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📚 Leukemia — Pathology Assignment for Pharmacy Students

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Learning Objectives

1. Define leukemia and distinguish it from lymphoma
2. Classify leukemia into its four major types
3. Describe the pathogenesis, morphology, and clinical features of each type
4. Identify key diagnostic markers and chromosomal abnormalities
5. Relate pathophysiology to pharmacological treatment strategies

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Part 1: Introduction & Classification

Classification Overview

Key concept: Acute leukemias = accumulation of immature blasts (arrested differentiation). Chronic leukemias = accumulation of mature but abnormal cells with uncontrolled proliferation.

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Part 2: Acute Myeloid Leukemia (AML)

Pathogenesis

• FLT3 (tyrosine kinase) — most common; activating mutations drive proliferation
• NPM1, CEBPA — associated with better prognosis
• t(15;17) translocation → PML-RARα fusion gene → causes Acute Promyelocytic Leukemia (APL, AML-M3)
  • The fusion protein blocks granulocyte differentiation by aberrantly repressing retinoic acid target genes

Morphology

• Bone marrow replaced by myeloblasts (>20% blasts required for diagnosis)
• Blasts often contain Auer rods — needle-like cytoplasmic inclusions (pathognomonic for AML)
• Peripheral blood shows anemia, thrombocytopenia, variable WBC

Clinical Features

• Symptoms of bone marrow failure: fatigue (anemia), infections (neutropenia), bleeding (thrombocytopenia)
• Hepatosplenomegaly
• Without treatment: rapidly fatal (weeks to months)

Pharmacy Relevance

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Part 3: Acute Lymphoblastic Leukemia (ALL)

Pathogenesis

• B-ALL (~85%): often associated with translocations
  • t(12;21) → TEL-AML1 — good prognosis (most common childhood ALL)
  • t(9;22) → BCR-ABL (Philadelphia chromosome) — poor prognosis; ~25% of adult ALL
• T-ALL (~15%): associated with NOTCH1 mutations; mediastinal mass common in adolescent males

Morphology

• Bone marrow and blood packed with lymphoblasts
• Lymphoblasts: small to medium cells, scant cytoplasm, condensed chromatin
• No Auer rods (distinguishes from AML)

Clinical Features

• Abrupt onset: fever, pallor, bleeding, bone pain (due to marrow expansion)
• CNS involvement common → headache, cranial nerve palsies (requires CNS prophylaxis)
• Lymphadenopathy, splenomegaly

Pharmacy Relevance

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Part 4: Chronic Myeloid Leukemia (CML)

Pathogenesis

• BCR-ABL encodes a constitutively active tyrosine kinase
• It activates RAS and other proliferative pathways
• Normal myeloid progenitors require growth factors; CML progenitors are growth factor–independent
• Differentiation is preserved early → excessive but relatively normal-looking granulocytes

The discovery of BCR-ABL in CML is one of the most important milestones in oncology, as it led directly to the development of imatinib (Gleevec) — the prototype targeted cancer therapy.

Morphology

• WBC often >100,000 cells/µL
• Peripheral blood: neutrophils, immature granulocytes, basophilia and eosinophilia, elevated platelets
• Bone marrow: hypercellular with granulocytic and megakaryocytic hyperplasia
• Massive splenomegaly (extramedullary hematopoiesis → splenic infarcts)

Disease Phases

Clinical Features

• Insidious onset: fatigue, weight loss, night sweats
• Dragging sensation in left upper abdomen (splenomegaly)
• Labs: markedly elevated WBC with left shift, low leukocyte alkaline phosphatase (LAP) score

Pharmacy Relevance

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Part 5: Chronic Lymphocytic Leukemia (CLL)

Pathogenesis

• Neoplastic proliferation of mature but immunologically incompetent B cells
• Cells accumulate in blood, marrow, lymph nodes, and spleen
• Associated with deletions of 13q14, 11q, 17p (TP53), and trisomy 12
• 17p deletion (TP53 loss) → poor prognosis, resistance to chemotherapy

Morphology

• Blood and marrow: flood of small mature lymphocytes
• Characteristic "smudge cells" on peripheral smear (fragile lymphocytes ruptured during slide preparation)
• Lymph nodes: diffuse effacement by small round lymphocytes

