Hyperleukocytosis and leukostasis in hematologic malignancies

INTRODUCTION — Hyperleukocytosis describes a white blood cell (WBC) count >100 x 10⁹/L (100,000/microL) in a patient with leukemia. Hyperleukocytosis is most often seen in patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia.

Leukostasis (ie, symptomatic hyperleukocytosis) is a medical emergency. Leukostasis is a clinical diagnosis in which respiratory distress, central nervous system abnormalities, or other organ dysfunction is attributable to hyperleukocytosis. Leukostasis occurs most often in AML and is uncommon with other hematologic malignancies. Pathologically, leukostasis is associated with WBC plugs in the microvasculature and decreased tissue perfusion.

Untreated leukostasis is associated with high mortality rates. Prompt recognition and management is required to improve outcomes of patients with leukostasis.

The epidemiology, clinical presentation, diagnosis, and management of hyperleukocytosis and leukostasis in hematologic malignancies are reviewed here.

Other complications of AML are discussed separately. (See "Acute myeloid leukemia: Overview of complications".)

DEFINITIONS — Hyperleukocytosis is a laboratory-based diagnosis, while leukostasis is a clinical diagnosis.

Hyperleukocytosis — Hyperleukocytosis is defined as a white blood cell (WBC) count >100 × 10⁹/L (100,000/microL) in a patient with leukemia [1]. Some publications have described hyperleukocytosis as >50 x 10⁹/WBC/L [2].

Leukostasis — Leukostasis refers to symptoms or clinical findings associated with hyperleukocytosis. Leukostasis most often affects the central nervous system and lungs, but other organ systems (eg, heart, kidneys) may also be affected.

The nature and severity of leukostatic symptoms are influenced by the type of leukemia, level of WBC count, and comorbid conditions. In general, symptoms of leukostasis are more common in leukemias with large, poorly deformable blasts, such as acute myeloid leukemia (AML); leukostasis is much less common with leukemias of lymphoid origin.

Management of hyperleukocytosis and leukostasis (ie, symptomatic hyperleukocytosis) varies with the underlying hematologic malignancy.

●Acute myeloid leukemia – Management of hyperleukocytosis in patients with AML is discussed below. (See 'Acute myeloid leukemia' below.)

●Other hematologic malignancies – Management of hyperleukocytosis in patients with other hematologic malignancies is discussed below. (See 'Other leukemias' below.)

EPIDEMIOLOGY — The incidences of hyperleukocytosis and leukostasis vary by the category of leukemia and the patient population.

●Acute myeloid leukemia – Up to one-fifth of patients with newly diagnosed acute myeloid leukemia (AML) have hyperleukocytosis, but only a subset of these patients (eg, one-quarter of patients with hyperleukocytosis) have symptoms of leukostasis. Both hyperleukocytosis and leukostasis are associated with increased mortality in patients with AML, but the risk is greater in those with leukostatic symptoms.

Hyperleukocytosis in AML has been associated with certain cytogenetic and molecular abnormalities. Hyperleukocytosis is more common in AML with monocytic features, mutated FLT3, and KMT2A (MLL) rearrangements involving chromosome 11q23 [3].

In a retrospective multicenter study of 779 patients with AML and white blood cell (WBC) count >50 x 10⁹/L, symptoms of leukostasis were reported in 27 percent [2]. For the entire population, 30-day mortality was 17 percent, and two-, three-, and five-year rates of overall survival (OS) were 35, 31, and 28 percent, respectively. Compared with asymptomatic hyperleukocytosis, patients with leukostasis had inferior median OS (7.4 versus 15.1 months; odds ratio [OR] 1.59 [95% CI 1.26-2.00]) and inferior 30-day mortality (OR 3.59 [95% CI 2.17-5.96]) in a multivariable analysis [2].

●Acute lymphoblastic leukemia – Hyperleukocytosis was seen in 10 to 30 percent of patients with newly diagnosed acute lymphoblastic leukemia (ALL) [4]. The incidence appears to be highest in infants, patients between the ages of 10 and 20 years, males, and those with a T cell phenotype [4,5]. Symptoms of leukostasis are rarely associated with hyperleukocytosis in ALL, while tumor lysis syndrome and disseminated intravascular coagulation are more common.

