Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation

Jorge Cortes, Jeff H. Lipton, Delphine Rea, Raghunadharao Digumarti, Charles Chuah, Nisha Nanda, Annie Claude Benichou, Adam R. Craig, Mauricette Michallet, Franck E. Nicolini, Hagop Kantarjian

Research output: Contribution to journalArticle

Abstract

Chronic myeloid leukemia (CML) patients with the BCR-ABL T315I mutation do not benefit from therapy with currently approved tyrosine kinase inhibitors. Omacetaxine mepesuccinate is a protein synthesis inhibitor that has demonstrated activity in cells harboring the T315I mutation. This phase 2 trial assessed the efficacy of omacetaxine in CML patients with T315I and tyrosine kinase inhibitor failure. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily, days 1-14, every 28 days until hematologic response or a maximum of 6 cycles, and then days 1-7 every 28 days as maintenance. Results for patients treated in chronic phase are reported here. Patients (n - 62) received a median of 7 (range, 1-41) cycles. Complete hematologic response was achieved in 48 patients (77%; 95% lower confidence limit, 65%); median response duration was 9.1 months. Fourteen patients (23%; 95% lower confidence limit, 13%) achieved major cytogenetic response, including complete cytogenetic response in 10 (16%). Median progression free-survival was 7.7 months. Grade 3/4 hematologic toxicity included thrombocytopenia (76%), neutropenia (44%), and anemia (39%) and was typically manageable by dose reduction. Nonhematologic adverse events were mostly grade 1/2 and included infection (42%), diarrhea (40%), and nausea (34%). Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219.

Original languageEnglish (US)
Pages (from-to)2573-2580
Number of pages8
JournalBlood
Volume120
Issue number13
DOIs
StatePublished - Sep 27 2012
Externally publishedYes

Fingerprint

Leukemia, Myeloid, Chronic Phase
Protein-Tyrosine Kinases
Mutation
Protein Synthesis Inhibitors
Toxicity
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Cytogenetics
homoharringtonine
Neutropenia
Thrombocytopenia
Nausea
Disease-Free Survival
Anemia
Diarrhea
Maintenance

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. / Cortes, Jorge; Lipton, Jeff H.; Rea, Delphine; Digumarti, Raghunadharao; Chuah, Charles; Nanda, Nisha; Benichou, Annie Claude; Craig, Adam R.; Michallet, Mauricette; Nicolini, Franck E.; Kantarjian, Hagop.

In: Blood, Vol. 120, No. 13, 27.09.2012, p. 2573-2580.

Research output: Contribution to journalArticle

Cortes, J, Lipton, JH, Rea, D, Digumarti, R, Chuah, C, Nanda, N, Benichou, AC, Craig, AR, Michallet, M, Nicolini, FE & Kantarjian, H 2012, 'Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation', Blood, vol. 120, no. 13, pp. 2573-2580. https://doi.org/10.1182/blood-2012-03-415307
Cortes, Jorge ; Lipton, Jeff H. ; Rea, Delphine ; Digumarti, Raghunadharao ; Chuah, Charles ; Nanda, Nisha ; Benichou, Annie Claude ; Craig, Adam R. ; Michallet, Mauricette ; Nicolini, Franck E. ; Kantarjian, Hagop. / Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. In: Blood. 2012 ; Vol. 120, No. 13. pp. 2573-2580.
@article{70a57c8968e94c7da2a54aad30fecc13,
title = "Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation",
abstract = "Chronic myeloid leukemia (CML) patients with the BCR-ABL T315I mutation do not benefit from therapy with currently approved tyrosine kinase inhibitors. Omacetaxine mepesuccinate is a protein synthesis inhibitor that has demonstrated activity in cells harboring the T315I mutation. This phase 2 trial assessed the efficacy of omacetaxine in CML patients with T315I and tyrosine kinase inhibitor failure. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily, days 1-14, every 28 days until hematologic response or a maximum of 6 cycles, and then days 1-7 every 28 days as maintenance. Results for patients treated in chronic phase are reported here. Patients (n - 62) received a median of 7 (range, 1-41) cycles. Complete hematologic response was achieved in 48 patients (77{\%}; 95{\%} lower confidence limit, 65{\%}); median response duration was 9.1 months. Fourteen patients (23{\%}; 95{\%} lower confidence limit, 13{\%}) achieved major cytogenetic response, including complete cytogenetic response in 10 (16{\%}). Median progression free-survival was 7.7 months. Grade 3/4 hematologic toxicity included thrombocytopenia (76{\%}), neutropenia (44{\%}), and anemia (39{\%}) and was typically manageable by dose reduction. Nonhematologic adverse events were mostly grade 1/2 and included infection (42{\%}), diarrhea (40{\%}), and nausea (34{\%}). Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219.",
author = "Jorge Cortes and Lipton, {Jeff H.} and Delphine Rea and Raghunadharao Digumarti and Charles Chuah and Nisha Nanda and Benichou, {Annie Claude} and Craig, {Adam R.} and Mauricette Michallet and Nicolini, {Franck E.} and Hagop Kantarjian",
year = "2012",
month = "9",
day = "27",
doi = "10.1182/blood-2012-03-415307",
language = "English (US)",
volume = "120",
pages = "2573--2580",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "13",

