Critical Care Medicine

Acute leukemic blast crisis, Hyperleukocytosis, Leukostasis

Leukostasis

Synonyms

  • Hyperleukocytosis

  • Leukemic blast crisis

Related Conditions

  • Acute myelogenous leukemia

  • Acute lymphoblastic leukemia

  • Chronic myelogenous leukemia

  • Chronic lymphocytic leukemia

1. Description of the problem

What every clinician needs to know

Patients with both acute (AML, ALL) and chronic leukemias (CML, CLL) frequently present with hyperleukocytosis. This is a laboratory definition to describe a marked elevation of leukemia cells in the peripheral blood. Arbitrary cutoffs to define hyperleukocytosis range from 50,000-100,000 cells/mm3.

A subset of patients with hyperleukocytosis can develop the clinical condition of leukostasis, a life-threatening oncologic emergency where leukemia cells (typically but not always immature blasts) are thought to cause organ dysfunction by impairment of microvascular perfusion. Most commonly the pulmonary and CNS microvascular beds are affected.

Clinical features

Pulmonary

This is the most common clinical manifestation of leukostasis. It can range from mild respiratory distress to severe life-threatening hypoxia with widespread alveolar/interstitial infiltrates on X-ray or CT imaging. Keep in mind that pulse oximetry will be more accurate than an arterial blood gas (ABG) study if this diagnosis is suspected. Leukemic blasts will cause pseudohypoxemia on ABG (so-called leukocyte larceny) due to continued oxygen consumption in the ABG syringe.

Neurologic

Symptoms can range from mild confusion to somnolence to stupor and coma. The presentation may not always be in a global distribution and patients may present with focal neurological deficits. Common signs/symptoms at the time of presentation include headache, blurred vision, visual loss, gait instability, tinnitus, cranial nerve deficits, retinal hemorrhage, papilledema and nuchal rigidity.

Other clinical manifestations

  • Acute MI/arrhythmia

  • Bowel ischemia/infarction

  • Acute renal failure

  • Limb ischemia

  • Priapism

Key management issues

Prevention of leukostasis

The main goal for patients with hyperleukocytosis is to reduce the leukocyte count rapidly and safely to minimize the risk for the development of clinical leukocytosis. Depending on risk, measures to consider include (1) use of cytotoxic chemotherapy; (2) hydroxyurea; and (3) leukapheresis.

Treatment of leukostasis

Once patients have developed signs and symptoms consistent with clinical leukostasis, leukocytoreduction must be implemented emergently. Measures to consider include (1) use of cytotoxic chemotherapy; (2) hydroxyurea; and (3) leukapheresis.

2. Emergency Management

Stabilizing the patient

If a patient is suspected to have organ dysfunction secondary to leukostasis, this should be considered to be an oncologic emergency. Determine if the patient has a known diagnosis of a hematologic malignancy. If not, make sure that you order a peripheral blood smear and peripheral blood flow cytometric analysis for immediate review.

It is imperative to order these tests so that the oncologist or fellow can promptly establish the diagnosis at the time of consultation. It is appropriate to request an emergent medical oncology and pathology consultation regardless of time of day. Once a definitive diagnosis is made, disease-specific therapies aimed at cytoreduction can be considered.

Consider contacting a local tertiary care center with an established leukemia program for hospital-to-hospital transfer early on in the diagnostic evaluation. Patients with suspected organ dysfunction from leukostasis should also be considered for critical care consultation and placement in the intensive care unit for aggressive monitoring.

Bleeding and thrombotic complications (secondary to coagulopathy or cytopenias) are always on the differential and can cause clinical complications that can mimic the presentation of leukostasis. All patients with hyperleukocytosis should have a DIC panel (PT, PTT, fibrinogen, fibrin split products, D-dimer and peripheral smear) performed at the time of diagnosis. Maintaining an active type and screen is mandatory.

CNS: If the patient has CNS symptoms, consider appropriate alternative diagnoses such as CVA, dural venous thrombosis and hemorrhage (intraparenchymal, subdural and subarachnoid). At a minimum, a non-contrast CT of the head is mandatory if the patient is stable enough. Consider MRI/MRA and MRV imaging in collaboration with neurology consultation.

