# Clinical Cases: Chronic Leukemias

## Case 1: Chronic Myeloid Leukemia (CML)

### Patient Presentation
**Demographics:** 52-year-old male

**Chief Complaint:** Incidentally discovered elevated white blood cell count

**History of Present Illness:**
The patient presented to his primary care physician for a routine health maintenance visit. He feels generally well but reports mild fatigue and early satiety over the past few months. He has noticed some left-sided abdominal fullness. He has no fever, night sweats, weight loss, or bone pain. Complete blood count obtained during the visit showed markedly elevated WBC.

**Physical Examination:**
- Vital signs: BP 132/82, HR 76, RR 14, Temp 36.8C
- General: Well-appearing middle-aged man
- HEENT: No lymphadenopathy
- Cardiac: Regular rhythm, no murmurs
- Lungs: Clear
- Abdomen: Splenomegaly extending 8 cm below left costal margin
- Skin: No petechiae, no bruising
- Neurologic: Normal

### Workup and Results

**Complete Blood Count:**
- WBC: 125,000/uL
- Differential:
  - Neutrophils: 45%
  - Bands: 12%
  - Metamyelocytes: 15%
  - Myelocytes: 18%
  - Promyelocytes: 4%
  - Blasts: 2%
  - Basophils: 6%
  - Eosinophils: 4%
- Hemoglobin: 11.8 g/dL
- Platelets: 485,000/uL

**Peripheral Blood Smear:**
- Full spectrum of myeloid maturation ("myelocyte bulge")
- Basophilia and eosinophilia
- No significant dysplasia
- Occasional circulating blasts (<5%)

**Additional Labs:**
- LDH: 450 U/L (elevated)
- Uric acid: 8.5 mg/dL
- Leukocyte alkaline phosphatase (LAP) score: 8 (low; normal 30-150)
- Vitamin B12: 1,850 pg/mL (elevated)

**Bone Marrow Biopsy:**
- Hypercellular (95%)
- Marked myeloid hyperplasia
- 3% blasts (chronic phase)
- Cytogenetics: t(9;22)(q34;q11) - Philadelphia chromosome present

**Molecular Testing:**
- BCR-ABL1 by PCR: Positive (p210 transcript)
- BCR-ABL1 quantitative: 85% (International Scale)

### Clinical Image

![CML Blood Smear](case_01_image.jpg)

*Peripheral blood smear in chronic myeloid leukemia demonstrating the full spectrum of myeloid maturation from blasts to mature neutrophils, with characteristic myelocyte bulge and basophilia.*

### Diagnosis
**Chronic Myeloid Leukemia - Chronic Phase**

Diagnostic criteria:
- Philadelphia chromosome positive t(9;22)
- BCR-ABL1 fusion gene present
- Chronic phase: <10% blasts, no accelerated/blast phase features
- Characteristic peripheral blood findings with low LAP score

### Treatment Plan
1. **First-line tyrosine kinase inhibitor (TKI):**
   - Imatinib 400 mg daily, OR
   - Second-generation TKI (dasatinib 100 mg daily or nilotinib 300 mg BID) for faster, deeper response

2. **Monitoring milestones:**
   - 3 months: BCR-ABL1 ≤10% (early molecular response)
   - 6 months: BCR-ABL1 ≤1%
   - 12 months: BCR-ABL1 ≤0.1% (major molecular response, MMR)
   - Goal: Deep molecular response (MR4, MR4.5)

3. **Response assessment:**
   - Quantitative BCR-ABL1 PCR every 3 months
   - Bone marrow at diagnosis and if suboptimal response
   - Mutation analysis if treatment failure

4. **Long-term considerations:**
   - Near-normal life expectancy with TKI therapy
   - Consider treatment-free remission (TFR) trial if sustained deep molecular response for ≥2 years
   - Lifelong therapy if TFR not achieved

5. **If failure or intolerance:**
   - Switch to alternative TKI
   - Mutation analysis (especially T315I which requires ponatinib)
   - Consider allogeneic transplant for advanced disease

### Teaching Points
1. CML is defined by the Philadelphia chromosome creating BCR-ABL1 fusion tyrosine kinase
2. The low LAP score distinguishes CML from leukemoid reaction (which has high LAP)
3. TKI therapy has transformed CML from fatal disease to chronic manageable condition
4. Monitoring BCR-ABL1 transcript levels is essential for assessing response
5. Treatment-free remission is possible after sustained deep molecular response
6. Disease phases: chronic (<10% blasts) → accelerated (10-19%) → blast crisis (≥20%)
7. Basophilia is characteristic of CML and helps distinguish from other causes of leukocytosis

---

## Case 2: Chronic Lymphocytic Leukemia (CLL)

### Patient Presentation
**Demographics:** 72-year-old female

**Chief Complaint:** Incidentally found lymphocytosis; now with progressive lymphadenopathy and fatigue

**History of Present Illness:**
The patient was diagnosed with CLL 4 years ago when routine labs showed lymphocytosis. She was initially observed with "watch and wait" approach. Over the past 6 months, she has noticed enlarging lymph nodes in her neck and armpits, worsening fatigue, and unintentional 12-pound weight loss. She has had drenching night sweats for the past month. She has had 2 sinus infections in the past 4 months requiring antibiotics.

