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Leukemia — Pathology Assignment

Subject: Pathology | For: Pharmacy Students

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Definition

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Classification

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1. Acute Myeloid Leukemia (AML)

Definition

Pathogenesis

• Mutations impairing differentiation — affect transcription factors required for myeloid maturation (e.g., fusions like t(8;21) → RUNX1-RUNX1T1; inv(16); t(15;17) → PML-RARA in acute promyelocytic leukemia)
• Mutations promoting growth/survival — activate growth factor receptor signaling pathways (e.g., mutations in FLT3, RAS, KIT)

Acute Promyelocytic Leukemia (APL/M3 AML): A critical subtype caused by t(15;17), creating the PML-RARA fusion protein. This blocks differentiation at the promyelocyte stage. Treatment with all-trans retinoic acid (ATRA) causes the leukemic promyelocytes to differentiate and undergo apoptosis — a landmark example of differentiation therapy in oncology, highly relevant to pharmacy students.

Key Features

• Age: Mainly adults; most common acute leukemia in adults
• Blast cutoff: ≥20% blasts in bone marrow or blood = diagnostic
• Morphology: Large blasts with Auer rods (pathognomonic — pink needle-like cytoplasmic inclusions found in AML only)
• Symptoms: Fatigue/pallor (anemia), infections (neutropenia), bleeding (thrombocytopenia) — the triad of bone marrow failure

Lab Findings

• Elevated WBC (or may be normal/low)
• Decreased RBCs, platelets
• Auer rods on blood smear (pathognomonic for AML)
• Bone marrow biopsy: ≥20% myeloblasts

Treatment (Pharmacology Relevance)

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2. Acute Lymphoblastic Leukemia (ALL)

Definition

Pathogenesis

• Arises from precursor B or T lymphoblasts
• Common chromosomal abnormalities:
  • t(12;21) [ETV6-RUNX1]: Most common in pediatric B-ALL; favorable prognosis
  • t(9;22) [BCR-ABL / Philadelphia chromosome]: Present in ~25% of adult ALL; poor prognosis without targeted therapy
  • Hyperdiploidy (>50 chromosomes): favorable prognosis in children

Key Features

• Age: Peak in children (2–5 years); also occurs in adults
• Morphology: Lymphoblasts — medium-sized cells with scant cytoplasm, dispersed chromatin, and small nucleoli. No Auer rods (distinguishes from AML)
• Immunophenotype: B-ALL expresses CD19, CD10, TdT; T-ALL expresses CD3, CD7, TdT
• Sanctuary sites: CNS and testes — leukemic cells can hide here (important for therapy)

Symptoms

Treatment (Pharmacology Relevance)

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3. Chronic Myeloid Leukemia (CML)

Definition

Pathogenesis — The Philadelphia Chromosome

• Constitutively activates signaling pathways (RAS, PI3K/AKT, STAT5)
• Promotes cell proliferation and survival
• Suppresses apoptosis

The BCR-ABL fusion gene is present in granulocytic, erythroid, megakaryocytic, and B-cell precursors, indicating that CML arises from a transformed hematopoietic stem cell.

Clinical Phases

Key Features

• Age: Peak incidence in 4th–5th decade; adults 25–60 years
• Blood smear: Marked leukocytosis with full spectrum of myeloid maturation (neutrophils, bands, metamyelocytes, myelocytes, basophilia, eosinophilia)
• Splenomegaly: Often massive (extramedullary hematopoiesis)
• LAP (Leukocyte Alkaline Phosphatase): Low or absent (vs. reactive leukocytosis where LAP is high)

Treatment (Pharmacology Relevance) — Landmark Drug Class

Pharmacy Note: Imatinib is the prototype tyrosine kinase inhibitor (TKI) and is one of the most significant drugs in oncology history. It transformed CML from a fatal disease into a manageable chronic condition. Understanding TKI resistance mechanisms (e.g., T315I "gatekeeper" mutation) is important.

