Myeloid Leukemia Flashcards
What are some differentiating factors between ACUTE and CHRONIC leukemia?
Acute: rapid onset, highly symptomatic, made of ONLY immature blasts!
Chronic: slow, mostly asymptomatic, mix of immature blasts and mature leukocytes
What is used to diagnose leukemia?
Bone marrow aspirate & biopsy
What age range is most common for AML?
≥65
What are risk factors for AML?
≥65
Prior chemo (secondary AML, harder to treat)
Radiation therapy
Smoking
Benzene/pesticide/petrochemical exposure
What are major signs/symptoms of AML? (4)
Anemia
Thrombocytopenia
Neutropenia
TLS
Hyperleukocytosis is a common AE of AML. What is a classic presentation? What drug may be used to temporarily decrease leukocyte count?
“Blood sludging” - SoB, stupor, vision changes, stroke, respiratory failure, renal failure, ischemia, retinal hemorrhage
Hydroxyurea used for count control, use until induction therapy can be started
What are some common ADEs of the drug used to treat hyperleukocytosis in AML?
Hydroxyurea AEs: N/V/D, TLS
Long-term toxicity = cutaneous ulcerations, mucositis, Alopecia/hyperpigmentation
use acutely for count control before induction therapy ONLY!
What % blasts isolated in bone marrow autopsy indicates AML?
≥ 20% blasts
What is a major prognostic marker to look for in AML?
Cytogenetics - predicts favorability of remission, risk of relapse, overall survival
What is the major cytogenetic target for AML? What are TWO mutations that could occur?
FMS-Like Tyrosine Kinase (FLT3)
Mutations:
- Internal Tandem Duplication (ITD) [worse prognosis]
- Tyrosine Kinase Domain (TKD) point mutations
Other than FLT3, what are two other molecular mutations in AML?
Isocitrate dehydrogenase (IDH)
DNA methyltransferase 3A (DNMT3A) [no drugs for this yet]
What determines if an AML patient can get aggressive induction chemo?
Age (<60?)
- if >60, must have NO comorbidities/end organ dysfunction
Performance status (can the walk?)
What is the “7+3” gold standard for induction chemo in AML?
Cytarabine infusion x 7 days
+
Daunorubicin/idarubicin x 3 days
What are additional induction therapies other than 7+3 that can be used in AML? Which one is nasty and most people throw up?
Quizartinib (FLT3-ITD target)
Midostaurin (FLT-TKD target) - nasty one, most pts dont tolerate
Gilteritinib (dual FLT/AXL inhibitor) approved for refractory AML
Gemtuzumab Ozogamacin (GO) [favorable/intermediate cytogenetics]
Liposomal daunorubicin + cytarabine
AML patients usually become “leukemia-free” by day ____ after induction therapy. Complete remission is usually around day ____.
Leukemia free = day 14
Complete remission = day 28
Once an AML pt finishes induction chem, what post-remission therapy can be used?
High dose cytarabine (HiDAC) x 3 doses + filgrastim
Liposomal daunorubicin + cytarabine
Use only in favorable cytogenetics and young!
Who should be considered for allogeneic stem cell transplant in AML?
Intermediate/poor cytogenetic risk
Secondary AML (after prior chemo)
Done after INDUCTION + 1 CYCLE CONSOLIDATION
If an AML candidate is not fit to receive induction chemo, they can trial what therapies?
“Low intensity chemo”
Gemtuzumab O
Target therapies (quizartinib, Midostauron, etc)
What are some “low intensity chemo” treatments for AML?
Hydromethylating agents (Decitabine/Azacitidine) + venetoclax
Low-dose cytarabine [LDAC] + venetoclax
Ivosidenib + venetoclax
(LDAC + gladegib, but glasdegib is not great)
What is the MOA of venetoclax (low intensity chemo adjunct)?
Inhibits anti-apoptotics (allows for apoptosis of cells infected with leukemia)
What treatments could be used in refractory/relapse AML?
NOT induction therapy!
HiDAC + mitoxantrone (like daunorubicin)
GO
“Low-intensity chemo” (venetoclax-based therapies)
target therapy if mutation present
Name the 3 FLT3 mutation-targeting drugs. Which is the best tolerated? What are its FDA approved indications?
Quizartinib (FLT3-ITD)
Midostaurin (cannot be used in relapse AML)
Gilteritinib (FDA approved for relapse AML! BEST TOLERATED)
Name the two IDH inhibitors (AML target therapy). Which targets IDH1 and which targets IDH2? What are its FDA approved indications?
