374 Original Article
Leukapheresis and Exchange Transfusion in Children
with Acute Leukemia and Hyperleukocytosis. A Single
Center Experience
Erfahrungen mit Leukapherese und Austauschtransfusion in der Behandlung
hyperleukozytärer akuter Leukämien im Kindesalter
Authors
Affiliation
Key words
●▶ hyperleukocytosis
●▶ leukapheresis
●▶ exchange transfusion
●▶ tumor lysis syndrome
Schlüsselwörter
●▶ Hyperleukozytose
●▶ Leukapherese
●▶ Austauschtransfusion
●▶ Leukostase
●▶ Tumor-Lyse-Syndrom
Bibliography
DOI 10.1055/s-0029-1239533
Klin Padiatr 2009; 221: 374–378
© Georg Thieme Verlag KG
Stuttgart · New York t
ISSN 0300-8630
Correspondence
Dr. Roland Haase
Martin-Luther-Universität
Halle-Wittenberg
Klinik für Kinder- und
Jugendmedizin
Ernst-Grube-Straße 40
06097 Halle/Saale
Germany
Tel.: +49/345/557 2484
Fax: +49/345/557 2650
roland.haase@
medizin.uni-halle.de
Haase R et al. Leukapheresis and Exchange Transfusion in Children … Klin Padiatr 2009; 221: 374–378
R. Haase, N. Merkel, O. Diwan, K. Elsner, C. M. Kramm
Klinik für Kinder- und Jugendmedizin, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany
Abstract
& &
Background: The risk of severe complications
or death during the initial period of acute leuke-
mia was markedly decreased due to the progress
in pediatric oncology and use of simple measures
like hyperhydration, forced diuresis, treatment of
hyperuricemia, correction of electrolyte and coa-
gulation disturbances and the careful use of anti-
leukemic drugs. The incidence of leukostasis and
tumor lysis syndrome depends on absolute initial
white blood cell counts and the underlying type of
leukemia. Leukapheresis or exchange transfusion
may improve the prognosis of high risk patients.
Methods: Records of all pediatric patients who
were newly diagnosed with acute leukemia bet-
ween 1/1998 und 12/2008 were retrospective-
ly reviewed for presence of hyperleukocytosis
(white blood cell count > 100 GPT/l) at diagno-
sis and subsequent leukapheresis or exchange
transfusion in regards to the clinical outcome.
Results: At diagnosis 11 (14 %) of 77 children
with acute leukemia (7 acute lymphoblastic
leukemia/ALL; 4 acute myeloblastic leukemia/
AML) had hyperleukocytosis. 4 patients (2 ALL, 2
AML) received exchange transfusion and 2 others
(1 ALL, 1 AML) underwent leukapheresis. Mar-
ked cytoreduction was achieved in all patients
within 24 h after therapy initiation. There were
no procedure-related adverse events. Symptoms
due to hyperleukocytosis markedly improved af-
ter cytoreduction.
Conclusion: Leukapheresis or exchange trans-
fusion together with conservative management
and specific oncological therapy may contribute
to rapid leukocyte reduction with acceptable
risk. The exact impact of leukapheresis or ex-
change transfusion on short and long term out-
come in pediatric patients with acute leukemia
and initial hyperleukocytosis has to be evaluated
in future multicentre studies or by the formation
of clinical registries.
Zusammenfassung
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Hintergrund: Das Risiko, in der Initialphase
akuter Leukämien zu versterben bzw. schwere
Komplikationen zu erleiden, hat sich durch Fort-
schritte der pädiatrischen Onkologie, aber auch
durch die konsequente Anwendung protektiver
Maßnahmen wie Hyperhydratation, forcierte
Diurese, Senkung des Harnsäurespiegels und die
Korrektur von Elektrolyt- und Gerinnungsstö-
rungen signifikant vermindert. Die Inzidenz von
Tumorlyse- und Leukostasesyndrom ist mit der
absoluten Zellzahl und dem Leukämietyp asso-
ziiert. Bei Patienten mit hohem Risiko kann ein
vorgeschaltetes mechanisches Verfahren zur
Zytoreduktion zur Verminderung der Leukämie-
zellen und möglicherweise zu einer Verbesse-
rung der Prognose führen.
Patienten: Monoinstitutionell wurden an
einem pädiatrisch-onkologischen Zentrum alle
pädiatrischen Patienten, die zwischen 1/1998
und 12/2008 an einer neudiagnostizierten aku-
ten Leukämie erkankten, retrospektiv hinsicht-
lich des akuten klinischen Verlaufs bei Auftretens
einer Hyperleukozytose (Leukozyten >100 GPT/I)
und Anwendung mechanischer zytoreduktiver
Verfahren untersucht.
Ergebnisse: Bei 11 (14 %) der 77 im Unter-
suchungszeitraum behandelten pädiatrischer
Patienten mit neu diagnostizierter akuter Leu-
kämie (7 Akute Lymphatische Leukämie/ALL; 4
Akute Myeloische Leukämie/AML) bestand zum
Diagnosezeitpunkt eine Hyperleukozytose. Bei 4
Kindern (2 ALL, 2 AML) wurde eine Austausch-
transfusion, bei 2 weiteren (1 ALL, 1 AML) eine
Leukapherese vorgenommen. Bei allen Patienten
mit mechanischer Zytoreduktion wurde eine
Zellzahlreduktion innerhalb von 24 Stunden
nach Therapiebeginn erreicht. Therapie assozi-
ierte Komplikationen traten nicht auf, Hyperleu-
kozytose bedingte Probleme waren im Verlauf
rückläufig. Blastenreduktion bei vertretbarem
 Original Article 375

