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Therapeutics > Exam 2 lecture 8 > Flashcards

Exam 2 lecture 8 Flashcards

1
Q

What are the two different kinds of leukemia? WHat is the difference between them?

A
  1. Chronic leukemias
    - chronic myeloid leukemia (CML)
    - chronic lymphocyte leukemia (CLL)
  2. Acute leukemia
    - acyte myeloid leukemia (AML)
    - acute lymphoblastic leukemia (ALL)

chronic is slow growing, but is harder to treat. We can not cure them

Acute leukemias can be cured

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2
Q

Who do leukemia mostly affect

A

children

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3
Q

What is CML and how does it occur?

A

It is unregulated myeloid proliferation that is caused by Philadelphia chromosome (bcr-abl). It turns into a constitutively active TKI

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4
Q

risk factors for CML?

A

ionizing radiation atomic bomb survivor.

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5
Q

Symotoms of CML?

A

usually asymptomatic. CBC is very high.
leukostasis may occur (medical emergency). WBC up into the millions.

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6
Q

Leukostasis risks

A

stroke

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6
Q

diagnosis of CML

A

CBC with differential and CMP with uric acid.
Bone biopsy required.

PCR to assess BCR-ABL transcript

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7
Q

What are the different phases pf CML

A

Chronic phase (90%)- no blasts (no signs of acute leukemia)

accelerated phase- Disease starts growing more rapidly. more blasts and thrombocytopenia and spleen is getting enlarged (10-19% blast)

Blast crisis- terminal stage of CML, clinically resemble acute leukemia. >20% blast

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8
Q

treatment of CML

A

only way to cure CML is allogenic hematopoietic stem cell.

TKIs for disease control.

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9
Q

What are the 3 different response criterias for CML

A

Hematologic response- complete:normal peripheral blood count and no immature cells

cytogenic response

molecular response-
early: BCR-ABL < or = 10%
Major (MMR): BCR-ABL <0.1% or >3 log decrease
Deep: BCR- ABL <0.01%

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10
Q

What is first line tx for CML

A

TKI. (imatinib)

NEVER MISS A DOSE!! risk for mutation increases

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11
Q

What are the 2nd gen tkis

A

Dasatinib, nilotinib, bosutinib.

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12
Q

Adverse effects of TKIs

A

Neutropenia
thrombocytopenia, liver enzyme elevation

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13
Q

Why do we have 2nd gen TKIs

A

some pts do not respond to Imatinib, Side effect profiles might be unfavorable for some patients.

dasatnib, nilotinib and bosutinib are all approved in 1st setting

bosutinib has a lot of GI side effects (not preferred)

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14
Q

3rd gen TKI? What is it approved for?

A

Ponatinib

approved for T315i mutation.

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15
Q

imatinib side effects and metabolism

A

nausea, muscle cramps
CYP3A4 for all TKIs

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16
Q

Dasatinib side effects

A

worst fluid retention and pleural effusion
AVOID ACID SUPPRESSOR

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17
Q

Nilotinib side effects, metabolism

A

Most metabolic symptoms, most QT prolongation
CYP3A4 like all of the others

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18
Q

Bosutinib side effects

A

BOSUTABAD, we do not want this
Diarrhea, hepatotoxicity, GI toxicity

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19
Q

Ponatinib side effects

A

Efficacious against most resistant clones.

ischemic rxns
vascular ecclusions
HTN
pancreatitis

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20
Q

What is a TKI other than ponatinib that can be used in T315I resistant CM

A

asciminib

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21
Q

2nd line tx of CML

A

dose escalation of imatinib

switching to 2nd gen

switch to 3rd gen if T315i mutation present

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22
Q

CML TKI discontinuation criteria

A

Patients may be able to discontinue if

never been in accelerated or blast phase
On TKI therapy for atleast 3 years
BCR-ABL < or = 0.01% (deep molecular response), stable deep molecular response for > 2 yrs

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23
Q

Monitoring imatinib and other TKIs after discontinuation

A
  1. quantifiable PCR
    - monthly for months 1 to 6
    -every other month months 7-12
    every 3 months

Patient must remain in major molecular response < or = 0.1%

loss of MMR-> restart TKI within 4 weeks

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24
Q

CLL usually diagnosed in

A

old white men

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25
Q

How does CLL happen?

