Irinotecan response

Individuals who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia following initiation of Irinotecan Hydrochloride Injection, USP treatment.

In a study of 66 patients who received single-agent Irinotecan Hydrochloride Injection, USP (350 mg/m² once-every-3-weeks), the incidence of grade 4 neutropenia in patients homozygous for the UGT1A1*28 allele was 50%, and in patients heterozygous for this allele (UGT1A1 6/7 genotype) the incidence was 12.5%. No grade 4 neutropenia was observed in patients homozygous for the wild-type allele (UGT1A1 6/6 genotype).

When administered as a single-agent, a reduction in the starting dose by at least one level of Irinotecan Hydrochloride Injection, USP should be considered for patients known to be homozygous for the UGT1A1*28 allele. However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment.

UGT1A1 Testing

A laboratory test is available to determine the UGT1A1 status of patients. Testing can detect the UGT1A1 6/6, 6/7 and 7/7 genotypes.

Please review the complete therapeutic recommendations that are located here: (1).

Interpreting Results

The RNPGx has proposed a decision tree for guiding irinotecan prescription based on the UGT1A1 genotype and the protocol’s theoretical dose:

• for low doses (< 180 mg/m² /week), presence of the UGT1A1*28 allele is not a major risk factor (little difference in risk of hematological or digestive toxicity irrespective of the genotype);
• for doses in the 180—230mg/m² spaced by 2—3-week intervals, patients who are homozygous for the UGT1A1*28 allele have a higher risk of hematological and/or digestive toxicity than patients who are heterozygous or non-carriers. For these *28/*28 patients, a 25% to 30% dose reduction is recommended, especially if the patient presents other risk factors for toxicity. Dose can be adjusted for subsequent cycles depending on the tolerance;
• for doses of 240mg/m² or higher spaced by 2—3 weeks intervals, homozygous UGT1A1*28 patients have a greatly increased risk of hematological toxicity (neutropenia) compared with other genotypes, contraindicating administration at this higher dose and leading to discussion of a standard dose depending on the associated risk factors. Administration of an intensive dose (240 mg/m²) is recommended only for *1/*1 patients, or for *1/*28 patients who have no other risk factors and who benefit from intensive surveillance.

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The first-intention of this strategy for analysis of UGT1A1 status is to detect the *28 variant, the most common deficiency variant observed in the Caucasian population, to be performed before initiating treatment. Referring to the level of evidence classification for RNPGx recommendations detailed in the article by Picard et al. in this issue, UGT1A1 genotyping is advisable for a standard dose (180—230mg/m²) and essential for intensified dose (> 240 mg/m²).

Thus, individualized treatment can be proposed based on the UGT1A1 genotype, with either a dose reduction for *28/*28 homozygous patients, or possibly dose intensification for non-carriers of the *28 allele.

For the other UGT1A1 alleles, genotyping is performed by a limited number of laboratories and is considered a second- intention test.

Moreover, the RNPGx suggests that this analysis could be performed concomitantly with other genetic explorations for colorectal cancer patients (search for KRAS, BRAF mutations. . .) and constitutional (search for DYPD variants) in order to guarantee optimal irinotecan therapy within adequate delay for optimal hospital practices.

Please review the complete therapeutic recommendations that are located here: (5).

UGT1A1 Intermediate Metabolizers (IM)NO action is needed for this gene-drug interaction.This genetic variation (IM) is more common in Western populations than the wild-type (*1/*1). This means that treatment is largely geared to patients with this genetic variation. Adjustment of the treatment is therefore not useful.

UGT1A1 Poor Metabolizers (PM)Genetic variation reduces conversion of irinotecan to inactive metabolites. This increases the risk of serious, life-threatening adverse events.Recommendation:1. Start with 70% of the standard doseIf the patient tolerates this initial dose, the dose can be increased, guided by the neutrophil count.

UGT1A1 *1/*28NO action is needed for this gene-drug interaction.This genetic variation (*1/*28) is more common in Western populations than the wild-type (*1/*1). This means that treatment is largely geared to patients with this genetic variation. Adjustment of the treatment is therefore not useful.

UGT1A1 *28/*28Genetic variation reduces conversion of irinotecan to inactive metabolites. This increases the risk of serious, life-threatening adverse events.Recommendation:1. Start with 70% of the standard doseIf the patient tolerates this initial dose, the dose can be increased, guided by the neutrophil count.

Please review the complete therapeutic recommendations that are located here: (4).