Exam 2 lecture 8 Flashcards
What are the two different kinds of leukemia? WHat is the difference between them?
- Chronic leukemias
- chronic myeloid leukemia (CML)
- chronic lymphocyte leukemia (CLL) - 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
Who do leukemia mostly affect
children
What is CML and how does it occur?
It is unregulated myeloid proliferation that is caused by Philadelphia chromosome (bcr-abl). It turns into a constitutively active TKI
risk factors for CML?
ionizing radiation atomic bomb survivor.
Symotoms of CML?
usually asymptomatic. CBC is very high.
leukostasis may occur (medical emergency). WBC up into the millions.
Leukostasis risks
stroke
diagnosis of CML
CBC with differential and CMP with uric acid.
Bone biopsy required.
PCR to assess BCR-ABL transcript
What are the different phases pf CML
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
treatment of CML
only way to cure CML is allogenic hematopoietic stem cell.
TKIs for disease control.
What are the 3 different response criterias for CML
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%
What is first line tx for CML
TKI. (imatinib)
NEVER MISS A DOSE!! risk for mutation increases
What are the 2nd gen tkis
Dasatinib, nilotinib, bosutinib.
Adverse effects of TKIs
Neutropenia
thrombocytopenia, liver enzyme elevation
Why do we have 2nd gen TKIs
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)
3rd gen TKI? What is it approved for?
Ponatinib
approved for T315i mutation.
imatinib side effects and metabolism
nausea, muscle cramps
CYP3A4 for all TKIs
Dasatinib side effects
worst fluid retention and pleural effusion
AVOID ACID SUPPRESSOR
Nilotinib side effects, metabolism
Most metabolic symptoms, most QT prolongation
CYP3A4 like all of the others
Bosutinib side effects
BOSUTABAD, we do not want this
Diarrhea, hepatotoxicity, GI toxicity
Ponatinib side effects
Efficacious against most resistant clones.
ischemic rxns
vascular ecclusions
HTN
pancreatitis
What is a TKI other than ponatinib that can be used in T315I resistant CM
asciminib
2nd line tx of CML
dose escalation of imatinib
switching to 2nd gen
switch to 3rd gen if T315i mutation present
CML TKI discontinuation criteria
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
Monitoring imatinib and other TKIs after discontinuation
- 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
CLL usually diagnosed in
old white men
How does CLL happen?
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)
CLL presentation
Indolent disease, may be an incidental finding.
constitutional symptoms-
lymphadenopathy
anemia
What are the two important cytogenetics associated with CLL
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
where does 17p deletion occur
G2 check point
how do we diagnose CLL
bone marrow biopsy and flow cytometry to look at cell surface markers CD 19, 20, 5, 23, 10
CLL treatment reserved for what type of patients
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
FIrst line treatment of CLL
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
what are some BTK inhibitor drugs
acalabrutinib
zanubrutinib
BRUT
both have less a fib than ibrutinib
what type of drug is venetoclax? MOA?
Inhibits BCL 2, resulting is release of BIM and PUMA. BIM and PUMA are pro apoptotic proteins
What are some drug interactions of venetoclax
p-GP and CYP 3A4
What do we do with relapse of CLL or refractory disease
treat the symptoms
toxicities of the BTK inhibitors and venetoclax
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)
how does AML happen?
Arises from single leukemic cell–> expands and acquires additional mutations to undergo proliferation . Leukemic cell have growth advantage leads to crowding out normal cells.
Risk factors for AML
-Myelodysplastic syndrome
-alkylating agents and topo II use
-genetic predispositions
presentation of AML
patients will have signs of pancytopenia (anemia, neutropenia, thrombocytopenia)
bone pain ( due to overactive bone marrow)
gum hypertrophy
how to diagnose AML
bone marrow biopsy- greater than 20% blasts
What is a gene in AML that is associated with poor prognosis
FLT3-ITD
WHat is a favorbale (good) risk for AML
core binding factor, responds really well to chemo
WHat are FLT3 mutations in AML associated with? What are drugs that target this mutation?
