Efficacy and Toxicity of FLAI-G-CSF and Mylotarg for Induction/Consolidation of AML Patients, Not Treatable with Conventional Chemotherapy.

Acute myeloid leukaemias (AMLs) usually share a high frequency and a high degree of Pgp-mediated multidrug resistance (MDR), one of the major causes of treatment failure. Patients older than 60 years, as well as patients with secondary AML and patients with relapsed/refractory disease do poorly with conventional chemotherapy. Gemtuzumab ozogamicin (Mylotarg) has shown some in vitro activity against CD33 positive AML blasts. As single agent it induces complete remission (CR) in almost 20 – 30% of cases with mild toxicity. Combinations with chemotherapy look promising. Moreover, several studies proved in vivo efficacy of fludarabine in combinations with cytarabine as anti MDR drug. Fifteen AML patients were treated with an induction regimen including fludarabine (25 mg/sqm/day for 3 days), cytarabine (1 g/sqm/day for 3 days), idarubicine (5 μg/sqm/day for 3 days), mylotarg (3 mg/sqm day +4) and G-CSF (5 mg/day starting on day +9, until hematological recovery). An identical consolidation cycle was administered if at least partial remission (PR) was achieved. Two patients were relapsed after standard induction chemotherapy. Median age at diagnosis was 66 (range 33 – 75). Median white blood cells count was 5.3 x 10⁹/L (range 0.5 – 47.4). Seven out of 15 patients presented with at least 1 adverse karyotype abnormality. Eight patients presented with a secondary AML. Ten out of 15 patients responded to induction cycle (8 CR and 2 PR). The following data regard the induction cycle. The median time to recovery of neutrophils > 1.0 x 10⁹/L was 20 days (range17 - not reached) The median time to recovery of platelets > 20 x 10⁹/L and > 100 x 10⁹/L was 21 days (range 13 - not reached) and 34 (range 19 - not reached) respectively. Two patients developed a grade II WHO FUO and 5 patients developed a grade II-III Gram+ bacteremia. Two patients had radiologically documented fungal infection (lung) and 1 patient had microbiologically documented aspergillosis of maxillary sinus. Non-hematological toxicity was mild. Only one patient developed a grade III WHO hemorragic syndrome (melena). No veno occlusive disease were observed.

Up to now 4 patients completed two cycles of chemotherapy. Three patients out of 15 died (1 progressive disease, 1 multi organ failure after allogeneic bone marrow transplantation, 1 myocardial stroke while in CR) and 7 patients out of 15 are in CR. In conclusion, these preliminary results suggest that FLAI-G-CSF-Mylotarg, as induction course, is an effective regimen with a limited hematological and non-haematologic toxicity and seems to be effective in this high risk subset of patients. A longer follow up and larger series of patients are indeed necessary to draw further conclusions.