HYPERLEUKOCYTOSIS

1. HYPERLEUKOCYTOSIS DR AHMAD AHMADZADEH HEMATOLOGIST-MEDICAL ONCOLOGIST

2. Hyperleukocytosis refers to a laboratory abnormality that has been variably defined as a total leukemia blood cell count greater than 50 x 109/L (50,000/microL) or 100 x 109/L (100,000/microL). leukostasis (also called symptomatic hyperleukocytosis) is a medical emergency most commonly seen in patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) in blast crisis. It is characterized by an extremely elevated blast cell count and symptoms of decreased tissue perfusion.

3. 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 with respiratory or neurological distress. Prompt treatment is indicated since, if left untreated, the one-week mortality rate is approximately 20 to 40 percent.

4. EPIDEMIOLOGY

5. The incidence of hyperleukocytosis and leukostasis vary by leukemia type and patient population. In general, symptoms of leukostasis are more common in leukemias with large, poorly deformable blasts, such as acute myeloid leukemia. Acute myeloid leukemia : Hyperleukocytosis is present in 10 to 20 percent of patients with newly diagnosed 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)

6. Acute lymphoblastic leukemia : Hyperleukocytosis is seen in 10 to 30 percent of patients with newly diagnosed acute lymphoblastic leukemia (ALL) . 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 . Symptoms of leukostasis are rarely seen in patients with ALL and hyperleukocytosis. Tumor lysis syndrome and disseminated intravascular coagulation are more common complications related to the elevated WBC count. 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 x 109/L (400,000/microL).

7. Chronic myeloid leukemia : Patients with chronic myeloid leukemia (CML) typically present with leukocytosis and a median WBC count of approximately 100 x 109/L (100,000/microL). Most often, these are segmented neutrophils, metamyelocytes, and myelocytes. Symptoms of leukostasis are very uncommon in patients in chronic phase but can be seen occasionally in patients with myeloid blast crisis and very elevated blast counts.

8. pathophysiology

9. The pathophysiology of leukostasis is not well understood. There are two main theories, which are not mutually exclusive: Leukostasis may be due to increased blood viscosity as a direct complication of a large population of leukemic blasts that are considerably less deformable than mature leukocytes .With increasing blast counts, plugs of these more rigid cells can develop in the microcirculation, thereby impeding blood flow (leukostasis). This situation can be worsened by red blood cell transfusions or the use of diuretics, both of which can increase whole blood viscosity.

10. Local hypoxemia may be exacerbated by the high metabolic activity of the dividing blasts and the associated production of various cytokines These cytokines can result in endothelial damage and subsequent hemorrhage that add to the hypoxic damage already present from reduced blood flow . Leukemic blasts can migrate into the surrounding tissues, causing additional damage .Thus, the lower incidence of clinically significant leukostasis and vascular injury in patients with CLL and ALL may be related to the lower metabolic and mitotic rate in the former and the lack of catabolic enzymes and cytokines in both.

11. SIGNS AND SYMPTOMS :  Although pathologic evidence of leukostasis can be found in most organs in patients with extremely high white blood cell (WBC) counts, the main clinical symptoms of leukostasis and causes of early death are related to involvement of the central nervous system (approximately 40 percent) and lungs (approximately 30 percent) . Pulmonary signs and symptoms include dyspnea and hypoxia with or without diffuse interstitial or alveolar infiltrates on imaging studies. Measurement of the arterial pO2 can be falsely decreased in patients with hyperleukocytosis, since the WBCs in the test tube utilize oxygen. Pulse oximetry provides a more accurate assessment of O2 saturation in this setting. Neurological signs and symptoms include visual changes, headache, dizziness, tinnitus, gait instability, confusion, somnolence, and, occasionally, coma.

12. LABORATORY ABNORMALITIES : Hyperleukocytosis may result in laboratory abnormalities, which can be due to interference with laboratory assays or may be a consequence of the high number of circulating blasts. 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 oximetry provides a more accurate assessment of O2 saturation. 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 careful review of the peripheral smear is appropriate in such settings.

