TKIs in Colon Cancer, CLL

Question 1

Many colon cancers have constitutively active ________

Answer 1

Ras or Raf mutations downstream from EGFR

Question 2

Panitumumab class

Answer 2

EGFR antibody

Question 3

Panitumumab quite active in

Answer 3

EGFR driven diseases:
colon cancer
Squamous cancers of the head and neck,
Squamous (HPV-driven) cancers of cervix and penis

Question 4

Panitumumab vs Cetuximab

Answer 4

Cetuximab was the first, but is now seldom used.

Panitumumab is associated with fewer infusion reactions.

Question 5

EGFR in colon vs lung

Answer 5

EGFR is often overexpressed in colon cancer, but unlike in Lung, is not commonly mutated

Question 6

Blocking antibodies against EGFR only work when

Answer 6

the cells have wild-type RAS and RAF

Question 7

most common leukemia in adults

Answer 7

Chronic lymphocytic leukemia

Question 8

CLL: Chronic example of a disease of _____, not ______

Answer 8

accumulation, not over proliferation

Question 9

CLL phenotypes

Answer 9

Has a node-predominant phenotype (SLL) and a leukemia phenotype (CLL). These are the same disease.

Question 10

CLL cure rate

Answer 10

Is generally considered incurable, but most patients die with it, not of it.

Question 11

CLL commonly presents with

Answer 11

autoimmune phenomena such as:
Immune thrombocytopenic purpura (ITP)
Auto-immune hemolytic anemia (AIHA)
Auto-immune agranulocytosis

Question 12

CLL patients typically have

Answer 12

hypogammaglobulinemia and often present with unusually virulent infections

Question 13

CLL often driven by

Answer 13

constitutive expression of non-mutated Bruton’s Tyrosine Kinase (BTK)

Question 14

historical standard tx for CLL

Answer 14

chlorambucil

Question 15

Rituximab

Answer 15

CD20 antibody

CLL

Question 16

Use of fludarabine and cyclophosphamide with Rituximab (FCR) was an incremental advance but —

what disease

Answer 16

this was extremely immunosuppressive and dangerous

CLL

Question 17

what revolutionized treatment for CLL

Answer 17

BTK inhibitors

Question 18

Site of action for ibrutinib

Answer 18

Covalent modifier of ATP binding site (Cysteine 481) on Bruton’s Kinase

Question 19

what does ibrutinib treat

active when?

Answer 19

CLL

Active against CLL with del 17p and del 11q which were largely refractory to existing options

Question 20

most common source of resistance to BTK inhibitors (CLL)

Answer 20

Most common is C481S, changing from nucleophilic –SH in active site to –OH.

Question 21

Other source of resistance to BTK inhibitors for CLL

Answer 21

Others are mutations in PLC-gamma, the main substrate for BTK (make constitutively active PLC-gamma)

Question 22

Idelalisib

Answer 22

blocks downstream of BTK (CLL)

Question 23

Venetoclax

Answer 23

the first Bcl-2 modulator to reset apoptotic threshold (CLL)

Question 24

single most successful approach to treating CLL yet.

Answer 24

inhibition of BTK