1 Röllig & Ehninger How I treat hyperleukocytosis in AML
How I treat Hyperleukocytosis in Acute Myeloid Leukemia
Christoph Röllig and Gerhard Ehninger
Medizinische Klinik und Poliklinik I, Universitätsklinikum der Technischen Universität
Dresden, Germany
Corresponding author:
Christoph Röllig
Medizinische Klinik und Poliklinik I
Universitätsklinikum „Carl Gustav Carus“
Fetscherstr. 74
01307 Dresden, Germany
Email: [email protected]
Running head: How I treat hyperleukocytosis in AML
Blood First Edition Paper, prepublished online March 16, 2015; DOI 10.1182/blood-2014-10-551507
Copyright © 2015 American Society of Hematology
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2 Röllig & Ehninger How I treat hyperleukocytosis in AML
Abstract
Hyperleukocytosis (HL) per se is a laboratory abnormality, commonly defined by a white
blood cell (WBC) count above 100,000/µL, caused by leukemic cell proliferation. Not the high
blood count itself, but complications such as leukostasis, tumor lysis syndrome (TLS) and
disseminated intravascular coagulation (DIC) put the patient at risk and require therapeutic
intervention. The risk of complications is higher in acute than in chronic leukemias, and
particularly leukostasis 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
particularly dismal prognosis due to i) a higher risk of early death resulting from HL
complications and ii) a higher probability of relapse and death in the long run.
Whereas initial high blood counts and high lactate dehydrogenase (LDH) as indicator for high
proliferation are part of prognostic scores guiding risk adapted consolidation strategies, HL at
initial diagnosis must be considered a hematological emergency and requires rapid action of
the admitting physician in order to prevent early death.
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3 Röllig & Ehninger How I treat hyperleukocytosis in AML
Incidence and pathophysiology
In untreated AML, about 5 to 20% of patients present with HL.1,2,3,4,5,6,7,8,9,10 In a patient with
HL, underlying diseases other than AML such as ALL, CLL and CML, particularly in
acceleration or blast crisis, should be considered as differential diagnosis. In addition to
classic cytology and flow-cytometric immunophenotyping, the rapid screening for the bcr-abl
transcript by FISH or PCR is of importance for diagnostic certainty. Although commonly
defined by WBC counts >100,000/µL, it should be noted that also WBC levels below this
arbitrary threshold can cause HL related complications (Figure 1). Retrospective analyses
have revealed an association with monocytic AML subtypes (FAB M4/5)11,12,9, chromosomal
MLL rearrangement 11q2313,9 and the FLT3-ITD mutation14,15,9, although only some patients
with these characteristics actually develop HL. In a cohort of 3,510 newly diagnosed AML
patients of the Study Alliance Leukemia study group (SAL), 357 patients (10%) had WBCs
>100,000/µL at initial diagnosis. Our explorative analyses revealed 28% FAB M4/5 in HL
patients as opposed to 16% in non-HL patients (comparison by Chi-squared test, p<0.001).
Further associations were seen regarding higher LDH (1,158 Ul/l versus 386 U/l; p<0.001),
FLT3-ITD (45% versus 16%; p<0.001), NPM1 (44% versus 24%; p<0.001), but no
association with MLL-PTD (2% versus 1%; p=1.0). The median ECOG performance status
score at initial diagnosis was higher in HL patients and less patients displayed favorable or
adverse cytogenetic aberrations (previously unpublished data).
