High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial

Johann Hitzler; Todd Alonzo; Robert Gerbing; Amy Beckman; Betsy Hirsch; Susana Raimondi; Karen Chisholm; Shelton Viola; Lisa Brodersen; Michael Loken; Spencer Tong; Todd Druley; Maureen O'Brien; Nobuko Hijiya; Amy Heerema-McKenney; Yi Chang Wang; Reuven Shore; Jeffrey Taub; Alan Gamis; E. Anders Kolb; Jason N. Berman

doi:10.1182/blood.2021012206

High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial

Johann Hitzler, Todd Alonzo, Robert Gerbing, Amy Beckman, Betsy Hirsch, Susana Raimondi, Karen Chisholm, Shelton Viola, Lisa Brodersen, Michael Loken, Spencer Tong, Todd Druley, Maureen O'Brien, Nobuko Hijiya, Amy Heerema-McKenney, Yi Chang Wang, Reuven Shore, Jeffrey Taub, Alan Gamis, E. Anders KolbJason N. Berman

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children's Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (<0.05%) and did not receive the historically administered HD-AraC course. Interim analysis of 114 SR patients revealed a 2-year EFS of 85.6% (95% confidence interval [CI], 75.7-95.5), which was significantly lower than for MRD⁻ patients treated with HD-AraC on AAML0431 (P = .0002). Overall survival at 2 years was 91.0% (95% CI, 83.8-95.0). Twelve SR patients relapsed, mostly within 1 year from study entry and had a 1-year OS of 16.7% (95% CI, 2.7-41.3). Complex karyotypes were more frequent in SR patients who relapsed compared with those who did not (36% vs 9%; P = .0248). MRD by error-corrected sequencing of GATA1 mutations was piloted in 18 SR patients and detectable in 60% who relapsed vs 23% who did not (P = .2682). Patients with SR ML-DS had worse outcomes without HD-AraC after risk classification based on flow cytometric MRD.

Original language	English (US)
Pages (from-to)	2337-2346
Number of pages	10
Journal	Blood
Volume	138
Issue number	23
DOIs	https://doi.org/10.1182/blood.2021012206
State	Published - Dec 9 2021

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health National Clinical Trials Network (NCTN) Operations Center, National Cancer Institute (U10CA180886), National Clinical Trials Network (NCTN) Statistics & Data Center (U10CA180899), and the St Baldrick's Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
The authors thank Vani Shanker for her constructive review of the manuscript. This work was supported by grants from the National Institutes of Health National Clinical Trials Network (NCTN) Operations Center, National Cancer Institute (U10CA180886), National Clinical Trials Network (NCTN) Statistics & Data Center (U10CA180899), and the St Baldrick's Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2021 American Society of Hematology

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Hitzler, J., Alonzo, T., Gerbing, R., Beckman, A., Hirsch, B., Raimondi, S., Chisholm, K., Viola, S., Brodersen, L., Loken, M., Tong, S., Druley, T., O'Brien, M., Hijiya, N., Heerema-McKenney, A., Wang, Y. C., Shore, R., Taub, J., Gamis, A., ... Berman, J. N. (2021). High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial. Blood, 138(23), 2337-2346. https://doi.org/10.1182/blood.2021012206

Hitzler, J, Alonzo, T, Gerbing, R, Beckman, A , Hirsch, B, Raimondi, S, Chisholm, K, Viola, S, Brodersen, L, Loken, M, Tong, S, Druley, T, O'Brien, M, Hijiya, N, Heerema-McKenney, A, Wang, YC, Shore, R, Taub, J, Gamis, A, Kolb, EA & Berman, JN 2021, 'High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial', Blood, vol. 138, no. 23, pp. 2337-2346. https://doi.org/10.1182/blood.2021012206

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abstract = "Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children's Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (<0.05%) and did not receive the historically administered HD-AraC course. Interim analysis of 114 SR patients revealed a 2-year EFS of 85.6% (95% confidence interval [CI], 75.7-95.5), which was significantly lower than for MRD− patients treated with HD-AraC on AAML0431 (P = .0002). Overall survival at 2 years was 91.0% (95% CI, 83.8-95.0). Twelve SR patients relapsed, mostly within 1 year from study entry and had a 1-year OS of 16.7% (95% CI, 2.7-41.3). Complex karyotypes were more frequent in SR patients who relapsed compared with those who did not (36% vs 9%; P = .0248). MRD by error-corrected sequencing of GATA1 mutations was piloted in 18 SR patients and detectable in 60% who relapsed vs 23% who did not (P = .2682). Patients with SR ML-DS had worse outcomes without HD-AraC after risk classification based on flow cytometric MRD.",

author = "Johann Hitzler and Todd Alonzo and Robert Gerbing and Amy Beckman and Betsy Hirsch and Susana Raimondi and Karen Chisholm and Shelton Viola and Lisa Brodersen and Michael Loken and Spencer Tong and Todd Druley and Maureen O'Brien and Nobuko Hijiya and Amy Heerema-McKenney and Wang, {Yi Chang} and Reuven Shore and Jeffrey Taub and Alan Gamis and Kolb, {E. Anders} and Berman, {Jason N.}",

note = "Funding Information: This work was supported by grants from the National Institutes of Health National Clinical Trials Network (NCTN) Operations Center, National Cancer Institute (U10CA180886), National Clinical Trials Network (NCTN) Statistics & Data Center (U10CA180899), and the St Baldrick's Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: The authors thank Vani Shanker for her constructive review of the manuscript. This work was supported by grants from the National Institutes of Health National Clinical Trials Network (NCTN) Operations Center, National Cancer Institute (U10CA180886), National Clinical Trials Network (NCTN) Statistics & Data Center (U10CA180899), and the St Baldrick's Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2021 American Society of Hematology",

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T1 - High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD

T2 - results of the COG AAML1531 trial

AU - Hitzler, Johann

AU - Alonzo, Todd

AU - Gerbing, Robert

AU - Beckman, Amy

AU - Hirsch, Betsy

AU - Raimondi, Susana

AU - Chisholm, Karen

AU - Viola, Shelton

AU - Brodersen, Lisa

AU - Loken, Michael

AU - Tong, Spencer

AU - Druley, Todd

AU - O'Brien, Maureen

AU - Hijiya, Nobuko

AU - Heerema-McKenney, Amy

AU - Wang, Yi Chang

AU - Shore, Reuven

AU - Taub, Jeffrey

AU - Gamis, Alan

AU - Kolb, E. Anders

AU - Berman, Jason N.

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Y1 - 2021/12/9

N2 - Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children's Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (<0.05%) and did not receive the historically administered HD-AraC course. Interim analysis of 114 SR patients revealed a 2-year EFS of 85.6% (95% confidence interval [CI], 75.7-95.5), which was significantly lower than for MRD− patients treated with HD-AraC on AAML0431 (P = .0002). Overall survival at 2 years was 91.0% (95% CI, 83.8-95.0). Twelve SR patients relapsed, mostly within 1 year from study entry and had a 1-year OS of 16.7% (95% CI, 2.7-41.3). Complex karyotypes were more frequent in SR patients who relapsed compared with those who did not (36% vs 9%; P = .0248). MRD by error-corrected sequencing of GATA1 mutations was piloted in 18 SR patients and detectable in 60% who relapsed vs 23% who did not (P = .2682). Patients with SR ML-DS had worse outcomes without HD-AraC after risk classification based on flow cytometric MRD.

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High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial

Abstract

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