Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: Retrospective analysis of patient data from five clinical trials

Preetesh Jain, Hagop Kantarjian, Mona Lisa Alattar, Elias Jabbour, Koji Sasaki, Graciela Nogueras Gonzalez, Sara Dellasala, Sherry Pierce, Srdan Verstovsek, William Wierda, Gautam Borthakur, Farhad Ravandi, Susan O'Brien, Jorge Cortes

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Several tyrosine kinase inhibitors (TKIs) are available for treatment of patients with chronic myeloid leukaemia in chronic phase (CML-CP). We analysed long-term molecular and cytogenetic response and survival outcomes for four TKI modalities used as frontline therapy for CML-CP. METHODS: In a retrospective cohort analysis, we included data from patients with CML-CP treated in prospective clinical trials with frontline TKI modalities at a single institution between July 31, 2000, and Sept 10, 2013. The main aim of the study was to determine whether achievement of complete cytogenetic response or major molecular response had similar prognostic implications irrespective of the frontline TKI modality used. We analysed each TKI modality for response assessment and analysed survival endpoints (event-free, failure-free, transformation-free, and overall survival) with the Kaplan-Meier method. Univariate and multivariate analyses were done with Cox proportional hazard regression. FINDINGS: Our analysis included 482 patients who were treated with imatinib 400 mg daily (n=68), imatinib 800 mg daily (n=200), dasatinib 50 mg twice daily or 100 mg daily (n=106), or nilotinib 400 mg twice daily (n=108). More patients receiving imatinib 800 mg or second-generation TKIs (ie, dasatinib or nilotinib) achieved complete cytogenetic response (58 [87%] of 67 for imatinib 400 mg vs 180 [90%] of 199 for imatinib 800 mg, vs 100 [96%] of 104 for dasatinib vs 99 [93%] of 107 for nilotinib), major molecular response (51 [76%] vs 171 [86%] vs 93 [90%] vs 97 [91%]), and 4·5 log or higher reduction in BCR-ABL transcripts (MR4·5 response 38 [57%] vs 148 [74%] vs 76 [71%] vs 76 [71%]). This finding was consistent over time (3-60 months). 5-year event free survival significantly differed between the imatinib 400 mg group and the other TKI groups (imatinib 800 mg p=0·029, dasatinib p=0·003, nilotinib p=0·031). There was no significant difference in 5-year failure-free survival (p=0·32, p=0·075, p=0·332), transformation-free survival (p=0·053, p=0·038, p=0·493), or overall survival (p=0·563, p=0·162, p=0·981). Multivariate analysis showed that therapy with imatinib 800 mg (HR 0·51, 95% CI 0·29-0·88, p=0·016), dasatinib (0·28, 0·12-0·66, p=0·004), or nilotinib (0·42, 0·20-0·89, p=0·024) predicted for better event-free survival compared with imatinib 400 mg, but that failure-free, transformation-free, and overall survival were similar irrespective of the TKI used. 28 (41%) patients receiving imatinib 400 mg, 85 (43%) receiving imatinib 800 mg, 23 (21%) receiving dasatinib, and 27 (25%) receiving nilotinib discontinued treatment for any reason. INTERPRETATION: Treatment with imatinib 800 mg or the second-generation TKIs dasatinib or nilotinib resulted in superior and deeper responses than did standard-dose imatinib, which were maintained after 5 years of follow-up. Results with imatinib 800 mg were similar to those with second-generation TKIs, although more patients discontinued therapy. FUNDING: MD Anderson Cancer Center, National Cancer Institute.

Original languageEnglish (US)
Pages (from-to)e118-e128
JournalThe Lancet Haematology
Volume2
Issue number3
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Leukemia, Myeloid, Chronic Phase
Cytogenetics
Clinical Trials
Protein-Tyrosine Kinases
Survival
Disease-Free Survival
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
Imatinib Mesylate
Dasatinib
Therapeutics
Multivariate Analysis
National Cancer Institute (U.S.)

ASJC Scopus subject areas

  • Hematology

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Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia : Retrospective analysis of patient data from five clinical trials. / Jain, Preetesh; Kantarjian, Hagop; Alattar, Mona Lisa; Jabbour, Elias; Sasaki, Koji; Gonzalez, Graciela Nogueras; Dellasala, Sara; Pierce, Sherry; Verstovsek, Srdan; Wierda, William; Borthakur, Gautam; Ravandi, Farhad; O'Brien, Susan; Cortes, Jorge.

In: The Lancet Haematology, Vol. 2, No. 3, 01.01.2015, p. e118-e128.

