Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML

• Published in: Blood Vol. 118; no. 6; pp. 1472 - 1480
• Main Authors: Scandura, Joseph M., Roboz, Gail J., Moh, Michelle, Morawa, Ewelina, Brenet, Fabienne, Bose, J. Robi, Villegas, Luis, Gergis, Usama S., Mayer, Sebastian A., Ippoliti, Cindy M., Curcio, Tania J., Ritchie, Ellen K., Feldman, Eric J.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 11.08.2011; Americain Society of Hematology; American Society of Hematology
• Subjects: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Azacitidine - administration & dosage; Azacitidine - adverse effects; Azacitidine - analogs & derivatives; Biological and medical sciences; Clinical Trials and Observations; Cytarabine - administration & dosage; Cytarabine - adverse effects; Daunorubicin - administration & dosage; Daunorubicin - adverse effects; Decitabine; Diarrhea - chemically induced; DNA Methylation - drug effects; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fever - chemically induced; Hematologic and hematopoietic diseases; Humans; Infections - chemically induced; Kaplan-Meier Estimate; Leukemia, Myeloid - drug therapy; Leukemia, Myeloid - genetics; Leukemia, Myeloid - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Myeloid Neoplasia; Nausea - chemically induced; Neutropenia - chemically induced; Treatment Outcome; Young Adult; Antineoplastic agent; Human; Acute myelogenous leukemia; Hematology; Decitabine; Priming; Malignant hemopathy; Induction treatment; Standards; Azanucleoside; Epigenetics; Phase I trial; Nucleoside analog; Pyrimidine nucleoside; Cancer
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-11-320093

We conducted an open-label phase 1 study exploring the feasibility, safety, and biologic activity of epigenetic priming with decitabine before standard induction chemotherapy in patients with less-than-favorable risk of acute myelogenous leukemia (AML). We directly compared the clinical and DNA-hypomethylating activity of decitabine delivered at 20 mg/m2 by either a 1-hour infusion (Arm A) or a continuous infusion (Arm B) for 3, 5, or 7 days before a single, standard induction with infusional cytarabine (100 mg/m2 for 7 days) and daunorubicin (60 mg/m2 × 3 doses). Toxicity was similar to that of standard induction chemotherapy alone. Although we did not identify a maximum tolerated dose, there was more gastro-intestinal toxicity with 7 days of decitabine priming. Decitabine induced DNA hypomethylation at all dose levels and there was a trend toward greater hypomethylation in CD34+ bone marrow cells when decitabine was delivered by a short pulse (Arm A). Twenty-seven subjects (90%) responded to therapy: 17 with complete remission (57%) and 10 with partial remission (33%). Of the patients with partial remission to protocol treatment, 8 achieved remission to their next therapy, bringing the overall complete remission rate to 83%. We conclude that epigenetic priming of intensive chemotherapy can be safely delivered in an attempt to improve response rates. This trial was registered at www.clinicaltrials.gov as NCT00538876.