaration of Helsinki and the rules of the Good Clinical Practice. The study protocol was approved by the Ethics Committee of the Coordinating center and the respective Ethics Committee for each center; patients’ data were anonymized and replaced by a unique identification code.
A total of 200 patients were enrolled between September 2017 and June 2019. A total of 119 (59.5%) patients were male, while 81 (40.5%) were female. Median age at diagnosis was 48.6 years (SD 15.7; min 6.8-max 86.5), and the median duration of treatment with branded imatinib was 8.9±4.0 (SD) years (range, 3.0–17.4). Accord was the most used generic (117 patients; 58.5%), followed by Teva (109; 54.5%), Sandoz (41; 20.5%), Mylan (1; 0.4%), and Reddy (1; 0.4%). During the observational period, 78% (156 patients) received only one type, while 19 (9.5%) used two types and 25 (12.5%) three types of generic imatinib (Table 1).
The median value of the 3 PCR performed before the switch was 0.4×10-4 (mean, 6.555×10-4, SD±21.426×10-4), while the median value after the switch was 0.1×10-4 (mean, 3.193×10-4; SD±11.818×10). Median PCR values after switch had reduced by 0.25 compared to values observed before the switch. A significant difference was found between these values (
Among the 200 patients enrolled, 170 (85.0%) had at least one AE of any grade on branded imatinib therapy, while 109 (54.5%) developed an AE of any grade after switching to the generic one. Sixteen patients (8.0%) reported a serious AE (G3-G4) during treatment with branded imatinib, while seven (3.5%) reported severe AE on generic imatinib treatment. No imatinib-related death was observed before or after the switch. No new safety concerns emerged after switching to generic: the types of AE were similar to those of branded imatinib. The frequent AEs with branded imatinib were muscle cramps (77 patients, 38.5%), edema of the limbs (41; 20.5%), diarrhea (38; 19.0%), periorbital edema (35; 17.5%), fatigue (33; 16.5%), and arthralgia (22; 11%). The frequent laboratory abnormalities were anemia (6; 3.0%), neutropenia (4; 2.0%), and elevated transaminase (4; 2.0%). After switching to the generic one, the more frequently reported AEs were muscle cramps (42; 21.0%), fatigue (22; 11.0%), periorbital edema (21; 10.5%), arthralgia (21; 10.5%), and diarrhea (20; 10.0%), and the most frequent laboratory abnormalities were anemia (1; 1.5%) and increase in serum lipase (3; 1.5%). After the switch, 14 patients (7%) reported muscular cramps; 15 (7.5%), cutaneous rash; 10 (5.0%), arthralgia; 9 (4.5%), diarrhea; 7 (3.5%), nausea; and 6 (3.0%), conjunctival hyperemia. Data of all AEs are shown in Table 2 and Fig. 2. The comparison between pre- and post-switch AEs showed a significant difference in favor of generic imatinib for muscular cramps (
Our study involved 200 patients from 12 centers in Lombardia, Italy, affected by CP-CML on first-line treatment with branded imatinib, which was switched to generic imatinib. Patients should have a stable disease, defined as a CCyR for at least 18 months and treatment with imatinib for at least 36 months, to avoid possible confounding factors in assessing the response to treatment after switching. Moreover, after 36 months of treatment, most side effects maybe stable, allowing a more precise report of relevant side effects.
In our study, we observed a significant improvement in PCR transcript values after the switch to generic imatinib. We hypothesized that this may be related to a longer period of treatment (one year after the switch to generic) rather than to a greater efficacy of generic imatinib. This is in contrast to the analysis presented at the ASH 2015 congress by Klil-Drori
The AEs reported in our study are comparable to those for branded imatinib pertaining to the type and intensity . Rather, the percentage of reported AEs was lower for generic imatinib, including osteoarticular pain, muscle cramps, and fatigue, with lower rates of G3-G4 events reported after the switch to the generic one (Table 2 and Fig. 2). However, some bias may have influenced the safety analysis: first, safety data were collected directly from clinicians and no ad-hoc questionnaire on AEs or quality of life was planned, possibly causing an underestimation of the AEs. Moreover, the fact that patients who switched to generic imatinib were treated for 1 more year could have contributed to a better tolerability of generic imatinib. Despite a general reduction in AEs, some patients reported concerns and fears about the introduction of the generic form of imatinib and thus could be particularly sensitive to any AE associated with generic imatinib. Another explanation of this could be an increased bioavailability of imatinib. A small proportion of patients reported the onset of new AEs after the switch, as reported in Table 2 and Fig. 2. However, this analysis is limited by the short observation period before the switch. Owing to intolerance, three patients had to switch back to branded imatinib in our study. Another Italian observational study on 294 patients treated for at least 6 months with branded imatinib and then switched to the generic, addressed the question on generic imatinib safety and showed that 17% of the patients reported worsening or new-onset AEs, while 6 (17.7%) patients had to revert to the branded drug .
We used five types of generic drugs according to individual hospital licenses at the time of patient enrollment. Direct comparison among the different generics was not performed because 22% of the patients (N=44) received 2 to 3 types of different generics, which makes this analysis unreliable. Moreover, our study was aimed to address this question. Small differences in bioequivalence may exist, but they seem not to affect the clinical outcomes. In fact, the FDA, EMA, and AIFA requested that kinetic profiles of generic drugs fall within a range of 80-125% of absorption rate with regard to that of the reference drug, assuming that these small differences in kinetic profile should not affect outcome . Generic drugs available in Italy are approved on this basis.
In our study, we did not analyze the efficacy and safety of upfront generic imatinib on newly diagnosed CML. Eskazan
Assessing safety and efficacy of generic imatinib formulations is of paramount importance: imatinib mesylate has dramatically changed the prognosis of CML patients and new generic formulations must guarantee similar efficacy and safety profiles. Pharmacoeconomics considerations must also be done to ensure a lower price (approximately 30%) of generic imatinib, especially in countries that do not guarantee free access to this life saving drug. For example, Padula
Finally, our data indicate that generic imatinib does not have deleterious effects on CML control and presents an acceptable safety profile, similar to that of branded imatinib. These data will be useful to clarify doubts and fears among CML patients and doctors about generic safety and effectiveness, provided that strict quality controls be implemented.
No potential conflicts of interest relevant to this article were reported.