Risiko beitragen. Inwieweit die Patienten kurz- oder auch lang-

fristig von zytoreduktiven Verfahren profitieren, kann nur in
multizentrischen Studien oder über Studien übergreifende kli-
nische Register geklärt werden.

Introduction
& traindications for rasburicase treatment, allopurinol was applied
At diagnosis, 5–22 % of children with acute leukemia present
with hyperleukocytosis (HL; > 100 000 cells/mm3) [18]. These
patients bear an increased risk of leukostasis syndrome (LSS),
tumor lysis syndrome (TLS), and death [9, 10, 17]. Guidelines for
prophylaxis and treatment of these complications are given in
several treatment protocols of the Society of Pediatric Oncology
and Hematology (GPOH) in Germany, Austria, and Switzerland
[1, 2, 16]. Patients with HL require strict clinical monitoring but
no obligatory admission to a pediatric intensive care unit (PICU).
Admission to PICU is only indicated in case of life threatening
complications due to underlying disease or treatment or perfor-
mance of potentially riskful cytoreductive procedures like leu-
for titering of urine pH). However, before 2004 or in case of con-
instead. Platelets were given at platelet counts < 50 000/mm3. To
avoid additional increase of blood viscosity a hematocrit of 20 to
25 % was accepted in hemodynamically stable patients. All blood
products were leukocyte-depleted, irradiated with 25–30 Gy,
and from cytomegalovirus-negative donors. Patients with signs
of infection were empirically treated with intravenous piperacil-
lin and sulbactam.
Chemotherapy
In addition to cytoreductive procedures all patients received
chemotherapy according to the corresponding treatment proto-
cols for acute leukemia (●
▶ Table 2).

