Hyperleukocytosis

Hyperleukocytosis (HL) is defined as a total white cell count greater than 100,000/mm³. Hyperleukocytosis is seen at presentation in 9-13% of children with acute lymphocytic leukemia (ALL) and 5-22% of children with acute myeloid leukemia (AML). It occurs in an even higher percentage of patients with chronic myeloid leukemia (CML). Patients with HL are at risk for acute complications due to rapid proliferation of leukemic blasts resulting in leukostasis and tumor lysis syndrome (TLS) as well as blast cell lysis leading to the release of anti- and procoagulant factors. High blast counts, especially in AML, are related to increased risk of early mortality secondary to leukostasis and leukemic cell lysis both before and after commencement of chemotherapy.

Clinical picture

Common complications of leukostasis are respiratory failure, pulmonary haemorrhage, and intracranial haemorrhage (ICH). ICH often presents at diagnosis in patients with ALL, AML as well as specifically AML M3 subtype (acute promyelocytic leukemia; APL).

Neurologic manifestations can range from headache and confusion to somnolence, stupor, and coma. Additional potential manifestations include priapism, dactylitis, retinal haemorrhage, renal infiltration /failure, bowel ischemia, congestive heart failure and cardiac tamponade.

Pathogenesis

The general principle of leukostasis syndrome is microcirculation thrombosis due to hyperviscosity of the blood. Sludging of circulating leukemic blasts (due to their size and count) causes mechanical obstruction of capillaries and consecutive mal-perfusion in the microcirculation (e.g., in organs such as brain, lungs, renal glomeruli).

Apart from the mechanical obstruction, leukemic blasts adhere to the endothelium and interact with it by production of cytokines.

These changes after cytokine-driven endothelial cell activation can be a loss of vascular integrity and modification of endothelial phenotype to prothrombotic phenotype. Prothrombotic changes of endothelial cells allow leukemic blasts migration and microhaemorrhages.

Management

The management of hyperleukocytosis includes supportive measures and reducing the number of leukemic blast cells by intensive chemotherapy, hydroxyurea, and leukapheresis. These measures shouldn’t be regarded to restore normal laboratory figures in patients with hyperleukocytosis who are asymptomatic. Also, neither hydroxyurea nor leukapheresis is able to show benefit on short- and long-term outcomes in patients with symptomatic hyperleukocytosis. The optimal management of symptomatic hyperleukocytosis is still uncertain, and there are no randomized studies demonstrating one is superior to each other. Therefore, its recommended to start intensive chemotherapy for eligible patients as soon as possible together with protective supportive measures.

Leukapheresis

Leukapheresis is used in an effort to quickly decrease a patient’s circulating blast count, which can both prevent the development of leukostasis and provide symptomatic relief of leukostasis. However, the impact of leukapheresis on early- and long-term mortality is controversial, with several studies producing conflicting results. As per the ASFA guidelines, the utilization of leukapheresis is listed as a strong recommendation with moderate-quality evidence for treatment of leukostasis symptoms and should be considered as a weak recommendation for leukostasis prophylaxis in higher-risk AML patients.

Hyperhydration

Randomized controlled trials are lacking in regard to the benefits of hyperhydration although multiple small studies, especially in pediatric ALL, have shown significant decrement in the WBC count with hydration alone, obviating the need for leukapheresis.

Hydroxyurea

Hydroxyurea was effective in rapidly lowering the WBC count in the majority of patients. However, there is no difference in early death or long-term outcome in those patients with and without HL.

Transfusion

Blood viscosity is usually unaltered in HL secondary to a decrease in the erythrocrit concomitant with the increased leukocrit. Therefore, blood transfusion should be avoided as it can lead to increased risk of leukostasis by increasing blood viscosity.

References

• Porcu P, Cripe LD, Ng EW et al (2000) Hyperleukocytic leukemias and leukostasis: a review of pathophysiology, clinical presentation and management. Leuk Lymphoma 39:1–18
• Kim H, Lee JH, Choi SJ et al (2006) Risk score model for fatal intracranial hemorrhage in acute leukemia. Leukemia 20:770–776
• Sung L, Aplenc R, Alonzo TA et al (2012) Predictors and short-term outcomes of hyperleukocytosis in children with acute myeloid leukemia: a report from the Children’s Oncology Group. Haematologica 97: 1770–1773
• Guyatt G, Gutterman D, Baumann MH et al (2006) Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians Task Force. Chest 129:174–181
• Schwartz J, Winters JL, Padmanabhan A et al (2013) Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth Special Issue. J Clin Apher 28:145–284
• James H, Caroline A, Anurag K. (2015). Supportive Care in Pediatric Oncology, A Practical Evidence-Based Approach. New York: Springer
• Philip Lanzkowsky (2022). Lanzkowsky’s Manual of Pediatric Hematology and Oncology. 7^th edition. London, UK: Elsevier