MIDAM Regimen (Mylotarg + Intermediaite Dose Aracytin + Mitoxantrone) Is an Effective Combination of Chemo-Immunotherapy for Relapsed/Refractory CD33+ AML Patients.

Introduction: Refractory and relapsed AML patients have very poor outcome. Recently we have described a new combination of chemo and immunotherapy (MIDAM regimen) in a series of 17 of these patients with encouraging results (Chevallier et al, Leukemia Research, 2005). Here we report an up-date of this protocol in 45 patients (including the 17 first ones) treated between February 2001 and June 2006. Analyzes were performed the first of August 2006. Median follow-up for survival patients is 11 months (range:2–61).

Characteristics of patients: Sexe: 24 male, 21 female; Median age: 55 years (range: 16–71, >60 years n=12); Status disease: Relapse n=31 (median diagnosis-relapse 15 months, range: 7–120; Previous autograft n=18), Refractory n=14 (including 4 with secondary AML); FAB: AML0 n=2, AML1 n=15, AML2 n= 12; AML3 n=1, AML4 n=6, AML5 n=5, AML6 n=2, AML7 n=2; Cytogenetic: high risk n=10, intermediate n= 30, good n=4, unknown n=1. Median % of CD33 expression: 98%, range 54–100. Inclusion criteria: CD33+ AML defined by a ratio of mean fluorescence intensity (MFI) of CD33 antigen of blasts/MFI of its isotypic control >=2; primary refractory AML after 2 courses (including high-dose Ara-C) of induction therapy in patients <=60 years or after 1 course of induction therapy in patients >60 years or with secondary AML; first relapse for patients >60 years or first relapse within 12 months or after stem cell transplantation for patients <=60 years.

MIDAM protocol: Mylotarg 9 mg/m² day 4 + Ara-C 1g/m²/12h day 1 to 5 + Mitoxantrone 12 mg/m²/day day 1 to 3.

Results: Overall Response (OR): 62.2% (CR n= 21, CRp n=7), OR in relapsed patients: n=21/31, 67.7% , OR in refractory patients: n= 7/14, 50%, OR in patients >60 years: n=10/12, 83%, OR in patients with high-risk cytogenetic: n=5/10, 50%. Overall Survival (OS): 6.5 months (range: 12 days-61 months). Relapse-free-survival: 6 months (range:1–59), OS in CR + CRp patients: 9.5 months (range: 2–61). Thirty one patients died, the cause of death being leukaemia (n=23), infection (n=3), acute GVHD (n=2), multiple organ failure (n=1), cerebral hemorrhage (n=1), veno occlusive disease (VOD) (n=1). Fourteen patients are alive including 11 in persistent response. Out of patients who achieved CR or CRp (n=28), 8 underwent allogeneic transplantation, 2 underwent an autologous transplantation, 11 received chemotherapy alone as consolidation, and 7 did not receive further chemotherapy. Among the 8 patients who received allogeneic transplantation, RFS is 15 months (7–61).

Toxicity: 2 VOD (4.4%) including one patient with complete resolution.

Conclusion: We confirm that the MIDAM protocol is an effective regimen in the treatment of relapsed/refractory CD33+AML, conferring a high rate of CR + CRp with tolerable hepatotoxicity, although Mylotarg is given at a full dose of 9 mg/m² in combination with chemotherapy.