REVIEW NAVNEET S. MAJHAIL, MD ALAN E. LICHTIN, MD CME Department of Hematology, Oncology, and Department of Hematology and Medical CREDIT Transplantation, University of Minnesota, Oncology, The Cleveland Clinic Foundation Minneapolis Acute leukemia with a very high leukocyte count: Confronting a medical emergency ■ ABSTRACT OST PATIENTS WITH ACUTE leukemias first M present to a general internist because of From 5% to 30% of adult patients with acute leukemias nonspecific symptoms of fatigue, weight loss, present with hyperleukocytosis—very high white blood and fever. In such cases, if the peripheral blood cell counts (> 100,000 cells/mm3)—and symptoms of count and other indices suggest acute leukostasis. These conditions are a medical emergency leukemia, the patient is referred to an oncolo- that needs prompt recognition and initiation of therapy to gy center. prevent respiratory failure or intracranial hemorrhage. However, from 5% to 30% of adult patients Patients should be referred as soon as possible for with acute myeloid leukemia or acute lym- induction chemotherapy and leukapheresis. phoblastic leukemia present quite differently: they have hyperleukocytosis (white blood cell ■ KEY POINTS counts > 100,000/mm3),1–4 they are acutely ill, Risk factors associated with hyperleukocytosis include and they have metabolic abnormalities, coagu- 1,2 younger age, certain types of leukemia, and cytogenetic lopathy, and multiple organ failure. The clin- ical picture often mimics infectious and hemor- abnormalities. rhagic complications of acute leukemia. This presentation is characteristic of acute Symptoms of hyperleukocytosis are primarily due to hyperleukocytosis and leukostasis and should leukostasis, a clinicopathologic syndrome caused by the be considered a medical emergency. If it is not sludging of circulating leukemic blasts in tissue recognized and treated quickly, the mortality microvasculature. rate can be up to 40%.1,5 Management must be started before the patient can be referred for Patients can present with symptoms ranging from treatment of the underlying leukemia. exertional dyspnea to severe respiratory distress. This article reviews the clinical manifesta- Neurologic manifestations can range from mild confusion tions of acute hyperleukocytosis and leukosta- and somnolence to stupor and coma. sis and discusses options for its management. ■ ETIOLOGY AND RISK FACTORS Initial management includes aggressive hydration; use of allopurinol and hydroxyurea; correction of abnormalities Hyperleukocytosis of metabolism, coagulation, and electrolytes; and Hyperleukocytosis is more common in acute prevention of tumor lysis syndrome. leukemias than in chronic leukemias. Its inci- dence ranges from 5% to 13% in adult acute Definitive treatment consists of leukocytoreduction (via myeloid leukemia (AML) and 10% to 30% in cytotoxic chemotherapy), hydroxyurea, and, in some cases, adult acute lymphoblastic leukemia (ALL).1–4 leukapheresis. The clinical presentation depends largely on CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 8 AUGUST 2004 633 Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. HYPERLEUKOCYTOSIS MAJHAIL AND LICHTIN the lineage and the number of circulating Pulmonary leukemic blasts. Despite a higher incidence Patients can present with symptoms ranging and degree of hyperleukocytosis in ALL vs from exertional dyspnea to severe respiratory AML, clinically manifest hyperleukocytosis is distress. However, chest radiography may be not commonly seen in ALL.1,2 normal or may reveal varying degrees of dif- Risk factors for hyperleukocytosis include fuse interstitial or alveolar infiltrates.13 younger age (it is most commonly seen in infants), Arterial blood gas samples should be certain types of leukemia (microgranular variants interpreted cautiously, as a spuriously low arte- of acute promyelocytic leukemia [AML-M3v], rial oxygen tension (pseudohypoxemia) can acute myelomonocytic leukemia [AML-M4], result from rapid consumption of plasma oxy- acute monocytic leukemia [AML-M5], and T-cell gen by the markedly increased number of ALL), and cytogenetic abnormalities (11q23 white blood cells.14 translocations or presence of the Philadelphia Pulse oximetry can more accurately assess chromosome).1,2 oxygenation status in this setting.15 Leukostasis Neurologic Symptoms of hyperleukocytosis are primarily Neurologic manifestations can range from due to leukostasis (FIGURE 1), a clinicopatho- mild confusion and somnolence to stupor and logic syndrome caused by the sludging of cir- coma. Focal central nervous system deficits culating leukemic blasts in tissue microvascu- may herald intracranial hemorrhage. lature.5,6 It is usually associated with a very