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.
Cancer Med
; 12(4): 4250-4258, 2023 02.
Article
em En
| MEDLINE
| ID: mdl-36151699
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 MR4.5 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/MR4 to MR4.5 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 MR4.5 incidence by 12 months was 33.3% (95% confidence interval, 18.0%-51.8%). The cumulative MR4.5 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 MR4.5 , 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 MR4.5 in more patients than stand-alone TKI treatment.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Leucemia Mielogênica Crônica BCR-ABL Positiva
/
Leucemia Mieloide de Fase Crônica
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article