AML Flashcards
Pathophysiology of APL
The retinoic acid alpha receptor gene (RARA) is encoded by the long arm of chromosome 17. It is mainly expressed in hematopoietic cells and has an important role in regulating gene expression. RAR alpha heterodimerizes with retinoid X receptor (RXR). In the absence of retinoid acid, RARA is bound by nuclear corepressor factor, and this causes transcriptional repression. In the presence of retinoic acid, RARA is activated and terminal differentiation of promyelocytes occurs.
In summary, PML/RARα acts through various mechanisms as a constitutive and potent transcriptional repressor of RARα-target genes
How does ATRA and arsenic work in APL?
ATRA and ATO dissociate the PML/RARa-RXR complex in ways that are dependent on caspases and proteasomes.
The degradation of PML-RARα may lead to release of transcription suppression and restoration of PML nuclear body structure. The blockade of other signaling pathways is also released, and the anti-apoptotic effect of PML-RARα is lost allowing induction of differentiation.
Pathophysiology of differentiation syndrome?
ATRA and ATO induce maturation of promyelocytes and promote tissue infiltration. There is also a systemic inflammatory response associated with increased cytokine expression, endothelial damage with capillary leak syndrome, and occlusion of the microcirculation.
Clinical features of differentiation syndrome?
Onset usually either within first week, or between weeks 3-4
Clinical manifestations:
Fever
hypotension
Weight gain (>5lbs)–> edema, effusions (pericardial, pleural), pulm edema
Dyspnea, hypoxia, CXR infiltrates
Rash (diffuse, erythematous)
Body pain
MOF (e.g., AKI)
Treatment of differentiation syndrome?
IV dexamethasone 10mg BID x minimum of 3 days, then taper
In most cases, continue ATRA, but consider holding if progressive or severe resp failure, renal failure, etc
Others: empiric Abx until r/o concomitant infection; consider diuresis if not hypotensive or in AKI; supplemental O2, mech vent PRN
~30% would die without treatment d/t resp failure or cerebral edema with treatment (steroids), most resolve within 24 hours; ~5% mortality
AML with normal cytogenetics, molecular tests to order prior to alloSCT?
FLT3-ITD
NMP1
Biallelic CEBPA
Others:
C-kit (if inv 16)
BCR-Abl (blast CML)
Morphology features of inv 3?
Abnormal megakaryocytes with increased platelet count
Morphology features of inv 16?
Dysplastic eosinophilia
Morphology features of APL?
Hypergranular vs hypo/microgranular (higher WBC)
Atypical promyelocytes (larger, bilobed/kidney-shaped nuclei, many violet granules, and multiple auer rods/cell)
Describe the WHO features of Acute monocytic leukemia?
Need >20% monoblasts, promonocytes
≥80% leukemic cells monocytic lineage (including monoblasts, promonocytes, monocytes)
Immunophenotyping: There is generally expression of at least two markers characteristic of monocytic differentiation such as CD14, CD4, CD11b, CD11c, CD64, CD68, CD36 and lysozyme. Variably express myeloid antigens CD13, CD33 (often very bright), C015 and C065.
CD34 is positive only in 30% of cases, while CD117 is more often expressed
Almost all HLA-DR+
Monoblasts are typically MPO negative; promonocytes may show some scattered MPO positivity
Auer rods are rare but possible
Describe the WHO features of Acute erythroid leukemia?
“Myeloid Neoplasms w/ Erythroid Predominance”
> 80% immature erythroid precursors w/ >/=30% proerythroblasts and <20% myeloblasts
The erythroblasts do not express markers of myeloid lineage and do not stain with MPO
Describe the WHO features of Acute megakaryocytic leukemia?
≥20% of blasts of which ≥50% are of MK lineage
Excludes cases of AML with: MDS changes
t (1;22), inv (3), t (3;3) – classified as AML w/ recurrent genetic abnormalities
Translocations classified as AML even without 20% blasts?
t(8;21), inv(16), t(16;16), and t(15;17).
Favourable Risk AML 2017 ELN
t(8;21)(q22;q22.1); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow†
Biallelic mutated CEBPA
Intermediate Risk AML 2017 ELN
Mutated NPM1 and FLT3-ITD high
Wild-type NPM1 without FLT3-ITD or with FLT3-ITD low (without adverse-risk genetic lesions)
t(9;11)(p21.3;q23.3); MLLT3-KMT2A
Cytogenetic abnormalities not classified as favorable or adverse
Poor Risk AML 2017 ELN
t(6;9)(p23;q34.1); DEK-NUP214
t(v;11q23.3); KMT2A rearranged
t(9;22)(q34.1;q11.2); BCR-ABL1
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1)
−5 or del(5q); −7; −17/abn(17p)
Complex karyotype, monosomal karyotype||
Wild-type NPM1 and FLT3-ITD high†
Mutated RUNX1
Mutated ASXL1
Mutated TP53
Causes of Hip pain post induction
Recurrent/refractory AML / extramedullary (myeloid sarcoma - joint involvement)
Bone marrow necrosis / expansion
Infection (OM, muscle, septic arthritis, etc.)