●Chronic lymphocytic leukemia – A significant proportion of patients with chronic lymphocytic leukemia (CLL) present with hyperleukocytosis. However, leukostatic symptoms are exceedingly rare, except with very high WBC counts (eg, >400 x 10⁹/L). (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Lymphocytosis'.)

●Chronic myeloid leukemia – Hyperleukocytosis is common with chronic myeloid leukemia (CML), since the median WBC count at presentation is approximately 100 x 10⁹/L; most of these WBCs are segmented neutrophils, metamyelocytes, and myelocytes. Symptoms of leukostasis are very uncommon in patients in chronic phase CML, but they can be seen in patients with very elevated myeloid blast counts (eg, in myeloid blast crisis) and underlying cardiac and/or pulmonary comorbidities.

PATHOPHYSIOLOGY OF LEUKOSTASIS — The level of white blood cell count, type, and percentage of circulating blasts, increased blood viscosity, and endothelial damage contribute to the pathophysiology of leukostasis [3,6].

Leukostasis is thought to be due to increased blood viscosity caused by a large population of leukemic blasts that are less deformable than mature leukocytes [7,8]. Plugs of these more rigid cells can develop in the microcirculation as blast counts increase, thereby impeding blood flow [9,10]. Red blood cell transfusions and dehydration (eg, from use of diuretics) can further increase whole blood viscosity.

Local hypoxemia may be exacerbated by the high metabolic activity of blasts, excessive cytokine production, and adhesion molecules that mediate blast-endothelial cell interactions [11,12]. Endothelial damage and subsequent hemorrhage add to the hypoxic damage from reduced blood flow. Leukemic blasts can migrate into the surrounding tissues, causing additional damage [13].

Leukostasis is most often seen in patients with acute myeloid leukemia; by contrast, chronic lymphocytic leukemia and acute lymphoblastic leukemia are infrequently associated with leukostasis despite frequent hyperleukocytosis. The lower incidence of leukostasis and vascular injury in lymphoid leukemias may be related to the lack of catabolic enzymes and cytokines and/or lower metabolic activity in the malignant cells.

PRESENTATION — Hyperleukocytosis is a laboratory finding, while leukostasis is a clinical condition based on end organ effects of hyperleukocytosis. (See 'Definitions' above.)

Clinical — The main clinical symptoms of leukostasis are related to the involvement of the central nervous system (approximately 40 percent) and lungs (approximately 30 percent) [4,9,10]. The gastrointestinal tract and cardiovascular system may also be compromised by leukostasis [4].

Imaging studies are important for assessing the cause of clinical abnormalities in this setting.

●Central nervous system – Neurologic signs and symptoms include visual changes, headache, dizziness, tinnitus, gait instability, confusion, somnolence, and, occasionally, coma.

In addition, patients with hyperleukocytosis have an increased risk for intracranial hemorrhage that persists for at least a week after the reduction of white cell count, perhaps due to reperfusion injury as previously ischemic areas of the brain regain blood flow.

Noncontrast computed tomography (CT) or magnetic resonance imaging should be performed in patients with new neurologic findings. Importantly, intravenous contrast dye should be avoided at a time when renal function may be compromised by leukostasis, tumor lysis syndrome, and dehydration.

●Respiratory – Dyspnea and hypoxia are common, and these symptoms may be accompanied by diffuse interstitial or alveolar infiltrates on imaging studies.

Pulse oximetry is more useful than measurement of arterial pO₂ for documenting hypoxia; arterial pO₂ can be falsely decreased with hyperleukocytosis, as discussed below. (See 'Laboratory abnormalities' below.)

●Fever – Approximately 80 percent of patients with leukostasis are febrile at presentation.

Fever in this setting may be due to inflammation associated with leukostasis or concurrent infection. An infectious workup should be performed, and empiric antibiotic therapy should be administered to patients with febrile neutropenia until an infectious cause is excluded. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

●Other – Less common clinical findings include myocardial ischemia, right ventricular overload, worsening renal insufficiency, priapism, acute limb ischemia, or bowel infarction [4].

Laboratory abnormalities — Hyperleukocytosis can cause laboratory abnormalities due to the high number of circulating blasts and/or interference with laboratory assays.

●Platelet count – The platelet count may be overestimated by automated blood cell counters because fragments of blasts on blood smear can be mistakenly counted as platelets. A manual platelet count and review of the peripheral smear can eliminate this artifact. (See "Approach to the patient with thrombocytosis", section on 'Blood smear'.)