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
How to treat AML
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)
What consolidation do we do for AML treatment
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.
- favorable risk- chemotherapy
- unfavorable risk- stem cell transplant (only after reission)
What induction regimens do we give with AML
- intensive induction eligible- continuous infusion cytarabine + anthracycline (7+3 regimen, most common) (idarubicin/danorubicin anthracyclin used) (mostly used in non frail patients)
- intensive induction ineligible- venetoclax +hypo- methylating agents (if patient can not tolerate 7+3)
- supportive care- blood products, prophylactic anti infectives, hydroxyurea
WHat side effects to worry about in anthracyclines
cardiotoxicity (idarubicin and danoribicin)
7+3 toxicity
Most side effects happen at naters.
anthracyclines may cause mucositis and nausea
After complete remission of due to induction in AML, what do we do?
consolidation occurs next
- high dose cytarabine (HiDAC)
or
- 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.
- Allogenic stem cell transplant
Side effects about HiDAC
Cerebellar side effects (mimic drunkness)
chemical conjunctivitis
BEfore every dose we check for cerebellar toxicity
WHat is a hypomethylating agent to be used with venetoclax
azacitidine
What is APL
a subset of AML (acute promyelotic leukemia)
10% of all AML
WHat gene is responsible for APL
t (15;17) = PML: RARA
treatment of APL. SIde effects?
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
signs and symptoms of differentiation syndrome
weight gain
fluid changes
cognition changes
How to treat differentiation syndrome
Hydroxyurea and steroids
diagnosis of AML
bone marrow biopsy
What is ALL? age of onset? Where is it most common?
Acyte lymphoblastic leukemia
median age- 17
Most common leukemia in children
How does ALL happen?
Arise from single leucemic cell-> expands and acquires additional mutations–> proliferation resulting in monoclonal popylation of leukemic cell
risk factors of ALL
genetic- 4% of children carry ALL germline cancer predisposition
radiotherapy
Viral infection (EBV)
presentation of ALL
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
Diagnosis of ALL? DO they stain purple like AML? Majority of ALL are what kind of cell?
bone marrow biopsy with greater or equal to 20% blasts
DO not stain purple like AML
Majority of ALL are B cell like lymphomas
What are the different cytogenic characteristics of ALL
standard risk- absence of all abnormalities
Hyperdiploidy
BCR : ABL without underlying CML
high-
hypodiploidy
Unfavorable cytogenics
TP53 mutations
BCR : ABL with CML precursor
what percent of ALL have ph+? What does this mean? How to treat this?
25% of adults. Worse prognosis.
Use TKI in chemo
ALL adult treatment overview
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
Why should ALL be given CNS prophylaxis or treatment?
ALL can hide in sanctuary sites (brain and testes)
most protocols include intrathecal chemo
ALL treatment based on Ph+ and Ph-
- Ph+
based on age/comorbidity
TKI + chemo
TKI+ steroids
TKI + blinatumomab
maintenance:
TKI + vincristine + prednisone
- 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
What are the multiagent chemo we use with ALL
HyperCVAD
What is HyperCVAD consisting of? How to give it?
Hyper-fractionated cyclophosphamide
Vincristine
Doxorubicin (Adriamycin)
Dexamethasone
Two part regimen
Part A- HyperCVAD
Part B- methylprednisolone, methotrexate, cytarabine
How to give hyperCVAD in ALL
Part A (hyper CVAD)
wait 21 days
Part B (methylprednisolone, methotrexate, cytarabine)
and then we do a bone marrow biopsy
How many cycles of HYper CVAD
4
What does blinatumomab bind to?
It is a BITE
so it binds CD 19 and CD 3
toxicity of blinatumomab
Cytokine release syndrome (CRS) and ICANS
When do we not start blinatumomab
WBC is 15,000 or more
Give them a big dose of steroids before giving dose to reduce wbc
