Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia

Neil P. Shah, Hagop M. Kantarjian, Dong Wook Kim, Delphine Réa, Pedro E. Dorlhiac-Llacer, Jorge H. Milone, Jorge Vela-Ojeda, Richard T. Silver, H. Jean Khoury, Aude Charbonnier, Nina Khoroshko, Ronald L. Paquette, Michael Deininger, Robert H. Collins, Irma Otero, Timothy Hughes, Eric Bleickardt, Lewis Strauss, Stephen Francis, Andreas Hochhaus

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Abstract

Purpose: Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose- and schedule-optimization study is reported. Patients and Methods: In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1:1:1:1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. Results: With minimum follow-up of 6 months (median treatment duration, 8 months; range, < 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11% of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P = .024) and grade 3 to 4 thrombocytopenia (22% v 37%; P = .004), and fewer patients required dose interruption (51% v 68%), reduction (30% v 55%), or discontinuation (16% v 23%). Conclusion: Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.

Original languageEnglish (US)
Pages (from-to)3204-3212
Number of pages9
JournalJournal of Clinical Oncology
Volume26
Issue number19
DOIs
StatePublished - 2008

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Leukemia, Myeloid, Chronic Phase
Cytogenetics
Pleural Effusion
Treatment Failure
Protein-Tyrosine Kinases
Disease-Free Survival
Disease Progression
Appointments and Schedules
Therapeutics
Imatinib Mesylate
Dasatinib
Safety

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. / Shah, Neil P.; Kantarjian, Hagop M.; Kim, Dong Wook; Réa, Delphine; Dorlhiac-Llacer, Pedro E.; Milone, Jorge H.; Vela-Ojeda, Jorge; Silver, Richard T.; Khoury, H. Jean; Charbonnier, Aude; Khoroshko, Nina; Paquette, Ronald L.; Deininger, Michael; Collins, Robert H.; Otero, Irma; Hughes, Timothy; Bleickardt, Eric; Strauss, Lewis; Francis, Stephen; Hochhaus, Andreas.

In: Journal of Clinical Oncology, Vol. 26, No. 19, 2008, p. 3204-3212.

Research output: Contribution to journalArticle

Shah, NP, Kantarjian, HM, Kim, DW, Réa, D, Dorlhiac-Llacer, PE, Milone, JH, Vela-Ojeda, J, Silver, RT, Khoury, HJ, Charbonnier, A, Khoroshko, N, Paquette, RL, Deininger, M, Collins, RH, Otero, I, Hughes, T, Bleickardt, E, Strauss, L, Francis, S & Hochhaus, A 2008, 'Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia', Journal of Clinical Oncology, vol. 26, no. 19, pp. 3204-3212. https://doi.org/10.1200/JCO.2007.14.9260
Shah, Neil P. ; Kantarjian, Hagop M. ; Kim, Dong Wook ; Réa, Delphine ; Dorlhiac-Llacer, Pedro E. ; Milone, Jorge H. ; Vela-Ojeda, Jorge ; Silver, Richard T. ; Khoury, H. Jean ; Charbonnier, Aude ; Khoroshko, Nina ; Paquette, Ronald L. ; Deininger, Michael ; Collins, Robert H. ; Otero, Irma ; Hughes, Timothy ; Bleickardt, Eric ; Strauss, Lewis ; Francis, Stephen ; Hochhaus, Andreas. / Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. In: Journal of Clinical Oncology. 2008 ; Vol. 26, No. 19. pp. 3204-3212.
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abstract = "Purpose: Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose- and schedule-optimization study is reported. Patients and Methods: In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1:1:1:1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. Results: With minimum follow-up of 6 months (median treatment duration, 8 months; range, < 1 to 15 months), marked and comparable hematologic (complete, 86{\%} to 92{\%}) and cytogenetic (major, 54{\%} to 59{\%}; complete, 41{\%} to 45{\%}) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8{\%} to 11{\%} of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7{\%} v 16{\%}; P = .024) and grade 3 to 4 thrombocytopenia (22{\%} v 37{\%}; P = .004), and fewer patients required dose interruption (51{\%} v 68{\%}), reduction (30{\%} v 55{\%}), or discontinuation (16{\%} v 23{\%}). Conclusion: Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.",
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T1 - Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia

AU - Shah, Neil P.

AU - Kantarjian, Hagop M.

AU - Kim, Dong Wook

AU - Réa, Delphine

AU - Dorlhiac-Llacer, Pedro E.

AU - Milone, Jorge H.

AU - Vela-Ojeda, Jorge

AU - Silver, Richard T.

AU - Khoury, H. Jean

AU - Charbonnier, Aude

AU - Khoroshko, Nina

AU - Paquette, Ronald L.

AU - Deininger, Michael

AU - Collins, Robert H.

AU - Otero, Irma

AU - Hughes, Timothy

AU - Bleickardt, Eric

AU - Strauss, Lewis

AU - Francis, Stephen

AU - Hochhaus, Andreas

PY - 2008

Y1 - 2008

N2 - Purpose: Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose- and schedule-optimization study is reported. Patients and Methods: In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1:1:1:1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. Results: With minimum follow-up of 6 months (median treatment duration, 8 months; range, < 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11% of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P = .024) and grade 3 to 4 thrombocytopenia (22% v 37%; P = .004), and fewer patients required dose interruption (51% v 68%), reduction (30% v 55%), or discontinuation (16% v 23%). Conclusion: Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.

AB - Purpose: Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose- and schedule-optimization study is reported. Patients and Methods: In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1:1:1:1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. Results: With minimum follow-up of 6 months (median treatment duration, 8 months; range, < 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11% of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P = .024) and grade 3 to 4 thrombocytopenia (22% v 37%; P = .004), and fewer patients required dose interruption (51% v 68%), reduction (30% v 55%), or discontinuation (16% v 23%). Conclusion: Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.

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