●Oxygenation – Pulse oximetry provides a more accurate assessment of O₂ saturation than arterial pO₂; the latter can be falsely decreased because of the enhanced metabolic activity of the malignant cells, even when the specimen is appropriately placed on ice during transport to the laboratory.

●Potassium – Serum potassium can be spuriously elevated due to its release from leukemic blasts during the in vitro clotting process. Measurement of potassium level from a heparinized plasma sample, rather than from serum, can circumvent this effect. (See "Causes and evaluation of hyperkalemia in adults", section on 'Pseudohyperkalemia'.)

●Coagulopathy – Disseminated intravascular coagulation (DIC) occurs in up to 40 percent of patients with hyperleukocytosis [4]. DIC may present with clinical bleeding or bruising, decreased fibrinogen (due to increased thrombin generation), and elevated fibrin degradation products and D-dimer (caused by increased fibrinolysis). (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

●Tumor lysis syndrome – The incidence of spontaneous tumor lysis syndrome (TLS) is increased in patients with hyperleukocytosis and/or leukostasis.

Laboratory abnormalities associated with TLS include increased elevated serum uric acid, potassium, and phosphate, often accompanied by hypocalcemia. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

DIAGNOSIS — Hyperleukocytosis refers to a white blood cell (WBC) count >100 x 10⁹/L (100,000/microL) in a patient with leukemia, whether this is accompanied by symptoms.

Leukostasis is an empiric clinical diagnosis that is made when a patient with leukemia and hyperleukocytosis presents with symptoms attributable to tissue hypoxia. The most common symptoms are respiratory or neurologic abnormalities, but cardiovascular, gastrointestinal, and other organ systems may be affected. A pathologic diagnosis of leukostasis is not required and is rarely obtained because of the risks associated with biopsy of affected tissues.

There should be a high degree of suspicion for diagnosing leukostasis, since some patients with acute myeloid leukemia and a lower WBC count can also manifest leukostatic symptoms (and pathologically proven leukostasis); such patients generally have a high percentage of circulating myeloblasts.

MANAGEMENT OF HYPERLEUKOCYTOSIS — Management of hyperleukocytosis and leukostasis (ie, symptomatic hyperleukocytosis) varies with the underlying hematologic malignancy.

The most common setting for leukostasis from hyperleukocytosis is acute myeloid leukemia.

Hyperleukocytosis is seen with other hematologic malignancies, but it is rarely associated with leukostasis (ie, symptoms).

Our approach to management of hyperleukocytosis is consistent with guidelines from the European LeukemiaNet, National Comprehensive Cancer Center Network, and the American Society for Apheresis [1,14].

ACUTE MYELOID LEUKEMIA — For patients with acute myeloid leukemia (AML) and hyperleukocytosis, with or without leukostatic symptoms, we suggest prompt initiation of cytoreductive chemotherapy rather than chemotherapy plus leukapheresis. Chemotherapy effectively reduces the extreme leukocytosis and associated symptoms; by contrast, effects of leukapheresis on hyperleukocytosis and symptom relief are transient and unproven.

We generally reserve leukapheresis for symptomatic patients who cannot promptly receive intensive induction chemotherapy; this approach avoids adverse effects of the leukapheresis procedure for most patients with hyperleukocytosis. Some clinicians add leukapheresis to chemotherapy in patients with asymptomatic hyperleukocytosis. (See 'Symptomatic patients' below.)

The choice of chemotherapy is guided by the patient's fitness for intensive induction chemotherapy, as described below. (See 'Medically fit' below.)

Patients with hyperleukocytosis should also receive supportive care to manage tumor lysis syndrome (TLS) and other metabolic complications, as discussed below. (See 'Supportive care' below.)

Large retrospective studies reported no clear benefit from the addition of leukapheresis to chemotherapy for the management of hyperleukocytosis in AML. No randomized trials have directly compared approaches for the management of hyperleukocytosis or leukostasis in AML.

●There was no difference in short-term survival for patients who received leukapheresis plus chemotherapy versus chemotherapy alone in a systematic review and meta-analysis of 13 studies of hyperleukocytosis and AML [15]. The analysis included 486 patients who underwent leukapheresis and 1257 patients who did not undergo leukapheresis, but chemotherapy differed between studies, and there was no standardized manner for selecting patients for leukapheresis. There was no difference in early mortality between leukapheresis plus chemotherapy versus chemotherapy alone, but patients with leukostatic symptoms were twice as likely to receive leukapheresis compared with those who had asymptomatic hyperleukocytosis.

