Stone R.M.,Dana-Farber Cancer Institute |
Mazzola E.,Dana-Farber Cancer Institute |
Neuberg D.,Dana-Farber Cancer Institute |
Allen S.L.,Antisoma |
And 18 more authors.
Journal of Clinical Oncology | Year: 2015
Purpose: Secondary acute myeloid leukemia (sAML), defined as AML arising after a prior myelodysplastic syndrome or after antineoplastic therapy, responds poorly to current therapies. It is often associated with adverse karyotypic abnormalities and overexpression of proteins that mediate drug resistance. We performed a phase III trial to determine whether induction therapy with cytarabine and amonafide L-malate, a DNA intercalator and non-ATP-dependent topoisomerase II inhibitor that evades drug resistance mechanisms, yielded a superior complete remission rate than standard therapy with cytarabine and daunorubicin in sAML. Patients and Methods Patients with previously untreated sAML were randomly assigned at a one-to-one ratio to cytarabine 200 mg/m2 continuous intravenous (IV) infusion once per day on days 1 to 7 plus either amonafide 600 mg/m2 IV over 4 hours on days 1 to 5 (A + C arm) or daunorubicin 45 mg/m2 IV over 30 minutes once per day on days 1 to 3 (D + C arm). Results The complete remission (CR) rate was 46% (99 of 216 patients) in A + C arm and 45% (97 of 217 patients) in D + C arm (P = .81). The 30- and 60-day mortality rates were 19% and 28% in A +C arm and 13% and 21% in D + C arm, respectively. Conclusion Induction treatment with A + C did not improve the CR rate compared with D + C in patients with sAML. © 2015 by American Society of Clinical Oncology.
Allen S.L.,Yeshiva University |
Kolitz J.E.,New York University |
Lundberg A.S.,Antisoma |
Bennett J.M.,University of Rochester |
And 2 more authors.
Leukemia Research | Year: 2010
Amonafide-l-malate (amonafide) is a unique DNA intercalator that maintains activity in the presence of MDR mechanisms, a frequent cause of treatment-failure in secondary AML. 43 patients with relapsed/refractory or secondary AML or CML blast crisis were enrolled into two phase I dose-escalation studies investigating amonafide as monotherapy or in combination with cytarabine. 3/17 patients in the monotherapy trial and 10/26 patients in the combination trial achieved a complete remission. Between both trials responses occurred in 9/20 patients with secondary AML. Both trials demonstrated an acceptable safety profile and significant antileukemic activity in patients with poor-risk AML, especially those with secondary AML. © 2009 Elsevier Ltd. All rights reserved.
Allen S.L.,Monter Cancer Center |
Expert Opinion on Investigational Drugs | Year: 2011
Introduction: Amonafide is a novel topoisomerase II (Topo II) inhibitor and DNA intercalator that induces apoptotic signaling by blocking the binding of Topo II to DNA. Amonafide retains cytotoxic activity even in the presence of P-glycoprotein (Pgp)-mediated multi-drug resistance (MDR), a major contributor to clinical treatment failure. Areas covered: In vitro, Pgp-mediated transport (efflux) of amonafide from myeloblasts obtained from patients with secondary acute myeloid leukemia (sAML) was significantly less than efflux of daunorubicin. Amonafide has shown efficacy in patients with sAML, as well as in patients with poor prognostic characteristics such as older age and unfavorable cytogenetics, all associated with MDR. Improved antileukemic activity is observed when amonafide is given together with cytarabine, rather than as monotherapy, with a complete remission rate of ∼40% in a recent Phase II trial in sAML. The efficacy of amonafide was maintained among poor-risk subsets of patients, including older patients and patients who had previous myelodysplastic syndrome or previous leukemogenic therapy. The safety profile was acceptable and manageable. Expert opinion: Amonafide plus cytarabine may have clinical utility in patients with sAML and in other poor-risk subgroups of acute myeloid leukemia (AML). Ongoing trials will help define the role for amonafide in the treatment of poor-risk AML. © 2011 Informa UK, Ltd.