A Study of the Toxicity of Gemtuzumab Ozogamicin in Primary and Relapsed AML, Administered Alone or Simultaneously with Intensive Chemotherapy.

Introduction: Gemtuzumab Ozogamicin (Mylotarg^®) is a humanized anti CD33 antibody linked to the cytotoxic drug calicheamicin, which has shown considerable antileukaemic effect in the treatment of relapsed AML. With special regard to its toxicity, we present our preliminary results of Mylotarg treatment when administered on compassionate basis as consolidating monotherapy, or combined with intensive chemotherapy.

Patients and methods: A total of 86 doses, corresponding to 65 courses were administered to 49 patients. Indications for Mylotarg treatment ( mono ~ monotherapy; comb ~ combination therapy. No.of courses are shown in parentheses): Primary AML: Reinduction ( mono:1; comb:3). Cytogenetic reinduction ( mono:3; comb:1). Consolidation ( mono:24; comb:2). Relapsed AML: Induction ( mono:4; comb:11). Reinduction ( mono:1; comb:2). Cytogenetic reinduction ( mono:1). Consolidation ( mono:10; comb:2).

Results: Up-front consolidation with Mylotarg as monotherapy ( 30 doses; 24 patients; mean Mylotarg dose 5.7 mg/m²). Fever: 51% of doses. Focal infections: 17%. Bacteremia 7%. Biochemical findings: Platelet nadir at day 10 ( < 20 bill./l: 25% doses). Neutrophil nadir at day 11 ( mean count = 0.12 bill./l). Hepatic toxicity ( grade 1; % of doses): Alkaline phosphatase 7%; ALAT: 13%; Bilirubin 0. A similar pattern was seen in the 10 relapsed patients consolidated with Mylotarg as monotherapy. One patient receiving an allogeneic transplant 3 months after Mylotarg treatment developed fatal VOD. Three other patients who undervent allogeneic stem cell transplantation 2, 2 and 3 months, respectively, after the administration of Mylotarg did not experience severe hepatic complications.

We compared twelve courses of Mylotarg combined with DaunoXome and high dose cytarabine with ( n=10) or without ( n=2) added fludarabine and etoposide, administered to10 patients in 1st relapse with 8 similar courses but without Mylotarg, administered to 7 patients with similar characteristics regarding age, CR1 duration and cytogenetics ( mean Mylotarg dose 4.4 mg/m²). More cases of grade 3 diarrhea ( 33% vs 13%) and bacteremia ( 67% vs 38%) were seen in the Mylotarg group, in which three patients suffered hypoplastic deaths. One of these patients developed intestinal perforation following postremission treatment. The two other patients, with an early refractory relapse, and a late relapse with high risk chromosomal aberation, respectively, died from infectious complications following 20 and 36 days of profound neutropenia. These 3 patients recieved 5.9, 8.3 and 5.0 mg/m² respectively, compared to the average Mylotarg dose of 4.4 mg/m2.

Conclusion: Mylotarg seems to increase toxicity when added to intensive chemotherapy in relapsed AML. The feasibility of this approach must await further studies evaluating toxicity, appropriate dosing and response pattern. When administered as consolidating monotherapy toxicity is modest.