13. Approximately 80 percent of patients with leukostasis are febrile, which may be due to inflammation associated with leukostasis or concurrent infection. Since an infectious cause cannot be easily excluded, we treat empirically for infection in all such patients. Less common signs or symptoms of leukostasis include electrocardiographic signs of myocardial ischemia or right ventricular overload, worsening renal insufficiency, priapism, acute limb ischemia, or bowel infarction . Occasionally, patients develop dyspnea and worsening hypoxemia following the initiation of chemotherapy due to the lysis of leukemic cells trapped in the lungs (eg, acute lysispneumopathy)

14. Serum potassium can be spuriously elevated due to its release from leukemic blasts during the in vitro clotting process. Potassium levels measured from heparinized plasma samples, rather than serum, can circumvent this effect. Disseminated intravascular coagulation (DIC) occurs in up to 40 percent of patients . DIC presents with various degrees of thrombin generation (eg, decreased fibrinogen) and increased fibrinolysis (eg, elevated fibrin degradation products and D-dimer). DIC may develop or worsen following chemotherapy. Spontaneous tumor lysis syndrome (TLS) is present in up to 10 percent of patients with leukostasis. Laboratory evidence of tumor lysis syndrome includes increased elevated serum concentrations of uric acid, potassium, and phosphate, often accompanied by hypocalcemia. TLS may develop or worsen following chemotherapy.

15. DIAGNOSIS :Leukostasis (symptomatic hyperleukocytosis) is diagnosed empirically when a patient with leukemia and a white blood cell (WBC) count over 100 x 109/L (100,000/microL) presents with symptoms thought to be due to tissue hypoxia, most commonly respiratory or neurological distress. The diagnosis requires a high degree 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 the microvasculature . A pathologic diagnosis of leukostasis is rarely obtained because of the risks associated with biopsy of affected tissues.

16. MANAGEMENT

17. Leukostasis (symptomatic hyperleukocytosis) constitutes a medical emergency, and efforts should be made to rapidly stabilize the patient and lower the white blood cell count. In most cases, rapid cytoreduction can be achieved with induction chemotherapy, which should be administered in conjunction with prophylaxis for tumor lysis syndrome. Adequate fluid resuscitation to prevent dehydration and ensure good urine flow is important.

18. Cytoreduction :  Twenty to 40 percent of patients with symptomatic hyperleukocytosis die within the first week of presentation . The mortality rate appears to be unrelated to the level of the white blood cell count, but patients with symptoms (eg, respiratory distress or neurological compromise) have a significantly worse prognosis when compared with patients who have hyperleukocytosis alone. Cytoreduction can be achieved through the use of chemotherapy ( hydroxyurea or remission induction chemotherapy) or leukapheresis.

19. 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 improve survival. There have been no prospective trials or large observational studies comparing these two options for the treatment of hyperleukocytosis and leukostasis. In general, we propose the following approach to patients with hyperleukocytosis: For patients with symptomatic or asymptomatic hyperleukocytosis, we suggest initial treatment with induction chemotherapy rather than hydroxyurea  or leukapheresis. This should be accompanied by tumor lysis syndrome prophylaxis with aggressive hydration and allopurinol.

20. Our preference for induction chemotherapy is primarily based upon the knowledge that such therapy is also a necessary step toward the successful treatment of patients with leukemia. There is little evidence to confirm that decreasing the white blood cell (WBC) count alone will reduce the early mortality rate. 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 metabolic disturbances, and those with delays in initiating prophylaxis for tumor lysis syndrome (TLS). If induction chemotherapy must be delayed, our approach to hyperleukocytosis depends upon whether or not the patient is having symptoms of hyperleukocytosis (ie, leukostasis):

21. For patients without symptoms of leukostasis who must have induction chemotherapy delayed, we suggest cytoreduction with hydroxyurea  rather than leukapheresis. Cytoreduction with hydroxyurea can precipitate or exacerbate hyperuricemia and occasionally precipitate TLS, therefore such patients also need intravenous hydration and TLS prophylaxis. For patients with symptoms of leukostasis who must have induction chemotherapy delayed, we suggest initial cytoreduction with leukapheresis in combination with hydroxyurea to lower or stabilize the WBC count.