Research output: Contribution to journalArticle

Jain, Preetesh ; Kantarjian, Hagop ; Alattar, Mona Lisa ; Jabbour, Elias ; Sasaki, Koji ; Gonzalez, Graciela Nogueras ; Dellasala, Sara ; Pierce, Sherry ; Verstovsek, Srdan ; Wierda, William ; Borthakur, Gautam ; Ravandi, Farhad ; O'Brien, Susan ; Cortes, Jorge. / Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia : Retrospective analysis of patient data from five clinical trials. In: The Lancet Haematology. 2015 ; Vol. 2, No. 3. pp. e118-e128.
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abstract = "BACKGROUND: Several tyrosine kinase inhibitors (TKIs) are available for treatment of patients with chronic myeloid leukaemia in chronic phase (CML-CP). We analysed long-term molecular and cytogenetic response and survival outcomes for four TKI modalities used as frontline therapy for CML-CP. METHODS: In a retrospective cohort analysis, we included data from patients with CML-CP treated in prospective clinical trials with frontline TKI modalities at a single institution between July 31, 2000, and Sept 10, 2013. The main aim of the study was to determine whether achievement of complete cytogenetic response or major molecular response had similar prognostic implications irrespective of the frontline TKI modality used. We analysed each TKI modality for response assessment and analysed survival endpoints (event-free, failure-free, transformation-free, and overall survival) with the Kaplan-Meier method. Univariate and multivariate analyses were done with Cox proportional hazard regression. FINDINGS: Our analysis included 482 patients who were treated with imatinib 400 mg daily (n=68), imatinib 800 mg daily (n=200), dasatinib 50 mg twice daily or 100 mg daily (n=106), or nilotinib 400 mg twice daily (n=108). More patients receiving imatinib 800 mg or second-generation TKIs (ie, dasatinib or nilotinib) achieved complete cytogenetic response (58 [87{\%}] of 67 for imatinib 400 mg vs 180 [90{\%}] of 199 for imatinib 800 mg, vs 100 [96{\%}] of 104 for dasatinib vs 99 [93{\%}] of 107 for nilotinib), major molecular response (51 [76{\%}] vs 171 [86{\%}] vs 93 [90{\%}] vs 97 [91{\%}]), and 4·5 log or higher reduction in BCR-ABL transcripts (MR4·5 response 38 [57{\%}] vs 148 [74{\%}] vs 76 [71{\%}] vs 76 [71{\%}]). This finding was consistent over time (3-60 months). 5-year event free survival significantly differed between the imatinib 400 mg group and the other TKI groups (imatinib 800 mg p=0·029, dasatinib p=0·003, nilotinib p=0·031). There was no significant difference in 5-year failure-free survival (p=0·32, p=0·075, p=0·332), transformation-free survival (p=0·053, p=0·038, p=0·493), or overall survival (p=0·563, p=0·162, p=0·981). Multivariate analysis showed that therapy with imatinib 800 mg (HR 0·51, 95{\%} CI 0·29-0·88, p=0·016), dasatinib (0·28, 0·12-0·66, p=0·004), or nilotinib (0·42, 0·20-0·89, p=0·024) predicted for better event-free survival compared with imatinib 400 mg, but that failure-free, transformation-free, and overall survival were similar irrespective of the TKI used. 28 (41{\%}) patients receiving imatinib 400 mg, 85 (43{\%}) receiving imatinib 800 mg, 23 (21{\%}) receiving dasatinib, and 27 (25{\%}) receiving nilotinib discontinued treatment for any reason. INTERPRETATION: Treatment with imatinib 800 mg or the second-generation TKIs dasatinib or nilotinib resulted in superior and deeper responses than did standard-dose imatinib, which were maintained after 5 years of follow-up. Results with imatinib 800 mg were similar to those with second-generation TKIs, although more patients discontinued therapy. FUNDING: MD Anderson Cancer Center, National Cancer Institute.",
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T1 - Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia

