Chronic Myeloid Leukemia (CML)

Definition

• Goldman-Cecil Medicine, p. 1940
• Robbins Pathologic Basis of Disease, p. 583

Epidemiology

• Accounts for ~14% of all leukemias in the US
• Approximately 8,000-9,000 new cases per year in the US
• Peak incidence in the 5th-6th decades of life (median age at diagnosis: ~65 years)
• Occurs in adults and, less commonly, children/adolescents
• No clear environmental cause; ionizing radiation is a recognized risk factor
• Washington Manual of Medical Therapeutics, p. 866
• Robbins Pathologic Basis of Disease, p. 583

Molecular Pathogenesis

• ABL1 (tyrosine kinase) from chromosome 9 fuses with BCR (breakpoint cluster region) on chromosome 22
• This creates the BCR-ABL fusion gene, encoding a 210 kDa constitutively active tyrosine kinase (p210 BCR-ABL)
• In ~90% of cases the translocation is cytogenetically visible; the remainder require FISH or PCR to detect

• Robbins Pathologic Basis of Disease, p. 583

Disease Phases

• 75% of patients in developed countries are diagnosed in chronic phase (often incidentally on CBC)

• Without treatment, median survival is ~3 years
• After ~3 years, ~50% transition through accelerated phase to blast crisis; the other 50% transform abruptly
• The existence of both myeloid and lymphoid blast crises confirms the pluripotent HSC origin of CML
• Blast crisis is typically triggered by acquired mutations in transcriptional regulators (e.g., AML1-ETO, RUNX1, or p53 mutations)
• Goldman-Cecil Medicine, p. 1938-1940
• Robbins Pathologic Basis of Disease, p. 583-585

Morphology

• Marked leukocytosis, often exceeding 100,000 cells/µL
• Full myeloid spectrum: neutrophils, band forms, metamyelocytes, myelocytes
• Basophilia and eosinophilia - characteristic and diagnostically important
• Blasts usually <10% in chronic phase
• Thrombocytosis (elevated platelets), sometimes markedly so

• Markedly hypercellular with massively increased maturing granulocytic precursors
• Elevated eosinophils and basophils
• Increased dysplastic megakaryocytes (small, abnormal forms)
• Erythroid progenitors normal or mildly decreased
• Characteristic "sea-blue histiocytes" - scattered macrophages with abundant wrinkled, green-blue cytoplasm
• Increased reticulin deposition; overt fibrosis is rare

• Often greatly enlarged due to extramedullary hematopoiesis
• May contain infarcts of varying ages
• Mild hepatomegaly and lymphadenopathy may also occur
• Robbins Pathologic Basis of Disease, p. 583

Clinical Presentation

• Onset is insidious - most patients are asymptomatic and diagnosed on routine CBC
• Constitutional symptoms: fatigue, weakness, weight loss, anorexia (from increased cell turnover and mild-moderate anemia)
• Left upper quadrant pain or fullness from splenomegaly (dragging sensation, early satiety)
• Acute left upper quadrant pain from splenic infarction
• Hyperviscosity symptoms if WBC very high
• Rarely: gout (hyperuricemia from cell turnover)
• Washington Manual of Medical Therapeutics, p. 866
• Robbins Pathologic Basis of Disease, p. 583

Diagnosis

1. Conventional cytogenetics (karyotype) - detects the Philadelphia chromosome in >90% of cases
2. FISH - detects BCR-ABL fusions including cryptic rearrangements not visible on karyotype
3. Quantitative RT-PCR (qPCR) - detects and quantifies BCR-ABL transcripts; the gold standard for monitoring

• Assess cellularity and morphology
• Determine blast percentage (phase)
• Evaluate for fibrosis
• Washington Manual of Medical Therapeutics, p. 866

Treatment

The TKI Revolution

• Both NCCN and ELN are agnostic about which TKI to use as frontline therapy
• For older patients: imatinib is reasonable (long track record, good tolerability)
• For younger patients hoping for treatment-free remission or childbearing: a 2nd-generation TKI is preferred (higher rates of deep response)
• Nilotinib: avoid in metabolic syndrome/cardiovascular disease
• Dasatinib: caution in patients with pulmonary or pleural disease
• Ponatinib is reserved for failure of ≥2 prior TKIs or T315I resistance mutation
• Harrison's Principles of Internal Medicine 22E, p. 882
• Washington Manual of Medical Therapeutics, p. 866

