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LEUKEMIA — A Pathology Assignment for Pharmacy Students

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1. INTRODUCTION AND DEFINITION

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2. CLASSIFICATION

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3. ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

3.1 Definition

3.2 Epidemiology

• Most common cancer of children — approximately 2,500 new cases diagnosed annually in the United States
• B-ALL peaks at ~3 years of age; T-ALL peaks in adolescence
• Slightly more frequent in boys than girls
• Hispanic/Latino children have the highest incidence of ALL among ethnic groups in the United States
• Both B-ALL and T-ALL also occur, less commonly, in adults

3.3 Pathogenesis & Molecular Mechanisms

1. Dysregulate transcription factors required for normal lymphoid development, causing maturation arrest and increased self-renewal
2. Activate kinase signaling (e.g., tyrosine kinase mutations, RAS signaling) to promote proliferation

Mutations in transcription factor genes alone are insufficient for ALL — additional driver mutations promoting growth are necessary, consistent with the multistep model of carcinogenesis.

3.4 Morphology

• Peripheral blood: Leukocytosis with lymphoblasts; cytopenias (anemia, thrombocytopenia) in some cases
• Bone marrow: Hypercellular; diffuse infiltration by lymphoblasts — medium-sized cells with scant cytoplasm, dispersed chromatin, and inconspicuous nucleoli
• Lymphoblasts are PAS-positive (contain cytoplasmic glycogen)
• Absent Auer rods (key distinguishing feature from AML)

3.5 Immunophenotype

• B-ALL: TdT+, CD19+, CD10+ (CALLA), CD20± , surface Ig−
• T-ALL: TdT+, CD2+, CD3+, CD5+, CD7+
• TdT (terminal deoxynucleotidyl transferase) is a nuclear enzyme expressed in immature lymphoblasts — a key diagnostic marker

3.6 Clinical Features

• Abrupt onset of symptoms reflecting bone marrow failure:
  • Fatigue, pallor (anemia)
  • Fever, infections (neutropenia)
  • Bleeding, petechiae (thrombocytopenia)
• Bone pain (marrow infiltration)
• Lymphadenopathy, hepatosplenomegaly
• CNS involvement — headache, vomiting (occurs in a minority but critical to treat/prevent)
• T-ALL: superior mediastinal mass (thymic enlargement) — may cause superior vena cava syndrome

3.7 Laboratory Findings

• Peripheral blood: elevated WBC (lymphoblasts), decreased RBC and platelets
• LDH elevated (reflects rapid cell turnover)
• Uric acid elevated (hyperuricemia — risk of tumor lysis syndrome)
• Bone marrow biopsy: >20% blasts (WHO criterion for acute leukemia)

3.8 Treatment & Pharmacology

3.9 Prognosis

• Children with B-ALL: ~90% cure rate with modern chemotherapy (one of the great successes of oncology)
• Adults: 5-year survival ~40%; worse prognosis
• Favorable factors: age 1–10 years, hyperdiploidy, ETV6::RUNX1 fusion, low WBC at diagnosis
• Unfavorable factors: Philadelphia chromosome (t(9;22)), KMT2A rearrangement, hypodiploidy, adult age, T-ALL with complex cytogenetics

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4. ACUTE MYELOID LEUKEMIA (AML)

4.1 Definition

4.2 Epidemiology

• Most common acute leukemia in adults; median age at diagnosis ~65 years
• Accounts for ~80% of acute leukemias in adults
• Incidence increases with age
• Slightly more common in males

4.3 Etiology and Risk Factors

• Prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm ("secondary AML")
• Chemotherapy / radiation exposure — alkylating agents, topoisomerase II inhibitors (e.g., etoposide)
• Occupational exposure to benzene
• Genetic predisposition: Down syndrome (trisomy 21) — markedly increased risk in children; Fanconi anemia; Bloom syndrome

4.4 Pathogenesis & Molecular Mechanisms

• Class I mutations — activate tyrosine kinase/RAS signaling → promote proliferation (e.g., FLT3-ITD, RAS mutations)
• Class II mutations — disrupt transcription factors → block differentiation / maturation arrest (e.g., PML::RARA, RUNX1::RUNX1T1, CBFβ::MYH11)

4.5 Morphology

• Peripheral blood: Myeloblasts with prominent nucleoli and Auer rods
• Auer rods — pink, needle-shaped cytoplasmic inclusions of abnormal primary granules; pathognomonic for AML
• Bone marrow: Markedly hypercellular; >20% myeloblasts (WHO criterion); near-complete replacement of normal marrow
• Myeloperoxidase (MPO) stain positive in myeloid lineage cells

