Hyperleukocytosis and Leukostasis in Hematologic Malignancies

Official reprint from UpToDatewww.uptodate.com ©2016 UpToDate

AuthorCharles A Schiffer, MD

Section EditorRichard A Larson, MD

Deputy EditorRebecca F Connor, MD

Hyperleukocytosis and leukostasis in hematologic malignancies

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Apr 2016. | This topic last updated: Mar 22, 2016.INTRODUCTION — Hyperleukocytosis refers to a laboratory abnormality that has been variably defined as atotal leukemia blood cell count greater than 50 x 10 /L (50,000/microL) or 100 x 10 /L (100,000/microL). Incontrast, leukostasis (also called symptomatic hyperleukocytosis) is a medical emergency most commonly seenin patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) in blast crisis. It ischaracterized by an extremely elevated blast cell count and symptoms of decreased tissue perfusion.Leukostasis is a pathologic diagnosis in which white cell plugs are seen in the microvasculature. Clinically,leukostasis is typically diagnosed empirically when a patient with leukemia and hyperleukocytosis presents withrespiratory or neurological distress. Prompt treatment is indicated since, if left untreated, the one-week mortalityrate is approximately 20 to 40 percent.The epidemiology, clinical presentation, diagnosis, and management of hyperleukocytosis and leukostasis inhematologic malignancies will be reviewed here. Other complications of leukemia are presented separately. (See"Overview of the complications of acute myeloid leukemia" and "Overview of the complications of chroniclymphocytic leukemia".)EPIDEMIOLOGY — The incidence of hyperleukocytosis and leukostasis vary by leukemia type and patientpopulation. In general, symptoms of leukostasis are more common in leukemias with large, poorly deformableblasts, such as acute myeloid leukemia.

PATHOPHYSIOLOGY OF LEUKOSTASIS — The pathophysiology of leukostasis is not well understood. Thereare two main theories, which are not mutually exclusive:

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Acute myeloid leukemia – Hyperleukocytosis is present in 10 to 20 percent of patients with newlydiagnosed acute myeloid leukemia (AML). It is more common in patients with myelomonocytic (FAB-M4)leukemia, monocytic (FAB-M5) leukemia, or the microgranular variant of acute promyelocytic leukemia(FAB-M3) [1,2]. Symptoms of leukostasis occur less frequently and typically affect patients with white bloodcell (WBC) counts over 100 x 10 /L (100,000/microL).

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Acute lymphoblastic leukemia – Hyperleukocytosis is seen in 10 to 30 percent of patients with newlydiagnosed acute lymphoblastic leukemia (ALL) [3]. The incidence appears to be highest in infants, patientsbetween the ages of 10 and 20 years, males, and those with a T cell phenotype [3,4]. Symptoms ofleukostasis are rarely seen in patients with ALL and hyperleukocytosis. Tumor lysis syndrome anddisseminated intravascular coagulation are more common complications related to the elevated WBCcount.

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Chronic lymphocytic leukemia – A significant proportion of patients with chronic lymphocytic leukemia (CLL)present with hyperleukocytosis. Symptoms of leukostasis are rare unless the WBC count exceeds 400 x10 /L (400,000/microL).

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Chronic myeloid leukemia – Patients with chronic myeloid leukemia (CML) typically present withleukocytosis and a median WBC count of approximately 100 x 10 /L (100,000/microL). Most often, theseare segmented neutrophils, metamyelocytes, and myelocytes. Symptoms of leukostasis are veryuncommon in patients in chronic phase but can be seen occasionally in patients with myeloid blast crisisand very elevated blast counts.

