Onco 1: Leukemia Flashcards
Anthracycline (class) ADR
- myelosuppression - drop blood count (kind of what we want it to do in treatment of leukemia)
- cardiac tox (life time dose to reduce risk of HF)
cytarabine HiDAC ADR
hidac - high dose
- neurotox (cerebellar/motor area)-> neuro check prior to each dose
- conjunctivitis -> give dexamethasoe eye drops Q6H (or artificial tears Q1-2H) during and 3 days after HiDAC is compelte
- hand-foot syndrome (palmar rash)
gemtuzumab ozogamicin ADR
- infusion related reaction -> premedicate with APAP, benadryl, methylprednisolone
- hepatotox: including fatal veno-occlusive disease
azacitidine ADR
HMA
- constipation -> standing bowel regimen
- low-moderate emetogenicity -> pre medicate with ondansetron
secondary AML
- ## secondary prior to chemo; much poorer outcomes
- anthracyclines
- alkylators
- topoisomerase inhibitors
cytogenetics and AML
- predict ability to obtain remission with induction chemo, risk of relapse, and overall survival
- looks at chromosomal abnormalities in leukemia cells
FMS-like tyrosine kinase (FLT3) mutation
AML
- targetable proliferative mutation
- has subtypes
- internal tadem duplication (ITD) - worse prognosis
- tyrosine kinase domain (TKD)
isocitrate dehydrogenase (IDH) mutation
AML
IDH 1 and 2 are targetable mutations
risk stratification in AML
- based on cytogenetics and mutatiosn
- idnetifies prognosis relative to relapse (risk of relapse after remission)
- poor and intermediate risk likely to relapse without stem cell transplant
“clogged pipe”
AML
- hypercellular bone marrow: immature cells otugrow all other cells - crowding out -> cytopenia
- goal of AML treatment is hypocelllular to allow for normal hematopoeisis
hyperleukocytosis
- onco emergency
- can present with hyperviscosity syndrome (“blood sludging”)
- can present with
- SOB
- vision change
- stroke
- retinal hemorrhage
- resp failure
- cardiac ischemia
- renal failure
management of hyperleukocytosis
hydroxyurea: “count control”, it suppresses it until we can acutely treat - use until pt clinally stable and ready to start chemo
dose is whatever works tbh
hydroxyurea MOA
ribonucleotide reductase inhibitor
hydroxyurea ADR
- N/V/D
- TLS
- long term tox: unlikely to occur in the treatment of hyperleukcytosis dt short duration
- cutaneous vasculitic ulcerations
- mucositis
- alopecia
- hyperpigmentation
AML: who qualifies for aggressive induction chemo
- <60
- > 60 with NO signficiant comorbidites
- aggressvie dsiease
- canditiate for transplant
aggressive inductio chemo treatment pathway for AML
- cytarabine 7 days+ anthracyline 3 days (daunorubicin or idarubacin)
- bone marrow biopsy at day 14
- if pt leukemia free at bone biopsy: wait for count recovery and re-biopsy for documentation of complete remission; if NOT, reinduction or salvage therapy
- after complete remission: consolidation and consderation for bone marrow transplant
in step 1 can use lipossomal daunorubicin/cytarbine if pt qualifies
what is considered leukemia free at day 14 in AML?
bone biopsy
- 5-10% blasts
- hypocellular
- < 10-20% cells
what is cosidered complete remission in AML?
- <5% blasts
- ANC > 1000
- plts > 100,000
what to do if pt fails reinduciton or salvage therapy in AML?
