Azacitidine as epigenetic priming for chemotherapy is safe and well-tolerated in infants with newly diagnosed KMT2A-rearranged acute lymphoblastic leukemia: Children’s Oncology Group trial AALL15P1
Erin M. Guest,
John A. Kairalla,
Meenakshi Devidas,
Emily Hibbitts,
Andrew J. Carroll,
Nyla A. Heerema,
Holly R. Kubaney,
Margaret A. August,
Sidharth Ramesh,
Byunggil Yoo,
Midhat S. Farooqi,
Melinda G. Pauly,
Daniel S. Wechsler,
Rodney R. Miles,
Joel M. Reid,
Cynthia D. Kihei,
Lia Gore,
Elizabeth A. Raetz,
Stephen P. Hunger,
Mignon L. Loh,
Patrick A. Brown
Affiliations
Erin M. Guest
Division of Hematology, Oncology, Bone Marrow Transplant, Children’s Mercy Kansas City, University of Missouri-Kansas City School of Medicine, Kansas City, MO
John A. Kairalla
Department of Biostatistics, University of Florida, Gainesville, FL
Meenakshi Devidas
St. Jude Children’s Research Hospital, Memphis, TN
Emily Hibbitts
Department of Biostatistics, University of Florida, Gainesville, FL
Andrew J. Carroll
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL
Nyla A. Heerema
Department of Pathology, The Ohio State University, Columbus, OH
Holly R. Kubaney
Dell Children’s Medical Center of Central Texas, Austin, TX
Margaret A. August
Health Informatics and Technology, Children’s Mercy Kansas City, Kansas City, MO
Sidharth Ramesh
University of Pennsylvania, Philadelphia, PA
Byunggil Yoo
Research Informatics, Children’s Mercy Kansas City, Kansas City, MO
Midhat S. Farooqi
Department of Pathology and Laboratory Medicine, Children’s Mercy Kansas City, University of Missouri-Kansas City School of Medicine, Kansas City, MO
Melinda G. Pauly
Aflac Cancer and Blood Disorders Center at Children’s Healthcare of Atlanta and Emory University, Atlanta, GA
Daniel S. Wechsler
Aflac Cancer and Blood Disorders Center at Children’s Healthcare of Atlanta and Emory University, Atlanta, GA
Rodney R. Miles
University of Utah, Department of Pathology, Salt Lake City, UT
Joel M. Reid
Mayo Clinic, Rochester, MN
Cynthia D. Kihei
Saint Mary’s Hospital, West Palm Beach, FL
Lia Gore
Children’s Hospital Colorado, Center for Cancer and Blood Disorders, Denver, CO
Elizabeth A. Raetz
New York University Langone Health, New York, NY
Stephen P. Hunger
Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA
Mignon L. Loh
Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute and the Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WA, 98105
Infants less than 1 year old diagnosed with KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL) are at high risk of remission failure, relapse, and death due to leukemia, despite intensive therapies. Infant KMT2A-r ALL blasts are characterized by DNA hypermethylation. Epigenetic priming with DNA methyltransferase inhibitors increases the cytotoxicity of chemotherapy in preclinical studies. The Children’s Oncology Group trial AALL15P1 tested the safety and tolerability of five days of azacitidine immediately prior to the start of chemotherapy on day six, in four post-induction chemotherapy courses for infants with newly diagnosed KMT2A-r ALL. The treatment was welltolerated, with only two of 31 evaluable patients (6.5%) experiencing dose-limiting toxicity. Whole genome bisulfite sequencing of peripheral blood mononuclear cells (PBMCs) demonstrated decreased DNA methylation in 87% of samples tested following five days of azacitidine. Event-free survival was similar to prior studies of newly diagnosed infant ALL. Azacitidine is safe and results in decreased DNA methylation of PBMCs in infants with KMT2A-r ALL, but the incorporation of azacitidine to enhance cytotoxicity did not impact survival. Clinicaltrials.gov identifier: NCT02828358.
