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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 R. Haase, N. Merkel, O. Diwan, K. Elsner, C. M. Kramm

Affiliation Klinik für Kinder- und Jugendmedizin, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany

Key words Abstract Zusammenfassung

●▶ hyperleukocytosis & &

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

Haase R et al. Leukapheresis and Exchange Transfusion in Children … Klin Padiatr 2009; 221: 374–378
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 for titering of urine pH). However, before 2004 or in case of con-
& traindications for rasburicase treatment, allopurinol was applied
At diagnosis, 5–22 % of children with acute leukemia present instead. Platelets were given at platelet counts < 50 000/mm3. To
with hyperleukocytosis (HL; > 100 000 cells/mm3) [18]. These avoid additional increase of blood viscosity a hematocrit of 20 to
patients bear an increased risk of leukostasis syndrome (LSS), 25 % was accepted in hemodynamically stable patients. All blood
tumor lysis syndrome (TLS), and death [9, 10, 17]. Guidelines for products were leukocyte-depleted, irradiated with 25–30 Gy,
prophylaxis and treatment of these complications are given in and from cytomegalovirus-negative donors. Patients with signs
several treatment protocols of the Society of Pediatric Oncology of infection were empirically treated with intravenous piperacil-
and Hematology (GPOH) in Germany, Austria, and Switzerland lin and sulbactam.
[1, 2, 16]. Patients with HL require strict clinical monitoring but
no obligatory admission to a pediatric intensive care unit (PICU). Chemotherapy
Admission to PICU is only indicated in case of life threatening In addition to cytoreductive procedures all patients received
complications due to underlying disease or treatment or perfor- chemotherapy according to the corresponding treatment proto-
mance of potentially riskful cytoreductive procedures like leu- cols for acute leukemia (●
▶ Table 2).

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


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

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
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 – – – – – –
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

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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

Fig. 1 Course of leukocytes in patients with

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

Leukozyten (%)

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


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 cedures in addition to chemotherapy and supportive measures.
to 14.9 years) and seven with ALL (median age 8.5 years, range 2 Two children (1 boy with AML, 14 years, 53 kg body weight; 1
months to 15.4 years) presented with hyperleukocytosis boy with ALL, 15 years, 57 kg body weight) received LA, four
(●▶ Table 1). Initial leukocyte count of patients with HL was on children (2 boys with ALL, 2 girls with AML; median age 3
average 334 000/mm3 (median 290 000/mm3, range 115 000– months, range 2 months to 4 years; median body weight 5.8 kg,
861 000/mm3) compared to an average leukocyte count of range 5.4–16.5 kg) ET for initial blast reduction. All six patients
14 500/mm3 (range 600–75 600/mm3) in patients without HL. 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
Original Article 377

Table 3 Comparison of leukapheresis and exchange transfusion.

Leukapheresis Exchange transfusion

advantages established technique in oncologic centers no special equipment necessary
rapid physical removal of circulating blasts technique is known from ET in newborns
multiple procedures may recruit marginated rapid physical removal of circulating blasts
leukoblasts into the intravascular space multiple procedures may recruit marginated leukoblasts into the intravascular
CVL not absolutely necessary space
lower or no need for transfusion of erythrocytes, replacement of plasma may support the correction of metabolic abnormalities
platelets and plasma applicable also in children with a body weight < 10 kg
usually only little influence on coagulation
disadvantages special equipment and trained staff necessary most pediatricians are not trained in ET
CVL usually indicated in children with body CVL usually necessary, arterial access often indicated
weight < 20 kg or difficult peripheral venous access need for massive transfusion of erythrocytes and plasma, platelets transfusion
usually not applicable in children < 10 kga often necessary
labor and cost intensive severe coagulation disturbance possible
quick rebound of blasts cells possible not applicable in patients with a body weight > 20 kgb
doubtful influence on long term outcome labor and cost intensive
quick rebound of blasts cells possible
doubtful influence on long term outcome
LA was also reported in children with lower body, but usually for stem cell harvest and not in oncologic emergencies
ET was also reported in patients with a higher body weight, but usually for these patients LA is preferred [24]

