title: A therapeutic trial of decitabine and vorinostat in combination with chemotherapy for relapsed/refractory acute lymphoblastic leukemia.
abstract: DNA hypermethylation and histone deacetylation are pathways of leukemia resistance. We investigated the tolerability and efficacy of decitabine and vorinostat plus chemotherapy in relapse/refractory acute lymphoblastic leukemia (ALL). Decitabine (15 mg/m(2) iv) and vorinostat (230 mg/m(2) PO div BID) were given days 1-4 followed by vincristine, prednisone, PEG-asparaginase, and doxorubicin. Genome wide methylation profiles were performed in 8 matched patient bone marrow (BM) samples taken at day 0 and day 5 (postdecitabine). The median age was 16 (range, 3-54) years. All patients had a prior BM relapse, with five relapsing after allogeneic transplant. The most common nonhematological toxicities possibly related to decitabine or vorinostat were infection with neutropenia (grade 3; n = 4) and fever/neutropenia (grade 3, n = 4; grade 4, n = 1). Of the 13 eligible patients, four achieved complete remission without platelet recovery (CRp), two partial response (PR), one stable disease (SD), one progressive disease (PD), two deaths on study and three patients who did not have end of therapy disease evaluations for an overall response rate of 46.2% (CRp + PR). Following decitabine, significant genome-wide hypo-methylation was observed. Comparison of clinical responders with nonresponders identified methylation profiles of clinical and biological relevance. Decitabine and vorinostat followed by re-Induction chemotherapy was tolerable and demonstrated clinical benefit in relapsed patients with ALL. Methylation differences were identified between responders and nonresponders indicating interpatient variation, which could impact clinical outcome. This study was registered at www.clinicaltrials.gov as NCT00882206.
authors.affiliation: Division of Pediatric Hematology-Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Burke
authors.forename: Jatinder K
authors.initials: JK
authors.lastname: Lamba
authors.forename: Stanley
authors.initials: S
authors.lastname: Pounds
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Cao
authors.forename: Yogita
authors.initials: Y
authors.lastname: Ghodke-Puranik
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Lindgren
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Weigel
authors.forename: Michael R
authors.initials: MR
authors.lastname: Verneris
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control; D055502:Secondary Prevention; D000077337:Vorinostat; D055815:Young Adult
chemical_list: D006877:Hydroxamic Acids; D000077337:Vorinostat; D000077209:Decitabine; D001374:Azacitidine
keywords: Decitabine; Vorinostat; acute lymphoblastic leukemia; epigenetic; relapse