Ivosidenib = IDH1 target (“I” = 1 in Roman numeral)
- FDA approved for new and refractory AML
Enasidenib = IDH2
- FDA approved for refractory only
(All end in -sidenib)
What are some supportive care measures in AML?
Blood transfusions
Infection prophy while neutropenic (often febrile neutropenia)
TLS treatment allopurinol/rasburicase, hydration, etc refer to TLS)
Anthracyclines (used in AML) have what TWO major AEs?
Cardia toxicity
Myelosuppression
Cytarabine has what TWO major AEs? What is the test that must be done before each dose? What drug can treat one of the AEs?
NEUROTOXICITY
- must conduct “neuro checks”, observe motor skills
CONJUCTIVITIS
- treat w dexamethasone eye drops qty during and 3 days after
Gemtuzumab Ozogamicin has what AE that needs to be pretreated? What is its BBW?
AE: infusion related reactions
- pretreat w APAP, Benadryl, Methylprednisolone
BBW: hepatotoxicity including venous-occlusion
What are TWO AEs with low-intensity chemo in AML? Which needs to be premedicated?
Severe constipation (have standing bowel regimen meds ordered)
Emetogenic (premedicate w/ ondansetron)
What is a major AE of venetoclax?
Significant myelosuppression
Growth factors like filgrastim and sargramostim are used in AML in severe infections/neutropenia.
What should be we cautious of? What is a major AE and what can we treat it with?
Be cautious of POTENTIATING leukemia cells!
AE: bone pain (bc GROWTH factor), use loratidine or hydroxyzine for management
In CML, translocation occurs between the ____ gene and ____ gene, causing a _______ ___________. The gene thus is eternally active, synthesizing more WBCs.
Translocation at BCR and ABL genes
Creates Philadelphia chromosome
What does CML presentation look like?
MOSTLY ASYMPTOMATIC
Splenomegaly (>50%)
Anorexia, bone pain, fatigue
What are 3 key lab findings for diagnosis of CML?
Leukocytosis [WBC > 25 x 10^9/L]
Thrombocytosis
(+) Ph chromosome
What are the three phases of CML progression? What do we aim for?
Chronic, Accelerated, Blast phases
Aim: chronic
What is the class of drug that controls chronic phase CML? Why are they so good?
Tyrosine Kinase Inhibitors (TKI)
Oral tablet, specific cytogenetics targets
What are the available TKIs for CML?
1st gen: Imatinib
2nd gen: Dasatinib, Nilotinib
3rd gen: Bosutinib, Ponatinib (for T31 mutation only)
What mutation in CML is considered the most resistant, with poorer survival and increased disease progression?
T31-5I
What is a boxed warning on 2nd gen TKI Nilotinib?
QTc prolongation
What are the FDA approved indications of 3rd gen TKI Bosutinib?
Approved for:
- new CML
- Advanced disease with resistance/intolerance to other TKIs
If a CML patient has a LOW RISK score, what are first line therapies?
Any generation TKI
If a CML patient has a INTERMEDIATE/HIGH RISK score, what are first line therapies?
2nd or 3rd gen TKIs
What are 3rd line therapies for CML after 1st/2nd gen TKIs/Bosutinib?
Ponatinib - usually reserved for T315I mutation
Aciminib - STAMP inhibitor, effective against T315I
Omacetaxine mepesuccinate (off-market)
What are some BBWs for 3rd gen TKI Ponatinib? (3)
Vascular occlusion, HF, hepatotoxicity
What is the FDA indication for Asciminib?
STAMP inhibitor
Approved for previously received 2+ TKIs or with T315I mutation
What are the most common AEs of each TKI?
Imagining = Edema/fluid retention
Dasutinib = pleural effusions
Nilotinib = QTc prolongation and CVD
Bosutinib = GI effects
What are common side effects with Ponatinib (3rd get TKI)?
Elevated pancreatic enzymes
HTN
Skin toxicity
Thrombotic events
What needs to be monitored periodically while using 2nd gen TKI Nilotinib?
Lipid profile
Which CML drugs should be taken on an empty stomach? Which requires an acidic environment (no H2RAs or PPIs)?
Empty stomach = Nilotinib, asciminib
Need acidic environment = Dasatinib
What drugs are recommended for treatment of ACCELERATED phase CML?
2nd gen TKIs
Consider allogenic transplant
What drugs are recommended for treatment of BLAST phase CML?
TKI + induction therapy or low intensity chemo (basically AML + CML treatment)
