A potent chemotherapy agent wrapped within a monoclonal antibody selectively destroys the malignant cells responsible for acute lymphocytic leukemia (ALL) in either weekly or monthly dosing, researchers report at the 54th ASH Annual Meeting and Exposition.
This 'Trojan horse' assault on the cancer cells has significantly increased the response rate among patients with ALL, and now a clinical trial finds that weekly dosing works well and reduces side effects.
"The CD22 antigen is a specific marker for B-cell malignancies and is expressed in more than 90 percent of patients who have acute lymphocytic leukemia," said Susan O'Brien, M.D., professor in The University of Texas MD Anderson Department of Leukemia. "The antigen's specificity for B-cell cancers makes it a promising therapeutic target for intervention."
Bound to a potent toxin
The humanized antibody, known as inotuzumab ozogamicin, is attached to the toxin calicheamicin and binds to CD22. "After binding to the B cell, the antibody is internalized and the linker hydrolyzed, releasing the calicheamicin into only the malignant B cell," O'Brien said. "This enables us to bring in a very potent toxin that could not be given systemically and direct that toxin to the malignant B cell."
The experimental drug was first used in patients with B cell lymphoma. The main toxicity seen in the lymphoma trials was myelosuppression due primarily to deficiency of platelets.
"Myelosuppression is much less of an issue with acute leukemia, whether ALL or acute myelogenous leukemia, because you want to transiently wipe out the bone marrow to eradicate the leukemic cells," O'Brien said. "You expect to have myelosuppression as part of the therapy."
For this study, the researchers used the dose defined as tolerable in the lymphoma trials-1.8 mg/m2-as a starting point.
"We observed very good activity in this relapse/refractory population and an overall response rate of 57 percent," O'Brien said. "The main toxicities were infusion reactions either during or shortly after infusion of the antibody. Patients developed fever sometimes associated with a drop in blood pressure. These were generally grade 1-2 so they were mild and easily treatable." The treatment was also associated with grade 1-2 elevations of transaminases, enzymes that reflect liver function, which had also occurred in the lymphoma trials.
The researchers amended their protocol in an attempt to minimize toxicities. "We wondered whether we could reduce infusion reactions and liver function test elevations by giving the agent on a weekly basis instead of as a bolus every three to four weeks," O'Brien said. "The maximal plasma levels potentially would be lower, but the area under the curve might be the same because we would be giving the same total dose, just spread over three weeks."