●Retrospective analysis of 779 patients with AML and white blood cell (WBC) >50 x 10⁹/L reported no difference in outcomes between 113 patients who underwent leukapheresis and 666 patients who did not; clinical leukostasis was reported in one-quarter of the patients [2]. Use of leukapheresis had no impact on 30-day mortality, complete remission, or longer-term overall survival, according to multivariate analysis.

●Other studies have reported variable effects of leukapheresis on outcomes in AML with hyperleukocytosis, but there is no clear evidence that it reduced mortality [16-24].

Medically fit — For medically fit patients with AML, we suggest prompt initiation of intensive induction therapy rather than treatment with hydroxyurea or other single-agent therapy. Intensive induction therapy substantially reduces the WBC count within 24 hours and is the fastest and most effective way to control hyperleukocytosis and associated end-organ effects.

Fitness for intensive chemotherapy is determined by the patient's performance status and the nature and severity of comorbid conditions. Intensive induction therapy generally includes an anthracycline plus infusional cytarabine; in selected patients (eg, AML with mutated FLT3) a third agent may be added.

Administration and fitness for intensive remission induction therapy for AML are discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults".)

When intensive chemotherapy must be delayed by intercurrent medical conditions, management should be as described below. (See 'Not fit for prompt, intensive induction therapy' below.)

Not fit for prompt, intensive induction therapy — When intensive induction therapy cannot be administered promptly, management of hyperleukocytosis is guided by the presence of leukostatic symptoms.

A patient might not be eligible for prompt initiation of intensive chemotherapy because of compromised medical fitness; intercurrent complications (eg, sepsis, hemodynamic instability, renal insufficiency, other severe metabolic disturbances); delays in initiating prophylaxis for TLS; and/or poor venous access.

Symptomatic patients — For patients with leukostatic symptoms who cannot promptly receive intensive induction therapy, we suggest urgent leukapheresis plus hydroxyurea rather than either approach alone.

Leukapheresis can promptly reduce the elevated WBC count, but this effect is transient unless accompanied by cytoreductive chemotherapy. Hydroxyurea takes time to reduce hyperleukocytosis, during which time the leukostatic symptoms may progress. The intent of this approach is to rapidly reduce the WBC count until other medical conditions are stabilized or improved, thereby enabling administration of definitive chemotherapy.

For patients who cannot take oral hydroxyurea, treatment using a single dose of cytarabine (eg, 1 to 2 grams total dose) or gemtuzumab ozogamicin are acceptable alternatives. Use of gemtuzumab ozogamicin is discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Gemtuzumab ozogamicin'.)

Patients with leukostatic symptoms have an extremely high mortality rate without immediate therapy [16,18,25,26]; in one report, the death rate at one week reached 90 percent when both respiratory failure and neurologic compromise were present [16].

Leukapheresis — We generally reserve leukapheresis for patients with leukostatic symptoms who cannot promptly receive intensive induction chemotherapy, as described above. (See 'Symptomatic patients' above.)

Our restricted use of leukapheresis reflects the lack of a proven benefit with leukapheresis for hyperleukocytosis and reduces procedure-based adverse effects (AEs) yet recognizes the dire outcomes when cytoreduction is delayed in this setting.

●Procedure – Leukapheresis usually requires the placement of a large bore central venous catheter, is only available at select medical centers, and the technique lacks standardization. The procedure can also be done using antecubital veins if they are adequate for placement of large bore needles bilaterally.

Leukapheresis sessions are usually planned for four- to five-hour collections, with repeat sessions as needed. Some patients require multiple sessions to control the WBC count, while others do not respond to multiple sessions of leukapheresis [27].

There is general agreement that leukapheresis should not be used for patients with acute promyelocytic leukemia (APL) because it may worsen the intrinsic coagulopathy associated with this subtype of leukemia [28]. Placement of large intravenous leukapheresis catheters in these patients has been associated with venous thrombosis or life-threatening hemorrhage due to APL-related disseminated intravascular coagulopathy. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults", section on 'Coagulopathy and APL'.)

