Profile and Outcome of Hyperleukocytosis in Childhood
Acute Lymphoblastic Leukemia: Experience From a Tertiary Center
in India
Rachna Seth,
Prashant Singh, Kriti Puri, Arushi Arora, Anurag S. Rathore
Rachna
Seth, Prashant Singh, Kriti Puri, Pediatric Oncology Division, Department of Pediatrics, All
India Institute of Medical Sciences, New Delhi, India
Arushi
Arora, Anurag S. Rathore,
Department of Chemical Engineering, Indian Institute of Technology, New Delhi,
India
Correspondence to:
Rachna Seth, Additional
Professor, Division of Pediatric Oncology, Department of Pediatrics,m All India Institute of Medical Sciences, New Delhi,
India.
Email: drrachnaseth@yahoo.co.in
Received: August 12, 2015
Revised: September 22, 2015
Accepted: September 26,
2015
Published online: October 22, 2015
ABSTRACT
Hyperleukocytosis is an important cause of morbidity and
mortality among acute leukemia patients. The data on hyperleukocytosis from
this part of world is scarce. We therefore retrospectively reviewed the
clinical and morbidity profile of childhood acute leukemia presenting with
total leucocyte count (TLC) >100,000 over a duration of about 2.5 years at
our center. Of 140 acute leukemia patients, 24 had hyperleukocytosis at
presentation. All 24 patients were of lymphoid lineage. The Mean TLC was
193539(+ 92078)/microlitre, and TLC was >200000/microlitre in 16(66.67%)
patients. Tumor lysis was present in 12(50%) patients, while superior
mediastinal syndrome was present in 4(16.67%). Features of leukostasis were
present in 6(25%) patients (2 had neurological involvement, 3 had pulmonary
involvement and 1 had features of both pulmonary & neurological stasis).
Renal functions were deranged in 5(20.83%) patients. Further, 11(45.8%)
patients had hemorrhagic complications. All 24 patients received hyper hydration,
sodium bicarbonate and allopurinol. Chemotherapy was initiated once
metabolically stable. One patient died during the first induction and four
relapsed during follow-up. Childhood acute leukemia with hyperleukocytosis is
associated with significant morbidity which can be managed with immediate
hospitalization, aggressive management with hyper hydration, allopurinol,
alkalinization of the urine and intensive monitoring before beginning
chemotherapy.
© 2015 ACT. All rights reserved.
Key words: Hyperleukocytosis;
ALL; Tumor lysis syndrome; Superior mediastinal sndrome
Seth R, Singh P, Puri K, Arora A, Rathore AS. Profile and
Outcome of Hyperleukocytosis in Childhood Acute Lymphoblastic Leukemia:
Experience From a Tertiary Center in India. International
Journal of Hematology Research 2015; 1(3): 90-94 Available from: URL:
http://www.ghrnet.org/index.php/ijhr/article/view/1290
INTRODUCTION
Hyperluekocytosis, an oncologic emergency is defined as peripheral
leukocyte count exceeding 100,000 per microlitre[1]. It forms a poor
prognostic marker for treatment outcome and is an important cause of morbidity
and mortality requiring aggressive management. Hyperleukocytosis is seen in
9-13% children with acute lymphoblastic leukemia (ALL); 5-22% children with
acute myeloid leukemia (AML) and almost all children with chronic myeloid
leukemia (CML) in chronic phase[2]. Clinically significant
hyperleukostasis occurs when the peripheral leukocyte count (WBC) count exceeds
2,00,000/microlitre in AML and greater than 3,00,000/mm3 in ALL
& CML[2,3]. MAmongst all hematological malignancies, it is more
common in infantile ALL and AML, T-cell ALL with mediastinal mass, hypodiploid
ALL and blast phase of CML. These patients are at risk for severe complications
from hyperviscosity of blood[2].
Many children
will be asymptomatic. However, children presenting with a WBC count greater
than 100,000 per microlitre should be evaluated for signs and symptoms of
leukostasis and the associated complications. The two organs most commonly
affected are the lungs and the brain and the symptomatology also reflects this[1,2].