switch over to supportive care/comfort measures
treatment for pts who did NOT qualify for aggressive induction chem in AML
- low-intensity chemo
- azacitidine + venetoclax
- if pt has IDH1: ivosidenib+venetoclax
- if pt qualifies: gemtuzumab ozogamicin
- if pt progresses, switch to supportive care/comfort measures
pts who go down this route do NOT receive curative treatment
venetoclax DDI
azole antifungals -> dose reduce
relapse AML treatment
- venetoclax if pt has NOT received it in the past
- targeted relapse treatment
- gilteritinib: FLT - ITD or TKD
- ivosidenib: IDH1
- enasidenib: IDH2
AML consolidation treatment
-
pts with favorable outcomes:high dose cytarabine (HiDAC)
- give with growth factor (do NOT give growth facotrs to plts with active AML) - pt who have intermediate/high risk: can get stem cell trasplant
growth factor ADR
bone pain (treat with claritin)
AML inductio chemo: 7+3
- day 1-7: chemo admin (ADR: N/V, GI, fatigue)
- day 8-24: cell count nadir, plt transfusion, recovery (ADR: fatigue, fever, infection, high RBC)
- day 25+: complete cell count recovery - dcc from hospital once ANC > 500 and pt no longer transfusion dependent
AML additive agents to induction 7+3
- FLT3-ITD: quizartinib o days 8-21 of induciton and 6-19 of consolidation
- FLT3-TKD (and technically ITD): midostaurin BID with food on days 8-21 of induction and consolidation
- favorable/intermediate cytogenetics: gemtuzumab ozogamicin on days 1, 4, 7 of induction and day 1 of consoldiaiton
quizartinib ADR
cardiac (QT prolongation)
midostaurin ADR
smell so bad pts throw up
when to use liposomal daunorubicin/cytarabine instead of 7+3 in aggressive AML induction therapy
in pts with t-AML or AML with myelodysplatic related changes (AML-MRC)
better outcomes than 7+3 in secondary AML
mutation of interest in CML
9;22 translocation (philadelphia chromosome)
test for prior to treatment, if pt doesn’t have, it’s likely not CML
CML presentation
- mostly asymp
- splenomegaly
- WBC > 25 x 10^9
chronic phase CML
- <10% blasts
- treatment: TKI
- treatment goal: delayed progression, eradicate Ph chromosome
accelerated phase CML
- blasts 10-19%
- treatment: TKI (at probs a higher dose than chronic phase)
- treatment goal: control WBC, go back to chronic phase and avoid progression
blast phase CML
- blasts > 20%
- treatment: treat like AML and slap on a TKI
- treatment goal: suvivie iduciton, bridge to allogenic stem cell transplant
TKI class ADR
- myelosuppresision
- transaminitis
- electrolyte changes
TKI agents by generation
- 1st gen: imatinib
- 2nd gen: dasatinib, nilotiib
- 3rd: bosatinib, polatinib
- other; asciminib (binds ot Myristoyl pocket instead of ATP pocket)
which TKIs need to be dose adjusted in hepatic impairment
- imitinib
- nilotinib
- bosutinib
- ponatinib
whcih TKIs need to be dose adjusted in renal impairment
imitanib
T315I mutation
- the “gatekeeping mutation”
- mutation that prevents most TKIs from working
- treat the CML with ascimiib (preferred) or ponatinib
CML treatment monitoring
molecular response: look at transcript level of fusion protein (which leads ot proliferation) -> quantifiy amount of that protein in your blood
CML treatment: BCR-ABL goal
- @ 3 months: BCR-ABL < 10%
- @ 6 months: < 1%
- @ 12 months: < 0.1%
if not meeting goal, look into reaosns why
picking a TKI
low/intermediate risk: dasatinib preferred dt tolerability
- can also just do
- bosutinib
- nilotinib
- imatinib (not preferred in intermedate)
CML remssion treatmetn
can actually dc a TKI if pt is completely in remssion and meets other strict requirements
imatinib off target effect
inhibits
- PDGFR
- c-KIT
imatinib ADR
fluid build up: peripheral edema
imatinib: DDI
CYP 3A4 substrate and nihibitor
dasatinib off target effects
inhibits
- PDGFR
- c-KIT
- Src family kinases
results in edema
dasatinib ADR
fluid build up: pleural effusions
dasatinib DDI
CYP3A4 substrate
dasatinib admi
needs acidic environment to absorb -> no H2RA or PPI
nilotinib ADR
cardio (Qt porlongation, arrhythmias)
nilotinib admin
BID on ann empty stomach
nilotinib DDI
- CYP3A4 substrate and inhibitor
- CYP 2C8, 2C9, 2D6 action
bosutinib off target effects
ihibits
- Src kinases
- Lyn kiases
- Hck kinases
in terms of on-target effects has activity against a lot of mutations that early drugs don’t, however, does NOT cover T315I or V299L
bosutinib ADR
diarrhea for first 2 weeks
bosutinib DDI
CYP3A4 substrate
poatinib off targe effects
inhibits
- VEGFR
- PDGFR
- Src kinases
- FGFR
- FLT3
- RTK
- TIE2
active agaist all mutaitons
ponatinib ADR
- vascular occlusion - ppx asa
- HF
- hepatotox
it’s very poorly tolerated
ponatinib DDI
CYP 3A4 substrate
indication for asciminib
- if pt has T315I mutaiton or
- if pt has received 2+ TKi in past
CML
asciminib admi
empty stomach