G-CSF related
Avascular necrosis (more likely ALL due to steroids + asparaginase)
Hemartharosis/hematoma
Inflammatory/Gout
Referred pain (abdominal typhilitis)
Flow phenotype of APL
CD13+, CD33+, MPO+, CD34-, CD117-, HLADR- ; CD11b- (not monocytic)
CD56 = poor prognosis (extramedullary, CNS disease)
hypogranular variant of APL frequently co-expresses CD2, and can sometimes express CD34.
Indication for LP in AML?
- WBC > 40x10^9 some say 50,000/ul
- APL in relapse
- CD56+
- Inv (16) or chrms 11 abnormalities
- AMML (monocytic differentiation)
- Any signs and symptoms of CNS involvement (facial nerve palsy)
? Elevated LDH
What procoagulant and anticoagulants are affected in APL leading to increased risk of thrombosis and bleeding respectively?
Bleeding
1. elevated urokinase-type plasminogen activator
2. Decreased alpha2-antiplasmin
3. Decreased fibrinogen
4. Increased elastase to degrade antiplasmin
Thrombosis
1. Decreased tPA
2. Increased tissue factor
3. Increased PAI-1
4. Release of inflammatory cytokines (TNFalpha, other cytokines)
5. Decreased thrombomodulin
Reasons to stop ATRA or ATO?
- Arsenic acid toxicity (convulsions, muscle weakness, confusion and ECG abnormality
-Consider chelation therapy (Dimercaprol 3mg/kg IM) + constant heart monitor - APL differentiation syndrome (severe)- usually do not need to DC the drug
- Prolonged Qtc(withholding the drug for a QTc interval >450 msec in men and >460 msec in women)
- Hypersensitivity reaction/anaphylaxis
- Severe leukocytosis
- IIH (idiopathic intracranial HTN), usually will resolve after LP but consider holding if severe.
- Hepatotoxicity
DO not start in pregnancy/nursing mothers.
How does arsenic work in APL?
Binds to the PML moiety of the PML-RARa
At low dose (Synergism with ATRA):
-Induces differentiation
-Degrades PML/RARalpha fusion protein
At high dose:
-Increases apoptosis via caspase activation
Low-coco for APL induction, with doses.
ATRA: 45 mg/m2 per day in two divided doses until complete response.
Arsenic trioxide: 0.15 mg/kg per day until complete response.
Other translocation in APL (beside 15;17)?
1.NPM/RARA and t(5;17)
-responsive to ATRA therapy
2. NuMA/RARA and t(11;17)
-responsive to ATRA therapy
3. PLZF/RARA and t(11;17)
-resistant to ATRA therapy
4. STAT5B/RARA and t(17,17)(q21;q21)
-resistant to ATRA therapy
5.BCOR/RARA and t(X;17)(q11;q21.1)
-resistant to ATRA therapy
6. ZBTB16- RARa
-resistant to ATRA therapy
2 benefits and 2 issues/side effects with ATRA for APL
Benefits: induces complete remission; shortens duration of coagulopathy
Problems: diferentiation syndrome, has to be PO, other S/E: transaminitis, IIH, hypertriglyceridemia, dry skin/mucous membranes, bone pain.
What poor heme outcomes are associated with differentiation syndrome?
Increased incidence of relapse, esp. extramedullary relapse
lower PFS (EFS), OS
How do you document molecular response after induction and consolidation in APL?
*The median time to hematological CR in the APML4 protocol was 53 days
1.Induction
-BMBx after induction to look for CR
-If only in PR can continue induction therapy until CR achieved
2.Consolidation
-Repeat BMBx after consolidation to look CRm (molecular CR) w/ PML-RARA fusion transcript testing w/ RT-PCR
-If no CR, repeat in 4 weeks; if still no: treat as refractory
-If CRm achieved, proceed to maintenance
Recommend q3 month Bone Marrow monitoring for MRD until 2 years (if WBC <10 at initial presentation) and 3 years (if initial WBC >10 at initial presentation) after consolidation.
Side effects of ATRA?
