Amonafide L-Malate (AS1413) in Combination with Cytarabine Is Equally Effective in Older and Younger Patients with Secondary Acute Myeloid Leukemia (AML); Final Data From a Phase II Study.
Authors: Erba Harry P , O'Donnell Margaret , Allen Steven L , Baer Maria R , Powell Bayard L , Stone Richard M , Bennett John M , Lundberg Ante S , Capizzi Robert L , Rizzieri David A 
Published: October 2019

Abstract
Abstract 1047
Poster Board I-69

Background:
A major issue in the treatment of AML is the low response rate achieved with standard remission induction therapy in patients with “poor-risk” prognostic factors. One such poor-risk factor is secondary AML (sAML), AML following myelodysplasia or cytotoxic therapy for other malignancies. sAML is strongly associated with multi-drug resistance (MDR) mechanisms: up to 70% of sAML patients show overexpression of P-glycoprotein (Pgp) or other MDR mechanisms. Amonafide L-malate (amonafide, AS1413) is a unique DNA intercalator that is not a substrate for MDR, unlike anthracyclines commonly used in the treatment of AML. This phase II study evaluated amonafide in combination with cytarabine in patients with sAML.

Methods:
Patients received amonafide 600 mg/m2/day IV on days 1-5 and cytarabine 200 mg/m2/day IV by continuous infusion on days 1-7. Induction was repeated if leukemia persisted on day 14 marrow examination. Consolidation consisted of hematopoietic stem cell transplant (HSCT; n=10) or intermediate-dose (n=13)/high-dose (n=7) cytarabine, depending on age and HSCT donor availability. Bone marrows were centrally reviewed. The primary endpoint was complete remission with (CR) or without (CRi) hematopoietic recovery; secondary endpoints were duration of remission (DOR), survival and safety.

Results:
88 patients with a median age of 62.5 years (range 23-87) were treated; Of these, 45 (51%) had received prior leukemogenic therapy (tAML) and 43 (49%) had prior MDS; 1 (1%) had favorable, 36 (41%) had intermediate and 42 (48%) had unfavorable cytogenetics. Overall CR + CRi rate was 42% (CRi 3%); median duration of remission (DOR) was 312 days. CR rates and DOR among age <60 and ≥60, 13/33 (39.4%), 312 days and 24/55 (43.6%), 316 days; among tAML and prior MDS, 18/45 (40%), 512 days and 19/43 (44.2%), 186 days; intermediate and unfavorable cytogenetics, 23/36 (61.1%), 282 days and 10/42 (23.8%), 322 days. Median overall survival for the whole population was 200 days and for responders 435 days. Non-hematologic grade ≥ 3 adverse events included febrile neutropenia (35%), hypotension (16%), pneumonia (14%), respiratory failure (11%), and bacteremia (11%). The death rate within 28 days of induction therapy was 20.5%. Median time to hematopoietic recovery of neutrophil count > 500/cmm and platelets of 20,000/cmm was 29 and 28 days, respectively.

Conclusions:
Amonafide produced a high complete remission rate and durable responses in both older and younger patients with sAML. Efficacy was maintained across several poor-prognosis subgroups frequently characterized by MDR, for which amonafide is not a substrate. A phase III study (ACCEDE) is evaluating amonafide + cytarabine vs. daunorubicin + cytarabine in patients with sAML.

Disclosures:
Erba: Genzyme: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria; Pharmion: Honoraria; MGI Pharma: Honoraria; Cephalon: Honoraria, Research Funding; Wyeth: Research Funding; Antisoma: Research Funding; Lilly: Research Funding; Gemin-X: Research Funding; Kanisa: Research Funding. O'Donnell:Genzyme: Consultancy; Eisai: Consultancy; Celgene: Consultancy. Allen:Antisoma: Research Funding. Powell:Antisoma: Research Funding. Stone:Celgene: Consultancy, Speakers Bureau; Merck: Consultancy; Genzyme: Consultancy; Eisai: Consultancy. Bennett:Antisoma: Consultancy. Lundberg:Antisoma: Employment. Capizzi:Antisoma: Consultancy. Rizzieri:Antisoma: Research Funding.