**Physical Examination:**
- Vital signs: BP 128/78, HR 82, RR 16, Temp 37.0C
- General: Fatigued-appearing elderly woman
- HEENT: Bilateral cervical lymphadenopathy (2-3 cm, non-tender)
- Axillae: Bilateral lymphadenopathy (3 cm)
- Cardiac: Regular rhythm
- Lungs: Clear
- Abdomen: Splenomegaly (6 cm below costal margin), no hepatomegaly
- Inguinal: Bilateral lymphadenopathy (2 cm)

### Workup and Results

**Complete Blood Count:**
- WBC: 85,000/uL
- Absolute lymphocyte count: 78,000/uL
- Hemoglobin: 9.8 g/dL (baseline 4 years ago: 13.2)
- Platelets: 95,000/uL (baseline: 185,000)

**Peripheral Blood Smear:**
- Marked lymphocytosis with mature-appearing small lymphocytes
- Numerous smudge cells (basket cells)
- No blasts

**Flow Cytometry:**
- CD19+, CD5+, CD23+, CD20 (dim), FMC7 negative
- Light chain restriction: Kappa

**Additional Workup:**
- Beta-2-microglobulin: 5.8 mg/L (elevated)
- LDH: 320 U/L (elevated)
- Direct Coombs (DAT): Positive (IgG)
- Haptoglobin: 25 mg/dL (low)
- Reticulocyte count: 6% (elevated)
- FISH: del(13q14) only - favorable
- IGHV mutation status: Mutated - favorable
- TP53: Wild-type (no mutation or deletion)

**CT Imaging:**
- Diffuse lymphadenopathy above and below diaphragm
- Splenomegaly

### Clinical Image

![CLL Smudge Cells](case_01_image.jpg)

*Peripheral blood smear in chronic lymphocytic leukemia demonstrating mature small lymphocytes and characteristic smudge cells (basket cells) from fragile CLL cells rupturing during smear preparation.*

### Diagnosis
**Chronic Lymphocytic Leukemia - Rai Stage IV with Autoimmune Hemolytic Anemia**

Staging and risk:
- Rai Stage IV (anemia + thrombocytopenia)
- IGHV mutated (favorable)
- del(13q) only (favorable)
- TP53 wild-type (favorable)
- B symptoms present
- Concurrent AIHA (DAT positive with hemolysis)

### Treatment Plan
1. **Treatment indication (meets criteria):**
   - Progressive cytopenias (marrow failure)
   - Constitutional symptoms (B symptoms)
   - Progressive lymphadenopathy
   - Bulky splenomegaly

2. **First-line therapy (without del(17p)/TP53 mutation):**
   - Venetoclax + obinutuzumab (time-limited therapy) OR
   - BTK inhibitor (ibrutinib, acalabrutinib, or zanubrutinib)
   - Given IGHV mutated status, may also consider FCR if fit and young

3. **AIHA management:**
   - Prednisone 1 mg/kg for autoimmune hemolysis
   - Will likely improve with CLL treatment

4. **Monitoring:**
   - CBC every 1-2 weeks initially
   - Response assessment per iwCLL criteria
   - Monitor for venetoclax tumor lysis (ramp-up dosing)

5. **Supportive care:**
   - IVIG if recurrent infections with hypogammaglobulinemia
   - Vaccinations (pneumococcal, influenza)
   - PJP prophylaxis with some regimens

### Teaching Points
1. CLL is the most common adult leukemia in Western countries
2. The immunophenotype (CD5+, CD19+, CD23+, dim CD20) distinguishes CLL from mantle cell lymphoma
3. Smudge cells result from fragile CLL lymphocytes rupturing during smear preparation
4. IGHV mutation status and FISH cytogenetics are critical prognostic factors
5. del(17p) or TP53 mutation predicts poor response to chemoimmunotherapy; BTK inhibitors preferred
6. Autoimmune cytopenias (AIHA, ITP) are common complications of CLL
7. Watch and wait is appropriate for early-stage asymptomatic disease
8. Richter transformation to aggressive lymphoma occurs in ~5% of patients

---

## Case 3: Hairy Cell Leukemia

### Patient Presentation
**Demographics:** 55-year-old male

**Chief Complaint:** Recurrent infections, fatigue, and abdominal fullness

**History of Present Illness:**
The patient has had 3 episodes of bacterial pneumonia over the past year. He reports progressive fatigue and early satiety with 15-pound weight loss. He has noticed increasing abdominal fullness on the left side. He has no lymphadenopathy, fevers, or night sweats. He is a non-smoker with no significant past medical history.

