APML

Question 1

🔬 Pathophysiology

Answer 1

• Caused by t(15;17) translocation → fusion gene PML-RARA.
  • This fusion protein blocks differentiation of promyelocytes → accumulation of immature, pro-coagulant cells.
  • ATRA (all-trans retinoic acid) binds RARA → promotes differentiation into neutrophils → reverses leukemia + DIC.

Question 2

Importance in ICU

Answer 2

Most mortality- early- if survives - 90%cure rate.

=>3main reasons for early mortality:
* Disseminated intravascular coagulation (DIC)
* Differentiation syndrome
* Sepsis

*	Requires urgent recognition + early protocolized treatment.

Question 3

Epidemiology and
Clinical Presentation

Answer 3

📊 Epidemiology
* ~10% of AML cases
* Affects younger patients (median age ~40 years

🧾 Clinical Presentation
=>Typical leukemia symptoms:
* Anemia (fatigue)
* Leukopenia (infections)
* DIC- Marked bleeding (seen in ~90%):
* Petechiae, bruising
* Intracranial/pulmonary hemorrhage

Question 4

🔍 Diagnosis

Answer 4

=> Coagulopathy pattern (key clue):
* ↓ Platelets
* ↑ PT; normal or ↑ PTT
* ↑ D-dimer (profoundly high)
* Variable fibrinogen (often ↓)

=>Definitive:
* PCR for PML-RARA fusion
* Morphology: Auer rods, irregular azurophilic granule

Question 5

💊 Treatment Principles

Answer 5

1. Start ATRA immediately,
2. Prevent Differentiation syndrome;
3. Prevent Tumor Lysis;
4. Arsenic Trioxide along with ATRA;
5. Prevent Sepsis;
6. Treat DIC

Question 6

ATRA

Answer 6

->Start ATRA immediately on clinical suspicion (don’t wait for confirmation):
Has Minimal toxicity(except Teratogenesis so relatively CI in pregnancy)

GOAL for early ATRA- Prevent DIC

*	ATRA dose: 45 mg/m²/day in 2 divided doses

Question 7

🔥 Prevent differentiation syndrome

Answer 7

• All patients: steroid prophylaxis
  
  • Prednisone 0.5 mg/kg/day
  • If WBC >10 → dexamethasone 10 mg IV BD
  • Maintain euvolemia (consider diuresis if edema)

Question 8

⚠️ Arsenic Trioxide (ATO) – Additional Monitoring

Answer 8

• Used in combination with ATRA
  
  • Monitor:
  • QTc: baseline + twice weekly ECG
  • Mg >2–3, K >4
  • LFTs daily
  • Stop QT-prolonging drugs

Question 9

🧬 Avoid tumor lysis syndrome (TLS)

Answer 9

• Allopurinol 300 mg BD
  
  • Monitor lytes, uric acid daily

Question 10

🧫 Prevent/treat sepsis

Answer 10

• Neutropenic fever: start empiric antibiotics
  
  • Low threshold to work up for infection

Question 11

📉 Prevent/treat coagulopathy

Answer 11

• Avoid procedures if possible (prefer PICC over CVC)
  
  • **Hold anticoagulants/antiplatelets
    **
    ->Transfusion targets:
  • Platelets > 50
  • Fibrinogen > 150 mg/dL (give cryo)
  • INR < 1.5–2

Question 12

🧬 Pathophysiology of Coagulopathy in APL

Answer 12

APL coagulopathy involves both clotting and bleeding risks:

🧨 Two Main Drivers
1. Tissue Factor Overexpression (→ DIC)
* Leukemic blasts express excess tissue factor–>Activates coagulation cascade → (DIC)–> widespread microvascular thrombosis and consumption of platelets/coag factors.

2.	Annexin II Expression -->Activates tPA and uPA-->Excessive Plasmin generation→ Hyperfibrinolysis
*	Resembles the coagulopathy of exogenous tPA use (very “bleedy”).

🩸 Combined Effect
* Results in simultaneous DIC + hyperfibrinolysis.