Pulmonary: The differential for respiratory failure in the patient with acute leukemia is broad and beyond the context of this section. Common diagnoses to consider include pulmonary hemorrhage (DAH), differentiation syndrome (ATRA, arsenic, araC), infection in an immunocompromised host, hypoxia secondary to severe anemia, pulmonary embolus, malignant/inflammatory effusion and cardiac tamponade. Chest X-ray, EKG and CT chest should be considered to help make the diagnosis.

Supportive care measures

As soon as the diagnosis of leukemia with hyperleukocytosis/leukostasis is suspected, tumor lysis syndrome prophylaxis and treatment measures should be implemented. Treatment of hyperleukocytosis may exacerbate tumor lysis syndrome. Also:

  • Consider start of allopurinol and/or rasburicase.

  • Oxygen therapy should be administered.

  • IVFs (crystalloid) should be started promptly.

  • Keep active type and screen.

  • Unless it is a life-threatening emergency requiring transfusion of PRBCs, try to minimize their use until leukocytoreduction can be achieved. Blood products (especially PRBCs) may increase serum viscosity and precipitate and exacerbate leukostasis.

  • Monitor for DIC and treat accordingly to minimize bleeding risk.

  • Keep platelet count above 20,000 platelets/microliter to minimize bleeding risk.

  • Serial CBCs should be performed (q 6-8 hr) to assess progress of leukocytoreduction.

In addition, for leukocytoreduction in the setting of hyperleukocytosis and leukostasis, hydroxyurea (HU) is a well-tolerated oral option for therapy that has demonstrated effectiveness in blast count reduction. This should be considered in the setting of hyperleukocytosis and/or leukostasis. The main advantage of HU is that it can be administered immediately and continued until the WBC is in an acceptable range. This is especially useful in the situation where the definitive diagnosis has not yet been established, as this medical treatment can be effective in both myeloid and lymphoid malignancies.

In the setting of clinical leukostasis, the downside to this approach used as a single modality is that it takes 24-48 hours to significantly reduce the circulating blast count. Typical dosing of HU is 50-100 mg/kg/day in divided doses. A typical dosing strategy used in our practice is 2-3 grams HU po q 6 hours.

Leukapheresis is another method of cytoreduction, although it is typically reserved for patients with leukocyte counts higher than 100,000-200,000 cells/mm 3 with clinical leukostasis. It is exceedingly effective in reducing the circulating blasts by removing circulating WBCs and reinfusing leukocyte-depleted plasma.

However, the use of this method, although effective in decreasing leukocyte count, remains somewhat controversial. Studies do not suggest a clear correlation between the degree of cytoreduction and reduction in mortality. No currently widely accepted guidelines are available for leukapheresis, and there are no specific criteria for when to initiate or when to stop treatment.

Therefore, leukapheresis should be considered to be a temporizing measure. A major limitation of this modality is that it often takes a considerable amount of time (line placement, coordination between several hospital departments or American Red Cross) to implement this approach. Additionally, not every healthcare facility has this capability.

Cytotoxic chemotherapy is the best means to address the issues of hyperleukocytosis and clinical leukostasis. Treatment with disease-specific remission induction regimens can efficiently lower the WBC. The hematologist's input will be critical in selecting the appropriate regimen. The specifics of selection and timing of remission induction immuno-chemotherapy for both acute and chronic leukemias are beyond the scope of this section.

Radiation therapy: Extracranial irradiation has been proposed as a treatment option for hyperleukocytosis/leukostasis in the setting of CNS manifestations. Radiation doses of 400 cGy have been applied to the whole brain. Because of the significant morbidity associated with cerebral irradiation and the lack of systemic effect of the treatment, this modality is not routinely used.

3. Diagnosis

Diagnostic criteria and tests

Hyperleukocytosis is a laboratory diagnosis. Patients with hyperleukocytosis carry a diagnosis of acute or chronic leukemia with a measured WBC greater than 50,000-100,000 cells/mm3.

