Assessment of Clinical Safety and Estimate of Survival in Iraqi Patients with Chronic Myeloid Leukemia Switched From Glivec (β-Crystalline Form of Imatinib Mesylate) to an α-Crystalline Copy of Imatinib Mesylate

Several reports have recently been published documenting the experience of patients with Philadelphia chromosome positive chronic myeloid leukemia in the chronic phase (CML-CP) who were switched from Glivec (IM), the β-crystalline form of imatinib mesylate, to non-identical alternate copies of imatinib mesylate (IMac) including those composed of the α-crystalline form. As a result of pre-clinical tests performed during the early development of IM, the β-crystalline form of imatinib mesylate was selected for further development due to its superior stability. In one case report evaluation, 126 Iraqi patients with CML-CP were switched from IM to an IMac that was the α-crystalline form of imatinib mesylate. At the time of switch to IMac, patients had previously received 400mg IM once-daily for an average of 50 months and were at least in complete hematologic response (CHR). Post-switch, patients were initially placed on the same IMac dose and followed-up on a monthly basis; more frequently in cases of poor response or adverse events. By 3 months post-switch, 22 (17%) patients had lost hematologic response and of these patients 18 (14%) and 4 (3%) had progressed to accelerated phase (AP) and blast crisis (BC), respectively. By 6 months post-switch, an additional 20 patients (16%; 33% total) had lost hematologic response. Safety assessment for IMac in this cohort has not been previously published.

To assess the clinical safety and to estimate the survival of Iraqi CML patients switched from IM to IMac.

Patient case records were retrospectively reviewed for safety findings as assessed by the treating physician. A previously published Markov transition-state model was used to compare projected life-years (LYs), progression-free life-years (PFLY), and quality-adjusted life-years (QALYs) of IM patients switched to IMac vs. patients not switched. Patients entered the model after a mean 50 months of IM therapy. At that time, based on the IRIS trial results, patients were considered to have CHR (4.7%), partial (6.5%) or complete (88.9%) cytogenetic response. Patients remaining on IM transitioned within these 3 responses levels and no hematologic response, AP, BC, and death according to the original model probabilities. For patients switched to IMac, transition rates were based exclusively on response rates observed in the Iraqi study (Scenario 1) or on the Iraqi study for the first 6 months, and thereafter based on the transition rates originally in the Markov model (Scenario 2). Utilities were from the original model.

Non-hematologic adverse event (AE) rates observed in patients who were switched to IMac are reported (Table). Patients remaining on IM were predicted to experience 15.7 LYs, 14.5 PFLYs, and 13.4 QALYs. Corresponding numbers for patients switched to IMac were 2.4 LYs, 1.1 PFLYs, 1.4 QALYs (in Scenario 1) and 11.4 LYs, 10.2 PFLYs, and 9.6 QALYs (in Scenario 2). Results were also sensitive to response distribution at model entry.

The clinical safety, efficacy, and tolerability of IM have been established from more than 10 years of clinical experience. Recent introduction of generic versions of imatinib (including α-crystalline form) allows assessment of whether patients switching from IM to a generic version are able to achieve the same clinical outcomes as with the branded drug. The Iraqi case report is the largest cohort currently available for such review. This case report suggests that switching from IM to an IMac that does not have the safety and/or efficacy may result in substantial loss of LYs, PFLYs, and QALYs. Robust pharmacovigilance programs may need to be established to differentiate safety findings for originator drugs vs. substandard generic versions.

Botteman:Novartis: Consultancy. Magestro:Novartis: Employment, Equity Ownership. Manley:Novartis Pharma AG: Employment. Zernovak:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Woodman:Novaris Pharmaceuticals Corp: Employment, Equity Ownership.