What are the main types of leukemia, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML)?

Types of Leukemia

Leukemia is classified into four main types based on the cell lineage (myeloid vs. lymphoid) and disease tempo (acute vs. chronic): Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), and Chronic Myeloid Leukemia (CML). 1, 2, 3

Classification Framework

The classification system divides leukemias along two axes:

By Cell Lineage:

• Lymphoid leukemias: Arise from abnormal lymphocyte precursors (B-cell or T-cell lineage)
• Myeloid leukemias: Originate from abnormal myeloid stem cells

By Disease Tempo:

• Acute leukemias: Characterized by immature blast cells (≥20% bone marrow lymphoblasts for ALL diagnosis) 1
• Chronic leukemias: Feature more mature cells with slower progression

The Four Major Types

1. Acute Lymphoblastic Leukemia (ALL)

Immunophenotypic Subtypes:

• Precursor B-cell ALL: Constitutes ~75% of adult ALL cases 1
  • Pre-pre-B-cell (pro-B): TdT+, CD19/CD22/CD79a+, CD10-
  • Common B-cell: CD10+ expression
  • Pre-B-cell: Cytoplasmic immunoglobulins present
• Mature B-cell ALL: ~5% of adult cases, surface immunoglobulin+, TdT- 1
• T-cell lineage ALL: ~25% of adult cases, cytoplasmic or surface CD3+, variable CD1a/CD2/CD5/CD7 1

Key Genetic Subtypes (critical for prognosis and treatment planning) 1:

• Philadelphia chromosome positive [t(9;22)]: Most common in adults (25%), increases with age (40% in patients >50 years)
• Hyperdiploidy (>50 chromosomes): Favorable prognosis
• Hypodiploidy: Poor prognosis (1-2% of cases)
• MLL rearrangements [t(4;11)]: Poor prognosis
• TEL-AML1 [t(12;21)]: Favorable prognosis

Age Distribution: Most common childhood leukemia (75-80% of pediatric acute leukemias), median age at diagnosis 17 years 2

2. Acute Myeloid Leukemia (AML)

Classification by Genetic Abnormalities 3:

• AML with t(8;21); RUNX1-RUNX1T1
• AML with inv(16) or t(16;16); CBFB-MYH11
• Acute promyelocytic leukemia with t(15;17); PML-RARA
• AML with t(9;11); MLLT3-MLL
• AML with t(6;9); DEK-NUP214
• AML with inv(3) or t(3;3); RPN1-EVI1
• AML (megakaryoblastic) with t(1;22); RBM15-MKL1
• Provisional entities: AML with mutated NPM1, AML with mutated CEBPA

Other Categories 3:

• AML with myelodysplasia-related changes
• Therapy-related myeloid neoplasms
• AML, not otherwise specified (includes subtypes by differentiation: minimal, without maturation, with maturation, myelomonocytic, monoblastic/monocytic, erythroid, megakaryoblastic, basophilic)

3. Chronic Lymphocytic Leukemia (CLL)

Diagnostic Criteria 4:

• Requires ≥5 × 10⁹/L clonal B lymphocytes in peripheral blood maintained for ≥3 months
• Characteristic phenotype: CD19+, CD5+, CD20+, CD23+, with kappa or lambda light chain restriction
• CLL and small lymphocytic lymphoma (SLL) are the same disease with different presentations

Essential Prognostic Testing 4:

• FISH with 4 probes (mandatory)
• IGHV mutational status (before first treatment)
• TP53 mutation detection (before first and subsequent treatments)
• Del(17p) assessment

Epidemiology: Most common adult leukemia in Western countries, median age 72 years 4

4. Chronic Myeloid Leukemia (CML)

Defining Feature 5, 6:

• Philadelphia chromosome [t(9;22)(q34;q11.2)] resulting in BCR-ABL1 fusion gene
• Produces p210 protein with deregulated tyrosine kinase activity in most cases
• Variant transcripts: p190 (e1a2), p230 (e19a2), atypical transcripts (1-2% of cases)

Disease Phases 5:

• Chronic phase (CP-CML): Most patients diagnosed in this phase
• Accelerated phase (AP-CML): Transitional phase with specific criteria
• Blast phase (BP-CML): ≥30% blasts (ELN criteria) or ≥20% (WHO criteria) 6

Epidemiology: Accounts for 15% of adult leukemias, median age 67 years, estimated 8,450 new cases annually in the US 5

Mixed Phenotype Acute Leukemia (MPAL)

A distinct category for acute leukemias with ambiguous lineage 1, 3:

• Bilineage: Two distinct blast populations, one meeting AML criteria
• Biphenotypic: Single blast population expressing markers of multiple lineages
• Can include BCR-ABL1-positive or MLL-rearranged cases meeting MPAL criteria
• Requires exclusion of CML blast phase for BCR-ABL1-positive cases

Clinical Pitfalls

Important Caveats:

• Myeloid markers (CD13, CD33) may be expressed in ALL without excluding the diagnosis 1
• In 5% of CML cases, Philadelphia chromosome is not detectable by conventional cytogenetics; FISH or RT-PCR confirmation of BCR-ABL1 is required 6
• Philadelphia-negative, BCR-ABL1-negative cases represent atypical CML, a separate disease entity 6
• The 20% blast threshold for ALL diagnosis can be bypassed if specific recurring cytogenetic abnormalities are present with <20% blasts 3
• Early precursor T-cell ALL represents a distinct subtype with poor outcomes despite contemporary treatment 1

Contemporary Survival Outcomes

Prognosis varies dramatically by type and age 7, 8:

• Philadelphia-positive ALL: Transformed from incurable (pre-2000) to 80%+ 5-year survival with BCR-ABL1 TKIs
• CML: Normal life expectancy achievable with TKI therapy
• CLL: 90%+ long-term survival rates with targeted therapies
• Pediatric ALL: 84% 5-year survival in children, 75% in adolescents
• Adult AML: Outcomes remain challenging, particularly in older/unfit patients, complex karyotype, TP53-mutated, and secondary AML cases