Clinical Features

• Often asymptomatic, discovered incidentally on CBC
• Hypogammaglobulinemia → recurrent bacterial infections
• Autoimmune hemolytic anemia (AIHA) and thrombocytopenia in some
• Richter transformation: ~5% transform to aggressive diffuse large B-cell lymphoma

Staging (Rai System — simplified)

Pharmacy Relevance

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Part 6: Summary Comparison Table

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Part 7: Practice Questions

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Key Terms Glossary

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🩸 Leukemia — Pathology Assignment

For Pharmacy Students | Intermediate Level

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SECTION A: STUDY NOTES

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1. Introduction

• Anemia → fatigue, pallor
• Thrombocytopenia → bleeding, petechiae
• Neutropenia/leukopenia → recurrent infections

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2. Classification

1. Lineage — Myeloid vs. Lymphoid
2. Clinical course — Acute (immature blasts, rapid) vs. Chronic (mature cells, indolent)

Acute leukemias = differentiation is arrested → immature blasts accumulate Chronic leukemias = differentiation is preserved → mature but abnormal cells accumulate

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3. Acute Myeloid Leukemia (AML)

Epidemiology

• Most common acute leukemia in adults (median age ~65)
• ~10,000 new cases/year in the US

Pathogenesis

1. Block myeloid differentiation (class II mutations, e.g., PML-RARα, CEBPA mutations)
2. Drive uncontrolled proliferation (class I mutations, e.g., FLT3, RAS activating mutations)

APL note for pharmacy students: The PML-RARα fusion protein blocks retinoic acid receptor signaling and prevents granulocyte differentiation. All-trans retinoic acid (ATRA) overcomes this block and drives terminal differentiation of blasts — a landmark example of differentiation therapy.

Morphology

• Bone marrow: >20% blasts (WHO diagnostic threshold)
• Peripheral smear: myeloblasts with large nuclei, prominent nucleoli
• Pathognomonic: Auer rods — red needle-like cytoplasmic granules in blasts; seen only in AML (not ALL)
• Extramedullary: hepatosplenomegaly; gingival hyperplasia (especially monocytic AML)

Clinical Features

• Sudden onset: fever, fatigue, bleeding, bone pain
• DIC is a serious complication, especially in APL — due to procoagulant release from granules
• CNS involvement less common than ALL

Treatment (Pharmacy Focus)

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4. Acute Lymphoblastic Leukemia (ALL)

Epidemiology

• Most common cancer in children (peak age 2–10 years)
• B-ALL: ~85% of cases; T-ALL: ~15%
• In adults: Ph-chromosome positive ALL is more common and has worse prognosis

Pathogenesis

Morphology

• Bone marrow: >20% lymphoblasts
• Lymphoblasts: small-to-medium, scant cytoplasm, condensed chromatin
• No Auer rods (distinguishes from AML)
• Immunophenotyping: TdT+ (terminal deoxynucleotidyl transferase — marker of lymphoblasts), CD10+ (B-ALL)

Clinical Features

• Rapid onset: fever, pallor, bone pain, lymphadenopathy, hepatosplenomegaly
• CNS involvement in ~5% at presentation → headache, vomiting, cranial nerve palsies
• Mediastinal mass: T-ALL in adolescent males (thymic involvement)
• Testicular infiltration in boys

Treatment (Pharmacy Focus)

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5. Chronic Myeloid Leukemia (CML)

Epidemiology

• Peak incidence: 25–60 years; ~4,500 new cases/year in the US

Pathogenesis — The Philadelphia Chromosome

Chromosome 9: ABL gene  ──┐
                           ├──► BCR-ABL fusion gene on Chr 22
Chromosome 22: BCR gene ──┘

• BCR-ABL encodes a constitutively active tyrosine kinase
• Activates downstream RAS, PI3K/AKT, and STAT5 pathways
• Reduces growth factor dependence → uncontrolled granulocyte proliferation
• Differentiation is preserved early → relatively mature-looking cells (unlike AML)

This was the first cancer linked to a specific chromosomal abnormality (Nowell & Hungerford, 1960) and the first to be cured with targeted molecular therapy (imatinib).

