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

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