From www.bloodjournal.org by guest on September 13, 2017. For personal use only.

How I Treat

How I treat hyperleukocytosis in acute myeloid leukemia

Christoph Rollig and Gerhard Ehninger
Medizinische Klinik und Poliklinik I, Universitatsklinikum der Technischen Universitat Dresden, Germany

Hyperleukocytosis (HL) per se is a labora-
tory abnormality, commonly defined by
a white blood cell count >100 000/mL,
caused by leukemic cell proliferation. Not
the high blood count itself, but complica-
tions such as leukostasis, tumor lysis syn-
drome, and disseminated intravascular
coagulation put the patient at risk and
require therapeutic intervention. The risk
of complications is higher in acute than in
chronic leukemias, and particularly leuko-
stasis occurs more often in acute myeloid
leukemia (AML) for several reasons. Only
a small proportion of AML patients present
with HL, but these patients have a partic-
ularly dismal prognosis because of (1) a
higher risk of early death resulting from
HL complications; and (2) a higher proba-
bility of relapse and death in the long run.
Whereas initial high blood counts and high
lactate dehydrogenase as an indicator for
high proliferation are part of prognostic
scores guiding risk-adapted consolidation
strategies, HL at initial diagnosis must be
considered a hematologic emergency and
requires rapid action of the admitting
physician in order to prevent early death.
(Blood. 2015;125(21):3246-3252)

Incidence and pathophysiology

In untreated acute myeloid leukemia (AML), ;5% to 20% of patients
present with hyperleukocytosis (HL).1-10 In a patient with HL, under-
lying diseases other than AML, such as acute lymphoblastic leukemia
(ALL), chronic lymphocytic leukemia, and chronic myeloid leukemia,
particularly in acceleration or blast crisis, should be considered as dif-
ferential diagnosis. In addition to classic cytology and ow-cytometric
immunophenotyping, the rapid screening for the bcr-abl transcript by
uorescence in situ hybridization or polymerase chain reaction is of
importance for diagnostic certainty. Although commonly dened by
white blood cell (WBC) counts .100 000/mL, it should be noted that
WBC levels below this arbitrary threshold can also cause HL-related
complications (Figures 1).11 Retrospective analyses have revealed an
association with monocytic AML subtypes (French-American-British
classication M4/5; Figure 2),9,12,13 chromosomal MLL rearrange-
ment 11q23,9,14 and the FLT3-ITD mutation,9,15,16 although only some
patients with these characteristics actually develop HL. In a cohort of
3510 newly diagnosed AML patients of the Study Alliance Leuke-
mia study group, 357 patients (10%) had WBCs .100 000/mL at
initial diagnosis. Our explorative analyses revealed 28% French-
American-British M4/5 in HL patients as opposed to 16% in non-HL
patients (comparison by x2 test, P , .001). Further associations were
seen regarding higher lactate dehydrogenase (1158 U/L vs 386 U/L;
P , .001), FLT3-ITD (45% vs 16%; P , .001), NPM1 (44% vs 24%;
P , .001), but no association with MLL-PTD (2% vs 1%; P 5 1.0). The
median Eastern Cooperative Oncology Group (ECOG) performance
status score at initial diagnosis was higher in HL patients, and fewer
patients displayed favorable or adverse cytogenetic aberrations (C.R.
and G.E., unpublished data).
Two main pathogenetic factors are responsible for the development
of HL: rst, a rapid blast proliferation leading to a high leukemic tumor
burden; second, disruption in normal hematopoietic cell adhesion
leading to a reduced afnity to the bone marrow.17 The high number
of leukocytes may cause 3 main complications: disseminated intravas-
cular coagulation (DIC), tumor lysis syndrome (TLS), and leukostasis.
DIC is caused by high cell turnover and associated high levels of
released tissue factor, which then triggers the extrinsic pathway via
factor VII.18 TLS may occur as a result of spontaneous or treatment-
induced cell death. Leukostasis is explained by 2 main mechanisms.
The rheological model is based on a mechanical disturbance in the
blood ow by an increase of viscosity in the microcirculation.19,20 The
fact that myeloid blasts are larger than immature lymphocytes or mature
granulocytes and that leukemic blasts are considerably less deformable
than mature leukocytes explains the higher incidence of leukostatic
complications in AML as opposed to ALL, chronic myeloid leukemia,
or chronic lymphocytic leukemia.8,21-23 However, the observation
that there is no clear correlation between the leukocyte count and the
severity and frequency of leukostatic complications6,24,25 points toward
additional cellular mechanisms involved in the genesis of leukostasis
such as interactions between leukemic cells and the endothelium,26,27
mediated by adhesion molecules.28 Bug et al described a signicant
association between expression of CD11c and a high risk of early death
in leukocytosis.29 Stucki and coworkers observed a secretion of tumor
necrosis factor-a and interleukin-1b by leukemic myeloblasts leading
to change in the makeup of adhesion molecules on the endothelial
cells.30 Several molecules such as intracellular adhesion molecule-1,
vascular cell adhesion molecule-1, and E-selectin were shown to be
upregulated. By this mechanism, leukemic cells can promote their own
adhesion to the endothelium and create a self-perpetuating loop in
which more and more blast cells migrate and attach to the endo-
thelium.30 Additionally, cytokine-driven endothelial damage, subse-
quent hemorrhage, hypoxic damage, and AML blast extravasation
followed by consecutive tissue damage by matrix metalloproteases
might contribute to the pathogenesis of leukostasis.31-34 Important
mechanisms of leukostasis are shown in Figure 3.35-37
Clinical manifestations and treatment options
Leukostasis, DIC, and TLS represent the 3 main clinical manifesta-
tions of HL, which can cause life-threatening complications in AML
patients. Early mortality in this patient group is higher than in AML