Response Monitoring

• Failure to achieve CHR by 3 months or MMR milestones at 3/6 months carries a poor prognosis and warrants TKI switch
• qPCR "halving time" after starting therapy predicts likelihood of treatment-free remission
• Washington Manual of Medical Therapeutics; Goldman-Cecil Medicine

Treatment-Free Remission (TFR)

• ~40-50% of patients who have been in deep molecular response (MR4.0+) for ≥2 years can successfully discontinue TKI therapy and remain in remission
• Most patients need at least 3 years of total therapy before attempting discontinuation

• 90% of those who relapse after stopping respond rapidly to TKI reintroduction

• Progression to advanced phase after discontinuation is exceedingly rare
• Eligibility criteria for discontinuation: patients should ideally enroll in a clinical trial; long-term consequences are still under study
• Goldman-Cecil Medicine, p. 1944

Resistance to TKIs

• ~25-50% caused by point mutations in the BCR-ABL kinase domain (e.g., T315I, Y253H, E255K)
• T315I ("gatekeeper" mutation): confers resistance to all 1st- and 2nd-generation TKIs; only ponatinib and asciminib remain active
• Other mechanisms: BCR-ABL amplification, clonal evolution (new cytogenetic abnormalities)

Survival - The TKI Era

• Harrison's Principles of Internal Medicine 22E, Figure 110-2

Allogeneic Stem Cell Transplantation (allo-SCT)

• No longer first-line therapy for chronic-phase CML given TKI efficacy
• Still a key option for:
  • Blast-phase CML
  • TKI-refractory cases
  • Accelerated phase not responding to TKIs
  • T315I mutation if ponatinib/asciminib not accessible or tolerated

Prognosis

• Chronic-phase CML on TKIs: Near-normal life expectancy; 10-year overall survival >85%
• Accelerated phase: TKI era has improved median survival to ~88 months (vs. 28 months pre-TKI)
• Blast phase: Remains grim; median survival 5-7 months despite TKIs
• Prognostic scoring systems (Sokal score, EUTOS score, ELTS score) stratify patients by WBC, spleen size, blast %, platelets, and age to predict outcome

Recent Evidence (2024-2026)

Differential Leukocyte Count - Normal Values (Peripheral Blood)

Relative Percentage (%) - Adults

Total = 100%

Absolute Count (cells/µL) - Adults

Total WBC (reference range): 4,000 - 11,000 cells/µL

Key Memory Aid (NLMEB Rule)

Neutrophils > Lymphocytes > Monocytes > Eosinophils > Basophils

Clinical Significance of Deviations

Note on CML (context from previous discussion)

• WBC often >100,000 cells/µL
• The full myeloid spectrum is present: blasts, promyelocytes, myelocytes, metamyelocytes, bands, segmented neutrophils
• Basophilia and eosinophilia are hallmark findings
• Blasts typically <10% in chronic phase

Differential Leukocyte Count in CML - by Phase

Chronic Phase CML - Peripheral Blood Differential

Total WBC: often 50,000 - 200,000 cells/µL (normal: 4,000-11,000) The key feature is the entire granulocytic maturation spectrum visible on the smear - from blasts all the way to mature neutrophils ("myelocyte bulge").

• Robbins Pathologic Basis of Disease, p. 583
• Goldman-Cecil Medicine, p. 1940
• Washington Manual of Medical Therapeutics, p. 866

Accelerated Phase CML - Key Differential Changes

• Goldman-Cecil Medicine, p. 1938
• Harrison's Principles of Internal Medicine 22E, p. 882

Blast Phase (Blast Crisis) - Differential

• Robbins Pathologic Basis of Disease, p. 584

Side-by-Side Comparison: Normal vs. CML Differential

Key Diagnostic Clue

Basophilia + eosinophilia + full myeloid spectrum on smear (from blasts to mature neutrophils) + WBC >50,000 = CML until proven otherwise.