Leukostasis is a clinical diagnosis (and also a diagnosis of exclusion). To meet the criteria for this condition the patient must carry a diagnosis (or suspected diagnosis) of leukemia and present with a markedly elevated WBC with signs/symptoms of end-organ dysfunction thought to be secondary to hypoperfusion/obstruction of the microvasculature secondary to hyperleukocytosis. Common organ systems involved include pulmonary and CNS. No specific laboratory test that can be performed to confirm this diagnosis. Common tests that may help support the diagnosis include:

  • WBC: Markedly elevated, above 50,000 cells/mm3.

  • Peripheral smear with increased numbers of immature blasts.

  • SaO2 on ABG will be falsely depressed. Make sure the test is sent on ICE to minimize metabolic activity of blasts.

  • Potassium levels may be falsely elevated (release of intracellular cations from blasts in test tube).

Other possible diagnoses

  • Pulmonary differential (hypoxic respiratory syndrome).

  • Diffuse alveolar hemorrhage (DIC, thrombocytopenia).

  • Transfusion-associated acute lung injury.

  • Differentiation syndrome (ATRA, arsenic).

  • Pneumonia (immunocompromised host).

  • Pneumonitis (drug reaction).

  • Pulmonary embolus (hypercoagulable state).

  • Severe anemia with concomitant respiratory distress.

  • Malignant effusions (especially lymphoid malignancies).

  • Leukemia infiltration of lung parenchyma (especially monocytic leukemia).

Neurologic presentation

  • Leukemic meningitis/nerve root involvement.

  • Subdural hematoma.

  • Retinal hemorrhage (multiple causes, including hyperleukocytosis).

  • Subarachnoid hemorrhage.

  • Intraventricular/parenchymal bleed.

  • Dural sinus thrombosis.

  • Septic emboli.

  • Infectious meningitis.

  • CVA (thrombotic).

  • ATRA (can cause headache).

  • Zofran (can cause headache).

4. Specific Treatment

There are no randomized data to support the selection of a particular cytoreductive therapy and thus there is no standard of care.

Most hematologists agree that if patients are at high risk for leukostasis and/or if they already have clinical evidence of end-organ dysfunction, one must act quickly to lower the WBC and minimize the risk of morbidity and mortality.

Options to consider

Hydroxyurea

HU is a well-tolerated oral option for therapy that has demonstrated effectiveness in blast count reduction. This should be considered in the setting of hyperleukocytosis and/or leukostasis.

The main advantage of HU is that it can be administered immediately and continued until the WBC is in an acceptable range. This is especially useful in the situation where the definitive diagnosis has not yet been established as this medical treatment can be effective in both myeloid and lymphoid malignancies.

In the setting of clinical leukostasis, the downside to this approach used as a single modality is that it takes 24-48 hours to significantly reduce the circulating blast count. Typical dosing of HU is 50-100 mg/kg/day in divided doses. A typical dosing strategy used in our practice is 2-3 grams HU po q 6 hours.

Leukapheresis

Leukapheresis is another method of cytoreduction, although it is typically reserved for patients with leukocyte counts above100,000-200,000 cells/mm3 with clinical leukostasis. It is exceedingly effective in reducing the circulating blasts by removing circulating WBCs and reinfusing leukocyte-depleted plasma.

The use of this method, although effective in decreasing leukocyte count, remains somewhat controversial. Studies do not suggest a clear correlation between the degree of cytoreduction and reduction in mortality. Currently, there are no widely accepted guidelines available for leukapheresis and no specific criteria for when to initiate or when to stop treatment.

Leukapheresis should be considered to be a temporizing measure. A major limitation of this modality is that it often takes a considerable amount of time (line placement, coordination between several hospital departments or American Red Cross) to implement this approach. Additionally, not every healthcare facility has this capability.