4.6 FAB Classification (Older, Still Clinically Referenced)

4.7 Clinical Features

• Abrupt onset of fatigue, pallor (anemia)
• Fever, recurrent infections (neutropenia)
• Bleeding, bruising, petechiae (thrombocytopenia)
• APL (M3): Life-threatening disseminated intravascular coagulation (DIC) due to release of procoagulant substances from granules
• Monocytic AML (M4/M5): Gingival hyperplasia, skin infiltration (leukemia cutis)
• Hepatosplenomegaly (less pronounced than in CML)
• Chloroma (myeloid sarcoma): Extramedullary mass of myeloid blasts, may appear greenish due to MPO

4.8 Treatment & Pharmacology

Pharmacy note: ATRA is a vitamin A derivative (retinoid) that acts on the PML-RARA fusion protein to restore differentiation — a landmark example of targeted, mechanism-based therapy.

4.9 Prognosis

• Without treatment: fatal within weeks to months
• With therapy: 5-year overall survival ~25–30% in adults; significantly better with favorable cytogenetics
• APL treated with ATRA + ATO: ~90% complete remission, ~70% cure
• Favorable: t(8;21), inv(16), NPM1 mutation without FLT3-ITD
• Unfavorable: TP53, complex karyotype, therapy-related AML, FLT3-ITD

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5. CHRONIC MYELOID LEUKEMIA (CML)

5.1 Definition

5.2 Molecular Basis — The Philadelphia Chromosome

• In >90% of cases, BCR::ABL1 arises from a reciprocal t(9;22)(q34;q11) translocation — the Philadelphia chromosome (Ph)
• The fusion produces a 210 kDa BCR-ABL tyrosine kinase (p210)
• This kinase is constitutively active → drives uncontrolled myeloid proliferation
• Cell of origin: pluripotent hematopoietic stem cell
• In remaining cases (~10%), the fusion is formed by cryptic rearrangements detectable only by FISH or PCR

5.3 Epidemiology

• Predominantly a disease of adults (median age 50–60 years)
• Rare in children (<10% of childhood leukemias)
• Slight male predominance

5.4 Pathogenesis

• RAS/MAPK pathway → cell proliferation
• PI3K/AKT pathway → cell survival, apoptosis resistance
• JAK-STAT pathway → cytokine-independent growth

5.5 Natural History — Three Phases

5.6 Morphology

• Peripheral blood: Marked leukocytosis (often 50,000–200,000 cells/μL); full spectrum of myeloid cells — neutrophils, bands, metamyelocytes, myelocytes, occasional myeloblasts; basophilia is characteristic
• Bone marrow: Hypercellular (90–100% cellularity); markedly expanded myeloid lineage with orderly maturation; increased basophils and eosinophils; megakaryocytes may be increased
• Spleen: Massive splenomegaly (extramedullary hematopoiesis); may weigh several kilograms
• Liver: Hepatomegaly due to extramedullary hematopoiesis

5.7 Laboratory Findings

• WBC markedly elevated (50,000–200,000/μL)
• Low or absent leukocyte alkaline phosphatase (LAP) score — distinguishes CML from leukemoid reactions
• Basophilia, eosinophilia
• Philadelphia chromosome on cytogenetics; BCR::ABL1 by PCR or FISH
• Mild anemia; thrombocytosis common early

5.8 Clinical Features

• Often insidious onset
• Fatigue, weight loss, night sweats
• Symptomatic from massive splenomegaly — early satiety, left upper quadrant pain
• May be discovered incidentally on routine CBC
• Blast crisis: fever, infections, bleeding — clinically identical to acute leukemia

5.9 Treatment & Pharmacology — TKI Revolution

Pharmacy note: Imatinib competitively inhibits the ATP-binding site of BCR-ABL, locking the kinase in an inactive conformation. Resistance frequently arises from point mutations in the kinase domain, especially T315I, which blocks TKI binding.