A

In CML (myeloid), myeloid cell grew a little more rapidly and lacked apoptosis, same thing but this is in lymphoid.

transformation of Lymphocyte into a malignant cell, clonal expansion and lymphocyte accumulation

CLL can convert to an aggressive lymphoma like CML (richeters transformation)

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26
Q

CLL presentation

A

Indolent disease, may be an incidental finding.

constitutional symptoms-
lymphadenopathy
anemia

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27
Q

What are the two important cytogenetics associated with CLL

A

Del (11q)- is associated with extensive lymphadenopathy, disease progression and shorter median survival. May respond well to fludabarine + alkylating agents

Del 17p is associated with worst outcomes. reflects the loss of key tumor suppressor TP53 gene. poor reponse to chemo

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28
Q

where does 17p deletion occur

A

G2 check point

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29
Q

how do we diagnose CLL

A

bone marrow biopsy and flow cytometry to look at cell surface markers CD 19, 20, 5, 23, 10

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30
Q

CLL treatment reserved for what type of patients

A

Stage III or IV disease
clinical symotoms
end organ dysfunction

WE DO NOT TREAT A NUMBER

Usually, CLL patients can have super high WBC counts and still be asymptomatic

31
Q

FIrst line treatment of CLL

A

If they have Del (17p)/TP52 mutation-
1. BTK inhibitor +/- obinutuzumab (continous tx)
2. Venetoclax + obinutuzumab

if they do not have del (17p)/TP53 mutation-
1. BTK inhibitor +/- anti CD20 mAb (continous treatment)
2. Venetoclax + obinutuzumab (fixed duration treatment)
3. chemo-immuno therapy (IGHV-mutated disease

32
Q

what are some BTK inhibitor drugs

A

acalabrutinib
zanubrutinib

BRUT

both have less a fib than ibrutinib

33
Q

what type of drug is venetoclax? MOA?

A

Inhibits BCL 2, resulting is release of BIM and PUMA. BIM and PUMA are pro apoptotic proteins

34
Q

What are some drug interactions of venetoclax

A

p-GP and CYP 3A4

35
Q

What do we do with relapse of CLL or refractory disease

A

treat the symptoms

36
Q

toxicities of the BTK inhibitors and venetoclax

A

ibrutinib- highest chance of a fib and bleeding
venetoclax- tumor lysis syndrome (ramp up dosing)
pgp and cyP3a4 drug intercations.

acalabrutinib- transiet lymphocytosis ((transient increase in lymphocyte count, does not signify disease progression)
zanubrutinib- transient lymphocytosis (transient increase in lymphocyte count, does not signify disease progression)

37
Q

how does AML happen?

A

Arises from single leukemic cell–> expands and acquires additional mutations to undergo proliferation . Leukemic cell have growth advantage leads to crowding out normal cells.

38
Q

Risk factors for AML

A

-Myelodysplastic syndrome
-alkylating agents and topo II use
-genetic predispositions

39
Q

presentation of AML

A

patients will have signs of pancytopenia (anemia, neutropenia, thrombocytopenia)
bone pain ( due to overactive bone marrow)
gum hypertrophy

40
Q

how to diagnose AML

A

bone marrow biopsy- greater than 20% blasts

41
Q

What is a gene in AML that is associated with poor prognosis

A

FLT3-ITD

42
Q

WHat is a favorbale (good) risk for AML

A

core binding factor, responds really well to chemo

43
Q

WHat are FLT3 mutations in AML associated with? What are drugs that target this mutation?

A

Associated with
-aggressive disease
-lower chance of complete remission
-higher rate of relapse

TKIs can target this mutation (midostaurin, quizartinib)
gliternib can only be used 2nd line

44
Q

How to treat AML

A

Bone marrow biopsy prior to treatment

1st goal is to induce complete remission (induce remission) usually by chemo

when counts come back we do another bone marrow biopsy

once we get remission, we give them more therapy (consolidation) (prevents relapse)

45
Q

What consolidation do we do for AML treatment

A

WE CAN NOT TAKE A PATIENT WITH ACTIVE ACUTE LEUKEMIA to stem cell transplant, it will not work. They have to be in a complete remission.

  1. favorable risk- chemotherapy
  2. unfavorable risk- stem cell transplant (only after reission)
46
Q

What induction regimens do we give with AML

A
  1. intensive induction eligible- continuous infusion cytarabine + anthracycline (7+3 regimen, most common) (idarubicin/danorubicin anthracyclin used) (mostly used in non frail patients)
  2. intensive induction ineligible- venetoclax +hypo- methylating agents (if patient can not tolerate 7+3)
  3. supportive care- blood products, prophylactic anti infectives, hydroxyurea
47
Q

WHat side effects to worry about in anthracyclines

A

cardiotoxicity (idarubicin and danoribicin)

48
Q

7+3 toxicity

A

Most side effects happen at naters.

anthracyclines may cause mucositis and nausea

49
Q

After complete remission of due to induction in AML, what do we do?