kapheresis (LA) or exchange transfusion (ET). Although LA and

Leukapheresis

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ET have been issues of several reports, their therapeutic efficacy
still has to be established in pediatric patients. Thus, the present
report summarizes a single centre experience with LA/ET in
children with acute leukaemia and hyperleukocytosis.
Patients and Methods
& mia calcium was not administered as in routine leukapheresis.
The charts of all pediatric patients with newly diagnosed acute
leukemia who had been admitted at our institution between Ja-
nuary 1998 and December 2008 were reviewed retrospectively
for HL (defined as leukocyte count > 100 000/mm3) at diagnosis.
Characteristics of patients with HL are given in ●
▶ Table 1.
Routine supportive therapy and monitoring
Continuous cardiovascular and respiratory monitoring was
mandatory for all patients. All children received intravenous hy-
perhydration [3 000–5 000 ml/m2/day]. Creatinine, uric acid, cal-
cium, potassium, and phosphate serum levels as well as blood
coagulation tests were closely monitored. To increase solubility
and renal clearance of uric acid and calcium phosphate a urinary
pH > 7.0 and ≤ 7.5 was adjusted with sodium bicarbonate. For
treatment of hyperuricemia rasburicase was preferentially used
since 2004 (these patients did not receive sodium bicarbonate
Leukapheresis. was performed with a continuous-flow blood
cell separator (COBE Spectra PMN manual program, COBE Inc.,
Munich, Germany) via a Sheldon catheter. For anticoagulation
acid citrate dextrose was used at a ratio of 1:12. The aim was a
marked reduction of leukocytes, preferentially to a
count < 100 000/mm3. In order to reduce the risk of hypercalce-
Complete blood cell counts, serum electrolytes, and coagulation
tests were determined one hour before and then every hour du-
ring leukapheresis.
Exchange transfusion
Exchange transfusion was manually performed by aspiration
and subsequent substitution of red packed cells (RPC) and fresh
frozen plasma (FFP) via central venous or arterial access. The fol-
lowing recommendations of the ALL-BFM 2000 treatment proto-
col were followed in general: Exchange volume of 100–150 ml/kg
body weight divided into single portions of 10–50 ml accompa-
nied by substitution of RPC and FFP in a ratio of 2(-3): 1, to be
adapted to the current clinical and hemodynamic situation of
the patient. The aim was a reduction of blasts by at least 50 %
and/or a leukocyte count < 100 000/mm3.

Table 1 Patients characteristics.

No Age/Sex Bodyweight Diagnosis Cytoreductive Leukocyte count at Complications

(kg) procedure diagnosis (103/mm3)
1 14y/m 53 AML LA 302 retinal bleeding, coagulation disturbance
2 15y/m 57 A LL LA 527 mediastinal mass, beginning respiratory insufficiency,
coagulation disturbance
3 2mo/m 5.4 A LL AT 861 respiratory insufficiency, hypovolemic shock
4 2mo/f 5.6 AML AT 290 renal insufficiency, beginning respiratory insufficiency, DIC
5 4mo/m 6 A LL AT 723 coagulation disturbance
6 4y/f 16.5 AML AT 318 renal insufficiency, coagulation disturbance
7 2.5y/m 13.9 A LL – 115 –
8 8y/m 39 A LL – 115 –
9 11y/m 51 A LL – 136 –
10 12y/m 45 A LL – 136 –
11 2y/f 12.7 AML – 152 –

Haase R et al. Leukapheresis and Exchange Transfusion in Children … Klin Padiatr 2009; 221: 374–378
376 Original Article

Table 2 Patients with hyperleukocytosis and cytoreductive procedure.

