CD33 splicing polymorphism can predict therapeutic efficacy of gemtuzumab ozogamicin in de novo AML

Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 monoclonal antibody that has been shown to improve the survival outcomes and reduce the relapse risk of Acute Myeloid Leukemia patients. Previous reports have shown that the CD33 Single Nucleotide Polymorphism (SNP), rs12459419, was associated with the outcome observed in patients treated with GO.

CD33-SNP, rs12459419 (C > T; Ala14Val), is located within the splice enhancer region of exon-2, leading to expression of an alternate splice isoform lacking exon-2. This alternate splice isoform (D2-CD33), would encode a protein product lacking the IgV domain Loss of the IgV domain can interfere with the binding and clinical efficacy of GO.

In an article published ahead of print in the Journal of Clinical Oncology on 23^rd June 2017, Jatinder K. Lamba from the UF Health Cancer Center, University of Florida, and colleagues discussed results from their study which evaluated the genotype frequency and functional significance of rs12459419, its association with CD33 cell-surface expression on leukemic blasts, and clinical response in AML patients treated with or without GO in the Children Oncology Group (COG) AAML0531 trial (NCT00372593).

In this study, the genotype frequency of rs12459419 was measured in 816 de novo AML patients (0–29 years) who were enrolled in the COG AAML0531 trial. Patients were randomly assigned to receive either five courses of standard chemotherapy (No-GO arm [n = 408]) or five courses of standard chemotherapy plus two doses of 3 mg/m² GO (GO arm [n = 408]).

The key results of the study were:

• CD33 SNP rs12459419 genotype frequency in all patients; CC genotype = 51% (n = 415), CT genotype = 39% (n = 316) and TT genotype = 10% (n = 85)
• The presence of rs12459419 variant T allele was significantly associated with increased levels of an alternatively spliced D2-CD33 isoform lacking exon-2; P < 1.0E ^-6
• T-allele was significantly associated with lower diagnostic leukemic cell CD33 surface intensity; P < 1.0E ^-6
• Relapse Risk (RR) in patients with CC genotype in the GO and No-GO arm; 26% ± 7% vs 49% ± 9%, HR = 0.468, P < 0.001
• Disease Free Survival (DFS) in patients with CC genotype in the GO and No-GO arm; 65% ± 7% vs 46% ± 9%, HR = 0.597, P = 0.004
• There was no clinical benefit in terms of RR or DFS in patients with either the CT or TT genotype in both the GO and No-GO arms
• CD33 CC genotype was an independent predictor of response to GO for RR (HR = 0.45, P < 0.001) and DFS (HR = 0.57, P = 0.03)

In summation, AML “patients with the CC genotype for rs12459419 have a substantial response to GO”. The authors concluded by suggesting that the CC genotype may be a potential biomarker for the selection of patients that would likely have a significant response to GO.

The authors further added that “the knowledge of CD33 genotype and prediction of response to GO provides opportunities to use patient genotypes for selecting CD33-targeted therapies” and proposed that “all prior GO containing studies be re-evaluated for response on the basis of the patients’ CD33 genotype”.

Abstract

Purpose

Gemtuzumab ozogamicin (GO), a CD33-targeted immunoconjugate, is a re-emerging therapy for acute myeloid leukemia (AML). CD33 single nucleotide polymorphism rs12459419 C>T in the splice enhancer region regulates the expression of an alternatively spliced CD33 isoform lacking exon2 (D2-CD33), thus eliminating the CD33 IgV domain, which is the antibody-binding site for GO, as well as diagnostic immunophenotypic panels. We aimed to determine the impact of the genotype of this splicing polymorphism in patients with AML treated with GO-containing chemotherapy.

Patients and Methods

CD33 splicing single nucleotide polymorphism was evaluated in newly diagnosed patients with AML randomly assigned to receive standard five-course chemotherapy alone (No-GO arm, n = 408) or chemotherapy with the addition of two doses of GO once during induction and once during intensification (GO arm, n = 408) as per the Children’s Oncology Group AAML0531 trial.

Results

The rs12459419 genotype was CC in 415 patients (51%), CT in 316 patients (39%), and TT in 85 patients (10%), with a minor allele frequency of 30%. The T allele was significantly associated with higher levels of D2-CD33 transcript (P < 1.0E−6) and with lower diagnostic leukemic cell surface CD33 intensity (P < 1.0E−6). Patients with the CC genotype had significantly lower relapse risk in the GO arm than in the No-GO arm (26% v 49%; P < .001). However, in patients with the CT or TT genotype, exposure to GO did not influence relapse risk (39% v 40%; P = .85). Disease-free survival was higher in patients with the CC genotype in the GO arm than in the No-GO arm (65% v 46%, respectively; P = .004), but this benefit of GO addition was not seen in patients with the CT or TT genotype.

Conclusion

Our results suggest that patients with the CC genotype for rs12459419 have a substantial response to GO, making this a potential biomarker for the selection of patients with a likelihood of significant response to GO.