Long QTc
Shingles
Hepatotoxicity
Hyper trigs
IIH/Pseudotumor cerebri
Leukocytosis
Differentiation syndrome
Typical retinoid toxicity (symptoms that are similar to those found in patients taking high doses of vitamin A): Headache, fever, dry skin, dry mucous membranes (mouth, nose), bone pain, nausea and vomiting, rash, mouth sores, itching, sweating, eyesight changes
Good and bad molecular in AML?
GOOD
-NPM1 + (FLT3-ITD – or low allelic ratio <0.5)
-Biallelic CEBPA
BAD
-NPM1 –/+ with FLT3-ITD + (adverse if high allelic ratio)
-Inv(16) with c-kit mutation
-Mutated RUNX1
-Mutated ASXL1
-Mutated TP53
Common toxicities of high dose araC
Myelosuppression
Cerebellar dysfunction
Ocular dysfunction (hemorrhagic conjunctivitis)
Liver toxicity
Fevers
Cytarabine Syndrome: fever, myalgia, bone pain, CP, rash, conjunctivitis, malaise
Rash
Thrombophlebitis
Agent for IDH2 mutated AML
Enasidenib
Agent for FLT3 mutated AML
Gilteritinib
Quizartinib
Sorafenib
Midostaurin (dirty drug, considered a mulitikinase as has off target effects)
Agent for CD33 mutated r/r AML
Gemtuzumab (anti-CD33 antibody-drug conjugate)
Pulled from the market in 2010 for hepatotoxicty and VOD. Re-approved in 2017 at 3mg/m2. Given on days 1,4,7
Also can be used as single agent in R/R setting.
Agent for IDH1 mutated r/r AML
Ivosidenib
Agents for older, unfit r/r AML
AZA + VTX
lDAC + VTX
Glasdegib + low dose (Ara-C or 7+3)
If good risk cyto (low dose cytarabine)
PO AZA
What precursor CD markers are missing in APL
CD34, CD117 and HLA-DR
(MPO+ and CD33+)
MOA of Rasburicase, why is it CI in G6PD?
Rasburicase ( which is exogenous urate oxidase) converts uric acid to allantoin → makes it more easily renally cleared
In pts with G6PD, hydrogen peroxide is formed as a breakdown product which leads to oxidate hemolysis.
HA, pancytopenia-? APL
Name 3 urgent investigations
Name 2 treatments that need to be initiated on a Sunday
3 Urgent Investigations:
CT Head
Fibrinogen
FISH for t(15;17)
2 Treatments that need to be initiated:
ATRA 45 mg/m2 in 2 divided doses, first dose STAT
Supportive transfusions (plt > 50, fibrinogen >1.5)
2 classes of therapy induced AML: name implicated drugs, latency period and characteristic cytogenetic abnormalities of each
Alkylating agents (cyclophosphamide,melpalan,chlorambucil,busulfan,dacarbazine,cisplatin)
Preceding MDS phase, evolution to AML after 5‐7 years, complex cytogenetics often involving chromosome 5 and/or 7.
Topoisomerase‐II inhibitors (danorubicin/etoposide/doxorubicin/mitoxantrone)
May have short MDS phase, shorter (1‐3 year) latency, frequent 11q23 (MLL), 21q22 (RUNX1), abnormalities with MLL/KMT2A rearrangements
What are 2 serious toxicities seen with ATO/ATRA regimen that is not seen with other ATRA containing regimens for APL?
Hepatotoxicity (63% vs. 6% grade 3-4)
QT prolongation (16% vs. 0%)
Data from Lo-Coco Trial
Population: newly diagnosed APL
Interventions: ATRA-ATO vs. ATRA-chemotherapy (idarubcin)
Outcome: event free survival after 2 years
Results: 97% vs 85%
Risk factors for invasive aspergillosis?
- Severe/prolonged neutropenia
- allogenic transplant
- GVHD
- CMV
- Glucosteroids (in ALL)
- History of previous IA
- Intensive chemotherapy (FLAG, NOVE >AZA)
- Prior immunodeficiency (GATA-2)
- Prior exposure (construction worker, farmer)
- Prior lung pathology (CF, COPD)
- Prior significant exposure to antibiotics
- ICU admission
- Immunosuppression post HSCT
How does Allopurinol work in TLS?
Inhibitor of xanthine oxidase, which is responsible for successive oxidation of hypoxanthine and xanthine, resulting in production of uric acid.
4 reasons to stop ATO therapy
- QTc prolongation > 500 msec (black box warning)
- Differentiation syndrome (black box warning)
- Encephalopathy (black box warning)
- Hepatoxicity (AST/ALT/bilirubin>5xULN)
Epigenetics
What are 2 characteristics you must have?
