lecture 22 -- germline mutations Flashcards
(16 cards)
what is the MOA of mercaptopurine?
antimetabolite that inhibits purine nucleotide synthesis (involved in DNA replication)
what are the characteristics of mercaptopurine?
cancer type – pediatric ALL
genes – TPMT, NUDT15
phenotype – myelosuppression
what is the MOA of irinotecan?
inhibits topoisomerase I (involved in DNA replication and transcription)
what are the characteristics of irinotecan?
cancer – colorectal, lung
genes – UGT1A1
phenotype – neutropenia, diarrhea
dosed in mg/m2
what is ALL?
acute lymphoblastic leukemia
cancer of the blood and bone marrow
most common childhood malignancy with a 90% survival rate
what is the recommended treatment of ALL?
maintenance chemotherapy (for up to 2y) including oral 6-mercaptopurine 50mg
how does ALL affect the immune system?
increased production of lymphoblasts, B lymphocytes, or T lymphocytes
decreased granulocytes, RBCs, and platelet production (which can lead to infection, anemia, and easy bleeding)
spreads to CNS
what does low TMPT or low NUDT15 activity mean?
elevated conc of mercaptopurine metabolites
hematological toxicity –> leading to myelosupression
what are TGNs?
thioguanine nucleotides
cytotoxic nucleotides that accumulate in the absence of TMPT
what is different about pts who have inherited little or no TMPT activity?
increased risk for severe toxicity from conventional doses of mercaptopurine so need dose reduction
optimal starting dose for homozygous pt is not established yet
needs to be gentoyped in clinic for this reason
how does having the mutation of UGT1A1*28 influence a pt?
increased risk for neutropenia and severe diarrhea
reduced function decreases SN-38 metabolism
what are the predictive factors for SN-38 toxicity?
age (if 65+ monitor, if over 70 reduce dose)
prior pelvic and abdominal radiotherapy
poor performance
status
increased bilirubin concentration
when should TMPT/NUDT15 genotyping occur?
prior to mercaptopurine initation (also AZA for immunosuppression)
if a positive test result for TMPT/ NUDT15 comes back, what does that mean?
there are reduced function alleles
should be dose reduction, but not defined starting dose yet
when should UGT1A1 genotyping be performed?
less common but could be used irinotecan
what is important to consider with UGT1A1 genotyping?
predictive for toxicity but benefit of higher dose often outweighs risk
important to consider other predictive clinical markers for toxicity when deciding on dose