Two main pathogenetic factors are responsible for the development of HL: first, a rapid blast
proliferation leading to a high leukemic tumor burden; second, disruption in normal
hematopoietic cell adhesion leading to a reduced affinity to the bone marrow.16 The high
number of leukocytes may cause three main complications: disseminated intravasal
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.17 TLS may occur as a result of spontaneous or treatment-induced cell
death. Leukostasis is explained by two main mechanisms. The rheological model is based
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4 Röllig & Ehninger How I treat hyperleukocytosis in AML
on a mechanical disturbance in the blood flow by an increase of viscosity in the
microcirculation.18,19 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
acute lymphoblastic leukemia, chronic myeloid leukemia or chronic lymphocytic
leukemia.20,8,21,22 However, the observation that there is no clear correlation between the
leukocyte count and the severity and frequency of leukostatic complications 6,23,24 point
towards additional cellular mechanisms involved in the genesis of leukostasis such as
interactions between leukemic cells and the endothelium,25,26 mediated by adhesion
molecules.27 Bug et al. described a significant association between expression of CD11c and
a high risk of early death in leukocytosis;28 Novotny et al. showed a correlation between
expression of CD56/NCAM and development of leukostasis in patients with myelomonocytic
subtypes of AML.29 Stucki and co-workers observed a secretion of tumor necrosis factor-
alpha (TNF-α) and interleukin-1 beta (IL-1β) by leukemic myeloblasts leading to change in
the make-up of adhesion molecules on the endothelial cells. Several molecules such as
intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-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 endothelium.30 Additionally, cytokine-
driven endothelial damage, subsequent hemorrhage, hypoxic damage and AML blast
extravasation followed by consecutive tissue damage by matrix metalloproteases might
contribute to the pathogenesis of leukostasis.31,32,33,34 Important mechanisms of leukostasis
are shown in Figure 3.
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5 Röllig & Ehninger How I treat hyperleukocytosis in AML
Clinical manifestations and treatment options
Leukostasis, DIC and TLS represent the three main clinical manifestations of HL which can
cause life-threatening complications in AML patients. Early mortality in this patient group is
higher than in AML without HL and ranges from 8% in the first 24 hours9 to around 20%
during the first week 9,35,36,29, the main causes of death being bleedings, thromboembolic
events, neurological and pulmonary complications. In AML without HL, the early death rate is
significantly lower, ranging around 3-9%.37 But also in long-term follow-up, HL is a negative
prognostic factor as indicated by significantly shorter overall survival (OS)38,1,5 In our SAL
database capturing 3,510 intensively treated patients with an age range between 15 and 87
years, early death in HL versus all other AMLs was 6% versus 1% (p<0.001) after one week
and 13% versus 7% after 30 days (p<0.001). The 5-year OS was 28% versus 31% indicating
a small but significant prognostic difference (p=0.004). When early-death patients were
excluded in the analysis of relapse-free survival (RFS), HL was still associated with an
unfavorable prognosis as shown in 5-year RFS rates of 30% and 34% (p=0.005). In
multivariate analyses of OS and RFS accounting for the influence of other established
prognostic factors such as age, cytogenetic risk, FLT3, NPM1, secondary AML, LDH and
ECOG, HL retained its significant impact on prognosis (previously unpublished data).
Because of excessive early mortality, HL in AML is a medical emergency and treatment
should start immediately.
Disseminated intravascular coagulation
DIC is a coagulopathy induced by the formation of small clots consuming coagulation
proteins and platelets, resulting in disruption of normal coagulation and severe bleeding
tendency.39 Acute DIC is characterized by a decrease in platelet count and fibrinogen, an
elevation of D-dimers and prolongation of prothrombin time and activated partial
thromboplastin time and occurs in 30-40% of HL-AML.23 Platelet transfusions and standard
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measures to restore normal coagulation such as substitution of fresh frozen plasma or
fibrinogen40 should be initiated immediately in these patients since not only the deranged
coagulation 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 anticoagulation, platelets counts should be around 20,000-
30,000/µL, in patients with full heparin anticoagulation around 50,000/µL. In the subgroup of
acute promyelocytic leukemia (APL), induction of differentiation 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.41
Tumor lysis syndrome
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.20 There is no evidence that
low-dose cytostatic treatment with a slow and gradual leukocyte reduction decreases the risk
of tumor lysis as opposed to standard-dose intensive induction.42 In patients with a curative
treatment concept, intensive chemotherapy should therefore start immediately and without a
“pre-phase”. Prevention strategies include hydration and prophylactic allopurinol. Close
monitoring during the first days of treatment will reveal tumor lysis characterized by elevation
of serum potassium, phosphorus, 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
