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.

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.

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.

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.

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.

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.