Dasatinib-induced nephrotic syndrome: a case of phenoconversion

We present the case of a 33-year-old chronic myeloid leukemia (CML) female patient, in whom the occurrence of nephrotic syndrome, during the treatment with tyrosine kinase activity inhibitors (TKIs), was potentially influenced by transient phenoconversion. Seven years after the CML diagnosis in 2004 and complete response, the patient experienced pain in the mandible and extremities. After this, imatinib was replaced by nilotinib, but generalized maculopapular rash was presented and successfully treated with antihistamines. The therapy was then discontinued due to planned pregnancy, and the patient experienced a relapse of CML with BCR-ABL/ABL1 transcripts of 18.9%. Dasatinib was introduced, and CML was in remission. Two years later, urine protein levels (6.19 g/L) and erythrocyte sedimentation rate were elevated (ESR=90 mm/3.6 ks). The patient was diagnosed with nephrotic syndrome. With dasatinib dose reduction, urine protein level returned to the reference range. In order to determine the best genotype-guided therapy, the patient underwent pharmacogenomic testing, showing a homozygous CYP3A4 genotype *1/*1, associated with extensive metabolizer (EM) enzyme phenotype, typical for normal rates of drug metabolism for TKIs. However, this was inconsistent with nephrotic syndrome occurrence. A possible explanation would be CYP3A4 EM genotype coding a poor metabolizer enzyme phenotype, leading to the drug accumulation in the patient's blood. This transient phenoconversion can be explained by inflammation with elevated ESR during nephrotic syndrome. This case shows that a broader approach that recognizes genetic, clinical, and epigenomic factors is required for a quality decision on the personalized therapy regimen.