T2 - Retrospective analysis of patient data from five clinical trials

AU - Jain, Preetesh

AU - Kantarjian, Hagop

AU - Alattar, Mona Lisa

AU - Jabbour, Elias

AU - Sasaki, Koji

AU - Gonzalez, Graciela Nogueras

AU - Dellasala, Sara

AU - Pierce, Sherry

AU - Verstovsek, Srdan

AU - Wierda, William

AU - Borthakur, Gautam

AU - Ravandi, Farhad

AU - O'Brien, Susan

AU - Cortes, Jorge

PY - 2015/1/1

Y1 - 2015/1/1

N2 - BACKGROUND: Several tyrosine kinase inhibitors (TKIs) are available for treatment of patients with chronic myeloid leukaemia in chronic phase (CML-CP). We analysed long-term molecular and cytogenetic response and survival outcomes for four TKI modalities used as frontline therapy for CML-CP. METHODS: In a retrospective cohort analysis, we included data from patients with CML-CP treated in prospective clinical trials with frontline TKI modalities at a single institution between July 31, 2000, and Sept 10, 2013. The main aim of the study was to determine whether achievement of complete cytogenetic response or major molecular response had similar prognostic implications irrespective of the frontline TKI modality used. We analysed each TKI modality for response assessment and analysed survival endpoints (event-free, failure-free, transformation-free, and overall survival) with the Kaplan-Meier method. Univariate and multivariate analyses were done with Cox proportional hazard regression. FINDINGS: Our analysis included 482 patients who were treated with imatinib 400 mg daily (n=68), imatinib 800 mg daily (n=200), dasatinib 50 mg twice daily or 100 mg daily (n=106), or nilotinib 400 mg twice daily (n=108). More patients receiving imatinib 800 mg or second-generation TKIs (ie, dasatinib or nilotinib) achieved complete cytogenetic response (58 [87%] of 67 for imatinib 400 mg vs 180 [90%] of 199 for imatinib 800 mg, vs 100 [96%] of 104 for dasatinib vs 99 [93%] of 107 for nilotinib), major molecular response (51 [76%] vs 171 [86%] vs 93 [90%] vs 97 [91%]), and 4·5 log or higher reduction in BCR-ABL transcripts (MR4·5 response 38 [57%] vs 148 [74%] vs 76 [71%] vs 76 [71%]). This finding was consistent over time (3-60 months). 5-year event free survival significantly differed between the imatinib 400 mg group and the other TKI groups (imatinib 800 mg p=0·029, dasatinib p=0·003, nilotinib p=0·031). There was no significant difference in 5-year failure-free survival (p=0·32, p=0·075, p=0·332), transformation-free survival (p=0·053, p=0·038, p=0·493), or overall survival (p=0·563, p=0·162, p=0·981). Multivariate analysis showed that therapy with imatinib 800 mg (HR 0·51, 95% CI 0·29-0·88, p=0·016), dasatinib (0·28, 0·12-0·66, p=0·004), or nilotinib (0·42, 0·20-0·89, p=0·024) predicted for better event-free survival compared with imatinib 400 mg, but that failure-free, transformation-free, and overall survival were similar irrespective of the TKI used. 28 (41%) patients receiving imatinib 400 mg, 85 (43%) receiving imatinib 800 mg, 23 (21%) receiving dasatinib, and 27 (25%) receiving nilotinib discontinued treatment for any reason. INTERPRETATION: Treatment with imatinib 800 mg or the second-generation TKIs dasatinib or nilotinib resulted in superior and deeper responses than did standard-dose imatinib, which were maintained after 5 years of follow-up. Results with imatinib 800 mg were similar to those with second-generation TKIs, although more patients discontinued therapy. FUNDING: MD Anderson Cancer Center, National Cancer Institute.

AB - BACKGROUND: Several tyrosine kinase inhibitors (TKIs) are available for treatment of patients with chronic myeloid leukaemia in chronic phase (CML-CP). We analysed long-term molecular and cytogenetic response and survival outcomes for four TKI modalities used as frontline therapy for CML-CP. METHODS: In a retrospective cohort analysis, we included data from patients with CML-CP treated in prospective clinical trials with frontline TKI modalities at a single institution between July 31, 2000, and Sept 10, 2013. The main aim of the study was to determine whether achievement of complete cytogenetic response or major molecular response had similar prognostic implications irrespective of the frontline TKI modality used. We analysed each TKI modality for response assessment and analysed survival endpoints (event-free, failure-free, transformation-free, and overall survival) with the Kaplan-Meier method. Univariate and multivariate analyses were done with Cox proportional hazard regression. FINDINGS: Our analysis included 482 patients who were treated with imatinib 400 mg daily (n=68), imatinib 800 mg daily (n=200), dasatinib 50 mg twice daily or 100 mg daily (n=106), or nilotinib 400 mg twice daily (n=108). More patients receiving imatinib 800 mg or second-generation TKIs (ie, dasatinib or nilotinib) achieved complete cytogenetic response (58 [87%] of 67 for imatinib 400 mg vs 180 [90%] of 199 for imatinib 800 mg, vs 100 [96%] of 104 for dasatinib vs 99 [93%] of 107 for nilotinib), major molecular response (51 [76%] vs 171 [86%] vs 93 [90%] vs 97 [91%]), and 4·5 log or higher reduction in BCR-ABL transcripts (MR4·5 response 38 [57%] vs 148 [74%] vs 76 [71%] vs 76 [71%]). This finding was consistent over time (3-60 months). 5-year event free survival significantly differed between the imatinib 400 mg group and the other TKI groups (imatinib 800 mg p=0·029, dasatinib p=0·003, nilotinib p=0·031). There was no significant difference in 5-year failure-free survival (p=0·32, p=0·075, p=0·332), transformation-free survival (p=0·053, p=0·038, p=0·493), or overall survival (p=0·563, p=0·162, p=0·981). Multivariate analysis showed that therapy with imatinib 800 mg (HR 0·51, 95% CI 0·29-0·88, p=0·016), dasatinib (0·28, 0·12-0·66, p=0·004), or nilotinib (0·42, 0·20-0·89, p=0·024) predicted for better event-free survival compared with imatinib 400 mg, but that failure-free, transformation-free, and overall survival were similar irrespective of the TKI used. 28 (41%) patients receiving imatinib 400 mg, 85 (43%) receiving imatinib 800 mg, 23 (21%) receiving dasatinib, and 27 (25%) receiving nilotinib discontinued treatment for any reason. INTERPRETATION: Treatment with imatinib 800 mg or the second-generation TKIs dasatinib or nilotinib resulted in superior and deeper responses than did standard-dose imatinib, which were maintained after 5 years of follow-up. Results with imatinib 800 mg were similar to those with second-generation TKIs, although more patients discontinued therapy. FUNDING: MD Anderson Cancer Center, National Cancer Institute.

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