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Leukostasis may be due to increased blood viscosity as a direct complication of a large population ofleukemic blasts that are considerably less deformable than mature leukocytes [5,6]. With increasing blastcounts, plugs of these more rigid cells can develop in the microcirculation, thereby impeding blood flow

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It is likely that both of these mechanisms, and additional yet unidentified mechanisms, are involved in thedevelopment of leukostasis. In vitro studies have demonstrated a dramatic rise in viscosity when leukocytesuspensions exceed a fractional volume of leukocytes (ie, leukocrit) of 12 to 15 mL/dL [11]. Attainment of such ahigh leukocrit requires an acute myeloid leukemia (AML) blast count of approximately 300 x 10 /L(300,000/microL) or an ALL blast count of approximately 600 x 10 /L (600,000/microL). This observation isconsistent with the increased incidence of leukostasis in AML compared with ALL. It also suggests that factorsother than white blood cell count are important in the pathogenesis of leukostasis, since symptoms of leukostasiscommonly occur at blast concentrations below these predicted thresholds.SIGNS AND SYMPTOMS — Although pathologic evidence of leukostasis can be found in most organs inpatients with extremely high white blood cell (WBC) counts, the main clinical symptoms of leukostasis andcauses of early death are related to involvement of the central nervous system (approximately 40 percent) andlungs (approximately 30 percent) [1,3,7].

Occasionally, patients develop dyspnea and worsening hypoxemia following the initiation of chemotherapy due tothe lysis of leukemic cells trapped in the lungs (eg, acute lysis pneumopathy) [12-15].LABORATORY ABNORMALITIES — Hyperleukocytosis may result in laboratory abnormalities, which can bedue to interference with laboratory assays or may be a consequence of the high number of circulating blasts.

(leukostasis) [1,7]. This situation can be worsened by red blood cell transfusions or the use of diuretics,both of which can increase whole blood viscosity.Local hypoxemia may be exacerbated by the high metabolic activity of the dividing blasts and theassociated production of various cytokines [8,9]. These cytokines can result in endothelial damage andsubsequent hemorrhage that add to the hypoxic damage already present from reduced blood flow [8,9].Leukemic blasts can migrate into the surrounding tissues, causing additional damage [10]. Thus, the lowerincidence of clinically significant leukostasis and vascular injury in patients with chronic lymphocyticleukemia (CLL) and acute lymphoblastic leukemia (ALL) may be related to the lower metabolic and mitoticrate in the former and the lack of catabolic enzymes and cytokines in both.

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Pulmonary signs and symptoms include dyspnea and hypoxia with or without diffuse interstitial or alveolarinfiltrates on imaging studies. Measurement of the arterial pO2 can be falsely decreased in patients withhyperleukocytosis, since the WBCs in the test tube utilize oxygen. Pulse oximetry provides a more accurateassessment of O2 saturation in this setting. (See 'Laboratory abnormalities' below.)

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Neurological signs and symptoms include visual changes, headache, dizziness, tinnitus, gait instability,confusion, somnolence, and, occasionally, coma. In addition, patients who present with hyperleukocytosishave an increased risk of intracranial hemorrhage that persists for at least a week after the reduction ofwhite cell count, perhaps from a reperfusion injury as areas of the brain that were ischemic from leukostasisregain blood flow. Because there can be other structural causes of central nervous system (CNS)symptoms, brain imaging with noncontrasted CT or MRI is indicated in patients with neurologicabnormalities. Clinicians must be cautious about using intravenous contrast dye at a time when renalfunction may be compromised by leukostasis or tumor lysis syndrome, and dehydration.

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Approximately 80 percent of patients with leukostasis are febrile, which may be due to inflammationassociated with leukostasis or concurrent infection. Since an infectious cause cannot be easily excluded,we treat empirically for infection in all such patients. (See "Overview of neutropenic fever syndromes" and"Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic celltransplant recipients (high-risk patients)" and "Treatment and prevention of neutropenic fever syndromes inadult cancer patients at low risk for complications".)

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Less common signs or symptoms of leukostasis include electrocardiographic signs of myocardial ischemiaor right ventricular overload, worsening renal insufficiency, priapism, acute limb ischemia, or bowelinfarction [3].

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Arterial pO2 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. Pulse oximetryprovides a more accurate assessment of O2 saturation.