Patient 1 2 3 4 5 6
leukocyte count 302 527.4 861 290 722.7 318
at diagnosis
(103/mm3)
procedure LA (4 × ) LA (4 × ) ET (3 × ) ET (1 × ) ET (1 × ) ET (2 × )
procedure details proceeded volume proceeded volume exchange volume exchange exchange vo- exchange volume
3 300–5 900 ml, 10 500–11 000 ml, 500–650 ml, leu- volume 992 ml, lume 2 025 ml, 2 270 and 500 ml, leu-
leukocyte reduction leukocyte reduc- kocyte reduction leukocyte leukocyte kocyte reduction to 21
to 72, 74, 69 tion to 73, 71, 95 to 40, 41 and 39 % reduction to reduction to and 74 % of the corre-
and 75 % of the and 91 % of the of the correspon- 29 % of the basic 10 % of the sponding basic value,
corresponding basic corresponding ba- ding basic value, value, leukocyte basic value, leukocyte count after
value, leukocyte sic value, leukocyte leukocyte count count after ET leukocyte first ET 68 000/mm3
count after last LA count after last LA after last ET 85 200/mm3 count after ET and after the second
102 000/mm3 312 000/mm3 74 000/mm3 75 000/mm3 93 000/mm3
procedure related – – – – – –
complications
protocol AML-BFM 2004 ALL-BFM 2000 Interfant-99 AML-BFM 1998 Interfant-2006 AML-BFM 2004
protocol protocol protocol protocol protocol protocol
cytotoxic hydroxycarbamid increasing doses of increasing doses hydroxycar- increasing cytarabine
treatment plus cytarabine plus prednisone of prednisone bamid plus doses of pred-
daunoxome (d3) cytarabine plus nisone
thioguanin

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follow up allogeneic SCT, disease free survi- death 2 years after allogeneic SCT, disease free disease free survival
disease free survival val after 3 years diagnosis (relapse) disease free survival after 2 after 1 year
after 4.5 years survival after 10 years
years

Fig. 1 Course of leukocytes in patients with

HL and leukapheresis (black) and exchange
100
transfusion (grey).

80
Leukozyten (%)

Patient 1
60 Patient 2
Patient 3
Patient 4
Patient 5
40 Patient 6

20

0
0 24 48 72 96 120 144 168 192 216 240 264 288
Stunden nach Aufnahme

Results chemotherapy and supportive measures alone. These children

& did not show or develop any severe complications due to HL or
Between 1/1997 and 12/2008 77 children with newly diagnosed underlying disease and did not require admission to PICU during
acute leukemias (64 children with ALL; 13 children with AML) induction treatment. Six patients (3 boys with ALL, 2 girls with
were admitted at the University Children’s Hospital in Halle AML, 1 boy with AML; median age 2.2 years, range 2 months to
(Saale), Germany. Male to female ratio was 1:1.2 (42 girls, 35 15 years; median leukocyte count 422 500/mm3, range 290 000–
boys), median age 5.9 years (range 2 months to 17.5 years). 861 000/mm3; ● ▶ Table 1) underwent further cytoreductive pro-

Four children with AML (median age 3.1 years, range 2 months
to 14.9 years) and seven with ALL (median age 8.5 years, range 2
months to 15.4 years) presented with hyperleukocytosis
(●▶ Table 1). Initial leukocyte count of patients with HL was on
average 334 000/mm3 (median 290 000/mm3, range 115 000–
861 000/mm3) compared to an average leukocyte count of
14 500/mm3 (range 600–75 600/mm3) in patients without HL.
cedures in addition to chemotherapy and supportive measures.
Two children (1 boy with AML, 14 years, 53 kg body weight; 1
boy with ALL, 15 years, 57 kg body weight) received LA, four
children (2 boys with ALL, 2 girls with AML; median age 3
months, range 2 months to 4 years; median body weight 5.8 kg,
range 5.4–16.5 kg) ET for initial blast reduction. All six patients
showed severe complications due to HL (● ▶ Table 1; coagulation

HL was treated in five children (4 boys with ALL, 1 girl with AML; problems in patients 1, 3, 4, 5, 6; respiratory symptoms in pati-
median age 8 years, range 2–12 years; median leukocyte count ents 2, 3, 4, renal insufficiency in patients 4 and 6). Especially,
136 000/mm3, range 115 000–152 000/mm3; ● ▶ Table 1) with the coagulation disorders secondary to HL represented an im-

Haase R et al. Leukapheresis and Exchange Transfusion in Children … Klin Padiatr 2009; 221: 374–378