The children may experience mental status disturbances, headaches, blurred
vision, seizures, coma and often resulting in a stroke like presentation,
papilledema or retinal artery or retinal vein distension[1-4]. The
pulmonary manifestations of leukostasis and hemorrhage include dyspnea,
cyanosis, hypoxia and acidosis[1,3]. Co-existent superior
mediastinal syndrome may mimic these symptoms[2]. Other symptoms of
hyperleukocytosis include gastrointestinal bleeds, priapism/clitoral
enlargement, hemopericardium or dactylitis[1-3]. Cerebral and
pulmonary hemorrhages worsen the symptoms of leukostasis. These complications
have mortality in the range of 40%, and require emergent treatment before
detailed leukemia work-up and referral. Early death in hyperleukostasis is due
to CNS hemorrhage or thrombosis, pulmonary leukostasis and metabolic
derangements including tumor lysis and renal insufficiency[2].
There is much
debate regarding the appropriate management of this medical emergency,
especially about the adequacy of conservative management, and the role of
cranial irradiation, exchange transfusion, leukopharesis, hydroxyurea and
induction chemotherapy, in isolation or combination.However therapy for
hyperleukostasis is tailored towards reduction of blood viscosity (hydration,
avoid transfusions & diuretics), alkalinisation of urine, allopurinol use
and chemotherapy should be started once the patient is metabolically stable[2].
There is little data, particularly from India, on the incidence, clinical and
morbidity profile in childhood ALL and hyperleukocytosis.
Our objective
was to study the clinical and morbidity profile of childhood acute leukemia
presenting with hyperleukocytosis being treated at the All India Institute of
Medical Sciences.
Definitions
Tumor lysis
syndrome (TLS) was
diagnosed using Cairo-Bishop criteria for diagnosis of TLS.5 Cairo-Bishop
definition of laboratory tumor lysis syndrome states that 2 or more of the
below mentioned criteria should be present, anytime 3 days before to 7 days
after starting the induction chemotherapy-
1. Uric acid
-4.76 mmol/L (8 mg/dl) or 25% increase from baseline
2. Potassium
-6.0 mmol/L (6mEq/L) or 25% increase from baseline
3. Phosphorous -2.1
mmol/L for children, (i.e. 6.5 mg/dl) or 1.45 mmol/L for adults (or 25%
increase from baseline)
4. Calcium
-1.75 mmol/L (8 mg/dl) or 25% decrease from baseline
Cairo-Bishop definition of
clinical tumor lysis syndrome (LTLS) states that the above mentioned criteria
plus any of the following criteria should be present-
1. Creatinine:
1.5 ULN (age adjusted)
2. Cardiac
arrhythmia/sudden death
3. Seizure
Superior mediastinal syndrome (SMS)/ Superior venecaval syndrome
(SVCS) was diagnosed clinically with tachypnea and/or respiratory distress,
stridor neck engorgement, facial fullness, snoring, difficulty in deglutition,
presence of mediastinal mass with tracheal narrowing confirmed with imaging[2,3].
Leukostasis in
acute leukemia
Pulmonary: Patient may have respiratory
distress, hypoxemia, and diffuse interstitial or alveolar infiltrate on chest
radiograph3 Normal chest radiographs in presence of respiratory distress and/or
hypoxia is also well recognized in pulmonary leukostasis.
Neurological: Symptoms include confusion,
somnolence, stupor, delirium, coma, headache, dizziness, tinnitus, gait
instability, blurred vision, diplopia and visual field defect. On
examination—papilledema, retinal vein distension, retinal hemorrhage,
occasionally cranial nerve defect and neck stiffness may be found[2-4].
Renal: Renal failure secondary to tumor
lysis, renal vein thrombos[2,6].
Coagulation defects: Thrombocytopenia disseminated
intravascular coagulation leading to bleeding from various sites e.g.
epistaxis, IV catheter, petechial haemorrhage, bleeding per rectum etc.
MATERIALS and METHODS
Retrospective review of case records of patients of acute leukemia with
total leucocyte count (TLC) greater than 100,000/microlitre presenting to the
Pediatric Oncology Clinics at the All India Institute of Medical Sciences, from
January 2009 to April 2011 were studied. Details of clinical symptoms and
physical examination were noted. Details regarding hemogram (total and
differential leukocyte count), morphologic characterization of blasts and flow
cytometric characterization of lineage were obtained for all patients.