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DIAGNOSIS — Leukostasis (symptomatic hyperleukocytosis) is diagnosed empirically when a patient withleukemia and a white blood cell (WBC) count over 100 x 10 /L (100,000/microL) presents with symptoms thoughtto be due to tissue hypoxia, most commonly respiratory or neurological distress. The diagnosis requires a highdegree of suspicion, and some patients have pathologically proven leukostasis at WBC counts below this level.Pathologically, leukostasis is diagnosed when a biopsy of involved tissue demonstrates white cell plugs in themicrovasculature [1,5-7]. A pathologic diagnosis of leukostasis is rarely obtained because of the risks associatedwith biopsy of affected tissues.MANAGEMENT — Leukostasis (symptomatic hyperleukocytosis) constitutes a medical emergency, and effortsshould be made to rapidly stabilize the patient and lower the white blood cell count. In most cases, rapidcytoreduction can be achieved with induction chemotherapy, which should be administered in conjunction withprophylaxis for tumor lysis syndrome. Because clinical deterioration can sometimes occur rapidly, most cliniciansalso advocate prompt initiation of cytoreductive therapy in patients with asymptomatic hyperleukocytosis.Adequate fluid resuscitation to prevent dehydration and ensure good urine output is important. (See "Tumor lysissyndrome: Prevention and treatment", section on 'Clinical impact of TLS'.)Cytoreduction — Twenty to 40 percent of patients with symptomatic hyperleukocytosis die within the first weekof presentation [16-22]. The mortality rate appears to be unrelated to the level of the white blood cell count, butpatients with symptoms (eg, respiratory distress or neurological compromise) have a significantly worseprognosis when compared with patients who have hyperleukocytosis alone.Cytoreduction can be achieved through the use of chemotherapy (hydroxyurea or remission inductionchemotherapy) or leukapheresis. While both modalities rapidly decrease the circulating white blood cell count,chemotherapy also destroys leukemia cells in the bone marrow and is the only treatment proven to improvesurvival. There have been no prospective trials or large observational studies comparing these two options forthe treatment of hyperleukocytosis and leukostasis.In general, we propose the following approach to patients with hyperleukocytosis:

The platelet count may be overestimated by automated blood cell counters because fragments of blasts onblood smear can be mistakenly counted as platelets. A manual platelet count and careful review of theperipheral smear is appropriate in such settings. (See "Approach to the patient with thrombocytosis",section on 'Spurious thrombocytosis'.)

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Serum potassium can be spuriously elevated due to its release from leukemic blasts during the in vitroclotting process. Potassium levels measured from heparinized plasma samples, rather than serum, cancircumvent this effect. (See "Causes and evaluation of hyperkalemia in adults", section on'Pseudohyperkalemia'.)

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Disseminated intravascular coagulation (DIC) occurs in up to 40 percent of patients [3]. DIC presents withvarious degrees of thrombin generation (eg, decreased fibrinogen) and increased fibrinolysis (eg, elevatedfibrin degradation products and D-dimer). DIC may develop or worsen following chemotherapy. (See"Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults".)

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Spontaneous tumor lysis syndrome (TLS) is present in up to 10 percent of patients with leukostasis [3].Laboratory evidence of tumor lysis syndrome includes increased elevated serum concentrations of uricacid, potassium, and phosphate, often accompanied by hypocalcemia. TLS may develop or worsenfollowing chemotherapy. (See "Tumor lysis syndrome: Definition, pathogenesis, clinical manifestations,etiology and risk factors".)

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For patients with symptomatic or asymptomatic hyperleukocytosis, we suggest initial treatment withinduction chemotherapy rather than hydroxyurea or leukapheresis. This should be accompanied by tumorlysis syndrome prophylaxis with aggressive hydration and allopurinol. (See 'Induction chemotherapy' belowand "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of TLS'.)Our preference for induction chemotherapy is primarily based upon the knowledge that such therapy is alsoa necessary step toward the successful treatment of patients with leukemia. There is little evidence toconfirm that decreasing the white blood cell (WBC) count alone will reduce the early mortality rate [23]. In

