Leukemias

Question 1

CML rseults from

Answer 1

acquired mutations + proliferation of myeloblasts

Question 2

what is characterized by the philadelphia chromosome

Answer 2

CML

Question 3

what is the philadelphia chromosome

Answer 3

Translocation between long arms of chromosomes 9 and 22 = joining of ABL gene of chromosome 9 and BCR gene of chromosome 22 = formation of BCR-ABL fusion oncogene
Results in super long chromosome 9 and shorter chromosome 22 (philadelphia chromosome, Ph+)

Question 4

joining of ABL gene of chromosome ___ and BCR gene of chromosome ___= formation of BCR-ABL fusion oncogene

Answer 4

9, 22

Question 5

what does the BCR-ABL gen cause

Answer 5

production of BCR-ABL protein = abnormal TK that has an ATP bindng site that can transfer phosphate groups to protein substrate, causing CML cells proliferate and avoid apoptosis

Question 6

CML S/S

Answer 6

splenomegaly
suppression of hematopoiesis
leukocytosis or leukostasis
up to 50% asumptomatic due to initial indolent phase of disease

Question 7

what is leukocytosis

Answer 7

WBC >25

Question 8

what is leukostasis

Answer 8

WBC >100

Question 9

dx of CML requires

Answer 9

cytogenetics for philadephia chromosome
molecular testing of QPCR
staging

Question 10

describe the 3 stages of CML and the amount of myeloblasts

Answer 10

chronic phase <10%
accelerated phase 10-20% or persistent leukocytosis, thrombocytosis, thrombocytopenia, splenomegaly unresponsive to tx
blast crisis >20%

Question 11

leukostasis in CML requires

Answer 11

asap hydroxyurea to rapidly lower WBCs + allopurinol to prevent tumor lysis syndrome

Question 12

MOA of BCR-ABL TKis

Answer 12

competitively binds to ATP binding site on BCR-ABL kinase = inhibits phosphorylation of proteins involved with signal transduction for CMl clone proliferation

Question 13

name the 3 TKis for CML

Answer 13

imatinib, dasatinib, nilotinib

Question 14

which TKis should be taken with food

Answer 14

imatinib, dasatinib

Question 15

which TKis should be taken without food? why

Answer 15

nilotinib - increases bioavailability

Question 16

which TKi is acid dependent absorption

Answer 16

dasatinib

Question 17

AEs of BCR-ABL TKis

Answer 17

myelosuppression
fluid retention
N/V
QT interval prolongation
hepatotoxicity
drug rash
diarrhea

Question 18

which TKis has a black box warning for QT prolongation

Answer 18

nilotinib and dasatinib- baseline ECG rec

Question 19

which TKi is most associated with fluid retention

Answer 19

dasatinib

Question 20

reasons for Tki failure

Answer 20

compliance
drug interactions
resistance- point mutation in ABL kinase domain that activates it

Question 21

what is the only cure for CML

Answer 21

allogenic stem cell transplant

Question 22

can CML pts ever d/c TKis

Answer 22

yes if they’ve been on BCR-ABL TKi for at least 5yrs + undetectable disease for 2yrs consecutively (monitor QPCR q1mth)
- may result in 50% relapse rate

Question 23

why are allogenic stem cell transplants rarely done in CML

Answer 23

cause TKis work fine
not everyone has a donor + transplant has many toxicities

Question 24

ALL sx

Answer 24

B sx like weight loss, night sweats, fever
pain in joints/ bones
CNS manifestations
cytopenias

Question 25

what is required for an ALL diagnosis

Answer 25

20% lymphoblasts

Question 26

chemo for ALL is usually the ______ protocol

Answer 26

modified Dana-Farber

Question 27

in addition to chemo, ALL usually adds

Answer 27

BCR-ABL TKi therapy (gene is present in 25% cases)

Question 28

drugs for LL

Answer 28

asparaginase methotrexate chemo

Question 29

asparaginase MOA in ALL

Answer 29

asparaginase hydrolyses all L-asparagine to L-aspartic acid and ammonia so the ALL cells have nothing to use to repro as they can't make themselves

Question 30

asparaginase AEs

Answer 30

severe hypersensitivity rxns- asparaginase from E coli has the highest incidence Prior intradermal test dose is recommended