5.10 Prognosis

• With modern TKI therapy: near-normal life expectancy for chronic-phase CML
• Treatment-free remission (TFR) is achievable in ~40–60% of patients who achieve deep molecular remission
• Blast crisis: median survival only 3–6 months even with treatment

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6. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) / SMALL LYMPHOCYTIC LYMPHOMA (SLL)

6.1 Definition

6.2 Epidemiology

• Most common leukemia in adults in the Western world
• Median age at diagnosis: 65–70 years
• Rare before age 50
• More common in males (2:1 ratio)
• Strong familial predisposition — first-degree relatives have 8-fold increased risk

6.3 Pathogenesis & Molecular Features

• Cell of origin: mature naïve or antigen-experienced B lymphocyte
• Cells are anti-apoptotic due to overexpression of BCL-2, driven by deletions of miR-15a and miR-16-1 on chromosome 13q14 (which normally suppress BCL-2)
• Frequently express CD5 (normally a T-cell marker) — a hallmark of CLL
• Driver mutations: del(13q14) — most common (favorable); del(11q) (involves ATM — unfavorable); del(17p)/TP53 (very poor prognosis); trisomy 12 (intermediate)
• Mutation status of IGHV gene is a key prognostic marker:
  • Mutated IGHV: favorable prognosis (post-germinal center origin)
  • Unmutated IGHV: unfavorable prognosis (pre-germinal center origin)
• ZAP-70 and CD38 expression correlate with unmutated IGHV and worse prognosis

6.4 Morphology

• Peripheral blood: Absolute lymphocytosis (>5,000 monoclonal B lymphocytes/μL); small, round lymphocytes with scant cytoplasm and clumped ("soccer ball") chromatin; smudge (basket) cells — fragile CLL cells disrupted during smear preparation
• Bone marrow: Diffuse infiltration in advanced disease
• Lymph nodes: Diffuse effacement by small lymphocytes; proliferation centers (pseudofollicles) are characteristic and contain larger, proliferating cells (prolymphocytes and paraimmunoblasts)

6.5 Immunophenotype

• CD5+, CD19+, CD20 (dim)+, CD23+, surface IgM/IgD (dim)+
• Co-expression of CD5 and CD19 is the hallmark of CLL
• Low-level surface immunoglobulin (distinguishes from mantle cell lymphoma, which is CD5+ but has bright surface Ig)

6.6 Clinical Features

• Often asymptomatic — discovered incidentally on CBC
• Progressive fatigue, lymphadenopathy, hepatosplenomegaly
• Immune dysfunction:
  • Hypogammaglobulinemia → recurrent bacterial infections (most common cause of death)
  • Autoimmune hemolytic anemia (warm AIHA) — Coombs-positive
  • Immune thrombocytopenia (ITP)
• Richter transformation: 5–10% transform to an aggressive large B-cell lymphoma (DLBCL) — rapid clinical deterioration, poor prognosis

6.7 Staging (Rai System)

6.8 Treatment & Pharmacology

Pharmacy note: Ibrutinib irreversibly inhibits Bruton's tyrosine kinase (BTK), a key signaling molecule downstream of the B-cell receptor (BCR). BTK inhibition deprives CLL cells of survival signals and causes them to exit their lymph node niches, initially raising lymphocyte counts — a class effect that should not be mistaken for disease progression.

6.9 Prognosis

• Highly variable; median survival ranges from 2–3 years (high-risk) to >10 years (low-risk)
• Favorable: mutated IGHV, del(13q14), Rai stage 0
• Unfavorable: del(17p)/TP53, unmutated IGHV, Rai stage III–IV, Richter transformation

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7. COMPARATIVE SUMMARY TABLE

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8. TUMOR LYSIS SYNDROME — A PHARMACIST'S CONCERN

• Hyperuricemia — uric acid crystallizes in renal tubules → acute kidney injury
• Hyperkalemia → cardiac arrhythmias
• Hyperphosphatemia → hypocalcemia → tetany, seizures

• Allopurinol — xanthine oxidase inhibitor; reduces uric acid production (prophylaxis)
• Rasburicase — recombinant urate oxidase; rapidly degrades uric acid (treatment and high-risk prophylaxis); contraindicated in G6PD deficiency
• Aggressive IV hydration
• Urinary alkalinization (controversial)

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9. REFERENCES

• Robbins, Cotran & Kumar. Pathologic Basis of Disease, 10th edition. Elsevier, 2023 (pp. 556–588)
• Robbins & Kumar. Basic Pathology, 11th edition. Elsevier, 2023 (pp. Chapter 13)
• Katzung, Masters & Trevor. Basic and Clinical Pharmacology, 16th edition. McGraw-Hill, 2021 (Chapter 55 — Cancer Chemotherapy)

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Note to students: For the pharmacy perspective, pay particular attention to the mechanism-based treatments (ATRA in APL, TKIs in CML and Ph+ ALL, BTK inhibitors in CLL, BCL-2 inhibitors) as these represent transformative drug classes that directly exploit the molecular lesion of each leukemia subtype.