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. 2023 Dec 1:10:1286241.
doi: 10.3389/fcvm.2023.1286241. eCollection 2023.

Rationale and design of the Children's Oncology Group study AAML1831 integrated cardiac substudies in pediatric acute myeloid leukemia therapy

Kasey J Leger  1 , Nora Robison  1 , Hari K Narayan  2 , Amanda M Smith  3 , Tenaadam Tsega  3 , Jade Chung  3 , Amber Daniels  3 , Zhen Chen  3 , Virginia Englefield  3 , Biniyam G Demissei  3 , Benedicte Lefebvre  3 , Gemma Morrow  4 , Ilona Dizon  5 , Robert B Gerbing  6 , Reena Pabari  7 , Kelly D Getz  8 , Richard Aplenc  8 , Jessica A Pollard  9   10 , Eric J Chow  1   11 , W H Wilson Tang  12 , William L Border  4   13 , Ritu Sachdeva  4   13 , Todd A Alonzo  6   14 , E Anders Kolb  15 , Todd M Cooper  1 , Bonnie Ky  3
Affiliations

Rationale and design of the Children's Oncology Group study AAML1831 integrated cardiac substudies in pediatric acute myeloid leukemia therapy

Kasey J Leger et al. Front Cardiovasc Med. .

Abstract

Background: Pediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline exposure. Early left ventricular systolic dysfunction (LVSD) compromises anthracycline delivery and is associated with inferior event-free and overall survival in de novo pediatric AML. Thus, effective cardioprotective strategies and cardiotoxicity risk predictors are critical to optimize cancer therapy delivery and enable early interventions to prevent progressive LVSD. While dexrazoxane-based cardioprotection reduces short-term cardiotoxicity without compromising cancer survival, liposomal anthracycline formulations have the potential to mitigate cardiotoxicity while improving antitumor efficacy. This overview summarizes the rationale and methodology of cardiac substudies within AAML1831, a randomized Children's Oncology Group Phase 3 study of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in comparison with standard daunorubicin/cytarabine with dexrazoxane in the treatment of de novo pediatric AML.

Methods/design: Children (age <22 years) with newly diagnosed AML were enrolled and randomized to CPX-351-containing induction 1 and 2 (Arm A) or standard daunorubicin and dexrazoxane-containing induction (Arm B). Embedded cardiac correlative studies aim to compare the efficacy of this liposomal anthracycline formulation to dexrazoxane for primary prevention of cardiotoxicity by detailed core lab analysis of standardized echocardiograms and serial cardiac biomarkers throughout AML therapy and in follow-up. In addition, AAML1831 will assess the ability of early changes in sensitive echo indices (e.g., global longitudinal strain) and cardiac biomarkers (e.g., troponin and natriuretic peptides) to predict subsequent LVSD. Finally, AAML1831 establishes expert consensus-based strategies in cardiac monitoring and anthracycline dose modification to balance the potentially competing priorities of cardiotoxicity reduction with optimal leukemia therapy.

Discussion: This study will inform diagnostic, prognostic, preventative, and treatment strategies regarding cardiotoxicity during pediatric AML therapy. Together, these measures have the potential to improve leukemia-free and overall survival and long-term cardiovascular health in children with AML. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04293562.

Keywords: CPX-351; cardiac biomarkers; cardiotoxicity; dexrazoxane; liposomal anthracycline; pediatric acute myeloid leukemia (AML); risk prediction.

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Conflict of interest statement

KL, Jazz Pharmaceuticals (consulting, advisory board participation); KL and EC, Abbott Diagnostics (research funding). The reviewer YR declared a shared committee COG with the authors to the handling editor. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
AAML1831 study schematic. AE, cytarabine/etoposide; Allo, allogeneic; AR, allelic ratio; DA, daunorubicin/cytarabine; DL, dose level, Gilt, gilteritinib; GO, gemtuzumab ozogamicin; HDAC, high-dose cytarabine/asparaginase (Capizzi II); HSCT, hematopoietic stem cell transplant; Ind, induction; Int, intensification; ITD, internal tandem duplication; MA, mitoxantrone/cytarabine; Maint, maintenance.
Figure 2
Figure 2
AAML1831 cardiac studies schematic. Cardiac biomarker and echocardiogram time points for subjects treated on Arms A/B (without concurrent gilteritinib). Anthracycline agents are denoted in blue. AE, cytarabine/etoposide; Allo, allogeneic; BL, baseline; DA, daunorubicin/cytarabine; GO, gemtuzumab ozogamicin; HDAC, high-dose cytarabine/asparaginase (Capizzi II); HSCT, hematopoietic stem cell transplant; Ind, induction; Int, intensification; MA, mitoxantrone/cytarabine.
Figure 3
Figure 3
Approach to anthracycline/anthracenedione (AC) dose modification for left ventricular systolic dysfunction (LVSD) on AAML1831. 1EF should be measured by the biplane Simpson's method. If unevaluable, use alternate EF measurement. If EF is unevaluable, use the shortening fraction (SF) threshold of SF < 24%. 2Only relevant to AC-containing cycles. For low EF prior to non-AC cycles, may proceed with therapy. Recommend cardiology consultation for consideration of cardiac remodeling medications to support cardiac function. 3For patients with persistent LVSD, cardiology consultation is strongly recommended for consideration of cardiac remodeling medications to support the recovery of cardiac function.
See this image and copyright information in PMC

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