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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 For personal use only. on October 31, 2017. by guest www.bloodjournal.org From

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Page 1: How I treat Hyperleukocytosis in Acute Myeloid Leukemia€¦ · Röllig & Ehninger How I treat hyperleukocytosis in AML Incidence and pathophysiology In untreated AML, about 5 to

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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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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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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18 Röllig & Ehninger How I treat hyperleukocytosis in AML

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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19 Röllig & Ehninger How I treat hyperleukocytosis in AML

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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20 Röllig & Ehninger How I treat hyperleukocytosis in AML

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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