Chronic Myeloid Leukemia (CML)

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

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

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]