What are 4 therapies that use epigenetics?
2 characteristics you must have
1. DNA methylation
2. Histone deacetylation
4 therapies:
1. Azacitadine
2. Decitabine
3. Rombidepsin
4. Vorinostat
5. Pabinonstat
What are the lineage requirements for Myeloid, B-cell and T-cell
Myeloid
1. MPO
2. Monocytic differentiation with at least 1 of: NSE, CD11c, CD14, CD64, lysoyme
B-cell
1. Strong CD19 with at least 1 of: CD79a, cytoplasmic CD22 or CD 10
2. Weak CD19 with at least 2 of: CD79a, cytoplasmic CD22 or CD 10
T cell
1. Cytoplasmic CD3
2. Surface CD3
Pt with APL on maintenance ATRA with signs of increased ICP. What is the diagnosis and treatment?
Pseudotumor cerebri (PTC).
TX
1. Decrease dose or hold ATRA until stable
2. Acetazolamide
3. Topiramate (Anti-seizure)
4. Therapeutic LP
Presence of what CD markers confers increased risk of extramedullary risk at presentation.
CD56
Patient with acute leukemia and severe hypokalemia, what is the probable subtype?
AMML
4 clinical poor prognostic factors in AML (ie. not cyto, molecular).
- Older age (>60 and especially >75)
- t-AML
- Extra medullary disease
- Progression from MDS or MPN
What molecular markers should you send at diagnosis for AML for prognostic significance or because there are specific drug targets which the pt may benefit from or they will change mangement (ie. risk stratify to favourable or poor)? (hint, there are 8).
- FLT3
- NPM1
- IDH1
- IDH2
- CEBPA
- ASXL1
- RUNX1
- Tp53
What patient populations should be considered for CPX351 (Vyxeos)?
Age 60-75 with:
1. t-AML
2. Secondary AML
3. AML with myelodysplasia- related changes
3 mutations that are consider founder mutations and may be present on MRD testing after CR and thus cannot be used to measure MRD status.
- RUNX1
- DMT3A
- ASXL1
The detection of these mutations may not represent the presence of AML MRD and thus may not be of prognostic significance for relapse.
Most common type of myeloid leukemia to develop in children with Down Syndrome?
Acute megakaryoblastic leukemia
Usually with acquired GATA1 mutations.
May be preceded by transient myeloproliferative disorder (TMD), a condition unique to these children.
What where the inclusion and exclusion criteria for the VIALE-A Study?
Inclusion:
1. New AML diagnosis
2. Not previously treated
3. Ineligible for induction therapy as defined by:
1. Age >75
2. Age 18-74 with 1 of:
-CHF requiring Tx
-LVEF <50%
-Chronic stable angina
-ECOG 2 or 3
-DLCO or FEV1 <65%
Exclusion:
1. Prior HM or VTX or chemo for MDS
2. Favourable risk cyto
What where the treatment arms for the VIALE-A Study including doses? What was the primary end point?
- Venetoclax 400mg daily D1-28 + AZA 75mg/m2 D1-7 q28days
- Placebo +AZA 75mg/m2 D1-7 q28days
VTX Ramp up:
D1:100mg
D2:200mg
D3-28:400mg (cycle 2 and beyond, keep on 400mg)
Primary endpoint: OS
14.7 months with venetoclax/azacitidine and 9.6 months with azacitidine alone
VIALE-A Study, what proportion of pts required dose interruption secondary to cytopenias?
75%
What are 5 treatments for AML (including APL) that can cause differentiation syndrome?
- ATRA +/- ATO
- Gilteritinib
- Quizartinib (FLT3 inhibitor)
- enasidenib (IDH2)
- ivosidenib (IDH1)
In pt with MPAL, what 2 molecular tests must be sent which may affect mangement?
- BCR-ABL (add a TKI)
- KMT2A (poor prognosis)
2 molecular mutations in myeloid neoplasms with germline predisposition without thrombocytopenia or organ dysfunction?
- DDX41
- CEBPA
low plts- RUNX1, ETV6 and ANKRD26
with BM failure- GATA 2, or a/w noonan’s or down syndrome.
AML on IDAC, gait ataxia. What is the diagnosis and what are 2 RFs for developing this condition?
- Cytarabine related cerebellar toxicity
RFs
1. Older age
2. Renal dyfxn as cleared by kidneys
What is Glasdegib (MOA) and what pt population does it show benefit in?
- once daily inhibitor of Hh signaling pathway- increases sensitivity to chemotherapy and reduces leukemic stem cell growth.
- Used in unfit, elderly pts with AML in combination of LDAC
Significant improvement in CR and OS.
