Impact of Transition to Generic Imatinib in the Molecular Response Among Patients with Chronic Myeloid Leukemia

Background: The introduction of Imatinib Mesylate (Gleevec™), a tyrosine kinase inhibitor (TKI), has revolutionized the management of Chronic Myeloid Leukemia (CML). Recently, on April 2, 2013, Health Canada approved two generic versions of imatinib mesylate (Apotex and TEVA) for sale in Canada—both of which, have been shown to be bioequivalent to the brand name Gleevec™, with similar serum imatinib levels and area under the curve after oral ingestion. In one of the largest case series reported to date (N=126), it has been reported that complete hematologic response (CHR) was lost in 33% of CML patients who were switched from brand name to generic imatinib. In an effort to assess the generalizability of this claim, we conducted a retrospective review of all patients with CML treated with Gleevec™ at a single tertiary care centre to evaluate whether there was a change in CHR or major molecular responses (MMR) in all patients who were switched to generic imatinib.

Method: We retrospectively evaluated adult CML patients who were treated from January 1, 2002 to December 2011 with brand name Imatinib (Gleevec™) and were switched to generic imatinib (Apotex or TEVA) during 2013. Patient-reported side effect profiles were also collected in a subset of patients before and after the change from Gleevec™ to generic. A follow-up period was defined as 12 months from the time of switch from brand name to generic. The primary outcome was a composite of rates of loss of CHR and/or MMR, based on the Canadian Consensus Group of the Management of Chronic Myelogneous Leukemia (CCGM-CML). Secondary outcome include side effect profiles, graded as per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), during the follow-up period.

Results: During our study period, a total 71 adult CML patients were identified. Of these, only 30 patients were included in the analysis. Among the 41 patients who were excluded, data could not be retrieved in 23 (32.4%), 9 (12.7%) were on dasatinib, 3 (4.2%) were on nilotinib, 2 (2.8%) were transplanted and 4 (5.6%) had died at the time of the switch. Data was collected using electronic medical records from patient clinic visits. The median age of all included patients was 54 years and 16 (53.3%) were male. The primary endpoint was seen in 2 of 30 patients (6.7%; 95% CI 3.5-25.6). There was a loss of MMR in 1 (3.3%) where the BCR-ABL transcript declined from a 4.19 log reduction to a 2.78 log reduction after switching to TEVA-imatinib. There was a loss of CHR in 1 (3.3%) patient, where a 20 g/L drop in hemoglobin was seen after switching to APO-imatinib. In both patients in whom the primary endpoint was seen, their imatinib dose was 200 mg before and after switching. Further, in both patients, these losses of response were transient. The secondary outcomes will be presented at the meeting.

Conclusion: The generic formulations of imatinib used in Canada do not seem to be associated with the same previously reported lack of clinical efficacy when compared to brand name Gleevec™ during a follow-up period of 12 months. Further, a loss of MMR and a loss of CHR were transient in the 2 of 30 patients identified. Despite these infrequent events, treating physicians should consider that a switch to a generic formulation may be a contributing factor for the patient’s loss of MMR or CHR. However, given the wide confidence intervals, larger studies and longer follow up are needed to address this issue.