Mylotarg 9 mg/m^² Combined with Intermediate Dose Aracytin and Mitoxantrone (MIDAM) in Relapsed/Refractory CD33+ Acute Myeloid Leukemia: A Single Center Phase II Experience.

When combined with chemotherapy, Mylotarg is currently used in lower doses, due to the risk of hepatic toxicity and veno-occlusive disease (VOD). We have used the dose of 9 mg/m² of Mylotarg (iv over 2 hours on day 4) in combination with Intermediate Dose Aracytin (1 g/m²/12 hours iv over 2 hours on days 1 through 5) and Mitoxantrone (12 mg/m²/day iv over 30 minutes on days 1 through 3), from February 2002 to January 2004, in 17 patients with refractory (n=4) or relapsed (n=13) acute myeloid leukemia (AML). Inclusion criteria were: 1) CD33+ de novo or secondary AML (except M3 AML); 2) Primary refractory AML (failure of 2 courses of induction therapy including high-dose aracytin in patients <= 60 years or of 1 course of induction therapy in patients > 60 years), or first relapse in patients > 60 years, or first relapse within 12 months of first complete remission (CR) or after stem cell transplantation in patients <= 60 years. There were 8 female and 9 male. Median age was 54 years (range: 21–68) including 7 patients > 60 years. FAB classification was 2 M0 AML, 6 M1 AML, 7 M2 AML, 1 M4 AML and 1 M5 AML (including 2 secondary AML). Karyotype was analyzed in 16/17 patients and was favorable in 1, intermediate in 11, unfavorable in 4 patients. Median percentage of CD33+ positive blasts was 99% (range: 65%–100%) with a median ratio intensity of 15 (range: 2–60,2). Six patients had relapsed after 1 or 2 autologous stem cell transplantation(s). The median duration of first CR was 15 months (range: 6–120). The most recent update was undertaken the first of June 2004. Twelve patients (70%) achieved CR and 1 patient had CR with delayed platelet recovery (CRp) with an overall response rate of 76%. The median time to remission (CR or CRp) was 47 days (25–73). All 4 refractory patients achieved CR or CRp. Six/7 patients > 60 years, 3/6 patients who had relapsed after autograft achieved CR. All 4 patients with poor risk cytogenetic and 8/11 patients with intermediate risk cytogenetic achieved CR.

All patients received GCS-F from day 7 till the end of aplasia. Median duration of neutropenia was 22 days (range: 11–40) and median duration of thrombocytopenia was 33 days (range: 8–70) in patients reaching CR. There were 2 toxic deaths (multiorgan failure on day 12 in a context of septic shock and renal failure and VOD on day 29). Four patients developed grade ¾ hepatic toxicity including the patient who died from VOD. Nine patients (53%) developed documented infection (including 2 aspergillosis and 1 fusobacterium infections).

Seven/13 CR patients relapsed between 2 and 23 months after MIDAM while 6 patients are still in second CR (median 21 months, range: 6–34) including 4 patients who received consolidation with stem cell transplantation. The median overall survival (OS) was 11 months (range: 12 days–36 months) and the median relapse free survival (RFS) was 11 months (range: 2–34). Probability of one year OS and RFS were 48% and 36% respectively. In conclusion, although the dose of Mylotarg given in combination with chemotherapy was not reduced (9 mg/m²), the toxicity profile was acceptable (1 VOD/17 patients). The MIDAM protocol appears to be highly effective specially in patients with poor risk cytogenetic and/or refractory disease.