Leukemia: Pathophysiology, Assessment, and Pharmacological Treatment
Leukemia is a group of hematologic malignancies characterized by abnormal proliferation of immature white blood cells in the bone marrow that suppresses normal hematopoiesis and infiltrates various organs, requiring specific diagnostic workup and targeted treatment based on leukemia subtype.
Pathophysiology
Leukemia results from clonal proliferation of hematopoietic stem cells in the bone marrow 1. The fundamental pathophysiological process involves:
- Genetic alterations: Chromosomal translocations (like t(9;22) in CML), gene mutations, and other genetic abnormalities drive leukemogenesis
- Unregulated cell growth: Malignant transformation leads to excessive production of immature white blood cells (blasts)
- Impaired differentiation: Leukemic cells fail to mature properly and accumulate in bone marrow
- Bone marrow failure: Crowding out of normal hematopoietic cells leads to anemia, thrombocytopenia, and neutropenia
- Organ infiltration: Leukemic cells infiltrate liver, spleen, lymph nodes, and other organs
In CML specifically, the Philadelphia chromosome resulting from t(9;22)(q34;q11) creates the BCR-ABL fusion gene, producing a constitutively activated tyrosine kinase that drives disease progression 2.
Classification
Leukemia is broadly classified into four main types:
Acute Myeloid Leukemia (AML)
- Rapid proliferation of immature myeloid cells (blasts ≥20% in bone marrow)
- Risk factors include prior chemotherapy, radiation exposure, and certain genetic disorders 3
- Further subclassified based on morphology, cytogenetics, and molecular markers
Acute Lymphoblastic Leukemia (ALL)
- Predominance of immature lymphoid cells
- More common in children
- Immunophenotyping crucial for diagnosis and classification
Chronic Myeloid Leukemia (CML)
- Characterized by Philadelphia chromosome and BCR-ABL fusion gene
- Progresses through three phases: chronic, accelerated, and blast crisis 3, 2
- Chronic phase: <10% blasts, elevated WBC count, often asymptomatic
- Accelerated phase: 10-29% blasts, >20% basophils
- Blast crisis: ≥30% blasts, resembles acute leukemia
Chronic Lymphocytic Leukemia (CLL)
- Accumulation of mature-appearing but functionally incompetent B lymphocytes
- Diagnosis requires ≥5 × 10^9/L monoclonal B lymphocytes 3
- Immunophenotype: CD5+, CD23+, CD20 dim+, surface immunoglobulin dim+
Clinical Assessment
History and Physical Examination
- Constitutional symptoms: Fatigue, weight loss, fever, night sweats
- Symptoms of bone marrow failure: Easy bruising/bleeding, recurrent infections, pallor
- Physical findings: Splenomegaly (present in >50% of CML cases), hepatomegaly, lymphadenopathy 2
Laboratory Evaluation
- Complete blood count (CBC): Leukocytosis, anemia, thrombocytopenia or thrombocytosis
- Peripheral blood smear: Presence of blasts, abnormal cell morphology
- Bone marrow examination: Essential for diagnosis, shows hypercellularity and increased blasts
- Cytogenetics: Mandatory to detect chromosomal abnormalities like t(9;22) in CML 3, 2
- Molecular studies: BCR-ABL testing for CML, FLT3, NPM1, CEBPA mutations in AML 3
- Immunophenotyping: Flow cytometry to determine lineage (myeloid vs. lymphoid) and specific subtypes
Risk Stratification
- Age: Older age associated with poorer outcomes
- Cytogenetics: Favorable (t(8;21), t(15;17), inv(16) in AML), unfavorable (complex karyotype)
- Molecular markers: FLT3-ITD mutations confer poor prognosis in AML
- Response to initial therapy: Early clearance of blasts associated with better outcomes
Pharmacological Treatment
Treatment varies significantly by leukemia type:
Acute Myeloid Leukemia (AML)
- Induction therapy: Anthracycline (daunorubicin) plus cytarabine ("7+3" regimen) 3, 4
- Daunorubicin 45-90 mg/m² daily for 3 days
- Cytarabine 100-200 mg/m² continuous infusion for 7 days
- Consolidation therapy: High-dose cytarabine or allogeneic stem cell transplantation
- Special considerations:
- Acute promyelocytic leukemia (APL): All-trans retinoic acid (ATRA) plus arsenic trioxide 3
- FLT3-positive AML: Consider adding FLT3 inhibitors
Chronic Myeloid Leukemia (CML)
- First-line therapy: Tyrosine kinase inhibitors (TKIs) 3, 2
- Imatinib 400 mg daily is standard first-line treatment
- Second-generation TKIs (dasatinib, nilotinib) for resistant disease
- Response monitoring: Regular molecular monitoring with quantitative PCR for BCR-ABL transcripts
- Treatment goals: Complete hematologic, cytogenetic, and molecular responses
Chronic Lymphocytic Leukemia (CLL)
- Watch and wait for asymptomatic early-stage disease 3
- Treatment indications: Progressive bone marrow failure, massive/symptomatic lymphadenopathy/splenomegaly, constitutional symptoms
- Treatment options:
- Purine analogs (fludarabine) or chlorambucil
- Anti-CD20 monoclonal antibodies (rituximab)
- BTK inhibitors (ibrutinib)
- BCL-2 inhibitors (venetoclax)
Treatment Complications
- Tumor lysis syndrome: Rapid destruction of malignant cells causing metabolic abnormalities
- Myelosuppression: Increased risk of infections, bleeding
- Cardiotoxicity: With anthracyclines, especially in elderly patients 4
- Secondary malignancies: Increased risk after chemotherapy and radiation
Monitoring and Follow-up
- Complete blood counts: Regular monitoring during and after treatment
- Bone marrow examination: To assess response and minimal residual disease
- Molecular monitoring: BCR-ABL quantification in CML
- Long-term surveillance: For relapse and treatment-related complications
Prognosis
Prognosis varies significantly by leukemia type:
- AML: 5-year survival ~40% in younger patients, <15% in elderly
- CML: With TKI therapy, 6-year progression-free survival of 84% and overall survival of 88% 3, 2
- CLL: Highly variable, with some patients living decades without treatment
The introduction of targeted therapies, particularly TKIs for CML, has dramatically improved outcomes for certain leukemia subtypes, transforming some from fatal diseases to chronic conditions with long-term survival.