Anti-Leukemic Drug Gemtuzumab Ozogamicin May Benefit Some AML Patients

A new study in JCO suggests that genetic variations within AML patients with CD33 may predict their response to gemtuzumab ozogamicin.

An old treatment may have a new role in combating acute myeloid leukemia (AML). Researchers at the University of Florida reported in the Journal of Clinical Oncology that genetic variations within patients with CD33 may be able to predict the effectiveness of the anti-leukemic drug gemtuzumab ozogamicin (GO). Cancer cells with adequate CD33 allow GO to bind to it and enter the cell, eventually killing it. Cells without CD33 or with altered CD33 due to genetic variation will not respond to GO.

In 2000, GO received accelerated approval from the U.S. Food and Drug Administration for treating relapsed AML in patients older than 60. However, it was withdrawn from the market when the drug’s benefits were questioned during postmarketing clinical trials. Now, subsequent studies in adult and pediatric AML patients are suggesting the drug may have been prematurely withdrawn. This current investigation suggests it may be possible to identify the subset of patients who have the potential to benefit from this agent.

“Gemtuzumab is a re-emerging drug that holds promise in AML treatment and binds to IgV domain of CD33. Our study identified a splicing polymorphism (C>T) in CD33 that results in loss of IgV domain and thus predicts clinical response to gemtizumab in AML patients. Patients with variant T allele that results in CD33 without IgV domain show no difference in outcome with or without gemtuzumab,” said lead study author Jatinder Lamba, PhD, associate professor of pharmacotherapy and translational research at the University of Florida in Gainesville.

The researchers observed a dramatic reduction in relapse risk from 49% to 26% and improved survival when given GO in patients with reference C allele that codes for full length CD33. Such a significant impact is rarely seen in AML, according to Dr. Lamba.

CD33 splicing single-nucleotide polymorphism was evaluated in newly diagnosed patients with AML randomly assigned to receive standard five-course chemotherapy alone (n = 408) or chemotherapy with the addition of two doses of GO once during induction and once during intensification (n = 408).

In this study, the rs12459419 genotype was CC in 415 patients (51%) and CT in 316 patients (39%). The rs12459419 genotype was TT in 85 patients (10%), with a minor allele frequency of 30%.  Disease-free survival was higher in patients with the CC genotype in the GO arm than in the No-GO arm (65% vs 46%). However, this benefit from GO was not observed in patients with the CT or TT genotype.

“We are very excited as our results show a dramatic impact of an inherited genetic variation to predict gemtuzumab response at much greater level than any of the known factors reported so far,” Dr. Lamba told OncoTherapy Network. “This will allow us to personalize gemtuzumab therapy by preemptive genotyping to predict who will benefit from addition of gemtuzumab (which is almost 50% of the AML patient population) to chemotherapy and at the same time avoiding exposure to significant toxicity for patients who are not likely to respond, thus allowing for safe and effective use of gemtuzumab.”