Indian J Pediatr (February 2013) 80(2):144–148 DOI 10.1007/s12098-012-0917-3
SYMPOSIUM ON PGIMER MANAGEMENT PROTOCOLS ON ONCOLOGICAL EMERGENCIES
Hyperleukocytosis: Emergency Management Richa Jain & Deepak Bansal & R. K. Marwaha
Received: 9 March 2012 / Accepted: 26 October 2012 / Published online: 24 November 2012 # Dr. K C Chaudhuri Foundation 2012
Abstract Hyperleukocytosis is defined as peripheral blood leukocyte count exceeding 100,000/mm3. Acute leukemia is the most common etiology in pediatric practice. Hyperleukocytosis is a medical emergency. The increased blood viscosity, secondary to high white cell count and leukocyte aggregates, results in stasis in the smaller blood vessels. This predisposes to neurological, pulmonary or gastrointestinal complications. In addition, patients are at risk for tumor lysis syndrome due to the increased tumor burden. Initial management includes aggressive hydration, prevention of tumor lysis syndrome, and correction of metabolic abnormalities. A red cell transfusion is not indicated in a hemodynamically stable child, as it adversely affects the blood viscosity. Leukapheresis is the treatment of choice for a very high count, or in patients with symptomatic hyperleukocytosis. The technical expertise required, a relative difficult venous access in younger children, risk of anticoagulation and possible non-availability of the procedure in emergency hours are limitations of leukapheresis. However, it is a rewarding procedure and performed with relative ease in centers that perform the procedure frequently. An exchange transfusion is often a practical option when hyperleukocytosis is complicated with severe anemia. The partial exchange aids in correcting both, without the risk of volume overload or hyperviscosity, which are the limitations of hydration and blood transfusion, respectively. Etiology and management of hyperleukocytosis in relevance to the pediatric emergency room is outlined.
R. Jain : D. Bansal (*) : R. K. Marwaha Hematology/Oncology Unit, Department of Pediatrics, Advanced Pediatrics Center, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India e-mail:
[email protected]
Keywords Acute lymphoblastic leukemia . ALL . CML . Hydration . India . Leukostasis . Priapism
Introduction Hyperleukocytosis is defined as peripheral blood leukocyte count exceeding 100,000/mm3 [1]. It typically occurs in hematological malignancies, including acute lymphoblastic leukemia(ALL), particularly T-cell ALL, infant ALL or hypodiploid ALL, and acute myeloid leukemia (AML). Chronic myeloid leukemia, especially in blast crisis may present with hyperleukocytosis [2]. Hyperleukocytosis complicates the course of leukemia in 5–22 % children [3, 4].
Differential Diagnosis Hyperleukocytosis should be differentiated from leukemoid reaction, when a high total leukocyte count (TLC) (typically >50,000/mm3) occurs in the presence of non-malignant disorders. It is observed in certain infections, including pertussis, staphylococcus aureus, Pneumococcus, tuberculosis and varied inflammatory conditions [5, 6]. Generally, the counts do not exceed 100,000/mm3. The predominant cells are mature lymphocytes and granulocytes. Differentiation can be done through history, examination and peripheral smear examination. A high number of nucleated RBCs (nRBC) in blood can also raise the TLC erroneously, especially when a counter is used. This is commonly observed in patients with thalassemia major and in neonates. The counter generates a raised value of TLC, as the nRBC’s are spuriously counted as leucocytes. The TLC generally is less than 100,000/mm3. Here again, the examination of peripheral smear will confirm the presence of nRBC’s, and a corrected TLC can be calculated.
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Complications of Hyperleukocytosis Hyperleukocytosis is an emergency as it may cause several complications, resulting in morbidity or mortality. Vascular obstruction can occur, leading to organ damage from tissue hypoxia, thrombosis or hemorrhage. Metabolic derangements are common due to high blast count. The most commonly affected organs are central nervous system (CNS) and the lungs [2, 7, 8]. A CNS bleed, leukostasis or thrombosis, either independently or in combination, can cause CNS symptoms. Manifestations include irritability, altered sensorium, seizures, focal neurological deficits and raised intracranial pressure. Pulmonary leukostasis may result in hypoxia, respiratory distress and can require respiratory support. Chest radiograph may show presence of diffuse infiltrates. Other organ systems can also be involved. Gastrointestinal hemorrhage may occur, resulting in bleed, hematemesis or pain abdomen. Priapism, clitoral engorgement and dactylitis are the rarer manifestations of leukostasis. An important complication relating to the high tumor burden in patients with hyperleukocytosis is the tumor lysis syndrome (TLS). TLS may present with isolated lab derangement, including hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia or with associated clinical symptoms, including oliguria or anuria, seizures, altered sensorium ranging from irritability and confusion to frank coma [9]. The most common time for TLS to occur is within 2–3 d following the initiation of chemotherapy, however spontaneous TLS may occur in the absence of any therapy.
