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Leukemia — Pharmacy Student Assignment

Learning Objectives

1. Define leukemia and classify the main types
2. Describe the pathophysiology and key features of each type
3. Identify clinical signs, symptoms, and diagnostic findings
4. Explain pharmacological treatment options including mechanisms, indications, and key side effects

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Section 1: Overview and Classification

Classification

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Section 2: Acute Myeloid Leukemia (AML)

Pathophysiology

• t(8;21) → RUNX1-RUNXT1 fusion → core binding factor AML (favorable prognosis)
• inv(16) → CBFβ-MYH11 fusion → core binding factor AML (favorable prognosis)
• t(15;17) → PML-RARα fusion → Acute Promyelocytic Leukemia (APL) — a unique, treatable subtype
• FLT3-ITD mutations → poor prognosis
• NPM1 mutations → favorable prognosis when without FLT3 mutation

Signs & Symptoms

• Fatigue, pallor (anemia)
• Bleeding, bruising (thrombocytopenia)
• Infections (neutropenia)
• Bone pain
• Hepatosplenomegaly

Diagnosis

• Blood smear: >20% blasts in blood/bone marrow (WHO criteria)
• Auer rods (pink cytoplasmic rods) — pathognomonic for AML
• Flow cytometry, cytogenetics, molecular testing (FLT3, NPM1, IDH1/2)

Treatment of AML

Standard Induction ("7+3")

Targeted Therapies

Acute Promyelocytic Leukemia (APL) — Special Case

⚠️ APL differentiation syndrome — a potentially fatal complication of ATRA/ATO therapy. Symptoms: fever, dyspnea, weight gain, pulmonary infiltrates. Managed with dexamethasone.

For Unfit/Elderly Patients

• Azacitidine or Decitabine (DNA methyltransferase inhibitors) — hypomethylating agents that restore tumor suppressor gene expression
• Venetoclax + Azacitidine — now standard of care for unfit newly diagnosed AML; venetoclax is a BCL-2 inhibitor that promotes apoptosis in cancer cells. Doubles complete remission rates compared to azacitidine alone — Goldman-Cecil Medicine

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Section 3: Acute Lymphoblastic Leukemia (ALL)

Pathophysiology

• Philadelphia chromosome-positive (Ph+) ALL: t(9;22) → BCR-ABL fusion → worst prognosis in adults; requires tyrosine kinase inhibitors (TKIs)
• CALLA-positive ALL (CD10+): most common B-ALL; best outcomes among B-cell types

Signs & Symptoms

• Headache, cranial nerve palsies (CNS leukemia)
• Lymphadenopathy, mediastinal mass (T-cell ALL)

Treatment of ALL

Induction (achieve complete remission)

Ph+ ALL — Add TKI

Newer/Targeted Agents

CNS Prophylaxis

Childhood ALL has >90% cure rates with conventional chemotherapy. Adult ALL is more challenging due to higher Ph+ rates and drug tolerance differences. — Goldman-Cecil Medicine

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Section 4: Chronic Myeloid Leukemia (CML)

Pathophysiology

1. Chronic phase — high WBC, splenomegaly, manageable
2. Accelerated phase — worsening, increasing blasts (10–19%)
3. Blast crisis — ≥20% blasts; behaves like acute leukemia

Signs & Symptoms

• Fatigue, weight loss, night sweats
• Massive splenomegaly (most prominent finding)
• Elevated WBC (often >100,000/μL)
• Basophilia, eosinophilia on blood smear

Treatment of CML — Tyrosine Kinase Inhibitors (TKIs)

For resistant/intolerant patients or those in accelerated/blast crisis, hematopoietic cell transplantation (HCT) is reserved as a last resort. — Goldman-Cecil Medicine

Key Pharmacist Points — TKI Monitoring:

• Imatinib: edema, nausea, hepatotoxicity; many CYP3A4 drug interactions
• Dasatinib: pleural effusion, pulmonary arterial hypertension
• Nilotinib: QT prolongation, hyperglycemia, pancreatitis — take on empty stomach
• Ponatinib: arterial thrombosis, hepatotoxicity

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Section 5: Chronic Lymphocytic Leukemia (CLL)

Definition

Epidemiology

• Median age at diagnosis: 70 years
• More common in men (2:1)
• Rare in Asians; more common in Whites
• Risk factors: family history (5–8x higher risk with affected first-degree relative), Agent Orange exposure

Staging (Rai System)

Treatment of CLL

Most newly diagnosed patients are followed without therapy ("watch and wait"). A substantial fraction never require treatment. — Goldman-Cecil Medicine

When to Treat (Indications):

• Symptomatic lymphadenopathy or splenomegaly
• Progressive anemia or thrombocytopenia
• Constitutional symptoms (fever, sweats, weight loss)
• Rapidly rising lymphocyte count

Modern Targeted Therapies (Preferred)

FCR Regimen (older, now less used but still relevant)

Targeted therapies against BTK and BCL-2 have revolutionized CLL management, providing effective, well-tolerated oral therapies with prolonged progression-free survival. — Goldman-Cecil Medicine

Key Pharmacist Points — CLL Drugs:

• Ibrutinib: inhibits BTK (Bruton Tyrosine Kinase) → blocks B-cell receptor signaling. Major risks: atrial fibrillation, bleeding, hypertension. Avoid with strong CYP3A4 inhibitors.
• Venetoclax: BCL-2 inhibitor → tumor lysis syndrome (TLS) is a major risk on initiation. Requires dose ramp-up protocol and prophylaxis (allopurinol, hydration).
• Rituximab/Obinutuzumab: infusion reactions, reactivation of hepatitis B — screen all patients before use.

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Section 6: Summary Comparison Table

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Section 7: Practice Questions

1. A 65-year-old male is diagnosed with newly diagnosed AML and is not a candidate for intensive chemotherapy. Which drug combination has become the new standard of care?
   • A) Cytarabine + Daunorubicin
   • B) Venetoclax + Azacitidine ✅
   • C) Imatinib + Prednisone
   • D) Fludarabine + Rituximab
2. A patient with CML is found to have a T315I mutation after failing two prior TKIs. Which agent is most appropriate?
   • A) Imatinib
   • B) Dasatinib
   • C) Nilotinib
   • D) Ponatinib ✅
3. Which drug used in ALL treatment works by depleting asparagine, an amino acid that leukemic cells cannot synthesize on their own?
   • A) Vincristine
   • B) Methotrexate
   • C) L-asparaginase ✅
   • D) Dexamethasone
4. A pharmacist is counseling a CLL patient starting venetoclax. Which serious complication requires dose ramp-up and prophylaxis at initiation?
   • A) Peripheral neuropathy
   • B) Pleural effusion
   • C) Tumor lysis syndrome ✅
   • D) QT prolongation
5. The differentiation syndrome associated with ATRA treatment in APL is managed with:
   • A) G-CSF
   • B) Dexamethasone ✅
   • C) Allopurinol
   • D) Methotrexate

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Key Drug Reference Card

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