allopurinol 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. 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 hyperuricaemia and TLS, rasburicase (urate
oxidase) effectively lowers uric acid levels by enzymatic degradation, even after a single and
low-dose application.43,44,45,46,47
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Leukostasis
Leukostasis refers to clinical symptoms and complications caused by HL. Whereas
pathologically, the definition of leukostasis is clear (Figure 4), the clinical diagnosis is rarely
made with high confidence.39 Leukostasis is empirically diagnosed when patients present
with acute leukemia, HL and respiratory or neurological symptoms. However, the clinical and
radiographic manifestations of leukostasis are difficult to distinguish from those of common
infections or hemorrhagic complications of acute leukemia.23 Novotny et al. developed a
score for the clinical probability of leukostasis and Piccirillo et al. showed a correlation
between Novotny’s score and early death in case of score 3 indicating highly probable
leukostasis. About 44-50% of AML patients with a WBC >100,000/µL have a high probability
of leukostasis based on clinical symptoms. Although less frequently, typical symptoms can
also occur in patients with leukocytosis below 100,000/µL.29,36 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 frequencies were reported by
other investigators.28,49,9 CT scan or magnetic resonance imaging (MRI) of the head may
reveal intracranial hemorrhage (Figure 1, 2). A chest x-ray or CT scan often will show
bilateral interstitial or alveolar infiltrates (Figure 1).39,48 The typical clinical symptoms of
leukostasis are listed in Table 1. Apart from tissue damage caused by stasis and leukocyte
infiltration, hemorrhage and thromboembolic events are frequent and relevant complications
of leukostasis.39,9,18
Immediate initiation of cytoreductive treatment in this chemosensitive disease is mandatory
and should not be delayed.39,50 In case that a rapid diagnosis cannot be made, the patient
should be transferred to a specialized hospital on the same day. Whereas there are widely
consented and accepted standards for the treatment of DIC and TLS, the use of
leukapheresis in HL and the mode of cytoreduction is still a matter of debate.
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Cytoreduction
Hydroxyurea (HU) is commonly used before a proper induction regimen is implemented in
order to lower the tumor burden and reduce the risk of tumorlysis. However, there is no data
indicating that this approach is superior to immediate induction or that tumorlysis can be
prevented by a low-dose cytoreduction strategy. Results of a recent systematic review lack
evidence for a superiority of this approach over standard-dose induction.42 In all patients
eligible for intensive curative treatment, standard-dose or high-dose cytarabine plus
anthracyclin or mitoxantrone should be initiated as soon as the HL diagnosis is made.51,52
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
damage53,54 should be considered and treated accordingly. In acute promyelocytic leukemia
(APL), treatment with ATRA should be initiated immediately, even if APL is only suspected.
After APL confirmation, idarubicin or arsenic trioxide (ATO) should be added for proper
cytoreduction treatment.55
Leukapheresis
The term leukapheresis stems from the Greek to take away or remove.39 Leukapheresis in
HL is based on the principle to rapidly remove excessive leukocytes by mechanical
separation. The mechanical removal of leukocytes by leukapheresis has become routinely
available in many hematological treatment centers. If apheresis equipment is not available,
judicious phlebotomies with concurrent blood and/or plasma replacement may be used as
alternative strategy to reduce HL.39 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 10-70%.56 The efficacy of
leukapheresis to reduce the number of WBC has been shown in several clinical trials.
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However, there are two main reasons 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.57
These cells are rapidly mobilized into the peripheral blood shortly after a successful
leukapheresis.23 The second and more important reason is that a beneficial clinical effect on
early clinical outcomes 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, i.e. relapse risk is higher and overall survival is shorter in AML patients with initial
HL. Concerning the prevention of early complications and early death, several clinical trials
delivered heterogeneous results. In a systematic review, Oberoi et al. identified 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 due to 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
(systematically versus occasionally versus not). In a comparison between institutions with
leukapheresis in all HL patients and institutions using a “never” or “sometimes” policy, no
beneficial effect could be shown. Similarly, the investigators of this comprehensive review did
not observe an inverse relationship between the percentage of patients receiving a
leukapheresis and the incidence of early death.42 Pastore et al. analyzed a HL patient
population based on a score correcting for disease-related risk factors in order to separate
the leukapheresis effect on early death. According to their analysis, leukapheresis had no
beneficial effect on early death, irrespective of the individual early death risk.9 All trials where
retrospective and not randomized and it is unlikely that such studies will ever be feasible
given the rarity of the condition, urgency for decision making and strong physician
preferences.