Pathophysiology Two potential mechanisms have been suggested to explain the complications caused by hyperleukocytosis. According to the traditional explanation, there is an increase in blood viscosity, secondary to high TLC and leukocyte aggregates, resulting in stasis in the smaller blood vessels. The second proposed mechanism is of adhesive interactions between the damaged endothelium of the vessel and leukemic blasts, precipitating leukostasis. The toxins and cytokines released by the vascular endothelium exacerbate the situation [1, 2]. Clinically significant hyperleukocytosis usually occurs in the presence of a TLC exceeding 300,000/mm3 in ALL, and more than 200,000/mm3 in AML. However, several factors may result in symptoms at a lower TLC. These include severe anemia, thrombocytopenia, renal dysfunction, superimposed infection, dehydration and acidosis. The CNS events and pulmonary leukostasis are more common in children with AML, while TLS is observed with a higher frequency in ALL [9–11]. In an analysis of 234 children with hyperleukocytosis from St Jude hospital, 19 % of children with AML had hemorrhagic complications,
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including intracranial or pulmonary bleeds, vs. 2.5 % with ALL [10]. Metabolic complications occurred more frequently in patients with ALL than AML. The early mortality was significantly higher in children with AML than ALL [10]. This difference is likely due to the larger size of blasts in AML, along with increased adhesiveness. Larger myeloblasts do not circulate freely in capillaries and small blood vessels, leading to sequestration and vascular damage. The symptoms may be more pronounced, and occur at lower TLC in children with monocytic leukemia, where the blasts have a higher propensity for adhesiveness and tissue invasion [12].
Investigations Complete blood count with examination of peripheral smear is the initial investigation in a patient with suspected leukemia, and this would reveal the diagnosis of hyperleukocytosis as well. It is a good practice to communicate directly with the pathologist to ensure a timely and reliable report. It is often possible for the pathologist to comment on the likely possibility of AML vs. ALL from examination of the peripheral smear, including cytochemical stains. All children, once diagnosed with hyperleukocytosis, should be evaluated for the attendant complications. Most importantly, they should be screened for TLS. Serum electrolytes (including sodium, potassium, calcium, phosphate) along with renal functions and uric acid should be requested immediately. A coagulogram should be performed as disseminated intravascular coagulation may be observed in AML; association increases the chances of hemorrhage. A blood gas analysis should be done to look for acidosis. A chest radiograph may reveal a mediastinal mass suggesting possibility of T cell-ALL, and pulmonary infiltrates in case of leukostasis or infection. Blood samples for uric acid and blood gas should be transported on ice, and analyzed early, as the high TLC may result in false lowering of uric acid and hypoxemia.
Management Initial management is directed towards aggressive hydration, use of allopurinol for prevention of TLS, and prevention or correction of metabolic abnormalities. The definitive management involves reduction of the tumor load by chemotherapy. An outline of management is illustrated in Fig. 1. Fluids All patients should be initiated on continuous intravenous hydration with potassium and calcium free fluids (N/2 or N/ 4 5 % Dextrose is appropriate), 2–4 times of normal
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Indian J Pediatr (February 2013) 80(2):144–148 Hyperleukocytosis
• • • •
Send tumor lysis work up, coagulogram, chest X-ray, blood gas Obtain EDTA sample for cross match Establish IV access; start potassium and calcium free fluids Start Allopurinol (250-500 mg/m2/d)
Symptomatic leukostasis or TLC > 200-300 x 10 3 /µ L
Asymptomatic No pulmonary or CNS stasis, no bleeds
Hb >6-7g%
Hb >6-7 g% Severe anemia with impending congestive cardiac failure (Hb 2–3 lakh), or in patients with symptomatic hyperleukocytosis [15]. It is the removal of circulating leukocytes from the blood and re-infusion of the leukodepleted blood. A single leukapheresis decreases the TLC by 20–50 %. Most patients require a single procedure; rarely more than two procedures are necessary [8, 16]. The difficult venous access in younger children, technical difficulty of the procedure in small children, particularly those less than 15 kg, risk of anticoagulation, inadequate experience and nonavailability of the procedure in emergency hours are the limitations. Exchange transfusion can be done with fresh whole blood or with a mix of packed red blood cells and plasma (in a ratio of 2– 3:1), with platelet supplementation. Recommended volume varies from 70 to 150 mL/kg, with an aim to reduce the blasts by at least 50 % [17, 18]. It