Baseline chest
X ray was done to look for mediastinal mass and evidence of pulmonary stasis.
Serum biochemistry to monitor for tumor lysis (calcium, phosphate, potassium,
uric acid, urine pH), lactate dehydrogenase (LDH) was done in all. Prothrombin
time was done for possible coagulopathy and fundus examination was done for
papilledema/retinal hemorrhages. Urine output was monitored for all patients.
All children with hyperleukocytosis were admitted into the pediatric
wards. All received hyperhydration (3 liters/sq meter intravenous fluids) at
admission with allopurinol. Alkalinization of urine was done with
sodabicarbonate for all patients. All children were monitored according to a
hypoerlukocytosis monitoring chart. Details regarding respiratory rate,
distress, oxygen requirement, pulmonary bleed, tachycardia, change in rhythm.
The TLC in all children was monitored twice daily, fluid therapy was modified,
blood component therapy given to target a hemoglobin of not greater than 6 g/dl
when hemodyanamically stable and platelet count of atleast 20,000/cubic mm and
urine pH monitoring was done for all.
Chemotherapy
was started after intravenous hydration was initiated, there were no
complications with normal renal parameters and child was metabolically stable
with no evidence of septicemia. WBC count, serum electrolytes and renal
function were done 12 hourly.
The morbidity profile is described
and data analyzed to identify adverse events which include mortality or
morbidity in the form of features of leukostasis, coagulopthy, bleeding etc.
Data was collected and analyzed using JMP software from SAS. Data was
pretreated before analysis. Categorical variables were assigned a numerical
value for each category. Continuous variables were examined for any outliers or
any other possible mistakes in data gathering. The software is capable of
handling missing data. After pretreatment was over, the data was analyzed to
correlate the various response variables (hemorrhagic complications, TLS etc)
to the various input variables (age, LDH, TLC etc). The regression coefficient
(R2) was used for evaluating the quality of the statistical model. A
R2> 0.8 was considered acceptable for this study. When
identifying the parameters that have the significant impact on a given
response, those that had p value < 0.05 were considered as relevant.
RESULTS
140 patients were diagnosed with acute leukemia (109 ALL and 31 AML) in
the study duration. 24 of these (19 males, 79.2%) had hyperleukocytosis at
presentation. Mean (±s.d.) age was 7.7 years (±3.3 years). No patient was younger than 1 year, while 8 patients
(33.3%) were older than 10 years. B-ALL accounted for 13 cases (54.2%), while
T-ALL was found in 9 (37.5%), and 2 patients could not be typed. (Table 1)
Mean TLC (±s.d.) was 193539 (±92,078)/microlitre, and TLC was
>200,000/microlitre in 16 (66.67%) patients (Table 1). Mean hemoglobin
concentration was 6.8 (±2) gm/dL. Mean platelet count was
45,826(±27,925)/microlitre. All patients
had thrombocytopenia. 7 (29.17%) patients had platelets 25000 to 50,000, while
another 7 (29.17%) patients had platelets < 25,000. LDH values were
available for 16 patients. Mean LDH was 1,140.6 (+1,014.6) U/dL, and 7 (29.17%)
patients had LDH >1000.Blasts in the CSF were present in one patient. SMS
was present in 4 patients (16.7%).
At the time of
presentation, renal functions were deranged in 5 patients (20.83%). These 5
patients also had tumor lysis syndrome at presentation. One patient in addition
to tumor lysis syndrome also had bilateral renal parenchymal disease with
bilateral mild hydronephrosis.
Nine patients
had significant respiratory symptoms like dyspnea and/or hypoxia at the time of
presentation. Out of these 4 patients (16.7%) had SMS. SMS was significantly
more common in T-ALL patients (p value-0.003). All the four patients
with SMS also had pericardial effusion and 3 out of these four had concurrent
pleural effusion. In addition to these four patients, one other patient also
had pericardial effusion. Resultantly, four patients (16.7%) had pulmonary
symptoms that could be definitely attributed to leukostasis.
Three patients
presented with CNS symptoms (headache, altered sensorium and blurred vision).