Submitted October 1, 2014; accepted February 2, 2015. Prepublished online 2015 by The American Society of Hematology
as Blood First Edition paper, March 16, 2015; DOI 10.1182/blood-2014-10-
551507.

3246 BLOOD, 21 MAY 2015 x VOLUME 125, NUMBER 21

 From www.bloodjournal.org by guest on September 13, 2017. For personal use only.
BLOOD, 21 MAY 2015 x VOLUME 125, NUMBER 21
Figure 1. Clinical case 1. A 42-year-old woman presented to her general
practitioner with general weakness and tooth pain. Laboratory assessment showed
a WBC count of 80 000/mL, hemoglobin of 6.4 mg/dL, and platelet count of 21 000/mL,
which led her physician to make an immediate referral to the local hospital, where
a differential blood count revealed 56% myeloid blasts. By that time, the patient
was in stable clinical condition with a minimally elevated C-reactive protein of
20 mg/L. She was put on 4 g hydroxyurea (HU) and planned for transferal to our
hospital the next morning. During the night, she developed dyspnea requiring oxygen
supply. We diagnosed an AML M4eo with inv(16) and started induction treatment
with cytarabine plus daunorubicin (7 1 3) at a WBC count of 70 000/mL. Immediate
leukapheresis was not possible because of the progressive dyspnea and the
increasingly deranged coagulation status. By the next day, the WBC count had gone
down to 19 000/mL, but the patient developed respiratory failure requiring mechanical
ventilation. The computed tomography (CT) scan result was highly suggestive for
leukostasis of the lungs (A), and cranial CT showed multiple focal supratentorial
hemorrhages (B). During the next few days, respiratory indices improved, and the
patient could be extubated. Early bone marrow response assessment showed
a good response with leukemia-free hypoplastic marrow, and after regeneration
of peripheral counts, a complete remission (CR) was diagnosed. The patient
has currently completed consolidation chemotherapy and is in ongoing CR. The
remarkable aspects of this case are (1) the fact that leukostasis developed rapidly
even at a WBC count below 100 000/mL, possibly because of the monocytic nature of
blasts11; (2) cytarabine alone led to a profound and rapid WBC reduction; and (3) the
patient recovered from mechanical ventilation because the underlying leuko-
stasis could be treated successfully. (A) Contrast-enhanced CT image (lung
window) through the upper fields of the lungs demonstrates parenchymal
infiltrates as well as diffuse ground-glass opacities suggestive for leukostasis
and myeloblast infiltration. There is sparing of the lung periphery. Note also bilateral
HOW I TREAT HYPERLEUKOCYTOSIS IN AML 3247
without HL and ranges from 8% in the rst 24 hours9 to ;20% during
the rst week,9,38,39,40 the main causes of death being bleeding, throm-
boembolic events, and neurologic and pulmonary complications. In
AML without HL, the early death rate is signicantly lower, ranging
from ;3% to 9%.41 However, also in long-term follow-up, HL is a
negative prognostic factor as indicated by signicantly shorter overall
survival (OS)1,5,42 In our Study Alliance Leukemia study group data-
base capturing 3510 intensively treated patients with an age range
between 15 and 87 years, early death in HL vs all other AMLs was 6%
vs 1% (P , .001) after 1 week and 13% vs 7% after 30 days (P , .001).
The 5-year OS was 28% vs 31% indicating a small but signicant
prognostic difference (P 5 .004). When early death patients were ex-
cluded in the analysis of relapse-free survival (RFS), HL was still as-
sociated with an unfavorable prognosis as shown in 5-year RFS rates of
30% and 34% (P 5 .005). In multivariate analyses of OS and RFS
accounting for the inuence of other established prognostic factors
such as age, cytogenetic risk, FLT3, NPM1, secondary AML, lactate
dehydrogenase, and ECOG, HL retained its signicant impact on pro-
gnosis (C.R. and G.E., unpublished data).
Because of excessive early mortality, HL in AML is a medical
emergency, and treatment should start immediately.
DIC
DIC is a coagulopathy induced by the formation of small clots con-
suming coagulation proteins and platelets, resulting in disruption of
normal coagulation and severe bleeding tendency.43 Acute DIC is char-
acterized by a decrease in platelet count and brinogen, an elevation of
D-dimers, and prolongation of prothrombin time and activated partial
thromboplastin time and occurs in 30% to 40% of HL-AML.24 Platelet
transfusions and standard measures to restore normal coagulation such
as substitution of fresh frozen plasma or brinogen44 should be initiated
immediately in these patients because not only the deranged coagu-
lation itself but also HL and the associated endothelial damage put the
patient at a considerable risk for severe and sometimes fatal bleeding
events. In patients without central nervous manifestations and no anti-
coagulation, platelet counts should be ;20 000 to 30 000/mL; in
patients with full heparin anticoagulation, ;50 000/mL. In the sub-
group of acute promyelocytic leukemia (APL), induction of differen-
tiation by administration of all-trans retinoid acid (ATRA) is the causal
and most important treatment of DIC and should be started in all
suspicious cases even before cytological and cytogenetic or molecular
proof.45
TLS
Although TLS is more common in lymphoid malignancies and ALL, it
can also occur in AML. In patients with leukostasis, TLS occurs in up to
10% of cases.21 There is no evidence that low-dose cytostatic treatment
with a slow and gradual leukocyte reduction decreases the risk of tumor
Figure 1 (continued) pleural effusions. Respiratory failure required mechanical
ventilation support as indicated by the endotracheal tube. A central venous catheter
in the right brachiocephalic vein and nasogastric tube in the esophagus can be seen.
(B) Horizontal plane of native cranial CT scan demonstrating multiple hyperdense
lesions in both brain hemispheres indicating hemorrhagic lesions. Accompanying
cerebral edema is characterized by loss of gray-white matter differentiation, com-
pression of lateral ventricles, and effacement of sulcal spaces.
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3248 ROLLIG and EHNINGER BLOOD, 21 MAY 2015 x VOLUME 125, NUMBER 21