is a safe procedure even in neonates or infants with hyperleukocytosis, and in neonates can be performed through the umbilical catheterization [19]. It is particularly beneficial when hyperleukocytosis is accompanied with severe anemia. The partial exchange aids in correcting both, without the risk for volume overload or hyperviscosity, which are the limitations of hydration and blood transfusion, respectively. In the authors experience, a partial exchange with ~2 bags of whole or reconstituted blood in a child weighing 15– 25 kg, corrects the anemia safely, following which aggressive hydration can be instituted. There has been no head to head comparison between exchange transfusion and leukapheresis on efficacy and safety. However, there is data to suggest that both the procedures may be equally efficacious in reducing the TLC, with a mean reduction in TLC of 50–60 % with either. The choice between the two would depend on the clinical scenario, with age, weight, ease of procedure and availability of equipment being some of the deciding factors [18]. In the authors’ institute, leukapheresis is increasingly preferred, in parallel with the increasing expertise and experience of the transfusion medicine services. Chemotherapy It is important to remember that leukapheresis or exchange transfusion is not the definitive therapy. They are temporary measures, which aid in stabilizing the patient, while establishing diagnosis and initiating chemotherapy. Chemotherapy must be initiated as early as possible. However, starting regular dose, multi-agent chemotherapy in patients with hyperleukocytosis may result in life-threatening metabolic derangements and TLS. This is particularly true for
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children with ALL, who have a high risk of TLS, and may develop renal shut down necessitating dialysis, with full dose chemotherapy given upfront. In patients with AML, on the other hand, regular chemotherapy can often be administered even with a high TLC, as the metabolic complications are less common. Lower doses of steroids alone may be given to children with ALL, while continuing hyper-hydration and other measures for control of hyperleukocytosis. In a study of 15 children with ALL and hyperleukocytosis, intravenous prednisone started at a low dose and gradually escalated over 5 d to full dose, led to significant reduction in TLC by day 3, without developing severe metabolic complications [20]. In authors experience, 2–3 d of steroids in patients with ALL as a single agent chemotherapy along with aggressive fluid therapy, as against initiation of multi-agent chemotherapy, is often successful in preventing TLS. Monitoring forms an integral part of management of a child with hyperleukocytosis. Clinical as well as lab parameters should be recorded. Vitals should be monitored frequently (q 3–4 hourly). Monitoring includes observation for respiratory distress and any hemodynamic instability which may indicate a bleed or congestive cardiac failure. Sensorium should be evaluated periodically as the earliest manifestations of a CNS event are generally headache or persistent vomiting. Adequate fluid intake and urine output (2–4 ml/kg/h) should be ensured. Urinary catheterization is not recommended in a conscious and hemodynamically stable child. It leads to unnecessary discomfort and increases the risk of infection. Lab monitoring includes daily or more frequent complete blood counts, and evaluation for TLS (serum electrolytes including K, Ca, iP, uric acid, urea and creatinine) every 8–12 hourly. Coagulogram should be repeated if initially deranged.
Indian Experience In a study from Delhi, Arya et al reported 38 % of patients with T-cell ALL to have hyperleukocytosis; the survival of Tcell ALL was equivalent to B-lineage ALL [21]. The incidence of hyperleukocytosis was 11 % in children with ALL in a study from Tata Memorial Hospital, Mumbai; leucocyte count at diagnosis did not affect the incidence of off therapy relapses [22]. Another study from the same center however reported a high TLC (>60,000/mm3) to be a poor prognostic marker in children with ALL [23]. From the authors center, hyperleukocytosis was documented in 111 (14.6 %) of 762 patients [24]. Significant lymphadenopathy (45 %), mediastinal adenopathy (26 %) and superior vena cava-obstruction (9 %) were accompanying clinical features. TLS was observed in 33 % and CNS complications (altered sensorium, raised intracranial pressure, stroke or intracranial hemorrhage) in 19 %. The estimated mean survival for the entire cohort was significantly inferior to that of other ALL patients [24]. With
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Indian J Pediatr (February 2013) 80(2):144–148
improved supportive care and risk-stratified chemotherapy the outcome is very likely to improve in the future. Conflicts of Interest None.
Role of Funding Source
None.
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