CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report from Randomized Phase III Children's Oncology Group Trial AAML0531
Gemtuzumab ozogamicin (GO) is a monoclonal antibody targeted against CD33 with known activity in AML. GO was studied in conjunction with standard five-course chemotherapy in the COG AAML0531 trial. A small pilot study indicated that there is an association between a SNP in CD33 (rs12459419) and the patient's response to GO. Specifically, CT and TT SNP genotypes are associated with a loss of exon 2, which contains the GO binding region, while the CC genotype preserves this binding region. The purpose of this study was to quantify the impact of this in patients with AML treated with GO and standard chemotherapy as part of AAML0531.
The COG AAML0531 trial enrolled patients with AML and randomized them to receive either a standard five-course chemotherapy or chemotherapy with the addition of two doses of GO (N=816; 50% received GO). Genotype at the CD33 SNP were determined at diagnosis for all patients.
Of the 816 patients, 415 had the CC genotype, 316 (39%) had the CT genotype and 85 (10%) had the TT genotype. There was no difference in genotype frequency by sex, treatment arm, disease characteristics or receipt of HSCT during treatment; however, there was a significantly higher rate of the SNP in white patients than in black patients (P=0.001). Patients with the CC genotype had a signficantly lower relapse risk in the GO arm of the trial compared to the No-GO arm (26% vs 49%; P=0.001), and higher disease-free survival (65% vs 46%; P=0.004). There was no difference found for the patients with CT or TT genotypes between the two treatment arms for either relapse rate or disease-free survival.
The limitations of this study include the incomplete understanding of the CD33 rs12459419 mechanism of action. Given the complexity of the effects of various promoter regions and other molecular factors, it is important to fully elucidate these mechanisms to understand the implications of the SNP better.