Gemtuzumab Ozogamicin Is an Acceptable Alternative to Anthracyclines in Combination with Standard Dose Infusional Cytarabine as Induction Therapy for Elderly Patients with Acute Myeloid Leukemia (AML).

Gemtuzumab ozogamicin (GO), a humanized IGG4 anti-CD33 antibody conjugated to calicheamicin, has demonstrated single agent efficacy in relapsed AML. Combination with other anti-leukemic drugs has required a significant dose reduction of GO to avoid excess liver toxicity. The maximally tolerated dose of GO in combination with cytarabine 100 mg/m2 by 24 hr infusion for 7 days, was established at 6 mg/m2 day 1 and 4 mg/m2 day 8 in a phase I trial involving relapsed patients as well as untreated adults with AML above the age of 60. From 7/03 to 7/05, 31 adults (M-17, F-14) with a median age of 70 (range 60–83) were treated with this regimen on a phase II trial. Patients with residual disease on day 14 were given cytarabine 100 mg/m2 by 24 hr infusion daily for 5 days without GO. Post remission therapy, generally included repetitive cycles of cytarabine 50 mg/m2 twice daily by subcutaneous injection in combination with rotating cycles of 6-thioguanine, cyclophosphamide, or daunorubicin. Patients with an antecedent hematological disorder (AHD) or secondary AML were not excluded, and prior treatment for myelodysplastic syndrome was allowed. An AHD was documented in 13/30 (43%) of patients and 3/30 (10%) had secondary AML. Unfavorable cytogenetics (−5, −7, 11q2,3 abnormalities and complex karyotypes) were present in 17/30 (56%) patients. Of the first 7 patients treated, 4 developed severe and fatal hyperbilirubinemia in conjunction with ascites, fluid retention and encephalopathy consistent with sinusoidal occlusion syndrome (SOS). Subsequent patients were treated with 6 mg/m2 of GO without the day 8 dose. Of these 24 patients, 4 developed grade 3 hyperbilirubinemia which was transient and not associated with SOS. Apart from this toxicity, other non-hematologic effects, including infusional reactions, mucositis, diarrhea, nausea, vomiting and anorexia were mild to moderate. No cardiac toxicity was observed in any patients including 3 patients with reduced left ventricular function documented prior to treatment. Overall 9/31 (29%) patients achieved a complete response (CR) and 1 achieved a CRp for an overall response rate of 32%. Of the 24 patients who received 1 dose of GO (6 mg/m2), the overall response rate was 9/24 (36%). The induction mortality rate in these 24 patients was 5/24 (21%). The median duration of response is 10.5 months (range 6 to 12 months) with 2 patients in ongoing CR at 12 months and 18 months respectively. This data demonstrates that GO administered on day 1 and day 8 leads to unacceptable liver toxicity in unselected patients with AML above the age of 60 yrs. However, in patients receiving a single dose of GO (6 mg/m2) in combination with cytarabine, the overall response rate and toxicity profile is comparable to a historical cohort of similarly unselected elderly AML patients treated with daunorubicin and cytarabine at our institution. We conclude that a single dose of GO (6mg/m2) is an equally safe and effective alternative to anthracycline in combination with standard doses of infusional cytarabine in adults with AML above the age of 60.