Side effects reduced by weekly dose of targeted drug for ALL, but activity not reduced

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. This Trojan Horse assault on the cancer cells has significantly increased the response rate among patients with ALL, and this clinical trial has found that weekly dosing works well and reduces side effects.

Inotuzumab ozogamicin is a humanized antibody that is attached to the toxin calicheamicin and binds CD22. Once it is bound to the B cell, the antibody is internalized and the linker is hydrolyzed, which releases calicheamicin only into the malignant B cell. Inotuzumab ozogamicin was first used in patients with B cell lymphoma, and myelosuppression was the main toxicity seen, primarily due to platelet deficiency.

“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,” said Susan O'Brien, MD, of The University of Texas M.D. Anderson Department of Leukemia. “You expect to have myelosuppression as part of the therapy.”

The main toxicities were infusion reactions either during or shortly after infusion of the antibody. Grade 1-2 fevers associated with a drop in blood pressure and elevations of transaminases also occurred.

In an attempt to minimized toxicities, the protocol was amended to give the agent on a weekly basis instead of as a bolus every 3 to 4 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 3 weeks.”

“We found exactly the same response rate with the weekly dose as with the monthly dose,” O'Brien said. “But we did notice that the infusion reactions and the elevations in the transaminases were less frequent with the weekly schedule. This is probably because the side effects are most likely related to the peak concentrations of the drug, and when you spread it over 3 weeks the peak concentrations are not as high.”

“We observed impressive activity in a relapsed, refractory population,” O'Brien said. “The toxicities were acceptable and were mainly grade 1-2 reactions to the drug itself, which is not uncommon because most antibodies are associated with mild infusion reactions. Transaminase elevations were predominately grade 1-2, and in the trial as a whole, fewer than 5% of the patients experienced grade 3-4 liver elevations.”

“One of the biggest complications in treating older patients with ALL is that the treatments cause myelosuppression, which makes patients more vulnerable to infection, and older patients are particularly susceptible to this and other complications,” she said. “The idea is to take a very well-tolerated antibody and combine it with chemotherapy. That way we might not have to use full-dose chemo and can reduce side effects.”

This study was presented at the American Society of Hematology Annual Meeting and Exposition in Atlanta, Georgia, held December 8-11, 2012.
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