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portant indication to initialize LA or ET for cytoreduction and atric oncology centres in Germany which were most recently
finally prevention and/or control of life-threatening hemor- defined by the highest legislative body in German health care
rhages. Indeed, all complications including coagulation disorders policy, the Gemeinsame Bundesausschuss (for review [15]).
improved within few days in correspondence to significantly re- LA and ET have been both reported as cytoreductive procedures
duced leukocyte counts (● ▶ Table 1, ●
▶ Fig. 1). Importantly, there in adults and children [5, 19, 21]. However, efficacy, safety, and
were no additional complications due to insertion of central ve- overal clinical benefit of these procedures are still not clear to
nous or arterial lines or Sheldon catheters and/or performance date. Because of the small number of pediatric patients eligible
of ET or LA. for ET or LA controlled studies comparing both techniques have
Further information regarding technical details of LA or ET, che- not been performed yet. Some smaller studies suggest that cyto-
motherapy, and outcome is given in ● ▶ Table 2. LA was perfor- reductive procedures may be helpful in preventing serious early
med over 1–2 h in patient 1 and 4–4.5 h in patient 2 correspon- complications of HL in childhood leukemia, but to date a long
ding to a processed one fold total blood volume in patient 1 and term benefit of ET or LA has not been proven [3–5, 12, 20]. For an
a 2.3 fold total blood volume in patient 2. Duration of ET (range individual patient the benefit of LA / ET is still not exactly pre-
205–1 560 min, mean 509 min, median 230 min) was longer than dictable [4].
of LA (range 60–280 min, mean 163 min, median 160 min) resul- And even if there was consensus on the clinical benefit of cyto-
ting in exchange volumes of 1–4.5 fold of total blood volume. All reductive procedures in pediatric patients with acute leukemia
patients showed marked cytoreduction after initiation of LA or and HL, there would be still no information available in which
ET. However, as shown in ● ▶ Fig. 1 initial blast reduction ap- patients LA or ET should be preferentially used [19]. However, ET
peared to occur faster with ET than with LA, but after 6 days is rarely applied in adults and in larger children probably due to
leukocyte counts were widely equalized in all patients irrespec- the required large exchange volumes which usually demand
tively of the applied cytoreductive measures. 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
Discussion had been preferentially designed for application in adults. Thus,
& necessary blood flow rates for blood cell separation are usually
In children with acute leukemia; morbidity and mortality rates difficult to establish in very young children during LA due to the
are significantly higher in case of initial HL than with low, nor- small calibers of venous access. Furthermore, the circulating
mal, or slightly elevated leukocytes at diagnosis [6, 8, 11, 17]. blood volume within the blood cell separator usually represents
AML and HL appear to represent an even worse prognosis with more than 10 % of total blood volume of children with a body
an early mortality rate of 16.9 % [8] compared to 3.9 % in pedi- weight of < 15 kg suggesting a potentially higher risk for acute
atric patients with ALL and HL [17]. Neurological complications volume deficit in case of technical problems. In children with a
including cerebral hemorrhage and pulmonary leukostasis body weight < 8 kg LA is usually technically not possible at all.
mostly accounted for the observed mortality and morbidity Experience with LA as a widely used routine technique e.g. for
[8, 17]. Interestingly, there was an improvement of early morta- stem cell harvest is available in many pediatric oncology centers
lity in pediatric patients with AML and HL during a later trial and/or associated transfusion centers. On contrary, experience
which may be contributable to a growing experience in clinical with ET is nowadays mostly restricted to older pediatricians
management of HL. Consequently, pediatric patients with acute who had been trained in the general techniques of ET for treat-
leukemia and HL should be preferentially treated in specialized ment of newborns with severe hyperbilirubinemia. Nowadays in
pediatric oncology centres with sufficient specialized staff and the era of phototherapy, there is a general lack of practical know-
experience in HL management including LA and ET. This postu- ledge about ET in most pediatric departments.
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
378 Original Article

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