All three were found to have hemorrhagic stroke on evaluation. All the 3
patients had platelet counts of more than 25,000. One out of these 3 patients
also had features of pulomonaryleukostasis. Features of leukostasis therefore
were present in 6 (25%) patients (2 had neurological involvement, 3 had pulmonary
involvement and 1 patient had features of both pulmonary & neurological
stasis). These were significantly more common in patients with T-ALL (p=0.024).
Eleven
patients (45.83%) had hemorrhagic complications, including petechiae,
epistaxis, gum bleeds, melena, and stroke. Male patients (p=0.0048),
those older than 10 years of age (p=0.0008), and those with T-ALL (p=0.0005)
had greater incidence of hemorrhagic complications. It was also seen that
higher TLC (> 2,00,000/cumm) and T lineage in combination were associated
with higher incidence of hemorrhagic complications (p=0.0004)
All 24
patients received hyperhydration (2-3times maintenance) and sodium bicarbonate.
Uniform chemotherapy comprising 4 drug induction was started for all. 9 (37.5%)
patients required ICU admission and intensive monitoring.
Tumor lysis
syndrome was encountered in 12 (50%) patients. Notably, the incidence of tumor
lysis syndrome was significantly greater in children with TLC greater than
200,000 per cu mm, as compared to those with TLC>100,000 per cu mm.
One patient died
during the first induction, due to tumor lysis syndrome and subsequent
cardiorespiratory arrest.
On follow up,
7 (29.17%) patients suffered adverse events of relapse or death during
follow-up, before completion of chemotherapy course. Of the 3 deaths, two
patients died during episode of febrile neutropenia during maintenance, while
one died of tubercular meningitis. Four patients relapsed, of whom one is
currently in remission, one is scheduled for transplant, and two patients
declined further therapy. Leukostatic symptoms at presentation (p<0.0001)
and hepatomegaly more than 5cm below costal margin (p=0.0009) were
associated with significantly greater risk of relapse.
DISCUSSION
In our retrospective study, we found around 17% prevalence of
hyperleukocytosis in acute leukemia patients. It has been previously reported
in 5-30% of the cases of acute leukemia, and in 10-30% of the cases of ALL[1,7].
Our prevalence of 17.1% is concordant, however all of the patients with
hyperleukocytosis in our study had ALL.
Hyperleukocytosis has been reported more commonly in infants, males, and
those with T-ALL[7,8]. We found age greater than 10 years, male sex
and T-ALL to be a potential predictor for occurrence of symptoms of
hyperleukocytosis i.e. hemorrhage and T-ALL alone for SMS and leukostasis,
hence signifying a greater need for aggressive leucoreduction in these subsets.
ALL with
hyperleukocytosis commonly presents with metabolic derangements (including
tumor lysis syndrome) or disseminated intravascular coagulation, rather than
leukostasis symptoms[7]. These complications have mortality in the
range of 40%, and require emergent treatment, before detailed leukemia work-up
and referral[7].
In a study on
178 ALL patients with hyperleukocytosis, Lowe et al (2005) found renal
derangements in 5% (9/178) of the patients, with about half of these (4
patients, 2.2%) requiring dialysis[9]. In a previous study on an
Indian pediatric ALL population, Basade et al found deranged kidney function in
44% (5 of 9 patients)[10]. We encountered a lower percentage of
renally impaired patients, and none require dialysis.
Neurological
complications were present in 9% (16 of 178) of Lowe et al’s study population,
which is lower than in our study[9]. Older age and higher WBC count
emerged as significant prognostic indicators of neurological complications,
however we did not find any such association.
Lowe et al
found pulmonary symptoms in only 6% of their patients, with a significantly
increased risk in patients with higher WBC count[9]. Three of these
patients required mechanical ventilation[9]. While we found a
comparable occurrence of 8.3% (2/24) of our patients, we did not find any
prognostic or predicative factor.
Hemorrhagic
phenomena were the most common complication of hyperleukocytosis in our study.
Platelet counts were between 10,000 and 20000 in 5 of these patients, while the
remaining 3 had platelet counts more than 40,000 per cu mm. Their greater
occurrence in male patients, those older than 10 years of age, and those with
T-ALL is in concordance with the poorer prognosis associated with these
characteristics.