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The use of these three approaches to cytoreduction is presented in more detail in the following sections.Induction chemotherapy — Induction chemotherapy is an essential component of the successful treatment

of patients with leukemia. In the setting of hyperleukocytosis, induction chemotherapy serves to both rapidlydecrease the circulating WBC count and target the leukemia cells in the bone marrow. Induction therapy typicallysubstantially reduces the WBC count within 24 hours. Details regarding the administration of induction therapyare presented separately. (See "Induction therapy for acute myeloid leukemia in younger adults" and "Treatmentof acute myeloid leukemia in older adults" and "Induction therapy for Philadelphia chromosome negative acutelymphoblastic leukemia in adults".)Patients with hyperleukocytosis are at higher risk of developing tumor lysis syndrome with inductionchemotherapy. This syndrome is best prevented via appropriate treatment with intravenous hydration to ensureadequate urine flow, allopurinol or rasburicase to reduce serum uric acid levels, and correction of any electrolytedisturbances or causes of reversible renal failure. (See "Tumor lysis syndrome: Prevention and treatment",section on 'Clinical impact of TLS'.)

Hydroxyurea — We typically reserve hydroxyurea for patients with asymptomatic hyperleukocytosis who areunable to receive immediate induction chemotherapy. Hydroxyurea, given at a total dose of 50 to 100 mg/kg perday orally, reduces the WBC count by 50 to 80 percent within 24 to 48 hours [24]. The usual hydroxyurea dose is2 to 4 grams orally every 12 hours, which is continued until the WBC count is below 50 x 10 /L (50,000/microL).Side effects of hydroxyurea are usually minimal and are typically limited to patients who are exposed tohydroxyurea for a prolonged period. Rare complications include fever and abnormal liver function tests.Hydroxyurea should not be used in pregnancy or in women who are breastfeeding.

Leukapheresis — The role of leukapheresis as an adjunct to the treatment of all patients withhyperleukocytosis is controversial. It is not clear whether survival is improved in patients treated withleukapheresis when compared with patients who receive cytoreductive chemotherapy promptly.Although intensive leukapheresis, with procedure times often lasting many hours, has been reported to produceimprovement in pulmonary and central nervous system symptoms, there are theoretical and practical limitationsto its benefits. It is precisely the patient in whom leukostasis is most likely to occur, that is, the patient with a highand rapidly rising blast count, in whom the technical limitations of leukapheresis are relevant. It is often difficult,even with highly efficient cell separators, to reduce the rapidly rising count. Cycle-specific chemotherapeuticagents (eg, induction chemotherapy) are more likely to be the most rapidly effective.Although some clinicians advocate its use for patients with asymptomatic hyperleukocytosis, we typically reserveleukapheresis for patients with symptomatic hyperleukocytosis who must have induction chemotherapypostponed. Our preference to reserve leukapheresis for this selected patient population is primarily based uponthe known risks associated with leukapheresis described below and an unclear benefit. Anecdotal reports haveclaimed dramatic responses [25-29], but larger retrospective analyses have demonstrated conflicting effects onearly mortality rates [19,22,30]. Given the paucity of data concerning the efficacy of leukapheresis in reducing

addition, clinical deterioration may occur even after the WBC count has been significantly reduced.An exception to this approach may occur in patients who cannot start induction chemotherapy immediately.Such patients include those who have poor venous access, renal insufficiency, or other severe metabolicdisturbances, and those with delays in initiating prophylaxis for tumor lysis syndrome (TLS). If inductionchemotherapy must be delayed, our approach to hyperleukocytosis depends upon whether or not thepatient is having symptoms of hyperleukocytosis (ie, leukostasis):For patients without symptoms of leukostasis who must have induction chemotherapy delayed, we suggestcytoreduction with hydroxyurea rather than leukapheresis. Cytoreduction with hydroxyurea can precipitateor exacerbate hyperuricemia and occasionally precipitate TLS, therefore such patients also needintravenous hydration and TLS prophylaxis. (See 'Hydroxyurea' below.)

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For patients with symptoms of leukostasis who must have induction chemotherapy delayed, we suggestinitial cytoreduction with leukapheresis in combination with hydroxyurea to lower or stabilize the WBCcount. (See 'Leukapheresis' below.)