Figure 2. Clinical case 2. A 68-year-old man sought medical help at the emergency unit of his local hospital because of weakness, bone pain, and night sweats over several
weeks. He was admitted because of HL of ;170 000/mL, anemia, and thrombocytopenia. After the diagnosis of AML M4 was made, HU and cytarabine were started, and the
patient was transferred to our hospital, presenting with a WBC count 70 000/mL and central neurologic deficits with speech impairment. A magnetic resonance imaging (MRI) scan
showed several meningeal lesions, but the cerebrospinal fluid cell count was normal, and infection parameters were negative. In order to avoid cerebrospinal fluid contamination
with leukemic blasts, lumbar puncture was postponed until peripheral blast clearance. We continued cytarabine induction and added daunorubicin for 3 days. WBC counts
declined rapidly after initiation of cytarabine; the patients ability to speak improved gradually, and a control MRI 7 days after admission showed multiple hemorrhagic lesions, most
pronounced in the hemispheres, with no signs of extramedullary leukemic lesions or meningeosis (A). In the consecutive aplasia, our patient developed Escherichia coli
septicemia and Systemic Inflammatory Response Syndrome (SIRS) requiring epinephrin support. Early response assessment revealed persisting AML in the bone marrow. After
having recovered from the sepsis, he developed a rapid relapse with WBCs rising up to 150 000/mL within 1 week (B,C). Intermediate-dose cytarabine plus mitoxantrone was
administered as salvage treatment. In the consecutive aplasia, our patient received allogeneic stem cell transplantation from a matched unrelated donor after reduced-intensity
conditioning with busulfan and fludarabin, leading to a rapid engraftment and the establishment of a stable donor chimerism. This case is highly suggestive for cerebral
manifestations of leukostasis, possibly associated with extravasation and extramedullary infiltration of myeloid blasts. Primary refractory disease could be overcome by higher-
dose cytarabine salvage treatment, and sustained response of this high-risk disease could be achieved by allogeneic stem cell transplantation. (A) T2-weighted axial plane of
cranial MRI scan showing multiple brain hemorrhages (in correlation with other sequences) at the stage of extracellular methemoglobin with marked perifocal edema. (B)
Peripheral-blood sample from patient 2 at hyperleukocytotic relapse (containing EDTA for anticoagulation). Cell settlement revealed a pronounced buffy coat containing excessive
numbers of leukemic cells (left tube) as opposed to blood from an age-matched healthy man (right tube). (C) Peripheral-blood smear of patient 2 at hyperleukocytotic relapse
(May-Grunwald and Giemsa stain, 3400) showing numerous myeloid blasts with wide cytoplasm and large euchromatin-containing nuclei with 1 or more nucleoli.

lysis as opposed to standard-dose intensive induction.46 In patients with
a curative treatment concept, intensive chemotherapy should therefore
start immediately and without a prephase. Prevention strategies in-
clude hydration and prophylactic allopurinol. Close monitoring during
the rst days of treatment will reveal tumor lysis characterized by el-
evation of serum potassium, phosphorus, and uric acid levels and
potentially by decline in calcium levels. Hyperuricemia can lead to
acute renal damage or even failure and should be treated with allo-
purinol or rasburicase depending on the uric acid levels. Established
TLS is managed similarly, with the addition of aggressive hydration
and diuresis, plus allopurinol or rasburicase for hyperuricemia. Addi-
tionally, electrolyte imbalances should be corrected. Whereas allopu-
rinol 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.47-51
Leukostasis
Leukostasis refers to clinical symptoms and complications caused
by HL. Whereas pathologically, the denition of leukostasis is clear
(Figure 4), the clinical diagnosis is rarely made with high condence.43
Leukostasis is empirically diagnosed when patients present with acute
leukemia, HL, and respiratory or neurologic symptoms. However, the
clinical and radiographic manifestations of leukostasis are difcult to
distinguish from those of common infections or hemorrhagic compli-
cations of acute leukemia.24 Novotny et al39 developed a score for the
clinical probability of leukostasis, and Piccirillo et al40 showed a cor-
relation between Novotnys score and early death in the case of a score
of 3 indicating highly probable leukostasis. Approximately 44% to 50%
of AML patients with a WBC count .100 000/mL have a high prob-
ability of leukostasis based on clinical symptoms. Although less fre-
quently, typical symptoms can also occur in patients with leukocytosis
below 100 000/mL.39,40 Organs most frequently affected are lung,
brain, and kidneys. In a study by Porcu et al, the proportions of patients
with respective symptoms were 39%, 27%, and 14%.6 Similar fre-
quencies were reported by other investigators.9,29,52 CT scan or MRI of
the head may reveal intracranial hemorrhage (Figures 1 and 2). A chest
radiograph or CT scan often will show bilateral interstitial or alveolar
inltrates (Figure 1).43,53 The typical clinical symptoms of leukostasis
are listed in Table 1. Apart from tissue damage caused by stasis and
leukocyte inltration, hemorrhage and thromboembolic events are fre-
quent and relevant complications of leukostasis. 9,19,43
Immediate initiation of cytoreductive treatment in this chemosen-
sitive disease is mandatory and should not be delayed.43,54 In case a
rapid diagnosis cannot be made, the patient should be transferred to a
specialized hospital on the same day. Whereas there are widely agreed
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BLOOD, 21 MAY 2015 x VOLUME 125, NUMBER 21 HOW I TREAT HYPERLEUKOCYTOSIS IN AML 3249

