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Cancers
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Advances in Pediatric Acute Myeloid Leukemia
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Advances in Pediatric Acute Myeloid Leukemia

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Pediatric Oncology".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 9373

Special Issue Editors

Dr. Todd M. Cooper

E-Mail Website
Guest Editor
Division of Hematology/Oncology, Cancer and Blood Disorders Center, Seattle Children’s Hospital, Seattle, WA 98105, USA
Interests: pediatric hematology
Dr. Edward A. Kolb

E-Mail Website
Guest Editor
Nemours Center for Cancer and Blood Disorders/Nemours Children’s Health, Wilmington, DE 19803, USA
Interests: hematology; leukemia
Dr. Branko Cuglievan

E-Mail Website
Guest Editor
Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Interests: acute myeloid leukemia

Special Issue Information

Dear Colleagues, 

The overall survival of children with acute myeloid leukemia (AML) remains near 70% using maximally toxic chemotherapy, allogeneic hematopoietic stem-cell transplantation (HSCT), and optimal supportive care measures. Incorporating cytogenetics and molecular profiling and detecting minimal residual disease after induction therapy has enabled risk stratification to tailor treatment intensity. Patients with favorable or undefined molecular signatures require 4 or 5 courses of an anthracycline- and cytarabine-based regimen to achieve a cure, and those with high-risk mutations undergo allogeneic HSCT. Patients who relapse require re-induction with salvage chemotherapy, in the hopes of attaining complete remission and undergoing HSCT again. Survivors are cancer-free but likely have long-term health complications of treatment.

In this special issue, we plan to put out an open call for papers amongst our colleagues nationally and internationally. Among those manuscripts we hope to cover the following topics:

  • Provide updates on current therapy for childhood AML
  • Share updated risk stratification
  • Propose international definitions for response criteria
  • Report on identification of novel molecular targets
  • Review novel approaches to high-risk and relapse therapy
  • Review approaches to enhance T-cell immune responses
  • Review updates on transplant approaches and post-transplant maintenance therapies
  • Advancing infectious and cardioprotective supportive care
  • Developing innovative strategies to improve the survival and long-term side effects in the adolescent and young adult populations.

Progress in these areas will be vital in our mission to discover better therapeutic strategies for children with this aggressive disease.

Dr. Todd M. Cooper
Dr. Edward A. Kolb
Dr. Branko Cuglievan
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • acute myeloid leukemia

  • pediatrics
  • adolescent and young adults
  • chemotherapy
  • transplantation
  • maintenance
  • supportive care
  • toxicities
  • bone marrow microenviroment
  • epigenetics
  • immunotherapies

Published Papers (4 papers)