Table 3 Comparison of leukapheresis and exchange transfusion.
Leukapheresis
advantages established technique in oncologic centers
rapid physical removal of circulating blasts
multiple procedures may recruit marginated
leukoblasts into the intravascular space
CVL not absolutely necessary
lower or no need for transfusion of erythrocytes,
platelets and plasma
usually only little influence on coagulation
disadvantages special equipment and trained staff necessary
CVL usually indicated in children with body
weight < 20 kg or difficult peripheral venous access
usually not applicable in children < 10 kga
labor and cost intensive
quick rebound of blasts cells possible
doubtful influence on long term outcome
a
LA was also reported in children with lower body, but usually for stem cell harvest and not in oncologic emergencies
b
ET was also reported in patients with a higher body weight, but usually for these patients LA is preferred [24]
portant indication to initialize LA or ET for cytoreduction and
finally prevention and/or control of life-threatening hemor-
rhages. Indeed, all complications including coagulation disorders
improved within few days in correspondence to significantly re-
duced leukocyte counts (● ▶ Table 1, ●
▶ Fig. 1). Importantly, there
were no additional complications due to insertion of central ve-
nous or arterial lines or Sheldon catheters and/or performance
of ET or LA.
Further information regarding technical details of LA or ET, che-
motherapy, and outcome is given in ● ▶ Table 2. LA was perfor-
med over 1–2 h in patient 1 and 4–4.5 h in patient 2 correspon-
ding to a processed one fold total blood volume in patient 1 and
a 2.3 fold total blood volume in patient 2. Duration of ET (range
205–1 560 min, mean 509 min, median 230 min) was longer than
of LA (range 60–280 min, mean 163 min, median 160 min) resul-
ting in exchange volumes of 1–4.5 fold of total blood volume. All
patients showed marked cytoreduction after initiation of LA or
ET. However, as shown in ● ▶ Fig. 1 initial blast reduction ap-
peared to occur faster with ET than with LA, but after 6 days
leukocyte counts were widely equalized in all patients irrespec-
tively of the applied cytoreductive measures.
Discussion
& necessary blood flow rates for blood cell separation are usually
In children with acute leukemia; morbidity and mortality rates
are significantly higher in case of initial HL than with low, nor-
mal, or slightly elevated leukocytes at diagnosis [6, 8, 11, 17].
AML and HL appear to represent an even worse prognosis with
an early mortality rate of 16.9 % [8] compared to 3.9 % in pedi-
atric patients with ALL and HL [17]. Neurological complications
including cerebral hemorrhage and pulmonary leukostasis
mostly accounted for the observed mortality and morbidity
[8, 17]. Interestingly, there was an improvement of early morta-
lity in pediatric patients with AML and HL during a later trial
which may be contributable to a growing experience in clinical
management of HL. Consequently, pediatric patients with acute
leukemia and HL should be preferentially treated in specialized
pediatric oncology centres with sufficient specialized staff and
experience in HL management including LA and ET. This postu-
lation [8] is in full concordance with the requirements for pedi-
Haase R et al. Leukapheresis and Exchange Transfusion in Children … Klin Padiatr 2009; 221: 374–378
Original Article 377
Exchange transfusion
no special equipment necessary
technique is known from ET in newborns
rapid physical removal of circulating blasts
multiple procedures may recruit marginated leukoblasts into the intravascular
space
replacement of plasma may support the correction of metabolic abnormalities
applicable also in children with a body weight < 10 kg
most pediatricians are not trained in ET
CVL usually necessary, arterial access often indicated
need for massive transfusion of erythrocytes and plasma, platelets transfusion
often necessary
severe coagulation disturbance possible
not applicable in patients with a body weight > 20 kgb
labor and cost intensive
quick rebound of blasts cells possible
doubtful influence on long term outcome
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atric oncology centres in Germany which were most recently
defined by the highest legislative body in German health care
policy, the Gemeinsame Bundesausschuss (for review [15]).
LA and ET have been both reported as cytoreductive procedures
