Germline mutations

Question 1

Germline Mutations

Answer 1

Heritable variations found within the individual

Question 2

Acute lymphoblastic leukemia (ALL)

Answer 2

bone marrow/blood cancer

increase lymphoblast B/T lymphocytes

Tx with oral 6-mercaptopurine 50 mg

Question 3

TPMT (good)

Answer 3

converts 6-MP to inactive form of 6-MMP

Question 4

NUDT15 (good)

Answer 4

inactivates thioguanine nucleotides TGN (toxic)

Question 5

Low NUDT and TPMT

Answer 5

hematological toxicity via reduced RBCs, WBCs, platelets

Question 6

TPMT *2, *3A, *3C

Answer 6

reduced function, more TGN

Question 7

Pts with no TPMT activity

Answer 7

increase risk of 6-MP toxicity, dose reduction of 6-MP

Question 8

Irinotecan

Answer 8

inhibits topoisomerase 1, causing cell death

1st line for metastatic colorectal cancer

Question 9

SN-38

Answer 9

active metabolite of Irinotecan, incactivated by UGT1A1

Question 10

UGT1A1*28

Answer 10

Gilbert’s syndrome PK AND PD

Most studied

Reduced function causes decreased function of SN-38 metabolism increase risk of neutropenia and diarrhea

Question 11

Irinotecan UGT1A1*28 dosing

Answer 11

should be lowered by 1 level, precise reduction not known SN-38 toxicity

Question 12

SN-38 Toxicity

Answer 12

Genotyping for UGT1A1 not widely accepted

Question 13

Known predictive factors for toxicity

Answer 13

Age >/= 65 yrs, monitor; 70 yrs, dose reduce
Prior pelvic and abdominal radiotherapy
Poor performance status
Increased bilirubin concentration

Question 14

TPMT/NUDT15

Answer 14

genotyping performed prior to 6-MP initiation

Question 15

UGT1A1 genotyping

Answer 15

predictive for toxicity, less common testing done for irinotecan