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early mortality and/or improving overall survival, leukapheresis cannot be recommended for routine therapy as aform of tumor "debulking" in patients with high blast counts.However, patients with symptomatic leukocytosis have an extremely high mortality rate without immediatetherapy [16-22]. When both respiratory failure and neurologic compromise are present, the death rate at oneweek reaches 90 percent [22]. Therefore, if facilities are available, we suggest leukapheresis for patients withleukemic blast counts greater than 50 to 100 x 10 /L (50 to 100,000/microL) and associated symptoms as atemporizing measure until chemotherapy can be initiated. It is difficult to predict the percent leukocyte countreduction in individual patients, but sessions are usually planned for four- to five-hour collections with repeatsessions as needed.It is generally agreed that leukapheresis should not be used for patients with acute promyelocytic leukemiabecause it may worsen the intrinsic coagulopathy associated with this subtype of leukemia [2]. Placement oflarge intravenous leukapheresis catheters in these patients has been associated with venous thrombosis orhemorrhage. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia inadults", section on 'Disseminated intravascular coagulation'.)Additional considerations include:

Supportive care — The following supportive care measures should be considered for all patients withhyperleukocytosis:

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Leukapheresis usually requires the placement of a large bore, central venous catheter, is only available atselect medical centers, and lacks standardization. The procedure can also be done using antecubital veinsif they are adequate for placement of large bore needles bilaterally.

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A small number of platelets are inevitably removed with the leukemic blasts, resulting in worseningthrombocytopenia.

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Some patients require multiple sessions to control their white blood cell (WBC) count, while many others,presumably those with the most rapidly proliferating acute myeloid leukemia (AML), do not respond tomultiple sessions of leukapheresis [31].

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The effect is generally transient with WBC counts typically rebounding after leukapheresis is discontinuedunless chemotherapy is begun.

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It is unclear whether leukapheresis can reverse vascular damage already sustained from leukostasis. Inaddition, symptomatic leukostasis can still develop after the WBC count has been lowered byleukapheresis.

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Symptomatic leukostasis can be precipitated by increases in whole blood viscosity following red blood celltransfusions. Such transfusions should be withheld, if possible, until the blast count is reduced. If atransfusion is necessary, it should be given slowly, administering a single unit of red blood cells over a fewhours, or during the leukapheresis procedure. Hydration is encouraged and diuretics are discouraged.

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Patients with hyperleukocytosis are at risk of tumor lysis syndrome (TLS), although this syndrome is lesscommon in patients with AML than in those with acute lymphoblastic leukemia (ALL) or Burkittleukemia/lymphoma. TLS is best prevented with intravenous hydration to ensure adequate urine flow,allopurinol to reduce serum uric acid levels, and the correction of any electrolyte disturbances or causes ofreversible renal failure. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impactof TLS'.)

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Although intravenous hydration is recommended for the management and prevention of tumor lysissyndrome, care should be taken to avoid overhydration and hypervolemia which could exacerbatepulmonary symptoms.Coagulation abnormalities, including disseminated intravascular coagulation (DIC), further increase the riskof local hemorrhage. Specific treatment aimed at the DIC should be considered. (See "Clinical features,diagnosis, and treatment of disseminated intravascular coagulation in adults" and "Initial treatment of acutepromyelocytic leukemia in adults", section on 'Control of coagulopathy'.)

