# Clinical Cases: Acute Leukemias

## Case 1: Acute Myeloid Leukemia (AML)

### Patient Presentation
**Demographics:** 62-year-old male

**Chief Complaint:** Progressive fatigue, easy bruising, and fever for 2 weeks

**History of Present Illness:**
The patient reports gradually worsening fatigue limiting his daily activities over the past month. He noticed easy bruising on his arms and legs, and bleeding from his gums when brushing teeth. He has had low-grade fevers for 2 weeks without clear source. He also reports mild bone pain in his legs and back. He has no significant past medical history and takes no medications.

**Physical Examination:**
- Vital signs: BP 110/68, HR 102, RR 18, Temp 38.2C
- General: Pale, fatigued-appearing man
- HEENT: Gingival hyperplasia with bleeding, pallor
- Lymph nodes: No lymphadenopathy
- Cardiac: Tachycardic, flow murmur
- Lungs: Clear
- Abdomen: Mild hepatomegaly, no splenomegaly
- Skin: Multiple ecchymoses, petechiae on lower extremities
- Neurologic: Normal

### Workup and Results

**Complete Blood Count:**
- WBC: 68,000/uL
- Differential: 78% blasts
- Hemoglobin: 7.2 g/dL (severe anemia)
- Platelets: 18,000/uL (severe thrombocytopenia)

**Peripheral Blood Smear:**
- Numerous large blasts with high N:C ratio
- Fine chromatin, prominent nucleoli
- Some blasts contain Auer rods
- Occasional blasts with cytoplasmic granules

**Bone Marrow Biopsy:**
- 82% blasts
- Auer rods identified
- Flow cytometry: CD34+, CD13+, CD33+, CD117+, MPO+, HLA-DR+

**Cytogenetics and Molecular:**
- Normal karyotype
- NPM1 mutation: Positive
- FLT3-ITD: Negative
- IDH1/2: Negative

**Chemistry:**
- LDH: 850 U/L (elevated)
- Uric acid: 9.2 mg/dL (elevated)
- Creatinine: 1.3 mg/dL

### Clinical Image

![AML Blast with Auer Rod](case_01_image.jpg)

*Peripheral blood smear demonstrating myeloblasts with Auer rods, pathognomonic crystallized azurophilic granules confirming myeloid lineage in acute myeloid leukemia.*

### Diagnosis
**Acute Myeloid Leukemia, NPM1-Mutated (Favorable Risk)**

Diagnostic criteria:
- ≥20% blasts in bone marrow
- Myeloid lineage confirmed by Auer rods and immunophenotype (CD13+, CD33+, MPO+)
- NPM1 mutation without FLT3-ITD = favorable risk category

### Treatment Plan
1. **Pre-treatment management:**
   - TLS prophylaxis: IV fluids, allopurinol
   - Transfusion support: PRBCs for anemia, platelets to maintain >10,000/uL
   - Infection workup and empiric antibiotics for fever

2. **Induction chemotherapy:**
   - 7+3 regimen: Cytarabine 100-200 mg/m2 continuous infusion x 7 days + Daunorubicin 60-90 mg/m2 x 3 days
   - Add midostaurin if FLT3 mutated

3. **Post-induction:**
   - Day 14 bone marrow to assess response
   - Day 28 bone marrow for CR assessment
   - Anticipate 3-4 weeks of pancytopenia

4. **Consolidation (if CR achieved):**
   - High-dose cytarabine (HiDAC) x 3-4 cycles
   - Given favorable risk (NPM1+ without FLT3-ITD), transplant not required in CR1

5. **Supportive care:**
   - G-CSF may be used post-chemotherapy
   - Antimicrobial prophylaxis during neutropenia

### Teaching Points
1. AML is defined by ≥20% myeloid blasts in bone marrow or blood
2. Auer rods are pathognomonic for myeloid lineage and confirm AML over ALL
3. Risk stratification by cytogenetics/molecular profile is critical for treatment decisions
4. NPM1 mutation without FLT3-ITD is favorable risk with ~60-70% cure rate with chemotherapy alone
5. The 7+3 regimen has been standard induction for decades
6. Gingival hyperplasia suggests monocytic differentiation (M4/M5 subtypes)
7. Tumor lysis syndrome prevention is essential given high blast count

---

## Case 2: Acute Promyelocytic Leukemia (APL)

### Patient Presentation
**Demographics:** 34-year-old female

**Chief Complaint:** Heavy menstrual bleeding, nosebleeds, and bruising for 1 week

**History of Present Illness:**
The patient noticed unusually heavy menstrual bleeding this cycle requiring pad changes every 1-2 hours. She has had multiple episodes of prolonged nosebleeds and spontaneous bruising. She reports fatigue and mild shortness of breath. She has no prior bleeding history. She developed a large hematoma on her thigh after minor trauma 3 days ago that is still expanding.