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4. Chronic Lymphocytic Leukemia (CLL)

Definition

Pathogenesis

• Arises from mature B cells that accumulate because of defective apoptosis (failure to die) rather than rapid proliferation
• Key genetic abnormalities:
  • del(13q14): Most common (55%); favorable prognosis
  • del(11q): Associated with aggressive disease
  • del(17p) / TP53 mutation: Worst prognosis; resistant to chemotherapy
  • Trisomy 12: Intermediate prognosis
• Mutational status of IGHV gene: Mutated IGHV = better prognosis

Key Features

• Age: Predominantly elderly (>60 years); rare before 40
• Blood smear: Monomorphic small mature lymphocytes with scant cytoplasm and clumped chromatin; characteristic smudge/basket cells (fragile leukemic cells broken during smear preparation)
• Immunophenotype: CD5+, CD19+, CD23+, weak surface Ig (co-expression of CD5 — a T-cell marker — on B cells is a hallmark)

Symptoms

• Often asymptomatic, discovered incidentally on CBC (B symptoms can occur in advanced disease)
• Lymphadenopathy, splenomegaly, hepatomegaly
• Autoimmune complications: AIHA (autoimmune hemolytic anemia), immune thrombocytopenia
• Hypogammaglobulinemia → recurrent infections

Staging (Rai System — Simplified)

Treatment (Pharmacology Relevance)

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Comparison Table: The Four Main Leukemias

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Pathology of the Bone Marrow in Leukemia

1. Normal hematopoiesis is suppressed → anemia, neutropenia, thrombocytopenia
2. Consequence of cytopenias:
   • Anemia → fatigue, pallor, dyspnea
   • Neutropenia → infections (bacterial, fungal)
   • Thrombocytopenia → bleeding (petechiae, ecchymoses, mucosal bleeding)
3. Extramedullary hematopoiesis — leukemic cells migrate to spleen, liver, and lymph nodes → organomegaly

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Pharmacy-Relevant Summary: Drug Targets in Leukemia

BCR-ABL kinase (CML/Ph+ ALL)  ──→  Imatinib, Dasatinib, Nilotinib, Ponatinib
BTK kinase (CLL, B-cell)       ──→  Ibrutinib, Acalabrutinib
BCL-2 (CLL, AML)               ──→  Venetoclax
FLT3 kinase (AML)              ──→  Midostaurin, Gilteritinib
PML-RARA fusion (APL/AML-M3)   ──→  ATRA (tretinoin), Arsenic trioxide
CD20 (B-cell leukemias)        ──→  Rituximab, Obinutuzumab
DNA synthesis (ALL, AML)       ──→  Methotrexate, Cytarabine, Fludarabine
Microtubules (ALL)             ──→  Vincristine
Topoisomerase II (AML)         ──→  Daunorubicin, Idarubicin

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Review Questions

1. What is the pathognomonic morphological finding in AML on peripheral blood smear?
2. Which chromosomal translocation defines CML, and what protein does it encode?
3. Why is ATRA effective specifically in acute promyelocytic leukemia (M3 AML)?
4. What cell surface markers distinguish CLL from other B-cell neoplasms?
5. A 7-year-old child presents with bone pain, lymphadenopathy, and 30% lymphoblasts in the marrow. What is the most likely diagnosis, and what is the most favorable cytogenetic finding?
6. How does venetoclax work, and in which leukemias is it used?
7. Compare the LAP score in CML versus a leukemoid reaction.
8. What is the "blast crisis" in CML, and why does it occur?
9. Which chromosomal deletion in CLL is associated with resistance to chemotherapy?
10. Name two sanctuary sites in ALL and explain why they are important for treatment planning.

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References

• Robbins, Cotran & Kumar — Pathologic Basis of Disease, 10th Ed. (Chapters: Myeloid Neoplasms, Lymphoid Neoplasms)
• Robbins & Kumar — Basic Pathology, 11th Ed.
• Goldman-Cecil Medicine, 27th Ed.

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