About the Condition

Definition and description

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder (a myeloproliferative neoplasm) characterized by presence of the Philadelphia chromosome, which results from a reciprocal translocation between chromosomes 9 and 22.

Hyperleukocytosis is a total white cell count > 100 x 109/L (some reserve the term for patients with leukemia, for example see Korkmaz, 2018).

Leukostasis is a clinicopathologic syndrome characterized by the presence of white cell plugs in the microvasculature and symptoms of microvascular occlusion, especially in the brain and lungs. Pham and Schwartz defined leukostasis as:

End-organ complication due to microvascular obstruction, hyperviscosity, tissue ischemia, and hemorrhage that are not due to infections, thromboembolism, or other underlying etiologies.

Korkmaz defines it as:

symptomatic hyperleukocytosis’ which is a medical emergency that needs prompt recognition and initiation of therapy to prevent renal and respiratory failure or intracranial haemorrhage

Prevalence

Chronic myeloid leukemia

  • accounts for about 15% of adult leukemias
  • incidence about 1-2 per 100,000 people/year, with no major geographic or ethnic variations

Leukostasis

  • More common in acute than chronic leukemia
  • Most common in acute myelogenous leukemia (AML)
    • occurs in AML patients with WBC count of > 100 x 109/L
    • in certain variants of AML, such as the M4 or M5 type, leukostasis might occur at lower counts
  • Occurs in ALL patients with WBC count of > 400 x 109/L
  • Rare in CML since most cells are segmented neutrophils, metamyelocytes, and myelocytes, which are smaller and more deformable than less mature cells; mostly seen in the accelerated phase or blast crisis RUSHAD: another source says: “Overall, it is most common in CML, probably related to the increased frequency of hyperleukocytosis and the high corpuscular volume of the promyelocytes
  • Rare in chronic lymphocytic leukemia (mostly reported in patients with WBC counts > than 1,000,000/uL)

Pathophysiology

Chronic myelogenous leukemia

  • Juxtaposition of ABL1 gene from chromosome 9 and breakpoint cluster region (BCR) gene from chromosome 22 creates the BCR-ABL1 fusion oncogene
  • Constitutively active tyrosine kinase (BCR-ABL1 protein) which causes abnormal activation of many cell signaling pathways, promoting hematopoietic cell transformation to CML

Hyperleukocytosis

  • May develop
    • Leukostasis
    • Tumor lysis syndrome
    • DIC

Leukostasis

  • Blood viscosity is a function of cell number (more precisely the leukocrit, which is higher in AML vs ALL, because AML blasts are larger than ALL blasts) and cell deformability
  • Blasts are less deformable than mature WBCs
  • Non-deformable blasts can occlude microvessels and reduce flow in the vessels
  • Increased blast-endothelial cell interactions may also contribute to leukostasis
  • Symptoms of leukostasis are eventually caused by insufficient oxygen supply of target organs
  • Leukemic blasts have a higher rate of oxygen consumption and thus may compete with tissue cells in areas of obstructed flow
  • WBC is usually >50–100 x 109/L
  • Symptoms correlate with blast and promyelocyte counts (but not when monoblasts are involved), possibly owing to their increased size and rigidity
  • However, there is generally a poor correlation between the threshold of WBC and/or blast count and the development of signs and symptoms of leukostasis

Diagnosis

Chronic myeloid leukemia

  • Suspect diagnosis based on blood count showing leukocytosis with basophilia and immature granulocytes (mainly metamyelocytes, myelocytes, promyelocytes, and a few or occasional myeloblasts)
  • Confirm diagnosis with identification of Philadelphia chromosome (t[9;22][q3.4;q1.1]) by bone marrow cytogenetics or FISH and BCR-ABL1 transcripts by quantitative RT-PCR in peripheral blood or bone marrow cells

Leukostasis

  • The leukostasis syndrome can only be proven by autopsy
  • Suspect diagnosis in patient with hyperleukocytosis and clinical evidence of end organ damage, especially brain and lungs
    • Brain
      • confusion
      • dizziness
      • headache
      • tinnitus
      • blurred vision
      • somnolence
      • stupor
    • Pulmonary
      • dyspnea
      • tachypnea
      • hypoxemia
      • diffuse alveolar hemorrhage
      • respiratory failure
    • Other (rare)
      • acute leg ischemia
      • renal vein thrombosis
      • priapism
      • arrhythmias
      • myocardial infarction
      • renal failure

Treatment

Chronic myeloid leukemia (stable phase)

  • Supportive care
  • First-line treatment with tyrosine kinase inhibitors (TKIs); options include:
    • imatinib
    • nilotinib 
    • dasatinib 
  • Further treatment depends upon response to first-line therapy

Leukostasis

Leukostasis is a medical emergency with risk of life-threatening cerebral infarcts, cerebral hemorrhage, or pulmonary insufficiency. The management includes intensive supportive care and cytoreduction. Treatment includes:

  • Supportive care
    • Prevention of tumor lysis syndrome by aggressive hydration and allopurinol
    • Respiratory support as needed
  • Cytoreduction
    • First line: cytoreductive therapy, for example hydroxyurea and TKI
    • Second line: leukapheresis (leukocytapheresis)
      • Bridging therapy to definitive treatment, cytoreductive therapy and/or chemotherapy
      • Should not lead to postponement of chemotherapy
      • Should be accompanied by hydroxyurea and/or chemotherapy to prevent WBC rebound after procedure
      • Adverse effects include citrate toxicity, blood loss ad platelet loss and risks related to venous access
      • A single leukapheresis procedure can reduce the WBC count by 20–50%; in a majority of patients, a single procedure may control leukostasis symptoms
      • Postprocedure CBC for the WBC count should be performed quickly, preferably within an hour from the completion, to assess the efficacy of the procedure
      • The best variable to assess for response to leukocytapheresis is the resolve of the patient’s symptoms of leukostasis
      • No randomized trials evaluating the efficacy of this procedure have been published