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Research

19 pages, 2222 KiB  
Article
Characteristics and Outcome of FLT3-ITD-Positive Pediatric Acute Myeloid Leukemia—Experience of Polish Pediatric Leukemia and Lymphoma Study Group from 2005 to 2022
by Małgorzata Czogała, Wojciech Czogała, Katarzyna Pawińska-Wąsikowska, Teofila Książek, Karolina Bukowska-Strakova, Barbara Sikorska-Fic, Paweł Łaguna, Anna Fałkowska, Katarzyna Drabko, Katarzyna Muszyńska-Rosłan, Maryna Krawczuk-Rybak, Marta Kozłowska, Ninela Irga-Jaworska, Karolina Zielezińska, Tomasz Urasiński, Natalia Bartoszewicz, Jan Styczyński, Jolanta Skalska-Sadowska, Jacek Wachowiak, Anna Rodziewicz-Konarska, Krzysztof Kałwak, Małgorzata Ciebiera, Radosław Chaber, Agnieszka Mizia-Malarz, Agnieszka Chodała-Grzywacz, Grażyna Karolczyk, Katarzyna Bobeff, Wojciech Młynarski, Katarzyna Mycko, Wanda Badowska, Renata Tomaszewska, Tomasz Szczepański, Katarzyna Machnik, Natalia Zamorska, Walentyna Balwierz and Szymon Skoczeńadd Show full author list remove Hide full author list
Cancers 2023, 15(18), 4557; https://doi.org/10.3390/cancers15184557 - 14 Sep 2023
Cited by 1 | Viewed by 1211
Abstract
Background: The FMS-like tyrosine kinase 3 (FLT3) gene mutated in 10–15% of pediatric acute myeloid leukemia (AML) is associated with an inferior outcome. The aim of the study was to analyze the outcome and characteristics of FLT3-ITD-positive pediatric AML. Methods: We retrospectively analyzed [...] Read more.
Background: The FMS-like tyrosine kinase 3 (FLT3) gene mutated in 10–15% of pediatric acute myeloid leukemia (AML) is associated with an inferior outcome. The aim of the study was to analyze the outcome and characteristics of FLT3-ITD-positive pediatric AML. Methods: We retrospectively analyzed the nationwide pediatric AML database from between 2005 and 2022. FLT3-ITD was found in 54/497 (10.7%) patients with available analysis. Three consecutive treatment protocols were used (AML-BFM 2004 Interim, AML-BFM 2012 Registry, AML-BFM 2019 recommendations). Results: Probabilities of 5-year overall (OS), event-free (EFS) and relapse-free survival were significantly lower in the FLT3-ITD-positive patients compared to FLT3-ITD-negative (0.54 vs. 0.71, p = 0.041; 0.36 vs. 0.59, p = 0.0004; 0.47 vs. 0.70, p = 0.0029, accordingly). An improvement in the outcome was found in the analyzed period of time, with a trend of better survival in patients treated under the AML-BFM 2012 and AML-BFM 2019 protocols compared to the AML-BFM 2004 protocol (5-year EFS 0.52 vs. 0.27, p = 0.069). There was a trend of improved outcomes in patients treated with FLT3 inhibitors (n = 9, 2-year EFS 0.67 vs. 0.33, p = 0.053) and those who received stem cell transplantation (SCT) (n = 26; 5-year EFS 0.70 vs. 0.27, p = 0.059). The co-occurrence of the WT1 mutation had a dismal impact on the prognosis (5-year EFS 0.23 vs. 0.69, p = 0.002), while the NPM1 mutation improved survival (5-year OS 1.0 vs. 0.44, p = 0.036). Conclusions: It seems that SCT and FLT3 inhibitors have a beneficial impact on the prognosis. Additional genetic alterations, like the WT1 and NPM1 mutations, significantly influence the outcome. Full article
(This article belongs to the Special Issue Advances in Pediatric Acute Myeloid Leukemia)
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15 pages, 743 KiB  
Article
Venetoclax for Acute Myeloid Leukemia in Pediatric Patients: A Texas Medical Center Experience
by Adriana Trabal, Amber Gibson, Jiasen He, David McCall, Michael Roth, Cesar Nuñez, Miriam Garcia, Meredith Buzbee, Laurie Toepfer, Aram Bidikian, Naval Daver, Tapan Kadia, Nicholas J. Short, Ghayas C. Issa, Farhad Ravandi, Courtney D. DiNardo, Guillermo Montalban Bravo, Sofia Garces, Andrea Marcogliese, Hana Paek, Zoann Dreyer, Julienne Brackett, Michele Redell, Joanna Yi, Guillermo Garcia-Manero, Marina Konopleva, Alexandra Stevens and Branko Cuglievanadd Show full author list remove Hide full author list
Cancers 2023, 15(7), 1983; https://doi.org/10.3390/cancers15071983 - 26 Mar 2023
Cited by 8 | Viewed by 2976
Abstract
The BCL-2 inhibitor venetoclax improves survival for adult patients with acute myeloid leukemia (AML) in combination with lower-intensity therapies, but its benefit in pediatric patients with AML remains unclear. We retrospectively reviewed two Texas Medical Center institutions’ experience with venetoclax in 43 pediatric [...] Read more.
The BCL-2 inhibitor venetoclax improves survival for adult patients with acute myeloid leukemia (AML) in combination with lower-intensity therapies, but its benefit in pediatric patients with AML remains unclear. We retrospectively reviewed two Texas Medical Center institutions’ experience with venetoclax in 43 pediatric patients with AML; median age 17 years (range, 0.6–21). This population was highly refractory; 44% of patients (n = 19) had ≥3 prior lines of therapy, 37% (n = 16) had received a prior bone marrow transplant, and 81% (n = 35) had unfavorable genetics KMT2A (n = 17), WT1 (n = 13), FLT3-ITD (n = 10), monosomy 7 (n = 5), TP53 (n = 3), Inv(3) (n = 3), IDH1/2 (n = 2), monosomy 5 (n = 1), NUP98 (n = 1) and ASXL1 (n = 1). The majority (86%) received venetoclax with a hypomethylating agent. Grade 3 or 4 adverse events included febrile neutropenia in 37% (n = 16), non-febrile neutropenia in 12% (n = 5), anemia in 14% (n = 6), and thrombocytopenia in 14% (n = 6). Of 40 patients evaluable for response, 10 patients (25%) achieved complete response (CR), 6 patients (15%) achieved CR with incomplete blood count recovery (CRi), and 2 patients (5%) had a partial response, (CR/CRi composite = 40%; ORR = 45%). Eleven (25%) patients received a hematopoietic stem cell transplant following venetoclax combination therapy, and six remain alive (median follow-up time 33.6 months). Median event-free survival and overall survival duration was 3.7 months and 8.7 months, respectively. Our findings suggest that in pediatric patients with AML, venetoclax is well-tolerated, with a safety profile similar to that in adults. More studies are needed to establish an optimal venetoclax-based regimen for the pediatric population. Full article