is not available, judicious phlebotomies with concurrent blood and/or

Figure 3. Pathogenetic mechanisms in leukostasis. Sludging of circulating
myeloblasts causes mechanical obstruction of small vessels and consecutive
malperfusion in the microvasculature (eg, in organs such as brain and lungs). Apart
from the mechanical obstruction, myeloblasts adhere to the endothelium by inducing
endothelial cell adhesion receptor expression including E-selectin, P-selectin, in-
tracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1
(VCAM-1). Myeloblasts can promote their own adhesion to unactivated vascular
endothelium by secreting tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b), or
additional stimulating factors (sequence of events represented by steps 1 to 3).30
Additional changes after cytokine-driven endothelial cell activation can be a loss of
vascular integrity and modification of endothelial phenotype from antithrombotic to
prothrombotic phenotype.35,36 Endothelial disintegration allows myeloblast migration
and blood extravasation and microhemorrhages. Tissue invasion of myeloblasts is
mediated by metalloproteinases (MMPs; particularly MMP-9), which are expressed
on the cellular surface and secreted into the extracellular matrix.31,33,34,37
upon and accepted standards for the treatment of DIC and TLS, the use
of leukapheresis in HL and the mode of cytoreduction are still a matter of
debate.
plasma replacement may be used as an alternative strategy to reduce
HL.43 In modern apheresis devices (blood cell separators), WBCs and
their precursors are separated from patients blood by centrifugation.
During a single leukapheresis, the WBC count can be reduced by 10%
to 70%.60 The efcacy of leukapheresis to reduce the number of WBCs
has been shown in several clinical trials. However, there are 2 main re-
asons why the use of leukapheresis in HL patients is still under debate.
First, the majority of the leukemic burden is located in the bone
marrow.61 These cells are rapidly mobilized into the peripheral blood
shortly after a successful leukapheresis.24 The second and more im-
portant reason is that a benecial clinical effect on early clinical out-
comes could not be shown consistently in clinical trials. From what we
know from all clinical trials employing leukapheresis in HL patients,
long-term prognosis cannot be changed (ie, relapse risk is higher and
OS is shorter in AML patients with initial HL). Concerning the pre-
vention of early complications and early death, several clinical trials
delivered heterogeneous results. In a systematic review, Oberoi et al46
identied 14 studies using leukapheresis systematically or occasionally
in 420 children and adult patients with HL AML. One additional study
with 45 patients generally not using leukapheresis was added for
comparison. The results of the trials could not be synthesized because of
heterogeneity, but there was neither a trend for higher or lower early
death in patients with and without leukapheresis nor did the early death
rates differ depending on the leukapheresis strategy used (systemat-
ically vs occasionally vs not). In a comparison between institutions with
leukapheresis in all HL patients and institutions using a never or
sometimes policy, no benecial effect could be shown. Similarly, the
investigators of this comprehensive review did not observe an inverse
relationship between the percentage of patients receiving a leukaphe-
resis and the incidence of early death.46 Pastore et al9 analyzed an HL

Cytoreduction

Hydroxyurea is commonly used before a proper induction regimen is

implemented in order to lower the tumor burden and reduce the risk of
tumor lysis. However, there are no data indicating that this approach is
superior to immediate induction or that tumor lysis can be prevented
by a low-dose cytoreduction strategy. Results of a recent systematic
review lack evidence for the superiority of this approach over standard-
dose induction.46 In all patients eligible for intensive curative treatment,
standard-dose or high-dose cytarabine plus anthracyclin or mitoxan-
trone should be initiated as soon as the HL diagnosis is made.55,56 This
applies to all HL patients with AML, both with and without signs of
leukostasis. In cases with unclear HL, HU may be used short term as
bridging strategy (Figure 1). If respiratory failure develops despite
falling WBC counts, pneumonia or cytarabine-induced pulmonary
damage57,58 should be considered and treated accordingly. In APL,
treatment with ATRA should be initiated immediately, even if APL is
only suspected. After APL conrmation, idarubicin or arsenic trioxide
should be added for proper cytoreduction treatment.59