**Physical Examination:**
- Vital signs: BP 118/72, HR 78, RR 16, Temp 36.9C
- General: Pale, thin male
- HEENT: Pallor, no lymphadenopathy
- Cardiac: Regular rhythm, soft flow murmur
- Lungs: Clear
- Abdomen: Massive splenomegaly extending to the pelvis
- No hepatomegaly, no peripheral lymphadenopathy

### Workup and Results

**Complete Blood Count:**
- WBC: 2,100/uL (low)
- Absolute neutrophil count: 450/uL (neutropenia)
- Absolute monocyte count: 80/uL (monocytopenia - characteristic)
- Lymphocytes: 1,400/uL
- Hemoglobin: 9.2 g/dL
- Platelets: 68,000/uL
- Pancytopenia with characteristic monocytopenia

**Peripheral Blood Smear:**
- Occasional abnormal lymphocytes with oval nuclei
- Fine, hair-like cytoplasmic projections
- Abundant pale blue cytoplasm

**Bone Marrow:**
- "Dry tap" on aspiration attempt
- Biopsy: Diffuse infiltration by abnormal lymphocytes
- "Fried egg" appearance due to cytoplasmic clearing
- Reticulin fibrosis present

**Immunophenotype (Flow Cytometry):**
- CD19+, CD20+, CD22+
- CD11c+, CD25+, CD103+
- Annexin A1+
- CD5 negative, CD23 negative

**Special Stains:**
- TRAP (tartrate-resistant acid phosphatase): Positive

**Molecular Testing:**
- BRAF V600E mutation: Positive (present in >95% of HCL)

**CT Imaging:**
- Massive splenomegaly (25 cm)
- No lymphadenopathy

### Clinical Image

![Hairy Cell Leukemia](case_01_image.jpg)

*Peripheral blood smear in hairy cell leukemia showing characteristic lymphocytes with oval/kidney-shaped nuclei and fine, hair-like cytoplasmic projections extending from the cell surface.*

### Diagnosis
**Hairy Cell Leukemia (HCL)**

Diagnostic criteria:
- Characteristic "hairy" lymphocytes on smear
- Immunophenotype: CD19+, CD20+, CD11c+, CD25+, CD103+, Annexin A1+
- TRAP positive
- BRAF V600E mutation positive
- Monocytopenia (virtually diagnostic)
- Massive splenomegaly without lymphadenopathy

### Treatment Plan
1. **First-line therapy:**
   - Cladribine (2-CdA) 0.1 mg/kg/day continuous infusion x 7 days
   - OR Pentostatin 4 mg/m2 every 2 weeks x 4-6 cycles
   - Single course achieves complete remission in >90%

2. **Expected course:**
   - Initial pancytopenia may worsen transiently
   - Nadirs at 1-2 weeks
   - Recovery over 4-8 weeks
   - Durable remissions lasting years to decades

3. **Supportive care during treatment:**
   - PJP prophylaxis (TMP-SMX)
   - Antiviral prophylaxis (acyclovir)
   - G-CSF if severe neutropenia with infection
   - Irradiated blood products (risk of TA-GVHD)

4. **Relapsed disease options:**
   - Repeat purine analog if long remission
   - Rituximab with or without purine analog
   - Vemurafenib (BRAF inhibitor) for refractory disease
   - Moxetumomab pasudotox (anti-CD22 immunotoxin)

5. **Monitoring:**
   - MRD assessment by flow cytometry
   - Long-term surveillance for relapse

### Teaching Points
1. Hairy cell leukemia has pancytopenia with characteristic monocytopenia
2. "Dry tap" on bone marrow aspiration due to reticulin fibrosis
3. The BRAF V600E mutation is present in >95% of cases and is a therapeutic target
4. TRAP positivity helps confirm diagnosis
5. Massive splenomegaly without lymphadenopathy is typical
6. Purine analogs (cladribine, pentostatin) achieve excellent long-term remissions
7. Atypical infections (Legionella, atypical mycobacteria) occur due to monocytopenia
8. HCL has excellent prognosis with high cure rates