Morphology

• WBC often >100,000 cells/µL (markedly elevated)
• Peripheral smear: granulocytes at all stages of maturation — neutrophils, bands, metamyelocytes, myelocytes + basophilia + eosinophilia
• Elevated platelets (thrombocytosis) early
• Bone marrow: hypercellular, granulocytic and megakaryocytic hyperplasia
• Massive splenomegaly (extramedullary hematopoiesis → risk of splenic infarcts)

Disease Phases

Clinical Features

• Onset insidious: fatigue, weight loss, night sweats, left upper quadrant fullness (splenomegaly)
• Low leukocyte alkaline phosphatase (LAP) score — key lab finding distinguishing CML from leukemoid reaction (where LAP is high)
• Philadelphia chromosome on cytogenetics (FISH or PCR for BCR-ABL) is diagnostic

Treatment (Pharmacy Focus)

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6. Chronic Lymphocytic Leukemia (CLL)

Epidemiology

• Most common leukemia in the Western world
• Predominantly affects the elderly (median age ~65); rare before 50
• Male predominance (2:1)

Pathogenesis

• CLL cells are anti-apoptotic (overexpress BCL-2), which explains their accumulation
• Immunologically defective → hypogammaglobulinemia → recurrent bacterial infections

Morphology

• Peripheral blood: massive accumulation of small, mature-looking lymphocytes
• Pathognomonic: "Smudge cells" (Gumprecht shadows) — fragile CLL lymphocytes that rupture during slide preparation
• Lymph nodes: diffuse effacement by small round lymphocytes
• Bone marrow infiltration: interstitial or nodular pattern

Staging (Rai System)

Clinical Features

• Often asymptomatic at diagnosis (incidental CBC finding)
• Recurrent infections (especially encapsulated bacteria — Streptococcus pneumoniae)
• Autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) in some patients
• Richter transformation (~5%): transformation to aggressive diffuse large B-cell lymphoma — sudden worsening, rapidly enlarging nodes, systemic symptoms

Treatment (Pharmacy Focus)

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7. Master Comparison Table

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SECTION B: QUESTIONS

Part I — Multiple Choice Questions (MCQs)

• A) t(9;22) — BCR-ABL
• B) t(15;17) — PML-RARα
• C) t(12;21) — TEL-AML1
• D) t(4;11) — MLL-AF4

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• A) PML-RARα
• B) BCR-ABL
• C) TEL-AML1
• D) MLL-AF4

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• A) Inhibits tyrosine kinase activity of BCR-ABL
• B) Induces DNA alkylation in leukemic blasts
• C) Overcomes differentiation block by displacing co-repressors from PML-RARα
• D) Depletes asparagine availability to leukemic blasts

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• A) Smudge cells
• B) Auer rods
• C) Hypersegmented neutrophils
• D) Target cells

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• A) Transformation to AML
• B) Autoimmune hemolytic anemia
• C) Richter transformation to diffuse large B-cell lymphoma
• D) Splenic infarction

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• A) Dasatinib
• B) Nilotinib
• C) Ponatinib
• D) Bosutinib

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• A) Rapid cell division driven by BCR-ABL kinase
• B) Overexpression of BCL-2 → resistance to apoptosis
• C) FLT3 mutation causing growth factor independence
• D) Loss of TP53 causing uncontrolled proliferation

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• A) Inhibiting topoisomerase II in lymphoblasts
• B) Depleting serum asparagine, which ALL cells cannot synthesize independently
• C) Binding to CD20 on B-lymphoblasts
• D) Blocking folate metabolism in dividing lymphoblasts

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Part II — Short Answer Questions (SAQs)

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SECTION C: MODEL ANSWERS

MCQ Answers

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SAQ Model Answers

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• In CLL: CLL cells constitutively overexpress BCL-2 as a survival mechanism — this is why they accumulate (they don't die). Venetoclax displaces pro-apoptotic proteins from BCL-2, restoring apoptosis.
• In AML: AML blasts (especially in elderly patients with lower-intensity mutations) also rely heavily on BCL-2 for survival, particularly in the setting of low oxidative phosphorylation dependency.

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• Cytarabine (Ara-C) × 7 days by continuous IV infusion
  • Mechanism: Pyrimidine analog; incorporated into DNA → inhibits DNA polymerase → chain termination; S-phase specific
• Daunorubicin (or Idarubicin) × 3 days IV bolus
  • Mechanism: Anthracycline; intercalates DNA → inhibits topoisomerase II → double-strand breaks; also generates free radicals

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Glossary of Key Terms

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