Leukapheresis

The term leukapheresis stems from the Greek to take away or to
remove.43 Leukapheresis in HL is based on the principle of rapidly re-
moving excessive leukocytes by mechanical separation. The mechan-
ical removal of leukocytes by leukapheresis has become routinely
available in many hematologic treatment centers. If apheresis equipment
Figure 4. Histopathological finding in leukostasis. Specimen from the leptome-
ninges of an AML patient postmortem stained with hematoxylin and eosin (3200). (A)
Large numbers of immature WBCs in a leptomeningeal capillary artery presumably
leading to reduced blood flow and thrombus formation with strands of fibrin, red blood
cells (RBCs), and WBCs. (B) Numerous myeloid blasts and some RBCs are present in
the extravascular space, infiltrating the leptomeningeal tissue.
 From www.bloodjournal.org by guest on September 13, 2017. For personal use only.
3250 ROLLIG and EHNINGER
Table 1. Symptoms of leukostasis
Organ Symptoms
Lung Dyspnea, hypoxemia, diffuse alveolar
hemorrhage, respiratory failure
Central nervous system Confusion, somnolence, dizziness, headache,
delirium, coma, focal neurologic deficits
Eye Impaired vision, retinal hemorrhage
Ear Tinnitus
Heart Myocardial ischemia/infarction
Vascular system Limb ischemia, renal vein thrombosis, priapism
For patients presenting with 1 or more of these symptoms not attributable to
preexisting or coexisting medical conditions, leukostasis is highly probable.39,40,60
patient population based on a score correcting for disease-related risk
factors in order to separate the leukapheresis effect on early death. Ac-
cording to their analysis, leukapheresis had no benecial effect on early
death, irrespective of the individual early death risk.9 All trials were
retrospective and not randomized, and it is unlikely that such studies
will ever be feasible given the rarity of the condition, urgency for de-
cision making, and strong physician preferences.
As part of a discussion, the efcient reduction of WBCs and the
standardized and generally well-tolerated procedure are brought for-
ward as arguments for using leukapheresis, whereas hypercalcemia, the
use of anticoagulants, aggravation of preexisting thrombopenia,24 and
the potential need for a central venous access43,46,61,62 may put patients
at procedural risk on top of their unstable condition. Last but not least,
infrastructural requirements and costs linked to leukapheresis have to be
taken into account.
In conclusion, leukapheresis may be benecial in patients present-
ing with a manifest leukostasis syndrome because leukapheresis re-
presents a causal therapeutic principle. Based on a grading score for
the probability of leukostasis in leukemia patients with HL and a vali-
dation analysis, patients with distinct symptoms have a high risk of
leukostasis-related early death (Table 1).39,40 Contraindications such
as cardiovascular comorbidities, hemodynamic instability, and coag-
ulation disturbances should be evaluated carefully in order to avoid an
extra procedural risk for the patient. Patients with a manifest leukostasis
in relation to HL and without contraindications should receive daily
leukapheresis. The blood volume to process should be between 2 and 4
times the patients blood volume. Clinical controls for hypocalcemia-
induced paresthesia and monitoring of oxygen saturation, blood pres-
sure, and heart rate are recommended during the intervention. If .20%
of the patients blood volume has been collected, uid replacement with
colloids or human albumin is recommended. Red cell transfusions
should be given only if inevitable and only at the end of leukapheresis
in order to avoid further increase of blood viscosity.63 Leukapheresis
can be repeated daily until symptoms of leukostasis have disappeared
or the WBC count is below 100 3 109/mL.60,63 Cytoreductive treatment