●Toxicity – Common AEs of leukapheresis include hypocalcemia (due binding of calcium by anticoagulants like citrate to prevent clotting of the apheresis circuit), bleeding, dizziness or other symptoms related to hypotension, blood loss, and allergic reactions [29]. Platelets are inevitably removed along with the leukemic blasts, which may worsen thrombocytopenia and/or exacerbate bleeding.

●Outcomes – It is difficult to predict the rapidity of reduction of the WBC count in an individual patient. A single episode of leukapheresis can reduce leukocytes by 10 percent to 70 percent [30]. However, unless chemotherapy is begun, WBC counts typically rebound after leukapheresis is discontinued.

Anecdotal reports describe improvement in pulmonary and central nervous system symptoms with leukapheresis. However, even with highly efficient cell separators it is difficult to reduce a rapidly rising WBC count, and it is in such patients where the technical limitations and AEs are most relevant. Symptomatic leukostasis can still develop and/or persist after the WBC count has been lowered by leukapheresis, and it is unclear whether leukapheresis can reverse vascular damage already sustained from leukostasis.

Hydroxyurea — Hydroxyurea is an oral medication that can reduce leukocytosis in patients who are not able to promptly receive intensive induction chemotherapy.

●Administration – The initial dose is hydroxyurea 2 to 4 grams orally every 12 hours (ie, 50 to 100 mg/kg total daily dose). This typically reduces the hyperleukocytosis by ≥50 percent within 24 to 48 hours. Hydroxyurea should be continued until the WBC count is ≤50 x 10⁹/L, and then the dose is tapered.

It is important to simultaneously provide intravenous hydration and prophylaxis for TLS because cytoreduction with hydroxyurea can precipitate or exacerbate hyperuricemia and/or precipitate TLS.

●Toxicity – Hydroxyurea can cause severe myelosuppression, oral ulcers/mucositis, gastrointestinal distress, and hair loss. AEs typically occur in patients who are exposed to high doses (ie, >4 gm/day) of hydroxyurea for a prolonged period (ie, several days). Rare complications include fever and abnormal liver function tests.

Asymptomatic hyperleukocytosis — For patients who have no clinical manifestations of leukostasis but are not fit for intensive induction therapy, we suggest cytoreduction with hydroxyurea and/or one dose of cytarabine (eg, 1 to 2 grams total dose).

Definitive lower-intensity treatment, especially if it includes venetoclax, is generally delayed until the WBC count is <25 x 10⁹/L to reduce the risk of TLS.

Induction therapy for AML in less-fit patients is discussed separately. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Medically unfit, but not frail'.)

OTHER LEUKEMIAS — Hyperleukocytosis can occur with chronic lymphocytic leukemia and acute lymphoblastic leukemia, but leukostatic symptoms attributable to leukostasis are exceedingly rare. If leukostatic symptoms are present, it is important to evaluate the patient for other causes of respiratory or neurologic dysfunction.

Patients with a myeloid blast crisis of chronic myeloid leukemia (CML) may experience leukostatic symptoms in association with hyperleukocytosis, especially if the blast count is high. Management of leukostasis in CML is like that for acute myeloid leukemia (see 'Acute myeloid leukemia' above), but treatment should also include a BCR::ABL1 tyrosine kinase inhibitor. (See "Treatment of chronic myeloid leukemia in blast crisis".)

Supportive care, including prophylaxis for tumor lysis syndrome and other metabolic complications of hyperleukocytosis, must also be provided, as described below. (See 'Supportive care' below.)

SUPPORTIVE CARE — All patients with hyperleukocytosis should receive supportive care measures to limit other consequences of hyperleukocytosis (eg, tumor lysis syndrome [TLS], other metabolic complications and bleeding).

Supportive care should be provided promptly since clinical deterioration can occur rapidly.

Adjunctive care for leukostasis — Appropriate supportive care is provided to minimize complications from hyperleukocytosis and its treatment.

●Coagulopathy – Coagulation abnormalities, including disseminated intravascular coagulation (DIC), increase the risk of hemorrhage from interventions, such as the placement of large bore catheters for leukapheresis. Bleeding may be exacerbated in the setting of hyperleukocytosis because of high blast counts, hyperviscosity, and/or tissue hypoperfusion. Measures that can limit effects of DIC are discussed separately. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

DIC is especially common in patients with acute promyelocytic leukemia (APL). Leukapheresis is generally avoided in patients with APL, as described above. (See "Initial treatment of acute promyelocytic leukemia in adults", section on 'Control of coagulopathy'.)

