Deep molecular response in patients with chronic phase chronic myeloid leukemia treated with the plasminogen activator inhibitor‐1 inhibitor TM5614 combined with a tyrosine kinase inhibitor. (23rd September 2022)

• Record Type: Journal Article
• Authors: Takahashi, Naoto; Kameoka, Yoshihiro; Onizuka, Makoto; Onishi, Yasushi; Takahashi, Fumiaki; Dan, Takashi; Miyata, Toshio; Ando, Kiyoshi; Harigae, Hideo
• Is Part Of: Cancer medicine. Volume 12:Number 4(2023)
• Page Start: 4250
• Page End: 4258
• Publication Date: 2022-09-23
• Subjects: BCR‐ABL1 -- chronic myeloid leukemia -- PAI‐1 inhibitor -- tyrosine kinase inhibitor; 616.994005
• DOI: 10.1002/cam4.5292
• Languages: English
• ISSNs: 2045-7634

Abstract

Abstract: Background: We recently showed that pharmacological inhibition of plasminogen activator inhibitor‐1 (PAI‐1) activity, based on TM5614, increases cell motility and induces the detachment of hematopoietic stem cells from their niches. In this TM5614 phase II clinical trial, we investigated whether the combination of a PAI‐1 inhibitor and tyrosine kinase inhibitors (TKIs) would induce a deep molecular response (DMR) in patients affected by chronic myeloid leukemia (CML) by quantifying BCR‐ABL1 transcripts. Methods: Patients with chronic phase CML treated with a stable daily dose of TKIs for at least 1 year and yielding a major molecular response (MMR) but not achieving MR 4.5 were eligible for this study. After inclusion, patients began to receive TM5614 as well as a TKI. The primary objective was an evaluation of the cumulative incidence of patient progression from an MMR/MR 4 to MR 4.5 by 12 months. Results: Thirty‐three patients were enrolled in the study. The median age was 59.0 years and 58% were male. No Sokal high‐risk patients were enrolled in this trial. The median TKI treatment duration was 4.8 years. At the start of this study, seven patients and 26 patients received imatinib and second‐generation TKIs, respectively. The cumulative MR 4.5 incidence by 12 months was 33.3% (95% confidence interval, 18.0%–51.8%). The cumulative MR 4.5 spontaneous conversion over 12 months was estimated as 8% with TKIs alone based on historical controls. The halving time of BCR‐ABL1 at 2 months was significantly shorter for patients who achieved an MR 4.5, by 12 months than for the other patients (cutoff value: 48 days; sensitivity: 0.80; specificity: 0.91; ROC‐AUC: 0.83). During this study, bleeding events and abnormal coagulation related to the drug were not reported, and TM5614 was found to be highly safe. Conclusion: TM5614 combined with TKI was well tolerated and induced MR 4.5 in more patients than stand‐alone TKI treatment.