Cytotoxic chemotherapy

This is the best means to address the issues of hyperleukocytosis and clinical leukostasis. Treatment with disease-specific remission induction regimens can efficiently lower the WBC. The hematologist's input will be critical in selecting the appropriate regimen. The specifics of selection and timing of remission induction immuno-chemotherapy for both acute and chronic leukemias are beyind the scope of this section.

5. Disease monitoring, follow-up and disposition

If leukostasis is not recognized early and dealt with effectively, the mortality rate can approach 20-40%.

Pathophysiology

The exact mechanism of damage by hyperleukocytosis continues to be an area of active research. Although hyperleukocytosis is often defined as WBC above 100,000/mm3, patients can develop symptoms of leukostasis with WBC as low as 50,000/mm3.

Leukocrit hypothesis

One hypothesis regarding the etiology of hyperleukocytosis is that a critical “leukocrit” (fractional volume of leukocytes) is reached, which results in increased blood viscosity, impaired blood flow and the subsequent development of leukostasis.

Leukemic myeloblasts are theorized to initiate leukostasis more frequently than leukemic lymphoblasts because the MCV of myeloblasts is typically twice as large as the MCV of lymphoblasts.

Cellular adhesion/cytokine hypothesis

More recent work has focused on cellular adhesion molecules and leukemic cell response to local cytokines in the pathophysiology of leukostasis. Direct interactions between leukemic blasts and the endothelium may lead to leukocyte aggregation and formation of thrombi.

Variation in expression of adhesion molecules between myeloblasts and lymphoblasts may also explain why patients with AML have higher rates of leukostasis. Similarly, variations in endothelial cell surface expression of adhesion molecules may also explain why some areas, including the pulmonary and CNS vasculature, seem more prone to complications of leukostasis than others.

Locally produced cytokines may attract leukemic blasts to the area, resulting in increased viscosity, local stasis, and cellular damage resulting in thrombosis or hemorrhage.

Epidemiology

Risk factors for leukostasis

  • Acute leukemias (AML > ALL) (vs. chronic).

  • Myeloid phenotype (vs. lymphoid).

  • High WBC (especially percentage and absolute number of circulating blasts).

  • AML risk factors: Monocytic leukemias (M4, M5 subtypes), promyelocytic leukemia (M3 subtype, especially microgranular variant).

  • ALL risk factors: Presence of leukemic cell ploidy variants, Philadelphia chromosome, 11q23 rearrangements, male sex, younger age (especially infants and teenage patients), T-cell phenotype, mediastinal mass.

  • CML: presence of accelerated phase or blast crisis.

Prognosis

See above.

Special considerations for nursing and allied health professionals.

N/A

What's the evidence?

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Hoelzer, D. "Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults". Blood. vol. 71. 1988. pp. 123-31.

Karesh, JW. "prospective ophthalmic evaluation of patients with acute myeloid leukemia: correlation of ocular and hematologic findings".

Lightman, MA. "Rheology of leukocytes, leukocyte suspensions, and blood in leukemia. Possible relationship to clinical manifestations". J Clin Invest. vol. 52. 1973. pp. 350-8.

Lowe, EJ. "Early complications in children with acute lymphoblastic leukemia presenting with hyperleukocytosis". Pediatr Blood Cancer. vol. 45. 2005. pp. 10-5.

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Nelson, SC. "Management of leukemic hyperleukocytosis with hydration, urinary alkalinization, and allopurinol. Are cranial irradiation and invasive cytoreduction necessary?". Am J Pediatr Hematol/Oncol. vol. 15. 1993. pp. 351-5.

Porcu, P. "Leukocytoreduction for acute leukemia". Therapeutic Apheresis. vol. 6. 2002. pp. 15-23.

van Buchem, MA. "Leucostasis, an underestimated cause of death in leukaemia". Annals of Hematology. vol. 56. 1988. pp. 39-44.

van Buchem, M A. "Pulmonary leukostasis: radiologic-pathologic study". Radiology. vol. 165. 1987. pp. 739-41.

Porcu, P. "Hyperleukocytic leukemias and leukostasis: a review of pathophysiology, clinical presentation and management". Leukemia Lymphoma. vol. 39. 2000. pp. 1-18.

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