should start immediately at diagnosis of HL AML and must not be de-
layed or postponed by the leukapheresis procedure.
There is no evidence for a benecial effect of leukapheresis in HL
patients without clinical symptoms of leukostasis. Prophylactic leu-
kapheresis offers no advantage over intensive induction chemotherapy
and supportive care, including those patients with TLS.46,63 Based on
the pros and cons of the procedure, a routinely performed prophylactic
leukapheresis cannot be recommended. In APL, leukapheresis might
worsen the coagulopathy and increase the rate of complications and is
therefore not recommended.64
Future research evaluating therapies targeting cytokines and adhe-
sion molecules involved in myeloblast-endothelium interactions may
be worth exploring.46
BLOOD, 21 MAY 2015 x VOLUME 125, NUMBER 21
Conclusion: how I treat HL in AML
Based on these facts and considerations, we follow the treatment al-
gorithm shown in Figure 5. In patients with AML and HL, we assess
eligibility for intensive treatment. Treatment-eligible patients start with
standard induction treatment combining standard-dose cytarabine plus
daunorubicin (7 1 3). In parallel, we provide intravenous hydration
to ensure adequate urine ow, use allopurinol or rasburicase to reduce
serum uric acid levels, and check for signs of DIC or tumor lysis twice
daily until the WBC count has fallen below upper normal limits.
Patients with suspected APL should receive ATRA immediately and
additionally idarubicin after cytological or genetic APL conrmation.
In addition to idarubicin, the WBC count is further reduced by HU
until normal levels have been reached. DIC and TLS are treated with
standard supportive measures as mentioned previously. RBC transfu-
sions are withheld whenever possible until the WBC count is reduced.
If a transfusion is necessary, it is administered slowly. We give pro-
phylactic platelet transfusions to maintain a count of .20 000 to
30 000/mL or 50 000/mL in case of full heparin anticoagulation
until the WBC count has been reduced and the clinical situation has
been stabilized. Patients without leukostasis symptoms are not sched-
uled for leukapheresis. Patients with a clinically high likelihood of leu-
kostasis are checked for contraindications for leukapheresis such as
APL, coagulation disorders, cardiovascular comorbidities, or instable
circulation. Patients without contraindications are scheduled to receive
leukapheresis with a target WBC count below 100 000/mL or the dis-
appearance of clinical symptoms. In patients with contraindications for
immediate intensive induction treatment such as severe metabolic dis-
turbances or renal insufciency, we use HU for cytoreduction.
Once CR has been achieved, we make a decision on consolidation
treatment depending on donor availability and cytogenetic risk. If the
standard induction does not lead to CR, we use a salvage regimen based
on high-dose cytarabine, possibly including novel investigational
drugs. In rst CR, we recommend a patient with intermediate or adverse
cytogenetic risk and an available matched donor to undergo allogeneic
stem cell transplantation in rst remission based on the high relapse
probability of hyperleukocytotic AML after conventional chemother-
apy consolidation. In all other cases including core binding factor leu-
kemias without c-kit mutations, standard chemotherapy with high-dose
Figure 5. Treatment algorithm for AML with hyperleukocytosis. Supportive therapy
such as hydration, prophylaxis of TLS, and anti-infective treatment is necessary for all
patients. The asterisk indicates that the algorithm also applies to patients with leu-
kocytosis ,100 Gpt/L who present with symptoms suggestive for leukostasis.
 From www.bloodjournal.org by guest on September 13, 2017. For personal use only.