The management
of hyperleukostasis hinges on the two critical pegs of leucoreduction and
supportive fluid and electrolyte management. In their recent review, Ganzel et
al (2012) discuss the various strategies to prevent complications in these
patients[1]. Leukopharesis and exchange transfusion are propounded
as faster methods to decrease WBC count in hyperleukocytosis[1,9,11,12].
They are able to reduce WBC counts by 25-50% while also preventing electrolyte
imbalances and permitting further blood product support. However, they are
encumbered by their invasive nature and risk of complications, more
time-consuming, and greater financial and infrastructural cost. Further, there
is no unequivocal evidence supporting the efficacy of these aggressive
measures, as most of the complications and adverse events occur at presentation,
before any therapy can be instituted[7].
Our patients
were all managed with aggressive hydration, alkalinisation of urine, and
allopurinol administration, along with cytoreduction by induction chemotherapy.
There was one mortality during the initial induction phase (4.2%). Previously,
many researchers including Lowe et al, Castagnetti et al (2008),
Nelson et al (1997) and Basade et al (1995), have found conservative
cytoreduction to yield effective decline in WBC count and prevention of
leukostatic or hemorrhagic complications[9,10,13,14].
Hyperleucocytosis in leukemia is often complicated by tumor lysis characterized by elevation of
serum potassium, phosphorus, and uric acid levels and potentially by decline in
calcium levels. Prevention strategies include hydration and prophylactic
allopurinol.Prompt measures to reduce serum uric acid to prevent uric acid
nephropathy are required.
Hyperuricemia can lead to acute renal damage or even failure and should be treated
with allopurinol or rasburicase depending on the uric acid levels. Established
TLS is managed with the addition of aggressive hydration and diuresis, plus
allopurinol or rasburicase for hyperuricemia. Additionally, electrolyte
imbalances should be corrected. Whereas allopurinol is the less expensive
therapy for hyperuricemia, it only prevents the synthesis of new uric acid. In
cases with marked hyperuricemia and TLS, rasburicase (urate oxidase)
effectively lowers uric acid levels by enzymatic degradation, even after a
single and low-dose application[15]. The best management of TLS is
prevention. Prevention strategies include hydration and prophylactic
rasburicase in high-risk patients, hydration plus allopurinol or rasburicase
for intermediate-risk patients, and close monitoring for low-risk patients.
Primary management of established TLS involves similar recommendations, with
the addition of aggressive hydration and diuresis, plus allopurinol or
rasburicase for hyperuricemia[16]. The use of sodium bicarbonate to
alkalinize the urine had historically been recommended as part of TLS
prevention and management strategies (eg, when using allopurinol). However, it
is not recommended with the use of recombinant urate oxidase (rasburicase).
Considering the potential complications associated with alkalinization, such as
metabolic alkalosis and calcium phosphate precipitation, and the lack of clear
evidence demonstrating benefit, the use of sodium bicarbonate for the
prevention and treatment of TLS is currently not recommended[17,18].
In more recent
developments, Ozdemir et al (2009) studied the role of continuous
low-dose prednisone (6mg/m2/24h) infusion in leukocytoreduction in
their randomized control trial on 15 ALL pediatric patients with
hyperleukocytosis[19]. None of the patients developed metabolic or
leukostatic complications, suggesting a potential therapy at centers where
pharesis and exchange transfusion facilities may not be easily available. Liang (2011) studied the role of low dose
chemotherapy in preventing tumor lysis syndrome in patients with
hyperleucocytic acute leukemia[20]. Patients were treated with
etoposide and cytosine arabinoside at half-doses to reduce WBC count before
administering standard induction therapy.
We have found
male sex, age>10years, WBC count >200,000/cu mm and T-ALL as significant
factors for prognosis and monitoring in hyperleukocytic acute leukemia
patients. In a resource-limited setting, these may allow risk stratification,
with more frequent monitoring and prioritizing for more aggressive methods of
cytoreduction.
CONFLICT
OF INTERESTS
The authors have no conflicts of
interest to declare.
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Peer reviewer: Der-Cherng Liang, Professor, Division of Pediatric
Hematology-Oncology, Mackay Memorial Hospital, 92, Sec.2, Chung San N. Rd.,Taipei, 10449, Taiwan.
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