in adults and children [5, 19, 21]. However, efficacy, safety, and
overal clinical benefit of these procedures are still not clear to
date. Because of the small number of pediatric patients eligible
for ET or LA controlled studies comparing both techniques have
not been performed yet. Some smaller studies suggest that cyto-
reductive procedures may be helpful in preventing serious early
complications of HL in childhood leukemia, but to date a long
term benefit of ET or LA has not been proven [3–5, 12, 20]. For an
individual patient the benefit of LA / ET is still not exactly pre-
dictable [4].
And even if there was consensus on the clinical benefit of cyto-
reductive procedures in pediatric patients with acute leukemia
and HL, there would be still no information available in which
patients LA or ET should be preferentially used [19]. However, ET
is rarely applied in adults and in larger children probably due to
the required large exchange volumes which usually demand
more time and staff than for LA in larger patients. On the other
hand, LA is often less feasible in very young and small children
due to the technical requirements of blood cell separators which
had been preferentially designed for application in adults. Thus,
difficult to establish in very young children during LA due to the
small calibers of venous access. Furthermore, the circulating
blood volume within the blood cell separator usually represents
more than 10 % of total blood volume of children with a body
weight of < 15 kg suggesting a potentially higher risk for acute
volume deficit in case of technical problems. In children with a
body weight < 8 kg LA is usually technically not possible at all.
Experience with LA as a widely used routine technique e.g. for
stem cell harvest is available in many pediatric oncology centers
and/or associated transfusion centers. On contrary, experience
with ET is nowadays mostly restricted to older pediatricians
who had been trained in the general techniques of ET for treat-
ment of newborns with severe hyperbilirubinemia. Nowadays in
the era of phototherapy, there is a general lack of practical know-
ledge about ET in most pediatric departments.
378 Original Article
Personnel expenses may be comparable for LA and ET, both pro-
cedures appear to be equally staff and time intensive. But the
costs for consumables needed for LA certainly exceed the non-
personnel costs for ET. Although the system of health- and dia-
gnose-related groups which determines the compensation of
in-patients costs in many national health systems (reviewed in
regards to pediatric oncology in Germany in [13]) does not usu-
ally support cost-intensive measures, LA is usually reimbursed
in Germany by an extra budget. Nevertheless, LA represents a
more expensive measure for national health systems than ET.
Pros and cons of LA and ET are summarized in ● ▶ Table 3.
In the present series of six pediatric patients with acute leuke-
mia and HL, safe and efficient reduction of HL was reached by
combination of LA or ET with cautious cytoreductive chemothe-
rapy and supportive measures. The achieved reduction in leuko-
cyte counts was consistent with reported results in other pedi-
atric series [5, 21]. In all children, symptoms associated with
leukostasis or tumor lysis due to HL were relieved and fatal com-
plications like intracerebral hemorrhages did not occur. Howe-
ver, the number of patients is much too small for valid state-
ments about safety, efficiency, and overall benefit of cytoreduc-
tive procedures like LA and ET. More information is clearly nee-
ded. Given the low frequency of HL in acute leukemia of child-
hood, a prospective study does not appear as a feasible way to
acquire this information within a realistic time period. Alterna-
tively, the set-up of a clinical registry for these patients may be
more promising on a long term perspective [14] but also harbors
the risk of long running data recruitment before statistical eva-
luation can be performed. For a start, retrospective analysis of
already acquired treatment and follow-up data from previous
leukemia trials of the GPOH and from the German Childhood
Cancer Registry [7] will facilitate statistical evaluation for future
medical advice on management of HL in pediatric acute leuke-
mia to further reduce early morbidity and mortality in affected
patients.
Conflict of interest: The authors have no conflict of interest to
disclose.
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