Significant Reduction of BCR-ABL Transcripts after Switching to Imatinib Therapy in Patients with CML and Complete or Near-Complete Cytogenetic Responses to Interferon-Alpha (IFN).
Authors: Branford Susan , Hughes Timothy , Stylian Steven , Schwarer Anthony P. , Arthur Chris , Filshie Robin , Moreton Susan , Rodwell Robyn , Guzzo-Pernell Nancy , Taylor Deb , Larson Jenny , Koelmayer Rachel , Milner Alvin , Lynch Kevin , Taylor Kerry McDonald 
Published: October 2019

Abstract
IFN confers a survival advantage for the minority of patients with CML who achieve a complete cytogenetic response. The 10-year survival rate was reported as 72%. In the IRIS trial only 3% of patients remained on IFN after randomization and 65% crossed-over to imatinib. Imatinib offered superior compliance and toxicity profiles and clear quality of life advantages. Furthermore, patients on first line imatinib with a major molecular response (MMR) by 12 months had a 100% progression free survival to advanced phase. An important clinical question of whether IFN-responsive patients can experience further improvements with imatinib has not been answered. We studied 23 chronic phase patients treated with IFN for a median of 4.5 years (r1.6–14.3) who had achieved a complete (n=15) or near-complete (n=8) cytogenetic response. IFN was ceased and 400mg imatinib commenced in a clinical trial with the primary objective of determining if switching to imatinib in IFN-responsive patients improves response when assessed at the molecular level. Molecular assessment was undertaken for the first 12 months of imatinib therapy by measurement of peripheral blood BCR-ABL levels by quantitative PCR at 3 month intervals. A subset of 10 patients had follow-up molecular assessment for 3.8 to 4.5 years after commencing imatinib. Prior to IFN cessation all patients had detectable BCR-ABL and 16 of 23 had not achieved a MMR, which is a 3 log reduction of BCR-ABL from a standardized baseline value for untreated patients. At a median of 3 months of imatinib (r3–12) these 16 patients achieved MMR. A significant reduction of BCR-ABL over the 12 month assessment was considered >50% and this occurred in 15 of these 16 patients (median 98.4% reduction, r94.4–99.8). In the sole patient without a significant reduction, BCR-ABL returned to the pre imatinib level after repeated dose interruptions of 93 days and decrease to 200mg imatinib due to thrombocytopenia. Of the 7 patients with a MMR prior to IFN cessation, all 7 maintained this level of response after switching to imatinib. Therefore, over the 12 month assessment all patients either achieved MMR (n=16) or maintained MMR (n=7). One patient withdrew consent after 83 days. The 10 patients with longer molecular follow-up of up to 4.5 years of imatinib all maintained MMR. The typical molecular response is illustrated in the figure, which plots the log reduction of BCR-ABL from the standardized baseline for 3 patients assessed at regular time-points before and after switching to imatinib. In conclusion, the data suggest that switching to imatinib leads to rapid and significant improvement in IFN-responsive patients in terms of achieving MMR, a response with established prognostic value with imatinib therapy. The study should help patients and their physicians make evidence-based decisions about the potential benefits and risks of switching to imatinib with prior response to IFN.
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