22. 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 rapidly decrease the circulating WBC count and target the leukemia cells in the bone marrow. Induction therapy typically substantially reduces the WBC count within 24 hours. Patients with hyperleukocytosis are at higher risk of developing tumor lysis syndrome with induction chemotherapy. This syndrome is best prevented via appropriate treatment with intravenous hydration to ensure adequate urine flow,allopurinol  or rasburicase to reduce serum uric acid levels, and correction of any electrolyte disturbances or causes of reversible renal failure.

23. Hydroxyurea:  We typically reserve hydroxyurea for patients with asymptomatic hyperleukocytosis who are unable to receive immediate induction chemotherapy. Hydroxyurea, given at a total dose of 50 to 100 mg/kg per day orally, reduces the WBC count by 50 to 80 percent within 24 to 48 hours The usual hydroxyurea dose is 2 to 4 grams orally every 12 hours, which is continued until the WBC count is below 50 x 109/L (50,000/microL). Side effects of hydroxyurea are usually minimal and are typically limited to patients who are exposed to hydroxyurea 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

24. Leukapheresis:  The role of leukapheresis as an adjunct to the treatment of all patients with hyperleukocytosis is controversial. It is not clear whether survival is improved in patients treated with leukapheresis when compared with patients who receive cytoreductive chemotherapy promptly. Although intensive leukapheresis, with procedure times often lasting many hours, has been reported to produce improvement in pulmonary and central nervous system symptoms, there are theoretical and practical limitations to its benefits. It is precisely the patient in whom leukostasis is most likely to occur, that is, the patient with a high and rapidly rising blast count, in whom the technical limitations of leukapheresis are relevant.

25. Although some clinicians advocate its use for patients with asymptomatic hyperleukocytosis, we typically reserve leukapheresis for patients with symptomatic hyperleukocytosis who must have induction chemotherapy postponed. Our preference to reserve leukapheresis for this selected patient population is primarily based upon the known risks associated with leukapheresis described below and an unclear benefit. Anecdotal reports have claimed dramatic responses but larger retrospective analyses have demonstrated conflicting effects on early mortality rates . Given the paucity of data concerning the efficacy of leukapheresis in reducing early mortality and/or improving overall survival, leukapheresis cannot be recommended for routine therapy as a form of tumor "debulking" in patients with high blast counts.

26. patients with symptomatic leukocytosis have an extremely high mortality rate without immediate therapy . When both respiratory failure and neurologic compromise are present, the death rate at one week reaches 90 percent . Therefore, if facilities are available, we suggest leukapheresis for patients with leukemic blast counts greater than 50 to 100 x 109/L (50 to 100,000/microL) and associated symptoms as a temporizing measure until chemotherapy can be initiated. It is difficult to predict the percent leukocyte count reduction in individual patients, but sessions are usually planned for four- to five-hour collections with repeat sessions as needed.

27. It is generally agreed that leukapheresis should NOT be used for patients with acute promyelocytic leukemia because it may worsen the intrinsic coagulopathy associated with this subtype of leukemia. Placement of large intravenous leukapheresis catheters in these patients has been associated with venous thrombosis or hemorrhage.

28. A small number of platelets are inevitably removed with the leukemic blasts, resulting in worsening thrombocytopenia. The effect is generally transient with WBC counts typically rebounding after leukapheresis is discontinued unless chemotherapy is begun. It is unclear whether leukapheresis can reverse vascular damage already sustained from leukostasis. In addition, symptomatic leukostasis can still develop after the WBC count has been lowered by leukapheresis.

