Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias

Moshe Talpaz, Neil P. Shah, Hagop Kantarjian, Nicholas Donato, John Nicoll, Ron Paquette, Jorge Cortes, Susan O'Brien, Claude Nicaise, Eric Bleickardt, M. Anne Blackwood-Chirchir, Vishwanath Iyer, Tai Tsang Chen, Fei Huang, Arthur P. Decillis, Charles L. Sawyers

Research output: Contribution to journalArticle

Abstract

BACKGROUND: The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). METHODS: Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study. Dasatinib (15 to 240 mg per day) was administered orally in four-week treatment cycles, once or twice daily. RESULTS: A complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting. CONCLUSIONS: Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib.

Original languageEnglish (US)
Pages (from-to)2531-2541
Number of pages11
JournalNew England Journal of Medicine
Volume354
Issue number24
DOIs
StatePublished - Jun 15 2006
Externally publishedYes

Fingerprint

Philadelphia Chromosome
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid, Chronic Phase
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Blast Crisis
Cytogenetics
Mutation
Recurrence
Imatinib Mesylate
Dasatinib
Protein-Tyrosine Kinases
Chronic Disease
Genotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Talpaz, M., Shah, N. P., Kantarjian, H., Donato, N., Nicoll, J., Paquette, R., ... Sawyers, C. L. (2006). Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. New England Journal of Medicine, 354(24), 2531-2541. https://doi.org/10.1056/NEJMoa055229

Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. / Talpaz, Moshe; Shah, Neil P.; Kantarjian, Hagop; Donato, Nicholas; Nicoll, John; Paquette, Ron; Cortes, Jorge; O'Brien, Susan; Nicaise, Claude; Bleickardt, Eric; Blackwood-Chirchir, M. Anne; Iyer, Vishwanath; Chen, Tai Tsang; Huang, Fei; Decillis, Arthur P.; Sawyers, Charles L.

In: New England Journal of Medicine, Vol. 354, No. 24, 15.06.2006, p. 2531-2541.

Research output: Contribution to journalArticle

Talpaz, M, Shah, NP, Kantarjian, H, Donato, N, Nicoll, J, Paquette, R, Cortes, J, O'Brien, S, Nicaise, C, Bleickardt, E, Blackwood-Chirchir, MA, Iyer, V, Chen, TT, Huang, F, Decillis, AP & Sawyers, CL 2006, 'Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias', New England Journal of Medicine, vol. 354, no. 24, pp. 2531-2541. https://doi.org/10.1056/NEJMoa055229
Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. New England Journal of Medicine. 2006 Jun 15;354(24):2531-2541. https://doi.org/10.1056/NEJMoa055229
Talpaz, Moshe ; Shah, Neil P. ; Kantarjian, Hagop ; Donato, Nicholas ; Nicoll, John ; Paquette, Ron ; Cortes, Jorge ; O'Brien, Susan ; Nicaise, Claude ; Bleickardt, Eric ; Blackwood-Chirchir, M. Anne ; Iyer, Vishwanath ; Chen, Tai Tsang ; Huang, Fei ; Decillis, Arthur P. ; Sawyers, Charles L. / Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. In: New England Journal of Medicine. 2006 ; Vol. 354, No. 24. pp. 2531-2541.
@article{5c7e7e7663f4444e85e53a0b9f6d656d,
title = "Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias",
abstract = "BACKGROUND: The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). METHODS: Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study. Dasatinib (15 to 240 mg per day) was administered orally in four-week treatment cycles, once or twice daily. RESULTS: A complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting. CONCLUSIONS: Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib.",
author = "Moshe Talpaz and Shah, {Neil P.} and Hagop Kantarjian and Nicholas Donato and John Nicoll and Ron Paquette and Jorge Cortes and Susan O'Brien and Claude Nicaise and Eric Bleickardt and Blackwood-Chirchir, {M. Anne} and Vishwanath Iyer and Chen, {Tai Tsang} and Fei Huang and Decillis, {Arthur P.} and Sawyers, {Charles L.}",
year = "2006",
month = "6",
day = "15",
doi = "10.1056/NEJMoa055229",
language = "English (US)",
volume = "354",
pages = "2531--2541",
journal = "New England Journal of Medicine",
issn = "0028-4793",
publisher = "Massachussetts Medical Society",
number = "24",

}

TY - JOUR

T1 - Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias

AU - Talpaz, Moshe

AU - Shah, Neil P.

AU - Kantarjian, Hagop

AU - Donato, Nicholas

AU - Nicoll, John

AU - Paquette, Ron

AU - Cortes, Jorge

AU - O'Brien, Susan

AU - Nicaise, Claude

AU - Bleickardt, Eric

AU - Blackwood-Chirchir, M. Anne

AU - Iyer, Vishwanath

AU - Chen, Tai Tsang

AU - Huang, Fei

AU - Decillis, Arthur P.

AU - Sawyers, Charles L.

PY - 2006/6/15

Y1 - 2006/6/15

N2 - BACKGROUND: The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). METHODS: Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study. Dasatinib (15 to 240 mg per day) was administered orally in four-week treatment cycles, once or twice daily. RESULTS: A complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting. CONCLUSIONS: Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib.

AB - BACKGROUND: The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). METHODS: Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study. Dasatinib (15 to 240 mg per day) was administered orally in four-week treatment cycles, once or twice daily. RESULTS: A complete hematologic response was achieved in 37 of 40 patients with chronic-phase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting. CONCLUSIONS: Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib.

UR - http://www.scopus.com/inward/record.url?scp=33745102555&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745102555&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa055229

DO - 10.1056/NEJMoa055229

M3 - Article

C2 - 16775234

AN - SCOPUS:33745102555

VL - 354

SP - 2531

EP - 2541

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 24

ER -