Four Drugs Induction Therapy (fludarabine, cytarabine, idarubicin and gemtuzumab ozogamycin) for the Treatment of Elderly Acute Myeloid Leukemia Patients.

Current therapeutic strategies for the treatment of elderly acute myeloid leukemia (AML) patients are still unsatisfactory. Induction regimens relying on anthracycline and cytarabine combination (3+7) still represent the standard reference therapy, with complete remission (CR) rate of 35-60% but no more than 10-20% of patients living more than three years from diagnosis.

The addition of other drugs to overcome resistance and prevent subsequent relapse, has often shown greater toxicity without improving results.

We designed a phase II study aiming to assess toxicity and efficacy of My-FLAI regimen in patients with newly diagnosed AML aged more than 60 years. Fifty-one patients were enrolled with a median age of 68 years (range 60-76). The median leukocyte count was 10.2 ×10⁹/L (range 0.7-222.7). Twenty-five patients had a secondary AML and 31% had a complex kariotype. Fludarabine, cytarabine and idarubicin were administered for three consecutive days at the daily dose of 25 mg/m², 1 g/ m² and 5 mg/ m² respectively. Gemtuzumab ozogamycin (Mylotarg, My) was infused at day four at the dose of 5 mg. Patients achieving a CR after the induction course were planned to receive a second identical course of My-FLAI. Granulocyte colony-stimulating factor (G-CSF) was administered at physician's discretion to promote granulocytic recovery if clinically indicated.

Twenty-seven patients achieved a CR (one of these with an incomplete platelet recovery) and 4 obtained a partial response (marrow blast 5-19%) for an overall response rate (ORR) of 61%. Seventeen patients (33%) showed a resistant disease and three (6%) died during induction (DDI). Seventeen patients received an identical consolidation course. Seven patients were treated with cytarabine-based consolidation and the remaining 27 patients were not treated furthermore. The disease-free survival (DFS) and overall survival (OS) were 6 months (range 2.4-48.0) and 13 months (range 1.1-61.5) respectively. DFS appear to be more favorable in patients receiving additional therapy after two My-FLAI cycles (IDAC n=3; ASCT n= 4; experimental drugs n= 1; My n=4) in comparison to patients no further treated, being 12.8 (range 4.7-18.0) and 5.9 (range 2.4-48.0) months respectively. The median duration of G-CSF administration was 6 days (range 0-35) in induction and 8 days (range 0-15) in consolidation cycle. All patients developed a grade IV hematological toxicity. Median time to ANC recovery (>1 ×10⁹/L) was 21 days (range 10-52) after induction course and 18 days (range 12-20) after consolidation course. Median time to PLT recovery (PLT>20 ×10⁹/L and PLT>100 ×10⁹/L) was 18 days (range 9-54) and 23 days (range 15-78) after induction and 18 days (range 12-20) and 32 days (range 21-110) after the consolidation course. Thirty-six patients had infectious complication; 33 experienced a microbiologically documented infection (n=20 gram+, n=12 gram- n=1 candidemia). Eighteen patients had a fever of unknown origin (FUO) and 12 patients suffered from pulmonary infection (n=2 bacterial; n=8 probable fungal; n=2 aspergillosis). One patient developed a maxillary sinus aspergillosis. Grade III/IV haemorrhagic complications were observed in 5 patients. No severe gastro-intestinal adverse events were observed. With a median follow-up of 8.8 months (range 0.5-61.5) 41 patients died. Five patients died in first CR for cardiac failure (n=2) and for infective complication (n=3). The remaining died for disease. Nine patients are alive, four of them in first CR.

The four drug regimen My-FLAI is overall well tolerated in an elderly AML population. However, the efficacy did not appear to be superior to that of standard “3+7” regimen.

Supported by BolognAIL, AIRC, European LeukemiaNET, COFIN, FIRB 2006, Fondazione del Monte di Bologna e Ravenna

No relevant conflicts of interest to declare.