A

consolidation occurs next

  1. high dose cytarabine (HiDAC)

or

  1. continue venetoclax + hypomethylating agent for 2 cycles until complete response achieved. If they do not get a complete response after 2 cycles, we need to seek another regimen, if they do get a CR we can continue it indefinitely.
  2. Allogenic stem cell transplant
50
Q

Side effects about HiDAC

A

Cerebellar side effects (mimic drunkness)
chemical conjunctivitis

BEfore every dose we check for cerebellar toxicity

51
Q

WHat is a hypomethylating agent to be used with venetoclax

A

azacitidine

52
Q

What is APL

A

a subset of AML (acute promyelotic leukemia)

10% of all AML

53
Q

WHat gene is responsible for APL

A

t (15;17) = PML: RARA

54
Q

treatment of APL. SIde effects?

A

completely different treatment form AML
we give ATRA (all trans retinoic acid) and Arsenic trioxide (ATO)

watch out for differentiation syndrome

arsenic might cause QT prolongation

55
Q

signs and symptoms of differentiation syndrome

A

weight gain
fluid changes
cognition changes

56
Q

How to treat differentiation syndrome

A

Hydroxyurea and steroids

57
Q

diagnosis of AML

A

bone marrow biopsy

58
Q

What is ALL? age of onset? Where is it most common?

A

Acyte lymphoblastic leukemia

median age- 17

Most common leukemia in children

59
Q

How does ALL happen?

A

Arise from single leucemic cell-> expands and acquires additional mutations–> proliferation resulting in monoclonal popylation of leukemic cell

60
Q

risk factors of ALL

A

genetic- 4% of children carry ALL germline cancer predisposition
radiotherapy
Viral infection (EBV)

61
Q

presentation of ALL

A

signs of pancytopenia (anemia, neutropenia, thrombocytopenia)
bone pain
gum hypertrophy
lymphadenopathy
abdominal mass
painless testicular enlargement.
CNS involvement (every patient will get therapy for brain

62
Q

Diagnosis of ALL? DO they stain purple like AML? Majority of ALL are what kind of cell?

A

bone marrow biopsy with greater or equal to 20% blasts

DO not stain purple like AML

Majority of ALL are B cell like lymphomas

63
Q

What are the different cytogenic characteristics of ALL

A

standard risk- absence of all abnormalities
Hyperdiploidy
BCR : ABL without underlying CML

high-
hypodiploidy
Unfavorable cytogenics
TP53 mutations
BCR : ABL with CML precursor

64
Q

what percent of ALL have ph+? What does this mean? How to treat this?

A

25% of adults. Worse prognosis.

Use TKI in chemo

65
Q

ALL adult treatment overview

A

Induce remission

consolidate by giving chemo or blinatumomab or allogeneic stem cell transplant

maintenance therapy

ALL PATIENTS SHOULD BE GIVEN CNS PROPHYLAXIS OR TREATE+MENT

66
Q

Why should ALL be given CNS prophylaxis or treatment?

A

ALL can hide in sanctuary sites (brain and testes)

most protocols include intrathecal chemo

67
Q

ALL treatment based on Ph+ and Ph-

A
  1. Ph+
    based on age/comorbidity

TKI + chemo
TKI+ steroids
TKI + blinatumomab

maintenance:
TKI + vincristine + prednisone

  1. ph-
    a) adults and young adolescents (AYA)
    I) pediatric inspired regimen or multiagent chemo

b) 65+ (or comorbidities)
I) Multiagent chemo
II) inotuzumab ozogamicin
III) palliative steroids

c) <65
multiagent chemo

68
Q

What are the multiagent chemo we use with ALL

A

HyperCVAD

69
Q

What is HyperCVAD consisting of? How to give it?

A

Hyper-fractionated cyclophosphamide
Vincristine
Doxorubicin (Adriamycin)
Dexamethasone

Two part regimen
Part A- HyperCVAD
Part B- methylprednisolone, methotrexate, cytarabine

70
Q

How to give hyperCVAD in ALL

A

Part A (hyper CVAD)

wait 21 days

Part B (methylprednisolone, methotrexate, cytarabine)

and then we do a bone marrow biopsy

71
Q

How many cycles of HYper CVAD

A

4

72
Q

What does blinatumomab bind to?

A

It is a BITE

so it binds CD 19 and CD 3

73
Q

toxicity of blinatumomab

A

Cytokine release syndrome (CRS) and ICANS

74
Q

When do we not start blinatumomab

A

WBC is 15,000 or more

Give them a big dose of steroids before giving dose to reduce wbc

Therapeutics (38 decks)

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