Novel Antibody-Drug Conjugate Targets CD33-Positive AML

Acute myeloid leukemia (AML) is the most common type of acute leukemia that occurs in adults. Advances in treatment of AML have resulted in improved complete remission rates. Patients with AML need aggressive treatment with a goal to achieve complete remission because partial remission gives no significant survival benefit. As a result, researchers are keenly investigating novel therapies to combat this disorder.

CD33 gene expression as target for novel therapy

About 85 to 90 percent of patients with AML have CD33 expression on the surface of myeloblasts, making it a promising target regardless of age, risk factors or underlying heterogeneity. In light of this, researchers have completed a phase 1 trial targeting CD33 with Seattle Genetics’ experimental antibody-drug conjugate (ADC), SGN-CD33A. Anjali Advani, MD, Director of the Inpatient Leukemia Program at Cleveland Clinic’s Taussig Cancer Institute, is involved in the study: 623 Interim Analysis of a Phase 1 Trial of SGN-CD33A in Patients with CD33-Positive Acute Myeloid Leukemia (AML), which will be presented at the 56th American Society of Hematology (ASH) Annual Meeting.

According to Seattle Genetics, SGN-CD33A is designed to remain stable in the bloodstream and release its potent DNA-binding agent once internalized in cells with CD33 expression.

“The open label, 3+3 dose-escalation study is designed to evaluate SGN-CD33A in the areas of safety, tolerability, pharmacokinetics, and anti-leukemic activity.” says Dr. Advani.

Eligible patients must:

• Have CD33-positive AML
• Have relapsed disease following initial complete remission of over 3 months, or have declined conventional induction/consolidation

So far, researchers have treated 40 patients, 48 percent of whom are female, with a median age of 75 (age range – 27 to 86). Twenty of the subjects had relapsed AML after their first complete remission with intensive therapy. Three of these patients had intensive frontline therapy and one additional line of low-intensity therapy. The remaining 20 had declined conventional intensive therapy.

The study is ongoing and enrollment continues, but initial results are encouraging. Adverse events were typically manageable and were generally associated with underlying myelosuppression. Investigators found that SGN-CD33A demonstrated antileukemic activity with 47 percent blast clearance at the 40 mcg/kg dosage level. This experimental therapeutic also demonstrated rapid clearance of marrow blasts in subjects with poor risk factors.

An encouraging future for patients with CD33-positive AML

“The next planned study will evaluate SGN-CD33A in combination with standard induction, post-remission, and/or as a maintenance therapy for younger adults with newly diagnosed AML,” says Dr. Advani.

It’s also anticipated that the lower dose range of SGN-CD33A, when combined with frontline therapy, will have reduced toxicity and may allow for combination with other agents.

Investigators continue to evaluate the efficacy of SGN-CD33A as a maintenance therapy for AML patients.