}

TY - JOUR

T1 - Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation

AU - Cortes, Jorge

AU - Lipton, Jeff H.

AU - Rea, Delphine

AU - Digumarti, Raghunadharao

AU - Chuah, Charles

AU - Nanda, Nisha

AU - Benichou, Annie Claude

AU - Craig, Adam R.

AU - Michallet, Mauricette

AU - Nicolini, Franck E.

AU - Kantarjian, Hagop

PY - 2012/9/27

Y1 - 2012/9/27

N2 - Chronic myeloid leukemia (CML) patients with the BCR-ABL T315I mutation do not benefit from therapy with currently approved tyrosine kinase inhibitors. Omacetaxine mepesuccinate is a protein synthesis inhibitor that has demonstrated activity in cells harboring the T315I mutation. This phase 2 trial assessed the efficacy of omacetaxine in CML patients with T315I and tyrosine kinase inhibitor failure. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily, days 1-14, every 28 days until hematologic response or a maximum of 6 cycles, and then days 1-7 every 28 days as maintenance. Results for patients treated in chronic phase are reported here. Patients (n - 62) received a median of 7 (range, 1-41) cycles. Complete hematologic response was achieved in 48 patients (77%; 95% lower confidence limit, 65%); median response duration was 9.1 months. Fourteen patients (23%; 95% lower confidence limit, 13%) achieved major cytogenetic response, including complete cytogenetic response in 10 (16%). Median progression free-survival was 7.7 months. Grade 3/4 hematologic toxicity included thrombocytopenia (76%), neutropenia (44%), and anemia (39%) and was typically manageable by dose reduction. Nonhematologic adverse events were mostly grade 1/2 and included infection (42%), diarrhea (40%), and nausea (34%). Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219.

AB - Chronic myeloid leukemia (CML) patients with the BCR-ABL T315I mutation do not benefit from therapy with currently approved tyrosine kinase inhibitors. Omacetaxine mepesuccinate is a protein synthesis inhibitor that has demonstrated activity in cells harboring the T315I mutation. This phase 2 trial assessed the efficacy of omacetaxine in CML patients with T315I and tyrosine kinase inhibitor failure. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily, days 1-14, every 28 days until hematologic response or a maximum of 6 cycles, and then days 1-7 every 28 days as maintenance. Results for patients treated in chronic phase are reported here. Patients (n - 62) received a median of 7 (range, 1-41) cycles. Complete hematologic response was achieved in 48 patients (77%; 95% lower confidence limit, 65%); median response duration was 9.1 months. Fourteen patients (23%; 95% lower confidence limit, 13%) achieved major cytogenetic response, including complete cytogenetic response in 10 (16%). Median progression free-survival was 7.7 months. Grade 3/4 hematologic toxicity included thrombocytopenia (76%), neutropenia (44%), and anemia (39%) and was typically manageable by dose reduction. Nonhematologic adverse events were mostly grade 1/2 and included infection (42%), diarrhea (40%), and nausea (34%). Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219.

UR - http://www.scopus.com/inward/record.url?scp=84866860218&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866860218&partnerID=8YFLogxK

U2 - 10.1182/blood-2012-03-415307

DO - 10.1182/blood-2012-03-415307

M3 - Article

C2 - 22896000

AN - SCOPUS:84866860218

VL - 120

SP - 2573

EP - 2580

JO - Blood

JF - Blood

SN - 0006-4971

IS - 13

ER -