**Physical Examination:**
- Vital signs: BP 105/62, HR 108, RR 20, Temp 37.6C
- General: Pale, anxious woman with dried blood at nares
- HEENT: Nasal packing in place, conjunctival pallor
- Cardiac: Tachycardic, flow murmur
- Lungs: Clear
- Abdomen: Soft, no organomegaly
- Skin: Extensive ecchymoses, expanding thigh hematoma
- Neurologic: Normal (no signs of intracranial bleeding)

### Workup and Results

**Complete Blood Count:**
- WBC: 2,800/uL
- Differential: 45% abnormal promyelocytes
- Hemoglobin: 8.5 g/dL
- Platelets: 32,000/uL

**Coagulation Studies:**
- PT/INR: 16.5 sec / 1.4 (prolonged)
- aPTT: 42 sec (prolonged)
- Fibrinogen: 85 mg/dL (low; normal 200-400)
- D-dimer: 12,500 ng/mL (markedly elevated)

**Peripheral Blood Smear:**
- Hypergranular promyelocytes with abundant azurophilic granules
- Multiple Auer rods in some cells (faggot cells)
- Bilobed nuclei in some cells

**Bone Marrow:**
- 75% abnormal promyelocytes
- Flow cytometry: CD13+, CD33+, CD117+, HLA-DR negative, CD34 negative

**FISH/RT-PCR:**
- PML-RARA fusion: POSITIVE (confirms t(15;17))

### Clinical Image

![APL Faggot Cell](case_01_image.jpg)

*Peripheral blood smear in acute promyelocytic leukemia showing hypergranular promyelocyte with bundled Auer rods (faggot cell), virtually pathognomonic for APL with t(15;17).*

### Diagnosis
**Acute Promyelocytic Leukemia (APL) with DIC**

Key features:
- Hypergranular promyelocytes with faggot cells
- HLA-DR negative, CD34 negative immunophenotype
- PML-RARA fusion positive (defines APL)
- DIC with low fibrinogen and elevated D-dimer
- Low/normal WBC = standard risk APL

### Treatment Plan
1. **IMMEDIATE (do not wait for genetic confirmation):**
   - Start ATRA (all-trans retinoic acid) 45 mg/m2/day divided BID
   - Clinical suspicion of APL is sufficient to initiate ATRA

2. **DIC management (aggressive support):**
   - Transfuse cryoprecipitate to maintain fibrinogen >150 mg/dL
   - Platelet transfusion to maintain >30,000-50,000/uL
   - FFP as needed for active bleeding

3. **Definitive therapy (once diagnosis confirmed):**
   - ATRA + Arsenic trioxide (ATO) for standard-risk APL
   - Consider adding idarubicin if high-risk (WBC >10,000)

4. **Monitoring:**
   - Daily CBC, coags, fibrinogen until DIC resolves
   - Watch for differentiation syndrome (fever, dyspnea, weight gain, pulmonary infiltrates)
   - If differentiation syndrome: Start dexamethasone 10 mg BID immediately

5. **Prognosis:**
   - APL is the most curable adult AML subtype (>90% cure rate)
   - Early death from hemorrhage is main risk if not promptly treated

### Teaching Points
1. APL is a medical emergency - start ATRA on clinical suspicion before genetic confirmation
2. DIC is characteristic of APL due to release of procoagulant substances from granules
3. Maintain fibrinogen >150 mg/dL and platelets >30-50K until coagulopathy resolves
4. ATRA + ATO combination achieves >90% cure without traditional chemotherapy in standard-risk APL
5. Differentiation syndrome occurs when promyelocytes differentiate into neutrophils and release cytokines
6. HLA-DR and CD34 negativity help distinguish APL from other AML subtypes
7. Faggot cells (bundles of Auer rods) are virtually pathognomonic for APL

---

## Case 3: Acute Lymphoblastic Leukemia (ALL)

### Patient Presentation
**Demographics:** 6-year-old male

**Chief Complaint:** Bone pain, fatigue, and fever for 2 weeks

**History of Present Illness:**
The child has been complaining of leg and back pain for 2 weeks, refusing to walk at times. He has had decreased energy and appetite. His parents noticed he appears paler than usual and has had fevers up to 38.5C. He has had a few nosebleeds and bruises easily. His teacher noted he has been less active at school.

