Gemtuzumab Ozogamicin (Mylotarg^R) as Primary Induction Therapy for Elderly Patients with Acute Myeloid Leukemia: A Phase II Trial.

The prognosis of older adults with acute myeloid leukemia (AML) remains poor. Cytotoxic chemotherapy has been associated with low complete remission rates (30–50%), short relapse free survival and excessive toxicity in elderly patients with AML. There is a need for development of more effective and tolerable therapies for this population. Gemtuzumab ozogamicin (GO) is a humanized murine anti-CD33 monoclonal antibody, covalently linked to the antitumor antibiotic, calicheamicin. GO has been shown to be effective in patients with relapsed CD33+ AML, with an overall response rate of 26% in patients older than 60 years. From May 2001 to December 2003, 16 patients > 60 years of age with newly diagnosed CD33+ AML were treated with single-agent GO as induction chemotherapy. A two-stage design was employed; if fewer than 5 of the first 16 patients achieved CR, the study would be terminated. Treatment regimen: GO 9mg/m² was given on day #1. Hydroxyurea could be used to control hyperleukocytosis prior to the first dose of GO. A bone marrow biopsy was performed on day #8. If a response to GO was seen, then patients continued on study and received GO 6mg/m² IV on day #10. If progressive disease or no response was noted by day #8, patients were removed from the study. Post-remission therapy was at the discretion of the physician. Supportive care included GM-CSF and interleukin-11 beginning day #11, allopurinol, acyclovir, norfloxacin, IV hydration, and antiemetics. Patients received dexamethasone 8mg 12-18 hours prior to each dose of GO, as well as 30 minutes prior along with acetaminophen and diphenhydramine to help prevent infusion reactions. Patient characteristics: median age 69 (60–84); 9 patients with secondary AML; 8 patients with poor risk karyotypes and 8 with intermediate risk; performance status of 2 or less. Results: 4/16 patients achieved a CR (25%), 2 patients had no response, 9 progressed on therapy, and one patient died from sepsis and ARDS prior to a response evaluation. Therefore, the study was terminated after accrual of 16 patients. Two responders have relapsed, within 0.6 month and 9.7 months of CR. These two patients were ages 76 and 78, both with high risk karyotypes, and with de novo and secondary AML, respectively. The remaining two responders remain in CR for 27 months. These 2 patients were ages 65 and 79 at the time of treatment, both with de novo AML-M2 and normal karyotypes. Treatment-related toxicities included grade III-IV neutropenia (average duration 30 days) and thrombocytopenia (average duration 36 days), grade I-III infusion reaction in 5 patients, and grade III GI hemorrhage in 4 patients. Grade III-IV neutropenic fever occurred in 10 patients, of which there was only 1 patient with a life-threatening infection (VRE sepsis). There were 2 patients with grade III-IV elevation of hepatic transaminases, but hepatic veno-occlusive disease was not observed. 3/16 patients were able to receive the therapy as an outpatient. Conclusion: When used as induction chemotherapy for elderly patients with CD33+ AML, single agent GO produces response rates inferior to standard anthracycline-based induction regimens, with a comparable safety profile. However, two patients have had prolonged responses with single-agent GO, suggesting a possible role for this agent in a subset of elderly AML patients, yet to be defined.