29. Supportive care : •  The following supportive care measures should be considered for all patients with hyperleukocytosis: • Symptomatic leukostasis can be precipitated by increases in whole blood viscosity following red blood cell transfusions. Such transfusions should be withheld, if possible, until the blast count is reduced. If a transfusion is necessary, it should be given slowly, administering a single unit of red blood cells over a few hours, or during the leukapheresis procedure. • Hydration is encouraged and diuretics are discouraged. • Patients with hyperleukocytosis are at risk of tumor lysis syndrome (TLS), although this syndrome is less common in patients with AML than in those with ALL or Burkitt leukemia/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 of reversible renal failure.

30. Coagulation abnormalities, including disseminated intravascular coagulation (DIC), further increase the risk of local hemorrhage. Specific treatment aimed at the DIC should be considered. Patients should also receive prophylactic platelet transfusions to maintain a count of greater than 20 to 30,000/microL until the WBC count has been reduced and the clinical situation has been stabilized. The risk of intracranial hemorrhage is greatest after the 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. Thus, aggressive platelet support and correction of coagulopathy should continue for several weeks during the remission induction period. In addition, patients with leukostasis often require specialized, symptom-directed supportive care including mechanical ventilation for respiratory failure and/or stroke.

31. Is there a role for cranial irradiation?   Some centers advocate low dose cranial irradiation (eg, 400 cGy in a single fraction), in order to prevent further proliferation of leukemic cells in central nervous system sites. there are no comparative studies to determine whether the results with cranial irradiation are superior to those with chemotherapy alone, and we do not advocate the routine use of cranial irradiation in this setting. Nevertheless, it could be considered for patients with serious central nervous system symptoms related to leukostasis.

32. 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 presence of symptoms. 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 . If patients survive the initial period, they tend to have somewhat lower remission rates. Remission durations are also shorter, possibly because of a larger initial tumor mass, but more likely related to the biology and intrinsic chemotherapy resistance of the leukemia .

33. In patients with acute lymphoblastic leukemia (ALL), hyperleukocytosis is rarely complicated by leukostasis and the early death rate is less than 5 percent in childhood ALL . The challenge of leukostasis management in ALL involves preventing tumor lysis syndrome, disseminated intravascular coagulation, and the higher risk of relapse (approximately 50 percent by four years) .

34. SUMMARY

35. Hyperleukocytosis is a laboratory abnormality that has been variably defined as a total white blood cell (WBC) count greater than 50 x 109/L (50,000/microL) or 100 x 109/L (100,000/microL). leukostasis (also called symptomatic hyperleukocytosis) is a medical emergency that is most commonly seen in patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) in blast crisis and is characterized by an extremely elevated WBC count and symptoms of decreased tissue perfusion. The main clinical symptoms of leukostasis and causes of early death are related to involvement of the central nervous system and lungs. Clinically, leukostasis is diagnosed empirically when a patient with leukemia and a blast cell count over 50 to 100 x 109/L (100,000/microL) presents with respiratory or neurological distress. The initial management of a patient with hyperleukocytosis is directed at rapid lowering of the WBC count.

36. For patients with symptomatic or asymptomatic hyperleukocytosis, we suggest initial cytoreduction with induction chemotherapy rather than hydroxyurea  or leukapheresis For patients with asymptomatic hyperleukocytosis who must have induction chemotherapy delayed, we suggest cytoreduction with hydroxyurea  rather than leukapheresis . For patients with symptoms of leukostasis who must have induction chemotherapy delayed, we suggest initial leukapheresis in addition to hydroxyurea  (if possible) to lower or stabilize the WBC count .

37. Red blood cell transfusions should be withheld, if possible, until the blast count is reduced. If a transfusion is necessary, it should be administered slowly. Most patients with hyperleukocytosis are candidates for tumor lysis syndrome prophylaxis with aggressive intravenous hydration and allopurinol or rasburicase to decrease serum uric acid levels. Coagulation abnormalities require aggressive treatment with platelet transfusions and coagulation factors.

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