1845: CML was simultaneously first described by both Bennett in Edinburgh and Virchow in Germany
Autopsy Cases Demonstrated Massive Splenomegaly, Severe Anemia, Increased White Blood Cells
Bennett Described “Suppuration” of the Blood, Suggesting an Infection, But Virchow (Who Doubted that an Infection was Etiologic) Coined the Term “leukämie” (leukemia)
1878: Neumann in Germany names the disease “myelogene leukämie” (myelogenous leukemia)
Post-WWII: introduction of alkylating agents (derived from poison gas) for the treatment of CML
2001: introduction of tyrosine kinase inhibitors (TKI) for the treatment of CML (see Tyrosine Kinase inhibitors)
Epidemiology
Demographics
Annual Incidence: 1.6 cases per 100k adults
Relative Frequency: CML accounts for 15% of all adult leukemias
Risk Factors
Age: mean age of onset is 55-60 y/o
Ionizing Radiation Exposure
Male Sex
Physiology
Definitions
Proto-Oncogene is a Gene Which Can Be Damaged by Mutation (Mutation Leads to the Cancerous State)
Oncogene is a Proto-Oncogene with a Mutation
Philadelphia Chromosome
Gene Mutation: Philadelphia Chromosome results from reciprocal translocation of the human analog of the Abelson murine leukemia (ABL) gene from chromosome 9 to combine with the breakpoint cluster region (BCR) region on chromosome 22 -> [t(9;22)(q34;q11)]
Sensitivity
Philadelphia Chromosome is Sensitive, Being Present in 95% of CML Patients
The Remainder Have Either a Cryptic Translocation Which is Invisible on G-Banded Chromosome Preparations or an Alternate Translocation Involving Another Chromosome/Chromosomes within the Long Arm of Chromosomes 9 and 22
Philadelphia Chromosome Translocation Results in Expression of a BCR-ABL Fusion Protein: since ABL gene encodes for a membrane-associated tyrosine kinase, the fusion protein functions as a upregulated tyrosine kinase
BCR-ABL then Phosphorylates a Number of Cell Cycle Proteins and Enzymes, Inducing Cell Division and Inhibiting DNR Repair
BCR-ABL Fusion Protein Also Interacts with an IL-3 Receptor Subunit
Diagnosis
Blood Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) for BCR-ABL
Sensitivity
RT-PCR for for BCR-ABL Can Detect Disease Present in Only 1 Out of 10k-1 Million Cells
Clinical Utility of Assay
Diagnosis
Monitoring Response to Treatment
Detection of Residual Disease
Inexpensive: $300-500 per assay
Interpretation
Expressed in the Amount of BCR-ABL Gene Relative to a Reference Gene (Usually the ABL Gene)
For Example: 100% of cells express BCR-ABL from one allele and c-ABL from the normal allele, then BCR-ABL/ABL ratio would be about 0.5
Disadvantages
May Not Detect Some Rare BCR-ABL Fusion Variants
Difficult to Compare Results from Different Laboratories
Blood Fluorescence In Situ Hybridization (FISH)
Sensitivity: can detect disease when 1% of cells are affected
However, Since Marrow Hypercellularity Can Be Seen in Response to Granulocyte Colony Stimulating Factor (GCSF) and in Severe Inflammation/Infection, Cytogenetic Testing for the Philadelphia Chromosome is Necessary for Diagnosis
Replacement of Normal Fat by Marrow Cells
Increased Myeloid/Erythroid Ratio
Normal Myeloid/Erythroid Ratio: 2:1
CML Myeloid/Erythroid Ratio: may be as high as 6:1
Bone Marrow Karotype
Can Detect Disease When 5% of Cells are Affected
Clinical Phases
Chronic Phase
Epidemiology
Almost 90% of Cases are Diagnosed in this Phase
Diagnostic/Clinical Features
Asymptomatic: approximately 40% of cases are asymptomatic
Leukocytosis with Circulating Immature Myeloid Cells (see Leukocytosis, [[Leukocytosis]]): most notably eosinophils and basophils (see Peripheral Eosinophilia)
Mechanism: binds to BCR-ABL tyrosine kinase in its inactive confirmation (blocks binding of ATP) -> leads to growth arrest/apoptosis of BCR-ABL protein-expressing cells
Clinical Efficacy
Induces a complete clinical response (CCR) in 76% of patients at 18 months (compared to 14% of CML patients treated with interferon-cytarabine)
At 5 Years: 87% of patients had CCR, 83% had avoided progression, and 89% remained alive
Complete: nornal WBC/platelet counts and no splenomegaly
Cytogenetic Response :
Minor/Minimal: Ph+ cells are 36-65% or 65-95%
Partial: Ph+ cells are 1-35%
Complete: no Ph+ cells detected
Molecular Response
Major: <10% of cells are affected by blood RT-PCR
Complete: when blood RT-PCR is totally negative
Monitoring
Patients on tyrosine kinase inhibitors should have chemistries/CBC q2wks until complete hematologic response is achieved -> then, monthly F/U -> then, q3-4 month F/U when they are stable
Once FISH becomes negative or there is a big drop in RT-PCR, bone marrow should be done to confirm CCR -> then, RT-PCR should be done q3-4 months
RT-PCR values may fluctuate -> repeating values before changing therapy is advisable
Early in treatment, transient thrombocytopenia and neutropenia may occur before the clonal cells are suppressed