●Platelet support – Patients should receive prophylactic platelet transfusions to maintain a platelet count of ≥30 x 10⁹/L to 40 x 10⁹/L until the leukocyte count has been reduced and the clinical situation is stabilized.

Aggressive platelet transfusion support and correction of coagulopathy should continue for several days during the period of remission induction. Intracranial hemorrhage can also occur after the white blood cell (WBC) count has been markedly reduced, suggesting that a reperfusion injury may occur when the circulation is restored to previously hypoxemic or ischemic capillary beds. (See 'Pathophysiology of leukostasis' above.)

●Limit red blood cell transfusions – Symptomatic leukostasis can be precipitated or exacerbated by increases in whole blood viscosity following red blood cell (RBC) transfusions.

Transfusions should be withheld in asymptomatic patients, whenever possible, until the total WBC count and blast count are significantly reduced. If a transfusion is necessary due to symptomatic anemia/hypoxia, it should be given slowly (eg, a single unit of RBCs over several hours) or during leukapheresis. Hydration is encouraged and diuretics should be avoided.

●Central nervous system effects – Patients who experience a stroke may benefit from other aspects of supportive care, including blood pressure control, respiratory support, and management of metabolic issues, as discussed separately. (See "Initial assessment and management of acute stroke".)

Some centers administer low-dose cranial irradiation to reduce proliferation of leukemic cells in the central nervous system (CNS) in patients with CNS manifestations of leukostasis. No studies have compared outcomes with chemotherapy alone versus cranial irradiation plus chemotherapy. There is little toxicity associated with a single low-dose treatment with cranial irradiation that includes the retinae.

●Respiratory failure – Patients with leukostasis may require mechanical ventilation or other supportive care for respiratory failure. (See "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit".)

Tumor lysis syndrome and other metabolic complications — Patients with hyperleukocytosis are at a high risk of TLS and other metabolic complications of hyperleukocytosis. TLS is less common in patients with acute myeloid leukemia than with acute lymphoblastic leukemia or Burkitt leukemia/lymphoma.

TLS is best prevented by early initiation of aggressive intravenous hydration to ensure adequate urine flow, allopurinol or rasburicase to acutely reduce serum uric acid levels, and correction of electrolyte disturbances (particularly hyperphosphatemia) and other causes of reversible renal failure. This management should begin prior to or concomitant with the initiation of chemotherapy. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of tumor lysis syndrome'.)

PROGNOSIS — The prognostic impact of hyperleukocytosis and leukostasis depends on the type of leukemia and the presence of symptoms.

●Acute myeloid leukemia – The initial mortality rate for patients with acute myeloid leukemia (AML) and leukostasis has been estimated at 20 to 40 percent and appears to be unrelated to the severity of the hyperleukocytosis [16,18,31-33]. If patients survive the initial period, they tend to have somewhat lower remission rates and shorter remission duration; these effects may be related to a larger initial tumor mass, adverse biologic features, and/or intrinsic chemotherapy resistance [31,33].

Risk factors for mortality in patients with AML and hyperleukocytosis were identified in a retrospective analysis [16]. Compared with patients who lived more than one week after presentation, patients who died within the first week of presentation had significantly higher rates of coagulopathy (64 versus 18 percent), respiratory distress (100 versus 15 percent), renal failure (43 versus 29 percent), and neurologic symptoms (64 versus 12 percent) [16].

●Other hematologic malignancies – Hyperleukocytosis is rarely complicated by leukostasis in patients with acute lymphoblastic leukemia (ALL). The early death rate is <5 percent in childhood ALL [5].

In patients with leukostasis in ALL, in addition to evaluation for leukostasis, management requires prophylaxis for tumor lysis syndrome, controlling coagulopathy and thrombocytopenia, and reducing the higher risk for relapse (approximately 50 percent by four years) [4]. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)

Patients with chronic myeloid leukemia (CML) have a median white blood cell (WBC) count of 100,000/microL at presentation, but this is rarely associated with leukostasis unless there is a high percentage of blasts (eg, with blast crisis of CML) or if the WBC count is >400 x 10⁹/L. There is no clear WBC count threshold above which the risk for complications is increased enough to warrant a change in management. Nevertheless, clinicians should be alert to the possibility of leukostasis, especially in patients with other risk factors for cerebrovascular disease (eg, hypertension, atherosclerotic disease).