(This article belongs to the Special Issue Advances in Pediatric Acute Myeloid Leukemia)
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19 pages, 3604 KiB  
Article
Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional Chemotherapy Is Feasible and Well Tolerated
by Alexandra McLean Stevens, Eric S. Schafer, Minhua Li, Maci Terrell, Raushan Rashid, Hana Paek, Melanie B. Bernhardt, Allison Weisnicht, Wesley T. Smith, Noah J. Keogh, Michelle C. Alozie, Hailey H. Oviedo, Alan K. Gonzalez, Tamilini Ilangovan, Alicia Mangubat-Medina, Haopei Wang, Eunji Jo, Cara A. Rabik, Claire Bocchini, Susan Hilsenbeck, Zachary T. Ball, Todd M. Cooper and Michele S. Redelladd Show full author list remove Hide full author list
Cancers 2023, 15(4), 1344; https://doi.org/10.3390/cancers15041344 - 20 Feb 2023
Cited by 4 | Viewed by 2214
Abstract
Survival of pediatric AML remains poor despite maximized myelosuppressive therapy. The pneumocystis jiroveci pneumonia (PJP)-treating medication atovaquone (AQ) suppresses oxidative phosphorylation (OXPHOS) and reduces AML burden in patient-derived xenograft (PDX) mouse models, making it an ideal concomitant AML therapy. Poor palatability and limited [...] Read more.
Survival of pediatric AML remains poor despite maximized myelosuppressive therapy. The pneumocystis jiroveci pneumonia (PJP)-treating medication atovaquone (AQ) suppresses oxidative phosphorylation (OXPHOS) and reduces AML burden in patient-derived xenograft (PDX) mouse models, making it an ideal concomitant AML therapy. Poor palatability and limited product formulations have historically limited routine use of AQ in pediatric AML patients. Patients with de novo AML were enrolled at two hospitals. Daily AQ at established PJP dosing was combined with standard AML therapy, based on the Medical Research Council backbone. AQ compliance, adverse events (AEs), ease of administration score (scale: 1 (very difficult)-5 (very easy)) and blood/marrow pharmacokinetics (PK) were collected during Induction 1. Correlative studies assessed AQ-induced apoptosis and effects on OXPHOS. PDX models were treated with AQ. A total of 26 patients enrolled (ages 7.2 months–19.7 years, median 12 years); 24 were evaluable. A total of 14 (58%) and 19 (79%) evaluable patients achieved plasma concentrations above the known anti-leukemia concentration (>10 µM) by day 11 and at the end of Induction, respectively. Seven (29%) patients achieved adequate concentrations for PJP prophylaxis (>40 µM). Mean ease of administration score was 3.8. Correlative studies with AQ in patient samples demonstrated robust apoptosis, OXPHOS suppression, and prolonged survival in PDX models. Combining AQ with chemotherapy for AML appears feasible and safe in pediatric patients during Induction 1 and shows single-agent anti-leukemic effects in PDX models. AQ appears to be an ideal concomitant AML therapeutic but may require intra-patient dose adjustment to achieve concentrations sufficient for PJP prophylaxis. Full article
(This article belongs to the Special Issue Advances in Pediatric Acute Myeloid Leukemia)
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16 pages, 14000 KiB  
Article
Ex Vivo Drug Sensitivity Correlates with Clinical Response and Supports Personalized Therapy in Pediatric AML
by Debbie C. Strachan, Christine J. Gu, Ryosuke Kita, Erica K. Anderson, Michelle A. Richardson, George Yam, Graham Pimm, Jordan Roselli, Alyssa Schweickert, Maci Terrell, Raushan Rashid, Alan K. Gonzalez, Hailey H. Oviedo, Michelle C. Alozie, Tamilini Ilangovan, Andrea N. Marcogliese, Hiroomi Tada, Marianne T. Santaguida and Alexandra M. Stevens
Cancers 2022, 14(24), 6240; https://doi.org/10.3390/cancers14246240 - 18 Dec 2022
Cited by 2 | Viewed by 2361
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease that accounts for ~20% of all childhood leukemias, and more than 40% of children with AML relapse within three years of diagnosis. Although recent efforts have focused on developing a precise medicine-based approach towards treating [...] Read more.
Acute myeloid leukemia (AML) is a heterogeneous disease that accounts for ~20% of all childhood leukemias, and more than 40% of children with AML relapse within three years of diagnosis. Although recent efforts have focused on developing a precise medicine-based approach towards treating AML in adults, there remains a critical gap in therapies designed specifically for children. Here, we present ex vivo drug sensitivity profiles for children with de novo AML using an automated flow cytometry platform. Fresh diagnostic blood or bone marrow aspirate samples were screened for sensitivity in response to 78 dose conditions by measuring the reduction in leukemic blasts relative to the control. In pediatric patients treated with conventional chemotherapy, comprising cytarabine, daunorubicin and etoposide (ADE), ex vivo drug sensitivity results correlated with minimal residual disease (r = 0.63) and one year relapse-free survival (r = 0.70; AUROC = 0.94). In the de novo ADE analysis cohort of 13 patients, AML cells showed greater sensitivity to bortezomib/panobinostat compared with ADE, and comparable sensitivity between venetoclax/azacitidine and ADE ex vivo. Two patients showed a differential response between ADE and bortezomib/panobinostat, thus supporting the incorporation of ex vivo drug sensitivity testing in clinical trials to further evaluate the predictive utility of this platform in children with AML. Full article
(This article belongs to the Special Issue Advances in Pediatric Acute Myeloid Leukemia)
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