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Haematologica 2018 Volume 103(6):982-987
Clara D. Bloomfield,1 John C. Byrd,1 Richard Piekarz,6 Michael R. Grever1 and
Ferrata Storti Foundation
Acute Myeloid Leukemia
A novel regimen for relapsed/refractory adult acute myeloid leukemia using a KMT2A partial tandem duplication targeted therapy: results of phase 1 study NCI 8485
Alice S. Mims,1 Anjali Mishra,2 Shelley Orwick,2 James Blachly,1
Rebecca B. Klisovic,3 Ramiro Garzon,1 Alison R. Walker,1 Steven M. Devine,1
Katherine J. Walsh,1 Sumithira Vasu,1 Susan Whitman,2 Guido Marcucci,4
Daniel Jones,5 Nyla A. Heerema,5 Gerard Lozanski,5 Michael A. Caligiuri,2
3 William Blum
1Division of Hematology, Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH; 1Department of Medicine, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH; 3Department of Hematology and Medical Oncology, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA; 4Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA; 5Department of Pathology, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH and 6Investigational Drug Branch of CTEP, National Cancer Institute, Bethesda, MD, USA
ABSTRACT
KMT2A partial tandem duplication occurs in approximately 5-10% of patients with acute myeloid leukemia and is associated with adverse prognosis. KMT2A wild type is epigenetically silenced in KMT2A partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors in vitro, sensitizing myeloid blasts to chemotherapy. We hypothesized that epi- genetic silencing of KMT2A wildtype contributes to KMT2A partial tan- dem duplication-associated leukemogenesis and pharmacologic re- expression activates apoptotic mechanisms important for chemo- response. We developed a regimen for this unique molecular subset, but due to relatively low frequency of KMT2A partial tandem duplication, this dose finding study was conducted in relapsed/refractory disease regardless of molecular subtype. Seventeen adults (< age 60) with relapsed/refractory acute myeloid leukemia were treated on study. Patients received decitabine 20 milligrams/meter2 daily on days 1-10 and vorinostat 400 milligrams daily on days 5-10. Cytarabine was dose- escalated from 1.5 grams/meter2 every 12 hours to 3 grams/meter2 every 12 hours on days 12, 14 and 16. Two patients experienced dose limiting toxicities at dose level 1 due to prolonged myelosuppression. However, as both patients achieved complete remission after Day 42, the protocol was amended to adjust the definition of hematologic dose limiting tox- icity. No further dose limiting toxicities were found. Six of 17 patients achieved complete remission including 2 of 4 patients with KMT2A par- tial tandem duplication. Combination therapy with decitabine, vorino- stat and cytarabine was tolerated in younger relapsed/refractory acute myeloid leukemia and should be explored further focusing on the KMT2A partial tandem duplication subset. (clinicaltrials.gov identifier 01130506).
Introduction
Though acute myeloid leukemia (AML) is considered a curable disease, the majority of patients will succumb to their diagnosis. Prognosis has been based pri- marily on age and cytogenetic/molecular mutations at diagnosis with younger patients (<60 years) faring better, in particular those with European LeukemiaNet
Correspondence:
alice.mims@osumc.edu
Received: December 27, 2017. Accepted: March 21, 2017. Pre-published: March 22, 2017.
doi:10.3324/haematol.2017.186890
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/6/982
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