Question 31

methotrexate is used with _________ intrathecally as ______in ALL

Answer 31

chemo CNS prophylaxis

Question 32

methotrexate MOA

Answer 32

folate antagonist- inhibits dihydrofolate reductase required to convert folic acid to tetrahydrofolate (required for purine and thymidylate synthesis)

Question 33

what is an important factor to make sure methotrexate is safe

Answer 33

keep urine alkaline with sodium bicarb so it doesn't precipitate and cause kidney damage - start sodium bicarb PO/IV day before infusion

Question 34

methotrexate therapy usually requires ____ rescue

Answer 34

leucovorin

Question 35

how is leucovorin rescue used with methotrexate

Answer 35

Must receive doses of leucovorin q6h until lvls undetectable to rescue pt from life threatening myelosuppression and other toxicities

Question 36

methotrexate AEs

Answer 36

myelosuppression, organ toxicities (nephrotoxicity, hepatotoxicity, neurotoxicity)- pts require rescue leucovorin

Question 37

TLS results in what chem anomalies

Answer 37

hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia

Question 38

RFs for TLS

Answer 38

large bulky tumor, high LDH or WBCs, higher baseline SCr or uric acid high chemo aggressive lymphoma or leukemia

Question 39

sx of TLS

Answer 39

N/V, acute kidney injury (↑SCr), ↓urine output, edema, lethargy, HPTN, ECH changes (arrhythmias), muscle twitching, cramping, numbness, weakness, tetany, confusion and seizures

Question 40

drugs for TLS prevention

Answer 40

allopurinol rasburicase

Question 41

how does allopurinol treat TLS

Answer 41

inhibits xanthine oxidase (enzyme responsible for formation of uric acid)

Question 42

how does rasburicase treat TLS

Answer 42

recomb urate-oxidase enzyme that converts uric acid to allantoin + degrades uric acid already formed

Question 43

how to treat asymptomatic hyperkalemia from TLS

Answer 43

oral or rectal sodium polystyrene sulphonate

Question 44

how to treat symptomatic hyperkalemia from TLS

Answer 44

rapid acting insulin and 25% dextrose infusion

Question 45

what is the most common form of acute leukemia

Answer 45

AML

Question 46

sx of AMl

Answer 46

Rapidly fatal if not treated Cytopenias- drop in other cell lines (pancytopenia) Anemia: fatigue, malaise, weakness Thrombocytopenia: easy bruising, petechiae, ecchymosis, heavy and/ or long menses, bleeding like epistaxis, gingival bleed, conjunctival hemorrhage Neutropenia: infection, s/s may be absent due to nonfunctioning malignant WBC clones High myeloblast count

Question 47

diganosis of AML is

Answer 47

>20% myeloid blasts

Question 48

what are some predictors of outcome in adult ML

Answer 48

redictors of outcomes in adult AML Age: Outcomes better in <60yrs Performance status: fitter pts do better Duration of first remission Cytogenetics and molecular abnormalities- MOST IMPORTANT

Question 49

treatment plan for AML

Answer 49

Induction chemo → consolidation chemo → allogeneic stem cell transplant

Question 50

what is usually induction chemo for AML

Answer 50

7+3 7 days of continuous infusion cytarabine (rash common) 3 days of IV push anthracycline (idarubicin or daunorubicin) + midostaurin for FLT3 positive AML

Question 51

T or F: AML pts undergoing 7+3 still require allopurinol to prevent TLS

Answer 51

T- though TLS not as common as in ALL

Question 52

consolidation therapy in AAML is done with

Answer 52

HIDAC- high dose ARA-C (cytarabine)

Question 53

HIDAC AEs

Answer 53

ocular toxicity (Excessive tearing, pain, photophobia, sensation of foreign body) cerebellar toxicity

Question 54

how to treat ocular toxicity caused by HIDAC for AML

Answer 54

steroid eyedrops (dexamethasone or prednisolone) for duration of HIDAC therapy + 48hrs after last dose

Question 55

list some purposes of an allogenic HSCT

Answer 55

Rescue recipient from myeloablative therapy Replace abnormal hematopoietic component Establish graft vs leukemia (tumor) effect where donor cells destroy residual malignant cells in host - advantage over autologous HSCT

Question 56

stem cell sources for allogenic HSCT

Answer 56

boen marrow peripheral blood ubilical cord blood