Hyperleukocytosis And Leukostasis

The majority of patients with acute leukemia present with non-specific symptoms such as fatigue, weight loss, and fevers. Approximately 5-30% of adult patients with acute leukemia will have a more dramatic presentation related to an extraordinarily high leukocyte count, usually greater than 100,000/mm3. About 5-18% patients with adult AML5253 present with hyperleukocy-tosis, with a majority of them having symptoms referable to leukostasis.54 Even though hyperleukocytosis is generally considered to have a negative impact on prog-nosis,53,55 its independent prognostic value in AML is controversial due to its close association with other established markers of unfavorable disease such as age, karyotype, CNS involvement, and antecedent hemato-logical disorders.

The incidence of hyperleukocytosis in ALL is 10-30%. Hyperleukocytosis is a well-established negative prognostic factor for pediatric and adult ALL. Interestingly, in ALL, hyperleukocytosis rarely results in leukostasis. T-cell ALL, male sex, 11q23 rearrangements, and PhT ALL are all associated with a higher incidence of hyper-leukocytosis. The major consequence of an increased WBC count is leukostasis, which is sludging of the microcirculation with leukemic blasts. Leukemic blasts can also form microaggregates and white, bland thrombi in these small vessels, leading to further impairment in flow. Direct endothelial damage and bleeding can occur as a result of local hypoxemia that is exacerbated by the high metabolic activity of the dividing blasts. Pathological examination frequently reveals end-organ infiltration with leukemic blasts. This is a consequence of direct endothelial damage mediated by soluble cytokines released during the interaction between leukemic blasts and the endothelium, with subsequent migration of these blasts into the perivascular space. There is emerging evidence that the differential expression of certain adhesion molecules on the vascular endothelium of AML patients may facilitate interaction of the leukemic blast with the vascular endothelium, with subsequent migration.56 The pulmonary and cerebral vascular beds are the most clinically relevant targets of leukostasis. Cerebral involvement can range from subtle confusion and somnolence to frank intracerebral bleeding and coma. Early pulmonary involvement is signaled by mild dyspnea and respiratory alkalosis. Without treatment, this can progress to respiratory failure requiring mechanical ventilation. Typical chest X-ray findings include diffuse interstitial or alveolar infiltrates, but can be normal in the early stages.

Pulmonary leukostasis was found to be the single worst prognostic factor in patients with AML.57 Fever is almost always present at presentation, and usually is not related to infection. Spurious hypoxemia can be related to increased consumption of oxygen by the blasts in the blood collection tube, and can be avoided by immediate transportation of an arterial blood gas sample on ice.

The short-term prognosis for patients with AML with hyperleukocytosis remains poor. As predictive factors for leukostasis lack a high degree of specificity, aggressive supportive care and prompt cytoreduction are essential. At our center, we use hydroxyurea,5859 1-3 grams orally every 6 hours in combination with emergent leuka-pheresis for patients presenting with WBC counts > 100,000/mm3 or signs or symptoms indicative of leukostasis in AML. In ALL, the threshold to initiate leukapheresis is higher; usually >200,000/mm3 in many centers. In addition to clearing circulating blasts, leuka-pheresis is thought to improve the coagulopathy that may be present in these patients by replacement with fresh frozen plasma, thereby reducing the risk of hemorrhage. However, leukapheresis has never been shown convincingly to reduce the risk of developing clinically significant leukostasis or reducing early mortality.60 Though there are scanty reports in the literature regarding the use of cranial irradiation,61 it has been largely abandoned as a therapeutic modality due to toxicity, inconvenience, and lack of efficacy data.

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