Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia

Kenneth F. Bradstock, Emma Link, Juliana Di Iulio, Jeff Szer, Paula Marlton, Andrew Wei, Arno Enno, Anthony Schwarer, Ian D. Lewis, James D. Rozario, Luke Coyle, Gavin Cull, Phillip Campbell, Michael F. Leahy, Uwe H. Hahn, Paul Cannell, Campbell Tiley, Ray M. Lowenthal, John Moore, Kimberly Cartwright

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Purpose
Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy.

Patients and Methods
Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms,respectively). The primary end point was leukemia-free survival (LFS).

Results
Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation(P , .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95%CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm (P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups.

Conclusion
An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.
Original languageEnglish
Pages (from-to)1678 - 1685
Number of pages8
JournalJournal of Clinical Oncology
Volume35
Issue number15
DOIs
Publication statusPublished - 20 May 2017

Cite this

Bradstock, K. F., Link, E., Di Iulio, J., Szer, J., Marlton, P., Wei, A., ... Cartwright, K. (2017). Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia. Journal of Clinical Oncology, 35(15), 1678 - 1685. https://doi.org/10.1200/JCO.2016.70.6374
Bradstock, Kenneth F. ; Link, Emma ; Di Iulio, Juliana ; Szer, Jeff ; Marlton, Paula ; Wei, Andrew ; Enno, Arno ; Schwarer, Anthony ; Lewis, Ian D. ; Rozario, James D. ; Coyle, Luke ; Cull, Gavin ; Campbell, Phillip ; Leahy, Michael F. ; Hahn, Uwe H. ; Cannell, Paul ; Tiley, Campbell ; Lowenthal, Ray M. ; Moore, John ; Cartwright, Kimberly. / Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 15. pp. 1678 - 1685.
@article{4c41638a28a44644a696f679be8f3870,
title = "Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia",
abstract = "PurposeHigher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy.Patients and MethodsPatients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms,respectively). The primary end point was leukemia-free survival (LFS).ResultsTwo hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82{\%}) and 95 patients in the intensive arm (65{\%}) completed planned consolidation(P , .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47{\%} [95{\%} CI, 40{\%} to 56{\%}] v 35{\%} [95{\%}CI, 28{\%} to 44{\%}]; P = .045). At 5 years, the overall survival rate was 57{\%} in the intensive arm and 47{\%} in the standard arm (P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups.ConclusionAn increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.",
author = "Bradstock, {Kenneth F.} and Emma Link and {Di Iulio}, Juliana and Jeff Szer and Paula Marlton and Andrew Wei and Arno Enno and Anthony Schwarer and Lewis, {Ian D.} and Rozario, {James D.} and Luke Coyle and Gavin Cull and Phillip Campbell and Leahy, {Michael F.} and Hahn, {Uwe H.} and Paul Cannell and Campbell Tiley and Lowenthal, {Ray M.} and John Moore and Kimberly Cartwright",
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language = "English",
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pages = "1678 -- 1685",
journal = "Journal of Clinical Oncology",
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Bradstock, KF, Link, E, Di Iulio, J, Szer, J, Marlton, P, Wei, A, Enno, A, Schwarer, A, Lewis, ID, Rozario, JD, Coyle, L, Cull, G, Campbell, P, Leahy, MF, Hahn, UH, Cannell, P, Tiley, C, Lowenthal, RM, Moore, J & Cartwright, K 2017, 'Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia' Journal of Clinical Oncology, vol. 35, no. 15, pp. 1678 - 1685. https://doi.org/10.1200/JCO.2016.70.6374

Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia. / Bradstock, Kenneth F.; Link, Emma; Di Iulio, Juliana; Szer, Jeff; Marlton, Paula; Wei, Andrew; Enno, Arno; Schwarer, Anthony; Lewis, Ian D.; Rozario, James D.; Coyle, Luke; Cull, Gavin; Campbell, Phillip; Leahy, Michael F.; Hahn, Uwe H.; Cannell, Paul; Tiley, Campbell; Lowenthal, Ray M.; Moore, John; Cartwright, Kimberly.

In: Journal of Clinical Oncology, Vol. 35, No. 15, 20.05.2017, p. 1678 - 1685.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia

AU - Bradstock, Kenneth F.

AU - Link, Emma

AU - Di Iulio, Juliana

AU - Szer, Jeff

AU - Marlton, Paula

AU - Wei, Andrew

AU - Enno, Arno

AU - Schwarer, Anthony

AU - Lewis, Ian D.

AU - Rozario, James D.

AU - Coyle, Luke

AU - Cull, Gavin

AU - Campbell, Phillip

AU - Leahy, Michael F.

AU - Hahn, Uwe H.

AU - Cannell, Paul

AU - Tiley, Campbell

AU - Lowenthal, Ray M.

AU - Moore, John

AU - Cartwright, Kimberly

PY - 2017/5/20

Y1 - 2017/5/20

N2 - PurposeHigher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy.Patients and MethodsPatients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms,respectively). The primary end point was leukemia-free survival (LFS).ResultsTwo hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation(P , .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95%CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm (P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups.ConclusionAn increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.

AB - PurposeHigher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy.Patients and MethodsPatients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms,respectively). The primary end point was leukemia-free survival (LFS).ResultsTwo hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation(P , .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95%CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm (P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups.ConclusionAn increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.

U2 - 10.1200/JCO.2016.70.6374

DO - 10.1200/JCO.2016.70.6374

M3 - Article

VL - 35

SP - 1678

EP - 1685

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 15

ER -