As part of a discussion, the efficient reduction of WBCs and the standardized and generally
well tolerated procedure are brought forward as arguments for using leukapheresis whereas
hypercalcemia, the use of anticoagulants, aggravation of pre-exisiting thrombopenia,23 and
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the potential need for a central venous access42,57,39,58 may put the patient at procedural risks
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 beneficial in patients presenting with a manifest
leukostasis syndrome since leukapheresis represents a causal therapeutic principle. Based
on a grading score for the probability of leukostasis in leukemia patients with HL and a
validation analysis, patients with distinct symptoms have a high risk of leukostasis-related
early death (Table 1).29,36 Contraindications such as cardiovascular co-morbidities,
hemodynamic instability and coagulation disturbances should be evaluated carefully in order
to avoid a procedural extra risk for the patient. Patients with a manifest leukostasis in relation
to HL and without contraindicatios should receive daily leukapheresis. The blood volume to
process should be between 2 and 4 times the patient’s blood volume. Clinical controls for
hypocalcemia-induced paresthesia, monitoring of oxygen saturation, blood pressure and
heart rate are recommended during the intervention. If more than 20% of the patient’s blood
volume has been collected, fluid 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.59 Leukapheresis can be
repeated daily until symptoms of leukostasis have disappeared or the WBC count is below
100 x 109/µL.59,56 Cytoreductive treatment should start immediately at diagnosis of HL AML
and must not be delayed or postponed by the leukapheresis procedure.
There is no evidence for a beneficial effect of leukapheresis in HL patients without clinical
symptoms of leukostasis. Prophylactic leukapheresis offers no advantage over intensive
induction chemotherapy and supportive care, including those patients with TLS.59,42 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.60
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11 Röllig & Ehninger How I treat hyperleukocytosis in AML
Future research evaluating therapies targeting cytokines and adhesion molecules involved in
myeloblast-endothelium interactions may be worth exploring.42
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Conclusion: How I treat HL in AML
Based on these facts and considerations, we follow the treatment algorithm 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+3). In parallel, we provide intravenous hydration to ensure adequate
urine flow, we use allopurinol or rasburicase to reduce serum uric acid levels and check for
signs of DIC or tumor lysis twice daily until the WBC has fallen below upper normal limits.
Patients with suspected APL should receive ATRA immediately and additionally idarubicin
after cytologic or genetic APL confirmation. 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 above. Red blood cell transfusions are withheld
whenever possible until the WBC count is reduced. If a transfusion is necessary, it is
administered slowly. We give prophylactic platelet transfusions to maintain a count of greater
than 20,000-30,000/µL or 50,000/µL 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 scheduled for leukapheresis. Patients with a clinically high
likelihood of leukostasis 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/µL or the disappearance of clinical symptoms. In patients with contraindications for
immediate intensive induction treatment such as severe metabolic disturbances or renal
insufficiency, we use hydroxyurea for cytoreduction.
Once a complete remission (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 first CR, we recommend a patient with intermediate or adverse
cytogenetic risk and an available matched donor to undergo allogeneic stem cell
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transplantation in first remission based on the high relapse probability of hyperleukocytotic
AML after conventional chemotherapy consolidation. In all other cases including CBF
leukemias without c-kit mutations, standard chemotherapy with high-dose cytarabine will be
used as consolidation. Whenever possible, treatment should be part of a clinical trial or
registry in order to gain more knowledge and to improve treatment options in the future.
Acknowledgements
The authors would like to thank Michael Laniado (Institut und Poliklinik für Radiologische
Diagnostik, Universitätsklinikum TU Dresden), Rüdiger von Kummer and Dirk Daubner
(Abteilung Neuroradiologie, Universitätsklinikum TU Dresden) for providing radiographic
material for Figures 1 and 2A. The authors also thank Gustavo Baretton, Christian Zietz and
Friederike Kuithan (Institut für Pathologie, Universitätsklinikum TU Dresden) for tissue
sections and their interpretation in Figure 3, and Christiane Külper and Marika Erler
(Medizinische Klinik und Poliklinik I, Universitätsklinikum TU Dresden) for technical
assistance on cytological specimens in Figure 2C.
