New Antibody-targeted Chemotherapy Induces Remission in Some AML Patients

SEATTLE—A new chemotherapy agent called CMA-676 that specifically targets tumor cells led to remissions in 34% of patients with acute myeloid leukemia (AML) in relapse and was well tolerated. Eric Sievers, MD, of the Fred Hutchinson Cancer Research Center reported the results of the phase II trial at the ASH meeting.

Recently named gemtuzumab zogamicin, CMA-676 is a conjugate of an anti-CD33 antibody and the cytotoxic agent, calicheamicin. The antibody component causes the drug to bind to AML tumor cells, which express CD33. The calicheamicin component then kills the tumor cells, while not harming normal blood stem cells, which do not bear CD33 molecules.

The phase II clinical trial of CMA-676 enrolled 59 patients who had AML and were in their first relapse after a remission of at least 6 months. The subjects had received a variety of treatments before entering the study, although none had a transplant. The patients were given a 2-hour infusion of CMA-676 at a dose of 9 mg/m² ,which was repeated 2 weeks later.

Uneven Responses

Twenty of the 59 patients had a remission (defined as less than 5% blasts in the marrow, 1,500/mcL neutrophils, and no need for platelet transfusion). Of these 20, 12 then had a bone marrow transplant, and 3 underwent chemotherapy. As of March 1999, 12 patients were still in remission, with a median follow-up of 238 days. Of these 12, 2 had no further treatment, 2 had chemotherapy, and 8 had bone marrow transplants.

In the question and answer period, Dr. Sievers noted “patient’s leukemia was either exquisitely sensitive or unresponsive to the drug, with few responses in between.”

As might be anticipated with an agent targeted to an antigen expressed by normal myeloid precursors, hematological adverse effects were common. Most patients had fever, chills, and grade 4 neutropenia. Most needed to be hospitalized, usually for fever and neutropenia. Eight patients had grade 4 increases in bilirubin that were typically reversible. Severe bone pain, seizures, diabetes insipidus, and intracerebral bleeding were observed in individual patients. There were no renal, gastrointestinal, or cardiac toxicities.

Although some of these side effects were significant, they were comparably less severe than the adverse effects of standard AML chemotherapy drugs. Dr. Sievers concluded that CMA-676 was reasonably well tolerated and had an acceptable safety profile.

In addition to the Fred Hutchinson Cancer Research Center, the study was conducted at the University of Chicago, the M.D. Anderson Cancer Center in Houston, the University of Pennsylvania Cancer Center in Philadelphia, the University of Michigan in Ann Arbor, the Hopital Maisonneuve-Rosemont in Montreal, the University of Nebraska in Omaha, the City of Hope National Medical Center in Duarte, California, the University of Maryland in College Park, the University of Miami, Princess Margaret Hospital in Toronto, Canada, and Wyeth-Ayerst Research in Radnor, Pennsylvania.