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Leukemias

SNPs associated with AML treatment success

HT Staff Print | Email | Discuss
Published: 02/28/13
DNA_microarray_Credit_Guillaume_Paumier_230.jpg
DNA microarray
Credit: Guillaume Paumier

The presence of certain single-nucleotide polymorphisms (SNPs) can help signal which acute myeloid leukemia (AML) patients will benefit from treatment with gemtuzumab ozogamicin (GO), according to a study published in Clinical Cancer Research.

Researchers evaluated how SNPs in CD33 could affect clinical outcomes among pediatric patients treated with GO, an immuno-conjugate between anti-CD33 antibody and a cytotoxin known as calicheamicin, which binds to CD33 on leukemic cells.

In recent clinical trials, GO has been shown to induce remission and improve survival in a subset of patients with AML. However, there is wide inter-patient variation in response.

“The overall goal of our study was to use genetic data to predict beneficial or adverse response to a specific drug, thus opening up opportunities to use this information for drug optimization to achieve maximum therapeutic efficacy and minimum toxicity,” said study author Jatinder Lamba, PhD, of the University of Minnesota in Minneapolis.

“Our hope is that our research could serve as a marker of prognostic significance for clinicians to select the therapy that has the greatest odds of being effective for individual patients based on their CD33 genotype.”

Dr Lamba and her colleagues began this research by genotyping 4 CD33 SNPs—rs35112940 (G>A; Arg304Gly), rs12459419 (C>T; Ala14Val), rs2455069 (A>G; Arg69Gly), and rs1803254 (G>C; 3′UTR)—in 2 cohorts of pediatric patients with AML.

The 242 patients enrolled on the COG-AAML03P1 trial received induction chemotherapy containing GO. And the 172 patients on the St Jude AML02 trial underwent chemotherapy without GO.

In comparing these patients, the researchers found that the coding SNPs, rs35112940 and rs12459419, were significantly associated with clinical endpoints in patients who received GO but not in patients who did not take the drug. 

Among white patients who received GO, the 3-year overall survival rate from remission was 84% ± 8% for those homozygous (GG) for rs35112940, compared to 68% ± 15% for the other genotypes (P=0.018). The homozygous patients had a lower relapse risk and superior disease-free survival as well.

In addition, patients homozygous for the variant allele (TT) for rs12459419 were more likely to have favorable-risk disease than CC and CT genotypes (P=0.034). And homozygous patients had significantly lower diagnostic blast CD33 expression than the other patients (P<0.001).

“[These] findings lead us to believe that genetic variation in CD33 influences how AML patients’ leukemic cells respond to GO,” Dr Lamba said. “Understanding how genetics play a role in how drugs work is extremely useful, particularly for a drug like GO, which has shown a very heterogeneous response in AML patients.”

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