Document Detail


The durable clearance of the T315I BCR-ABL mutated clone in chronic phase chronic myelogenous leukemia patients on omacetaxine allows tyrosine kinase inhibitor rechallenge.
MedLine Citation:
PMID:  21030353     Owner:  NLM     Status:  In-Process    
Abstract/OtherAbstract:
PURPOSE: The onset of a BCR-ABLT315I mutation during the course of chronic myelogenous leukemia (CML) on tyrosine kinase inhibitors (TKIs) usually results in poor survival, and therapeutic options remain few in the absence of any allogeneic donor.
PATIENTS AND METHODS: We have investigated the affect of subcutaneous omacetaxine (OMA, or homo-harringtonine) cycles on unmutated and T315I-mutated BCR-ABL transcripts in a series of 8 TKI-resistant chronic-phase CML patients and we have addressed the question of whether the administration of OMA could resensitize patients to TKIs. Patients were regularly monitored for total disease burden and for BCR-ABLT315I transcripts using a new quantitative sensitive technique (sensitivity threshold, 0.05%), for up to 27 cycles of OMA.
RESULTS: Overall, patients demonstrated hematologic, cytogenetic, or molecular improvement. An initial rapid decline and a sustained disappearance of T315I-mutated transcripts were observed in 50% of patients, after a median of 10.5 cycles (range, 3-27 cycles) of OMA. As the unmutated leukemic burden reduction was modest, 2 patients were submitted to nilotinib after 9 months of sustained BCR-ABLT315I transcripts negativity on OMA and mutated transcripts remained undetectable after a median follow-up of 12 months on nilotinib challenge.
CONCLUSION: We suggest that OMA (ie, a non-targeted therapy) might provide a better disease control allowing the disappearance of the mutated clone probably elicited by the clone deselection after TKI release, and/or a preferential activity of OMA on the T315I-mutated cells through unknown mechanisms. These observations suggest that OMA could allow a safe TKI rechallenge in patients with resistant chronic-phase CML.
Authors:
Franck E Nicolini; Jean-Claude Chomel; Lydia Roy; Laurence Legros; Kaddour Chabane; Sophie Ducastelle; Emmanuelle Nicolas-Virelizier; Mauricette Michallet; Isabelle Tigaud; Jean-Pierre Magaud; Ali Turhan; François Guilhot; Sandrine Hayette
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Clinical lymphoma, myeloma & leukemia     Volume:  10     ISSN:  2152-2669     ISO Abbreviation:  Clin Lymphoma Myeloma Leuk     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-29     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101525386     Medline TA:  Clin Lymphoma Myeloma Leuk     Country:  United States    
Other Details:
Languages:  eng     Pagination:  394-9     Citation Subset:  IM    
Affiliation:
Hematology Department, E. Herriot Hospital, Lyon, France.
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