History
- 1845: CML was simultaneously first described by both Bennett in Edinburgh and Virchow in Germany
- Autopsy cases demonstrated massive splenomegaly, severe anemia, increased WBC -> 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 treatment of CML
- 2001: introduction of tyrosine kinase inhibitors (see Imatinib, [[Imatinib]]) for the treatment of CML
Epidemiology
- 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
Definitions
- Proto-Oncogene: gene that can be damaged by mutation -> mutation leads to the cancerous state
- Oncogene: proto-oncogene with a mutation
Physiology
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 that is invisible on G-banded chromosome preparations or an alternate translocation involving another chromosome/chromosomes within the long arm of chromosomes 9 and 22
- Specificity: Philadelphia chromosome is not specific
- Philadelphia chromosome can also be found in some cases of acute lymphocytic leukemia (ALL) (see Acute Lymphocytic Leukemia, [[Acute Lymphocytic Leukemia]]) or acute myeloid leukemia (AML) (see Acute Myeloid Leukemia, [[Acute Myeloid Leukemia]])
- Impact of Downstream Protein Expression: the 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 RT-PCR for BCR-ABL
- Sensitivity: 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 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
Bone Marrow Biopsy
- Hypercellular with Inceased Myeloid Precursors
- 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: 40% of cases are asymptomatic
- Abdominal Fullness
- Fatigue (see Fatigue, [[Fatigue]])
- Leukocytosis with Circulating Immature Myeloid Cells (see Leukocytosis, [[Leukocytosis]]): most notably eosinophils and basophils
- Splenomegaly (see Splenomegaly, [[Splenomegaly]]): common
- Thrombocytosis (see Thrombocytosis, [[Thrombocytosis]]): common
Treatment/Prognosis
- Prognosis: untreated, chronic phase lasts 3-5 years
Accelerated Phase
Diagnostic/Clinical Features
- CBC: platelets <100k (not due to therapy) or >1 million (despite therapy)
- Peripheral Blood/Bone Marrow
- 10-19% blasts or >20% basophils in blood or bone marrow
- Clonal cytogenetic abnormalities in addition to the Philadelphia chromsome
- Increasing Splenomegaly or Leukocytosis Unresponsive to Therapy
Treatment/Prognosis
- 4-Year Survival: 40% (even with Imatinib therapy)
Blast Crisis
Diagnostic/Clinical Features
- Peripheral Blood/Bone Marrow: >20% blasts in blood or bone marrow (sometimes with blast clusters on biopsy)
- Clinical Appearance
- 33% of cases clinically resemble acute lymphocytic leukemia (ALL) (see Acute Lymphocytic Leukemia, [[Acute Lymphocytic Leukemia]])
- 66% of cases clinically resemble acute myeloid leukemia (AML) (see Acute Myeloid Leukemia, [[Acute Myeloid Leukemia]])
- Extramedullary Chloroma (see Chloroma, [[Chloroma]])
Treatment/Prognosis
- Prognosis
- Without Imatinib Therapy: 3-5 mo survival
- With Imatinib Therapy: short survival (due mainly to presence of complex cytogenetic abnormalities that confer resistance to treatment)
- Typical Causes of Death
- Hemorrhage
- Infection
Clinical Manifestations
General Comments
- Asymptomatic: 20-50% of cases are asymptomatic (depending on stage of disease)
Cardiovascular Manifestations
- xxx
Dermatologic Manifestations
- Diaphoresis/Hyperhidrosis (see Diaphoresis, [[Diaphoresis]])
- Night Sweats (see Night Sweats, [[Night Sweats]])
Gastrointestinal Manifestations
- Early Satiety (see Early Satiety, [[Early Satiety]]): due to splenomegaly
- Left Upper Quadrant Abdominal Pain (see Abdominal Pain, [[Abdominal Pain]]): due to splenomegaly
- Weight Loss (see Weight Loss, [[Weight Loss]])
Hematologic Manifestations
- Anemia (see Anemia, [[Anemia]])
- Leukocytosis (see Leukocytosis, [[Leukocytosis]])
- Splenomegaly (see Splenomegaly, [[Splenomegaly]])
- Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]])
- Thrombocytosis (see Thrombocytosis, [[Thrombocytosis]])
Neurologic Manifestations
- Fatigue (see Fatigue, [[Fatigue]])
Pulmonary Manifestations
Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
- Mechanisms by Which Chronic Myeloproliferative Disorders Cause Pulmonary Hypertension
- Auto or Surgical Asplenia
- Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
- Congestive Heart Failure (CHF)
- Direct Obstruction of Pulmonary Arteries by Circulating Megakaryocytes
- High Cardiac Output
- Portopulmonary Hypertension
Pleural Metastases/Effusion (see Pleural Metastases, [[Pleural Metastases]] and Pleural Effusion-Exudate, [[Pleural Effusion-Exudate]])
- xxx
Other Manifestations
- xxx
Treatment
Tyrosine Kinase Inihibitors
Imatinib (Gleevec) (see Imatinib, [[Imatinib]])
- History: introduced in 2001
- Dose
- Chronic Phase: 400 mg PO qday
- Accelerated/Blast Phase: 600 mg PO qday
- Moderate Hepatic Dysfunction: reduce dose
- Cost: $32k/year (at 400 mg PO qday dosage)
- Least expensive of the three agents
- 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
- Adverse Effects: nausea, fluid retention, anemia, muscle cramps
- Resistance: there are about 40 BCR-ABL mutations that confer imatinib resistance (as well as less defined factors that confer resistance)
Dasatinib (Sprycel) (see Dasatinib, [[Dasatinib]])
- xxxx
Nilotinib (Tasigna) (see Nilotinib, [[Nilotinib]])
- xxx
Response to Therapy
- Hematologic Response
- 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
Bone Marrow/Stem Cell Transplant (see Bone Marrow Transplant, [[Bone Marrow Transplant]])
- xxx
References
- Pulmonary hypertension secondary to thrombocytosis in a patient with myeloid metaplasia. Chest 1993; 103:642–4 [MEDLINE]
- Unexplained pulmonary hypertension in chronic myeloproliferative disorders. Chest 2001;120:801–8 [MEDLINE]
- Incidence of pulmonary hypertension in patients with chronic myeloproliferative disorders. J Natl Med Assoc. 2006 Nov;98(11):1779-82 [MEDLINE]
- Pulmonary hypertension in patients with essential thrombocythemia and reactive thrombocytosis. Leuk Lymphoma. 2007 Oct;48(10):1981-7 [MEDLINE]