BLOOD, 21 MAY 2015 x VOLUME 125, NUMBER 21 HOW I TREAT HYPERLEUKOCYTOSIS IN AML 3251

cytarabine will be used as consolidation. Whenever possible, treat- sections and their interpretation in Figure 4, and Christiane Kulper and
ment should be part of a clinical trial or registry in order to gain more Marika Erler (Medizinische Klinik und Poliklinik I, Universitatskli-
knowledge and to improve treatment options in the future. nikum TU Dresden) for technical assistance on cytological specimens
in Figure 2C.

Acknowledgments
The authors thank Michael Laniado (Institut und Poliklinik fur Radio-
logische Diagnostik, Universitatsklinikum der Technischen Univer-
sitat [TU] Dresden) and Rudiger von Kummer and Dirk Daubner
(Abteilung Neuroradiologie, Universitatsklinikum TU Dresden) for
providing radiographic material for Figures 1 and 2A. The authors
also thank Gustavo Baretton, Christian Zietz, and Friederike Kuithan
(Institut fur Pathologie, Universitatsklinikum TU Dresden) for tissue
Authorship
Contribution: G.E. and C.R. wrote the manuscript.
Conict-of-interest disclosure: The authors declare no competing
nancial interests.
Correspondence: Christoph Rollig, Universitatsklinikum TU Dresden,
Fetscherstrasse 74, 01307 Dresden, Germany; e-mail: christoph.roellig@
uniklinikum-dresden.de.

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2015 125: 3246-3252

doi:10.1182/blood-2014-10-551507 originally published
online March 16, 2015

How I treat hyperleukocytosis in acute myeloid leukemia

Christoph Rllig and Gerhard Ehninger

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