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In addition, patients with leukostasis often require specialized, symptom-directed supportive care includingmechanical ventilation for respiratory failure and/or stroke. (See "Initial assessment and management of acutestroke" and "Overview of mechanical ventilation".)Is there a role for cranial irradiation? — Some centers advocate low dose cranial irradiation (eg, 400 cGy in asingle fraction), including treatment of the retina, in order to prevent further proliferation of leukemic cells incentral nervous system sites where drug delivery may theoretically be compromised. However, there are nocomparative studies to determine whether the results with cranial irradiation are superior to those withchemotherapy alone, and we do not advocate the routine use of cranial irradiation in this setting. Nevertheless, itcould be considered for patients with serious central nervous system symptoms related to leukostasis.PROGNOSIS — The prognostic impact of hyperleukocytosis and leukostasis (symptomatic hyperleukocytosis)depends upon the type of leukemia (acute myeloid leukemia or acute lymphoblastic leukemia) and the presenceof symptoms.The initial mortality rate for patients with acute myeloid leukemia (AML) and leukostasis has been estimated at20 to 40 percent and appears to be unrelated to the severity of the hyperleukocytosis [16-19,22]. If patientssurvive the initial period, they tend to have somewhat lower remission rates. Remission durations are alsoshorter, possibly because of a larger initial tumor mass, but more likely related to the biology and intrinsicchemotherapy resistance of the leukemia [16,18].Risk factors for mortality in patients with AML and hyperleukocytosis were identified in a retrospective analysis[22]. When compared with patients who lived more than one week after presentation, patients who died withinthe first week of presentation had significantly higher rates of coagulopathy (64 versus 18 percent), respiratorydistress (100 versus 15 percent), renal failure (43 versus 29 percent), and neurologic symptoms (64 versus 12percent) [22].In patients with acute lymphoblastic leukemia (ALL), hyperleukocytosis is rarely complicated by leukostasis andthe early death rate is less than 5 percent in childhood ALL [4]. The challenge of leukostasis management in ALLinvolves preventing tumor lysis syndrome, disseminated intravascular coagulation, and the higher risk of relapse(approximately 50 percent by four years) [3]. (See "Risk group stratification and prognosis for acutelymphoblastic leukemia in children and adolescents" and "Clinical features, diagnosis, and treatment ofdisseminated intravascular coagulation in adults" and "Tumor lysis syndrome: Prevention and treatment", sectionon 'Clinical impact of TLS'.)INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 to 6 gradereading level, and they answer the four or five key questions a patient might have about a given condition. Thesearticles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyondthe Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are writtenat the 10 to 12 grade reading level and are best for patients who want in-depth information and arecomfortable with some medical jargon.Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail thesetopics 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.)

SUMMARY AND RECOMMENDATIONS

Patients should also receive prophylactic platelet transfusions to maintain a count of greater than 20 to30,000/microL until the WBC count has been reduced and the clinical situation has been stabilized. Therisk of intracranial hemorrhage is greatest after the WBC count has been markedly reduced, suggestingthat a reperfusion injury may occur when the circulation is restored to previously hypoxemic or ischemiccapillary beds. Thus, aggressive platelet support and correction of coagulopathy should continue forseveral weeks during the remission induction period.

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

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REFERENCESCuttner J, Conjalka MS, Reilly M, et al. Association of monocytic leukemia in patients with extremeleukocytosis. Am J Med 1980; 69:555.

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Daver N, Kantarjian H, Marcucci G, et al. Clinical characteristics and outcomes in patients with acutepromyelocytic leukaemia and hyperleucocytosis. Br J Haematol 2015; 168:646.

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Lichtman MA, Rowe JM. Hyperleukocytic leukemias: rheological, clinical, and therapeutic considerations.6.

Hyperleukocytosis is a laboratory abnormality that has been variably defined as a total white blood cell(WBC) count greater than 50 x 10 /L (50,000/microL) or 100 x 10 /L (100,000/microL). In contrast,leukostasis (also called symptomatic hyperleukocytosis) is a medical emergency that is most commonlyseen in patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) in blast crisis and ischaracterized by an extremely elevated WBC count and symptoms of decreased tissue perfusion.

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The main clinical symptoms of leukostasis and causes of early death are related to involvement of thecentral nervous system and lungs. (See 'Signs and symptoms' above.)

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Clinically, leukostasis is diagnosed empirically when a patient with leukemia and a blast cell count over 50to 100 x 10 /L (100,000/microL) presents with respiratory or neurological distress. (See 'Diagnosis' above.)

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The initial management of a patient with hyperleukocytosis is directed at rapid lowering of the WBC count.(See 'Management' above.)

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For patients with symptomatic or asymptomatic hyperleukocytosis, we suggest initial cytoreductionwith induction chemotherapy rather than hydroxyurea or leukapheresis (Grade 2B). (See "Inductiontherapy for acute myeloid leukemia in younger adults" and "Treatment of acute myeloid leukemia inolder adults" and "Induction therapy for Philadelphia chromosome negative acute lymphoblasticleukemia in adults".)

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For patients with asymptomatic hyperleukocytosis who must have induction chemotherapy delayed,we suggest cytoreduction with hydroxyurea rather than leukapheresis (Grade 2C).