Chronic lymphocytic leukemia often presents with hyperleukocytosis, but symptoms of leukostasis are rare unless the WBC count exceeds 400 x 10⁹/L. There is no clear WBC count threshold above which the risk for complications is increased enough to warrant a change in management. Nevertheless, clinicians should be alert to the possibility of leukostasis, especially in patients with other risk factors for cerebrovascular disease (eg, hypertension, atherosclerotic disease). (See "Overview of the treatment of chronic lymphocytic leukemia".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Acute myeloid leukemia (AML) treatment in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Descriptions. (See 'Definitions' above.)

•Hyperleukocytosis – White blood cell (WBC) count >100 x 10⁹/L (100,000/microL) in a patient with leukemia.

•Leukostasis – Medical emergency with hyperleukocytosis plus symptoms of decreased tissue perfusion in central nervous system (CNS), lungs, and other organ systems.

●Epidemiology – Hyperleukocytosis can occur with acute myeloid leukemia (AML) and other hematologic malignancies, but leukostasis rarely occurs except with AML. (See 'Epidemiology' above.)

●Presentation – Hyperleukocytosis may be associated with symptoms of leukostasis, tumor lysis syndrome (TLS), disseminated intravascular coagulation (DIC), and other complications of AML. (See 'Presentation' above.)

•Clinical – Leukostatic symptoms primarily relate to the CNS (eg, visual changes, headache, dizziness, tinnitus, confusion, somnolence, coma) and lungs (eg, dyspnea); less often, the gastrointestinal tract, cardiovascular system, or other organs are affected. (See 'Clinical' above.)

•Laboratory – Hyperleukocytosis can be associated with laboratory findings of TLS and DIC. In addition, hyperleukocytosis can cause artifactual abnormalities of platelet count, oxygenation, and potassium.

Other leukemic complications are discussed separately. (See "Acute myeloid leukemia: Overview of complications".)

●Diagnosis. (See 'Diagnosis' above.)

•Hyperleukocytosis – Diagnosed by WBC count >100 x 10⁹/L in a patient with leukemia.

•Leukostasis – An empirical clinical diagnosis based on respiratory symptoms, new neurologic findings, or other end-organ effects attributable to hyperleukocytosis; a pathologic diagnosis of leukostasis is not required.

In patients with AML, leukostatic symptoms can occur with WBC count <100,000/microL, especially if there is a high percentage of blasts.

●Acute myeloid leukemia – For patients with AML and hyperleukocytosis, with or without leukostasis, we suggest prompt initiation of cytoreductive chemotherapy rather than chemotherapy plus leukapheresis (Grade 2C). Leukapheresis has no proven benefit in this setting. (See 'Acute myeloid leukemia' above.)

The choice of chemotherapy is guided by whether intensive induction therapy can be administered promptly.

•Medically fit – We initiate intensive induction therapy (eg, anthracycline plus cytarabine). (See 'Medically fit' above.)

•When intensive therapy cannot be given promptly – Management is guided by the presence of leukostatic symptoms:

-Symptomatic – For patients with leukostasis who cannot promptly receive intensive induction therapy, we suggest urgent leukapheresis plus hydroxyurea rather than either alone (Grade 2C). (See 'Symptomatic patients' above.)

-Asymptomatic – For asymptomatic patients, we suggest urgent treatment with hydroxyurea rather than leukapheresis (Grade 2C). (See 'Asymptomatic hyperleukocytosis' above.)

Hydroxyurea can be given concurrently with or prior to planned induction therapy; it can serve as a temporizing measure for patients who may later become eligible for intensive chemotherapy.

●Other leukemias – Hyperleukocytosis can occur with chronic lymphocytic leukemia and acute lymphoblastic leukemia, but leukostatic symptoms are exceedingly rare; if leukostatic findings are present, other causes for neurologic and respiratory symptoms should be evaluated. (See 'Other leukemias' above.)

Leukostasis with myeloid blast crisis of chronic myeloid leukemia is managed like AML, with the addition of a BCR::ABL1 tyrosine kinase inhibitor. (See "Treatment of chronic myeloid leukemia in blast crisis".)

●Supportive care – Cytoreduction for hyperleukocytosis should be accompanied by prophylaxis for TLS, hydration, and limited transfusions. (See 'Supportive care' above.)