Novel Immunologic Approach Promising for the Treatment of AML

The following is a report from the Scripps Cancer Center Annual Conference - Clinical Hematology & Oncology 2003, held February 15-18 in San Diego, California.

Gemtuzumab ozogamicin (Mylotarg®, Wyeth Laboratories), an antibody-targeted chemotherapy consisting of a humanized anti-CD33 monoclonal antibody linked to calichaemicin, a potent antitumor antibiotic, has been proven to be an effective treatment with acceptable toxicity for older patients with CD-33 positive acute myeloid leukemia (AML) in first relapse, according to Frederick R. Appelbaum, M.D., speaking at the Scripps Cancer Center's Annual Conference - Clinical Hematology & Oncology 2003.

"The creation of an effective immunologic approach to the treatment of acute myeloid leukemia has been a goal of many researchers over the past two decades," stated Dr. Appelbaum, Head of Medical Oncology and Professor of Medicine, Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, Washington. "Finally, with the development of Mylotarg®, there is one example of a therapy based at least in part on an immunologic approach that has won U.S. Food and Drug Administration (FDA) approval."

Unconjugated Monoclonal Antibodies
Unconjugated monoclonal antibodies can kill tumor cells in one of three ways. They can induce fatal immunologic injury via complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC). Secondly, they can react with cell receptors, resulting in signal transduction events that directly lead to apoptosis without a significant contribution from CDC or ADCC. Finally they can, at least theoretically, block the binding of other factors necessary for cell survival.

The only unconjugated antibodies systemically studied in AML target the CD33 antigen, a glycoprotein found on blasts from more than 90% of cases of AML. It is expressed on almost all normal early myeloid and erythroid progenitors, but is not on normal hematopoietic stem cells or non-hematopoietic tissue. Studies of murine anti-CD33 antibodies show that the antibody could be administered with relative toxicity are that there was a rapid saturation of antigenic sites or leukemic and normal cells. In Phase II studies, a chimeric humanized form of one anti-CD33 antibody, the HuM195, was administered to 35 patients and resulted in transient drops in peripheral blast counts. Only one patient with less than 30% blasts at the start of treatment achieved a complete remission. Attempts to augment the immunologic reactivity of HuM195 by combining it with interleukin 2 (Proleukin®, Chiron) did not lead to a marked increase in clinical activity. Current trials are examining HuM195 in combination with conventional chemo-therapy for patients with AML in first relapse.

Drug Conjugates and Immunotoxins
While unconjugated antibodies to CD33 have little clinical activity in AML, they are, however, able to saturate the antigenic sites on leukemic cells and to internalize after cell surface binding. When this capability is coupled with the fact that CD33 is absent from the surface of normal hematopoietic stem cell and all non-hematopoietic sites, it came to mind that antibodies to CD33 might serve as an effective vehicle to target potent drug conjugates to leukemic cells while sparing normal hematopoietic stem cells and normal organs.

Taking these concepts into consideration, the workers at Wyeth Laboratories together with investigators at the University of Washington, Seattle, developed the immunocon-jugate gemtuzumab ozogamicin. This treatment modality joins a humanized anti-CD33 IgG4 antibody to the antitumor antibody calicheamicin. The humanized monoclonal antibody is selective for the CD33 antigen expressed on normal myeloid precursor cells and leukemic blasts of more than 90% of patients with AML. It's cytotoxic effect leads to sub-stantial myelosuppression.

The antibody is conjugated to a highly potent cytotoxin, a calicheamicin derivative,-using a novel linker technology. Calicheamicin is a member of a new class of anti-tumor antibiotics known as enediynes. The antibiotic acts by cleaving double-stranded DNA at specific sequences. Mylotarg®, therefore, is a targeted treatment for patients with CD33-positive AML. The antibody component of the molecule targets the calicheamicin directly to CD33-positive cells, causing double-stranded breaks in the DNA and ultimately inducing death of the cells.

Clinical Trials with Myotarg® Monotherapy
In a Phase I dose-escalation trial involving 40 relapsed or refractory, CD33-positive AML patients, 20% (8 pts) of these individuals treated with Mylotarg® had leukemic blast cells eliminated from the blood and marrow. The dose escalation went from 0.25 mg/m²/dose to 9 mg/m²/dose every 14 days for 3 days. The dose escalation was stopped at 9 mg/m² because, at that dose, more than 90% of antigenic sites on leukemic cells were saturated.

The combined results of three open-label, single-arm, multicenter, outpatient Phase II studies have recently been reported. The trials, conducted in the United States, Canada, and Europe, enrolled 142 patients with CD33 positive AML in first relapse. The dosing regimen was two 9 mg/m² doses of Mylotarg® 14 days apart, with a 28-day followup after the second dose, without additional anti-leukemic therapy. The median patient age was 61 years (range 22 to 84 years) and the median duration of first remission was 11.1 months.

Overall, 30% of patients achieved remission, defined as less than 5% blasts in marrow, recovery of red blood cell and neutrophil counts to normal, and platelet transfusion independence. Most patients experienced the usual post-infusion syndrome of fever, chills, and hypotension, but this cleared by 8 hours. Although severe myelosuppression was common, mucositis and severe infections were not. Based on these data, Mylotarg® was approved in the US for the treatment of patients with CD33-positive AML in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy.

Clinical Studies with Combination Therapy with Mylotarg® and Chemotherapeutics
More recent Phase II trials have examined the value of Mylotarg® in combination with conventional chemotherapy for initial induction. In one trial, a regimen of daunomycin (Cerubidine®, Bedford) and cytarabine (Cytosar-U®) by continuous infusion on days 1-7 and Mytotarg® on day 4 resulted in an 86% complete response rate among 21 previously untreated AML patients aged 30 to 60 years. In a second study, carried out in the United Kingdom, a similar regimen resulted in complete responses in 87% of 62 previously untreated adults with AML. At the present time, a randomized study is being carried out by the Southwest Oncology Group to test the potential benefit of adding Mylotarg® to initial chemotherapy in younger adults with AML.

©Drug and Market Development 2003

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