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For patients with symptoms of leukostasis who must have induction chemotherapy delayed, wesuggest initial leukapheresis in addition to hydroxyurea (if possible) to lower or stabilize the WBCcount (Grade 2C).

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The following supportive care measures should be considered for all patients with hyperleukocytosis (see'Supportive care' above):

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Red blood cell transfusions should be withheld, if possible, until the blast count is reduced. If atransfusion is necessary, it should be administered slowly.

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Most patients with hyperleukocytosis are candidates for tumor lysis syndrome prophylaxis withaggressive intravenous hydration and allopurinol or rasburicase to decrease serum uric acid levels.(See "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of TLS'.)

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Coagulation abnormalities require aggressive treatment with platelet transfusions and coagulationfactors. (See "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation inadults" and "Initial treatment of acute promyelocytic leukemia in adults", section on 'Control ofcoagulopathy'.)

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Blood 1982; 60:279.Lester TJ, Johnson JW, Cuttner J. Pulmonary leukostasis as the single worst prognostic factor in patientswith acute myelocytic leukemia and hyperleukocytosis. Am J Med 1985; 79:43.

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Dombret H, Hunault M, Faucher C, et al. Acute lysis pneumopathy after chemotherapy for acutemyelomonocytic leukemia with abnormal marrow eosinophils. Cancer 1992; 69:1356.

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Oberoi S, Lehrnbecher T, Phillips B, et al. Leukapheresis and low-dose chemotherapy do not reduce earlymortality in acute myeloid leukemia hyperleukocytosis: a systematic review and meta-analysis. Leuk Res2014; 38:460.

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Lane TA. Continuous-flow leukapheresis for rapid cytoreduction in leukemia. Transfusion 1980; 20:455.28. Mehta AB, Goldman JM, Kohner E. Hyperleucocytic retinopathy in chronic granulocytic leukaemia: the roleof intensive leucapheresis. Br J Haematol 1984; 56:661.

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outcome in adult acute myelogenous leukemia presenting with hyperleukocytosis. Ann Hematol 2000;79:501.

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Contributor DisclosuresCharles A Schiffer, MD Grant/Research/Clinical Trial Support: Celgene [CLL, myeloma (pomalidomide,thalidomide)]; Novartis [CML (imatinib, nilotinib)]; Bristol Myers [CML (dasatinib)]; Ariad [CML (ponatinib)];Cephiad (PCR analytic machine). Data Safety Monitoring Boards: Teva [CML (omacetaxine)]; Ambit [AML(AC220)]; Pfizer [CML (bosutinib)]; Takeda (MLN4924). Consultant/Advisory Boards: Celgene [CLL, myeloma(pomalidomide, thalidomide)]; Onconova [MDS (rigosertib)]. Richard A Larson, MD Grant/Research/ClinicalTrial Support: Amgen [leukemia (blinatumomab)]; Astellas [leukemia (gilteritinib)]; Erytech [leukemia(GRASPALL)]; Ariad [leukemia (ponatinib)]; Novartis [leukemia (nilotinib)]; Ambit Bioscience [leukemia(quizartinib)]; Daiichi Sankyo [leukemia (quizartinib)]; Celgene [leukemia (AG-221)]. Consultant/Advisory Boards:Novartis [leukemia (imatinib, nilotinib)]; Ariad [leukemia (ponatinib)]; CVS/Caremark [leukemia (drug priorauthorization program)]; Pfizer [leukemia (gemtuzumab ozogamicin)]; Celgene Data Safety Monitoring Board[leukemia (azacitidine)]; Bristol Meyers Squibb Data Safety Monitoring Board [leukemia (dasatinib)]; Amgen[leukemia (blinatumomab)]; Astellas [leukemia (gilteritinib)]; Bayer [leukemia (copanlisib)]; Incyte [leukemia].Rebecca F Connor, MD Nothing to disclose.Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these areaddressed by vetting through a multi-level review process, and through requirements for references to beprovided to support the content. Appropriately referenced content is required of all authors and must conform toUpToDate standards of evidence.Conflict of interest policy


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Hyperleukocytosis and Leukostasis in Hematologic Malignancies