high number of circulating blasts (ie, hyper- Vascular leukocytosis), but leukostasis has also been Retinal hemorrhage, retinal vein thrombosis, described with blast counts of less than myocardial infarction, acute limb ischemia, 50,000/mm3.5,7 and renal vein thrombosis have all been Its pathophysiology is not fully under- described with leukostasis and acute hyper- stood. Earlier hypotheses suggested a critical leukocytosis. Treatment must “leukocrit” (fractional leukocyte volume) and Disseminated intravascular coagulation begin before an increase in whole blood viscosity as puta- (DIC) occurs in 30% to 40% of patients with tive mechanisms of leukostasis.8 AML and in 15% to 25% of patients with the patient can Leukostasis without hyperleukocytosis indi- ALL.1 Though more common in AML-M3 be transferred cates that other factors may be involved in its (also known as acute promyelocytic development. There is increasing evidence to leukemia), DIC can occur in all subtypes of to a tertiary suggest that interactions between leukemic acute leukemia. care center blasts and the surface of endothelial cells might be responsible for the aggregation of blasts in the Laboratory microcirculation. Also, a difference in the Laboratory evaluation should include careful expression of adhesion molecules on lym- assessment for thrombocytopenia, coagulopa- phoblast and myeloblast cell surfaces may thy, and tumor lysis syndrome. Platelets may explain the higher incidence of leukostasis in have to be counted manually, since a spurious AML vs ALL.9–12 elevation of the automated platelet count can occur due to the presence of fragments of ■ PRESENTATION AND EVALUATION: white and red blood cells.1,16,17 EARLY DEATHS DUE TO PULMONARY Fever is common. Although fever can be AND INTRACRANIAL COMPLICATIONS traced to infection in very few (< 5%) of these patients,2 infection needs to be ruled out, Although leukostasis can affect any organ since acute hyperleukocytosis can mimic sev- system, symptoms usually arise from involve- eral viral, bacterial, and fungal syndromes. ment of the pulmonary and cerebral microvasculature, and most early deaths are Prognosis based on the presentation due to respiratory failure and intracranial In acute hyperleukocytosis due to AML, pre- hemorrhage. dictors of a poor prognosis are renal failure, 634 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 8 AUGUST 2004 Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. ■ Hyperleukocytosis, leukostasis, and sludging Symptoms of hyperleukocytosis are mainly due to leukostasis, a clinicopathologic syndrome caused by the sludging of circulating leukemic blasts in tissue microvasculature. Blasts Neurologic symptoms range from mild confusion and somnolence to stupor and coma. Pulmonary symptoms range from exertional dyspnea to severe Vascular symptoms include respiratory distress. disseminated intravascular Chest radiographs may coagulation, retinal be normal or may reveal hemorrhage, myocardial varying degrees of infarction, acute limb diffuse interstitial or ischemia, and renal vein alveolar infiltrates. thrombosis. CCF ©2004 FIGURE 1 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 8 AUGUST 2004 635 Downloaded from www.ccjm.org on September 28, 2021. For personal use only. All other uses require permission. HYPERLEUKOCYTOSIS MAJHAIL AND LICHTIN respiratory distress, neurologic symptoms, or a significant reduction in the white blood cell coagulopathy; in ALL, adverse indicators are count. white blood cell counts more than Leukocytoreduction can be achieved by 250,000/mm3 or neurologic compromise.1,2,18 induction chemotherapy, hydroxyurea, and leukapheresis. Prompt initiation of induction ■ TREATMENT chemotherapy remains the mainstay of treat- ment of acute hyperleukocytosis and leukosta- The management of acute hyperleukocytosis sis. In patients with acute promyelocytic and leukostasis involves supportive measures leukemia, treatment with all-trans-retinoic and reducing the number of circulating acid should be initiated as soon as possible; all- leukemic blast cells. trans-retinoic acid stimulates the maturation of the myeloblasts of acute promyelocytic Supportive measures leukemia with a rapid reduction in the white Supportive measures should include: blood cell count. Hydroxyurea given at • Vigorous hydration with intravenous dosages of 50 to 100 mg/kg/day in three or four fluids. Intravenous fluids should be used judi- divided doses has been shown to reduce the ciously, however, with careful monitoring of leukocyte count by 50% to 60% within 24 to the fluid balance in patients with coexisting 48 hours and should be started at the time of cardiopulmonary comorbidities who might be initial diagnosis