**Physical Examination:**
- Vital signs: BP 100/60, HR 110, RR 22, Temp 38.2C
- General: Pale, irritable child preferring to lie still
- HEENT: Conjunctival pallor
- Lymph nodes: Cervical, axillary, and inguinal lymphadenopathy (1-2 cm nodes)
- Cardiac: Tachycardic, grade II/VI flow murmur
- Lungs: Clear
- Abdomen: Hepatomegaly (4 cm), splenomegaly (5 cm)
- Extremities: Tenderness to palpation over tibias and femurs
- Skin: Scattered petechiae and ecchymoses

### Workup and Results

**Complete Blood Count:**
- WBC: 45,000/uL
- Differential: 82% blasts
- Hemoglobin: 6.8 g/dL
- Platelets: 22,000/uL

**Peripheral Blood Smear:**
- Numerous small to medium blasts
- High nuclear-to-cytoplasmic ratio
- Scant agranular cytoplasm
- No Auer rods

**Bone Marrow Biopsy:**
- 95% blasts replacing normal hematopoiesis
- Flow cytometry: CD19+, CD10+, CD22+, TdT+, CD34+, CD20 (dim)
- Cytoplasmic IgM negative
- Myeloid markers negative

**Cytogenetics/Molecular:**
- Hyperdiploidy (54 chromosomes) - favorable
- ETV6-RUNX1 fusion: Negative
- BCR-ABL: Negative
- MLL rearrangement: Negative

**Lumbar Puncture:**
- No blasts in CSF (CNS negative)
- CSF WBC 2, protein 25, glucose 62

**Chest X-ray:**
- No mediastinal mass (rules out T-ALL)

### Clinical Image

![ALL Lymphoblasts](case_01_image.jpg)

*Peripheral blood smear in acute lymphoblastic leukemia showing lymphoblasts with high nuclear-to-cytoplasmic ratio, scant agranular basophilic cytoplasm, and fine chromatin pattern without Auer rods.*

### Diagnosis
**B-Cell Acute Lymphoblastic Leukemia - Standard Risk**

Classification:
- B-ALL (CD19+, CD10+, TdT+)
- Age 1-9 years (favorable)
- WBC <50,000/uL (favorable)
- Hyperdiploidy (favorable cytogenetics)
- CNS negative
- Standard risk by NCI criteria

### Treatment Plan
1. **Induction (4 weeks):**
   - Prednisone or dexamethasone
   - Vincristine weekly
   - Asparaginase (PEG-asparaginase)
   - Daunorubicin (if higher risk)
   - Intrathecal methotrexate for CNS prophylaxis

2. **Consolidation:**
   - Multiple cycles with rotating drug combinations
   - High-dose methotrexate
   - Continued intrathecal therapy

3. **Maintenance (2-3 years total therapy):**
   - Daily 6-mercaptopurine
   - Weekly oral methotrexate
   - Monthly vincristine and steroid pulses

4. **Monitoring:**
   - Minimal residual disease (MRD) assessment
   - End-induction MRD is strongest prognostic factor
   - TPMT testing for 6-MP dosing

5. **Prognosis:**
   - Standard-risk pediatric B-ALL: >90% cure rate
   - Favorable cytogenetics (hyperdiploidy) improves outcomes

### Teaching Points
1. ALL is the most common childhood malignancy, peak incidence ages 2-5 years
2. Bone pain is common in children with ALL due to marrow expansion
3. B-ALL (85%) vs T-ALL (15%) distinguished by immunophenotype
4. CD19+, CD10+ (CALLA), TdT+ defines precursor B-ALL
5. Risk stratification includes age, WBC, cytogenetics, and MRD response
6. CNS prophylaxis with intrathecal chemotherapy is mandatory in ALL
7. Maintenance therapy for 2-3 years distinguishes ALL treatment from AML
8. Pediatric-inspired regimens improve adult ALL outcomes