Maintenance Therapy With Interleukin‐2 for Childhood AML

Petit, Arnaud; Ducassou, Stéphane; Leblanc, Thierry; Pasquet, Marlène; Rousseau, Alexandra; Ragu, Christine; Cachanado, Marine; Nelken, Brigitte; Bertrand, Yves; Gautier, Michel; Gandemer, Virginie; Cuccuini, Wendy; Fenneteau, Odile; Lapillonne, Hélène; Auvrignon, Anne; Baruchel, André; Leverger, Guy

doi:10.1097/hs9.0000000000000159

Cited by 23 publications

(13 citation statements)

References 55 publications

(115 reference statements)

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“…We first screened a cohort of 276 pediatric patients with leukemia (37) for the presence of EG and confirmed that EG occurred in patients with AMKL and other AML (AML-M0 to AML-M5) subtypes (12), with an overall incidence of 4.7% (Fig. 1A and B; Supplementary Table S1; Supplementary Fig.…”

Section: Amkl Is Diagnosed At a Younger Age Than Aml In Pediatric Patientsmentioning

confidence: 81%

Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia

et al. 2019

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Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specifi c associations between age and phenotype. We observed that fusion oncogenes, such as ETO2-GLIS2 , are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2-GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and singlecell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2-GLIS2 -induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. SIGNIFICANCE:This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state.

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Section: Amkl Is Diagnosed At a Younger Age Than Aml In Pediatric Patientsmentioning

confidence: 81%

Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia

et al. 2019

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“…The randomized ELAM02 phase III trial evaluated whether the use of interleukin-2 after consolidation therapy would improve disease-free survival for newly diagnosed children with AML. Unfortunately, no differences in diseasefree and overall survival were observed between the intervention and control arm [60]. Similarly, two phase II clinical trials reported no improvements in disease-free and overall survival with expanded NK-cell infusions after consolidation therapy for newly diagnosed pediatric AML [61,62].…”

Section: Immune Cells In the Tme During And After Therapymentioning

confidence: 98%

“…To date, few clinical trials have assessed the role of immunotherapy as maintenance therapy for children with AML [60][61][62]. The randomized ELAM02 phase III trial evaluated whether the use of interleukin-2 after consolidation therapy would improve disease-free survival for newly diagnosed children with AML.…”

Section: Immune Cells In the Tme During And After Therapymentioning

confidence: 99%

Paving the Way for Immunotherapy in Pediatric Acute Myeloid Leukemia: Current Knowledge and the Way Forward

Koedijk

Werf

Calkoen

et al. 2021

Cancers

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Immunotherapeutic agents may be an attractive option to further improve outcomes and to reduce treatment-related toxicity for pediatric AML. While improvements in outcome have been observed with immunotherapy in many cancer types, immunotherapy development and implementation into patient care for both adult and pediatric AML has been hampered by an incomplete understanding of the bone marrow environment and a paucity of tumor-specific antigens. Since only a minority of patients respond in most immunotherapy trials across different cancer types, it will be crucial to understand which children with AML are likely to respond to or may benefit from immunotherapies. Immune cell profiling efforts hold promise to answer this question, as illustrated by the development of predictive scores in solid cancers. Such information on the number and phenotype of immune cells during current treatment regimens will be pivotal to generate hypotheses on how and when to intervene with immunotherapy in pediatric AML. In this review, we discuss the current understanding of the number and phenotype of immune cells in the bone marrow in pediatric AML, ongoing immunotherapy trials and how comprehensive immune profiling efforts may pave the way for successful clinical trials (and, ultimately, implementation into patient care).

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“…Cytokine therapy with interleukin-2 (IL-2) and interferon alpha (IFNa) have also been studied in a number of RCTs. Seven major RCTs have evaluated the role of IL-2 as maintenance therapy in patients with AML compared with observation (55)(56)(57)(58)(59)(60)(61). A patient level meta-analysis of six studies was performed in 2011 (62) and updated in 2015 ( 63), showed no benefit in terms of DFS or OS with this approach, as did the seventh trial published in 2018.…”

Section: Maintenance Immunotherapiesmentioning

confidence: 99%

Maintenance Therapy in AML

Reville

Kadia

2021

Front. Oncol.

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Recent advances in therapeutics coupled with steady improvements in supportive care for patients with acute myeloid leukemia (AML) have led to improved outcomes. Despite these advances, even in patients that achieve a complete remission with initial therapy high rates of relapse remain a clinical dilemma. For decades, investigators have attempted strategies of maintenance therapy to prolong both remission duration and overall survival in patients with AML. These approaches have included cytotoxic chemotherapy, immunotherapy, hypomethylating agents, and targeted small molecule therapy. Overall, the evidence in favor of maintenance therapy is limited. Recent strategies, especially with hypomethylating agents have begun to show promise as maintenance therapy in improving clinical outcomes. Ongoing and future studies will continue to elucidate the true role for maintenance therapy options in patients with AML. In this review we summarize prior and ongoing maintenance therapy approaches in AML and highlight some of the most promising strategies.

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Maintenance Therapy With Interleukin‐2 for Childhood AML

Abstract: Supplemental Digital Content is available in the text

Cited by 23 publications

References 55 publications

Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia

Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia

Paving the Way for Immunotherapy in Pediatric Acute Myeloid Leukemia: Current Knowledge and the Way Forward

Maintenance Therapy in AML

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