Authorship
Contribution: G.E. and C.R. wrote the manuscript.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Christoph Röllig, Universitätsklinikum TU Dresden, Fetscherstr. 74, 01307
Dresden, Germany; email: [email protected]
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Table 1. Symptoms of leukostasis.56 Patients presenting with one or more of these
symptoms not attributable to preexisting or coexisting medical conditions, leukostasis is
highly probable.29,36
Organ Symptoms
Lung Dyspnea, hypoxemia, diffuse alveolar
hemorrhage, respiratory failure
Central nervous system Confusion, somnolence, dizziness,
headache, delirium, coma, focal neurological
deficits
Eye Impaired vision, retinal hemorrhage
Ear Tinnitus
Heart Myocardial ischemia/infarction
Vascular system Limb ischemia, renal vein thrombosis,
priapism
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Figure Legends
Figure 1. Clinical case I. A 42-year old woman presented to her general practitioner with
general weakness and tooth pain. Laboratory assessment showed WBC of 80,000/µL, HB of
6.4 mg/dL, PLT of 21,000/µL, and led her physician to 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 CRP of 20 mg/L. She was
put on 4 g hydroxyurea 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+3) at WBC
of 70,000/µL. Immediate leukapheresis was not possible due to the progressive dyspnea and
the increasingly deranged coagulation status. By the next day, the WBC had gone down to
19,000/µL, but the patient developed respiratory failure requiring mechanical ventilation. The
computed tomography (CT) scan result was highly suggestive for leukostasis of the lungs (A)
while cranial CT showed multiple focal supratentorial hemorraghes (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 i) the fact that leukostasis developed rapidly even at
WBC below 100,000/µL, possibly due to the monocytic nature of blasts61, ii) cytarabine alone
led to a profound and rapid WBC reduction and iii) the patient recovered from mechanical
ventilation since the underlying leukostasis 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-grass opacities suggestive for
leukostasis and myeloblast infiltration. There is sparing of the lung periphery. Note also
bilateral 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
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cranial CT scan demonstrating multiple hyperdense lesions in both brain hemispheres
indicating hemorrhagic lesions. Accompanying cerebral edema is characterized by loss of
grey-white matter differentiation, compression of lateral ventricles and effacement of sulcal
spaces.
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Figure 2. Clinical case II.
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 around 170,000/µL, anemia and thrombocytopenia. After the diagnosis of AML M4 was
made, hydroxyurea and cytarabine were started and the patient was transferred to our
hospital, presenting with a WBC count 70,000/µL and central neurological deficits with
speech impairment. An MRI scan showed several meningeal lesions, but the cerebrospinal
fluid (CSF) cell count was normal and infection parameters were negative. In order to avoid
CSF contamination with leukemic blasts, lumbar puncture was postponed until peripheral
blast clearance. We continued cytarabine induction and added daunorubicin for three days.
WBC counts declined rapidly after initiation of cytarabine; the patient’s ability to speak
improved gradually and a control MRI seven 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 E.
coli septicemia and 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/µL within one 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
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perifocal edema. (B) Peripheral-blood sample from patient II 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 II at
hyperleukocytotic relapse (May-Grünwald and Giemsa stain, x400) showing numerous
myeloid blasts with wide cytoplasm and large euchromatin-containing nuclei with one or
more nucleoli.
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Figure 3. Pathogenetic mechanisms in leukostasis. Sludging of circulating myeloblasts
causes mechanical obstruction of small vessels and consecutive malperfusion in the
microvasculature, e.g. 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, ICAM-1 and VCAM-1. Myeloblasts can
promote their own adhesion to unactivated vascular endothelium by secreting TNF-alpha, IL-
1beta 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.62,63 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.34,33,31,64
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Figure 4. Histopathological finding in leukostasis. Specimen from the leptomeninges of
an AML patient post mortem stained with hematoxylin and eosin (H&E, x200). (A) Large
amounts of immature WBCs in a leptomeningeal capillary artery assumingly leading to
reduced blood flow and thrombus formation with strands of fibrin, red blood cells and WBCs.
(B) Numerous myeloid blasts and some RBCs are present in the extravascular space,
infiltrating the leptomeningeal tissue.
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21 Röllig & Ehninger How I treat hyperleukocytosis in AML
Figure 5. Treatment algorithm for AML with hyperleukocytosis. Supportive therapy such
as hydratation, prophylaxis of TLS, antiinfective treatment is necessary for all patients. *The
algorithm also applies to patients with leukocytosis <100 Gpt/l who present with symptoms
suggestive for leukostasis.
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22 Röllig & Ehninger How I treat hyperleukocytosis in AML
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Figure 3
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Figure 5
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doi:10.1182/blood-2014-10-551507Prepublished online March 16, 2015;
Christoph Röllig and Gerhard Ehninger How I treat hyperleukocytosis in acute myeloid leukemia
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