🧪 Other Contributing Factors
* Thrombocytopenia:consumption related
* Qualitative platelet dysfunction
* Cytokine-induced prothrombotic state

Question 13

Mx of coagulopathy

Answer 13

Haemorrhage- responsible for majority of early deaths
🧪 Transfusion Support
* Platelets: Maintain >30–50 ×10⁹/L
* Fibrinogen: Target >150 mg/dL (most critical)
* INR: Target <1.5–2
* Give FFP if INR elevated
* Monitor: Repeat coagulation studies q6h until stable

=>TXA- no strong evidence in support, not a routine
Consider in uncontrolled bleeding not responding to other measures discussed

=>Vit K

=> Avoid Heparin

Question 14

💊 APL-Specific Therapy

Answer 14

• ATRA (All-Trans Retinoic Acid):
  
  • Start immediately on suspicion, don’t wait for labs
  • Reduces expression of tissue factor & annexin II
  • Arsenic Trioxide (ATO):
  • Add to ATRA for synergistic effect on reducing coagulopathy
  • Monitor QTc, Mg, LFTs closely

Question 15

🚫 Avoid Harmful Interventions

Answer 15

• Avoid invasive procedures where possible:
  
  • No arterial lines, bronchoscopy, endoscopy, lumbar puncture
  • Prefer PICC for central access
  • Heparin is contraindicated
  • Associated with increased hemorrhagic risk

Question 16

🌪️ Differentiation Syndrome in Acute Promyelocytic Leukemia (APL)

(Also known as ATRA Syndrome)

Answer 16

🔬 Pathophysiology
->Triggered by ATRA and/or arsenic trioxide therapy.
* Causes rapid differentiation of malignant promyelocytes into neutrophils.
->Leads to:
* Cytokine storm (↑ IL-1β, TNF-α, IL-6)
* Capillary leak
* Tissue infiltration by activated neutrophils

Question 17

ATRA Syndrome cont..
📊 Epidemiology

Answer 17

⸻

*	Occurs in ~25% of patients during induction (most within first few days–weeks).
*	Risk ↑ with:
*	WBC >5 ×10⁹/L
*	WBC rising >10 ×10⁹/L after therapy initiation
*	Responsible for ~15% of APL early deaths.

⸻

Question 17

ATRA Syndrome cont..
🧬 Prophylaxis

Answer 17

-> Steroid prophylaxis:
* Prednisone 0.5 mg/kg/day (standard for most patients)
* If WBC >10 ×10⁹/L → Dexamethasone 10 mg IV BID

->Maintain fluid balance:
* Monitor weight closely; use diuretics if fluid overloaded

Question 18

ATRA Syndrome cont..
⚠️ Clinical Features

Answer 18

=> Timing:
* Severe DS often in week 1
* Moderate DS may peak in week 3

=>Symptoms:
*	Fever
*	Peripheral edema, weight gain
*	Hypotension, shock
*	Pulmonary infiltrates, pleural/pericardial effusions
*	AKI, hyperbilirubinemia
*	Sweet syndrome (rare neutrophilic dermatosis)

=>Radiology:
* Ground-glass opacities
* Septal lines
* Effusions

Question 19

ATRA Syndrome cont..

🔍 Differential Diagnosis
&

🧪 Evaluation

Answer 19

D/D
* Sepsis (especially pneumonia)
* Heart failure
* Tumor lysis syndrome
* Alveolar hemorrhage
* Pulmonary embolism

⸻

🧪 Evaluation
* Blood cultures
* Chest imaging (CXR/CT)
* Echocardiogram
* Monitor WBC trends
* Rule out infection if possible

Question 20

ATRA cont..
💊 Treatment

Answer 20

=> Steroids (first-line):
* Dexamethasone 10 mg IV q12h at first suspicion
* Escalate to q6h if no improvement
* Continue ≥3 days post-resolution, then taper

=>Supportive:
*	Vasopressors, fluid management, oxygen/ventilation as needed
*	Antibiotics:
    -Start empirically if infection not excluded
    -	Discontinue <48h if no source is found
    
  =>	ATRA/ATO management:
*	Mild DS: continue therapy
*	Severe DS (e.g. respiratory or renal failure): hold ATRA/ATO temporarily

=>Leukocytosis:
*	Use hydroxyurea if WBC >10 ×10⁹/L
*	**Avoid leukapheresis due to bleeding risk**

Question 21

Unique complications of ATO (Arsenic Tri Oxide) and Mx

Answer 21

Torsades
Hyperglycemia
Hepatotoxicity

->Prophylaxis against Torsade de Pointes:
Discontinue other QT-prolonging drugs.
Maintain K>4 mEq/L and Mg above 2-3 mg/dL.
Monitor the QT interval at least twice weekly. If the QT interval extends >500 ms, discuss with hematology whether to hold arsenic trioxide.
Monitor BGL and LFTs

Question 22

Pseudotumor cerebri

Answer 22

Occurs in 3% of APML pts
M/C in younger pts
Clinical features: Headache, visual disturbances,
Occular USG-pappiloedema
MRI useful- to r/o other causes
LP generally contranidicated in APML due to coagulopathy

Tt:
Hold ATRA
Steroids
Acetazolamide