from how i treat · a white blood cell count>100000/ml, caused by leukemic cell proliferation....

How I Treat

How I treat hyperleukocytosis in acute myeloid leukemiaChristoph 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 bloodcounts andhigh

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 patientspresent 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 flow-cytometricimmunophenotyping, the rapid screening for the bcr-abl transcript byfluorescence in situ hybridization or polymerase chain reaction is ofimportance for diagnostic certainty. Although commonly defined bywhite blood cell (WBC) counts.100 000/mL, it should be noted thatWBC levels below this arbitrary threshold can also cause HL-relatedcomplications (Figures 1).11 Retrospective analyses have revealed anassociation with monocytic AML subtypes (French-American-Britishclassification M4/5; Figure 2),9,12,13 chromosomal MLL rearrange-ment 11q23,9,14 and theFLT3-ITDmutation,9,15,16 although only somepatients with these characteristics actually develop HL. In a cohort of3510 newly diagnosed AML patients of the Study Alliance Leuke-mia study group, 357 patients (10%) had WBCs .100 000/mL atinitial diagnosis. Our explorative analyses revealed 28% French-American-British M4/5 in HL patients as opposed to 16% in non-HLpatients (comparison by x2 test, P, .001). Further associations wereseen 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 associationwithMLL-PTD (2%vs 1%;P5 1.0). Themedian Eastern Cooperative Oncology Group (ECOG) performancestatus score at initial diagnosis was higher in HL patients, and fewerpatients displayed favorable or adverse cytogenetic aberrations (C.R.and G.E., unpublished data).

Twomain pathogenetic factors are responsible for the developmentof HL: first, a rapid blast proliferation leading to a high leukemic tumorburden; second, disruption in normal hematopoietic cell adhesionleading to a reduced affinity to the bone marrow.17 The high numberof 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 ofreleased 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 theblood flow by an increase of viscosity in the microcirculation.19,20 Thefact thatmyeloidblasts are larger than immature lymphocytes ormaturegranulocytes and that leukemic blasts are considerably less deformablethan mature leukocytes explains the higher incidence of leukostaticcomplications in AML as opposed to ALL, chronic myeloid leukemia,or chronic lymphocytic leukemia.8,21-23 However, the observationthat there is no clear correlation between the leukocyte count and theseverity and frequencyof leukostatic complications6,24,25 points towardadditional cellular mechanisms involved in the genesis of leukostasissuch as interactions between leukemic cells and the endothelium,26,27

mediated by adhesion molecules.28 Bug et al described a significantassociation between expression of CD11c and a high risk of early deathin leukocytosis.29 Stucki and coworkers observed a secretion of tumornecrosis factor-a and interleukin-1b by leukemic myeloblasts leadingto change in the makeup of adhesion molecules on the endothelialcells.30 Several molecules such as intracellular adhesion molecule-1,vascular cell adhesion molecule-1, and E-selectin were shown to beupregulated.By thismechanism, leukemic cells can promote their ownadhesion to the endothelium and create a self-perpetuating loop inwhich 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 extravasationfollowed by consecutive tissue damage by matrix metalloproteasesmight contribute to the pathogenesis of leukostasis.31-34 Importantmechanisms 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 AMLpatients. Early mortality in this patient group is higher than in AML

Submitted October 1, 2014; accepted February 2, 2015. Prepublished online

as Blood First Edition paper, March 16, 2015; DOI 10.1182/blood-2014-10-

551507.

© 2015 by The American Society of Hematology

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

For personal use only.on January 2, 2016. by guest www.bloodjournal.orgFrom

without HL and ranges from 8% in the first 24 hours9 to;20% duringthe first week,9,38,39,40 the main causes of death being bleeding, throm-boembolic events, and neurologic and pulmonary complications. InAML without HL, the early death rate is significantly lower, rangingfrom ;3% to 9%.41 However, also in long-term follow-up, HL is anegative prognostic factor as indicated by significantly shorter overallsurvival (OS)1,5,42 In our Study Alliance Leukemia study group data-base capturing 3510 intensively treated patients with an age rangebetween 15 and 87 years, early death in HL vs all other AMLs was 6%vs 1% (P, .001) after 1week and 13%vs 7%after 30 days (P, .001).The 5-year OS was 28% vs 31% indicating a small but significantprognostic difference (P5 .004). When early death patients were ex-cluded in the analysis of relapse-free survival (RFS), HL was still as-sociatedwith an unfavorable prognosis as shown in 5-year RFS rates of30% and 34% (P 5 .005). In multivariate analyses of OS and RFSaccounting for the influence of other established prognostic factorssuch as age, cytogenetic risk, FLT3,NPM1, secondary AML, lactatedehydrogenase, and ECOG, HL retained its significant impact on pro-gnosis (C.R. and G.E., unpublished data).

Because of excessive early mortality, HL in AML is a medicalemergency, 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 ofnormal coagulation and severe bleeding tendency.43 Acute DIC is char-acterized by a decrease in platelet count and fibrinogen, an elevation ofD-dimers, and prolongation of prothrombin time and activated partialthromboplastin time and occurs in 30% to 40% of HL-AML.24 Platelettransfusions and standard measures to restore normal coagulation suchas substitution of fresh frozenplasmaorfibrinogen44 shouldbe initiatedimmediately in these patients because not only the deranged coagu-lation itself but also HL and the associated endothelial damage put thepatient at a considerable risk for severe and sometimes fatal bleedingevents. In patients without central nervous manifestations and no anti-coagulation, platelet counts should be ;20 000 to 30 000/mL; inpatients 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 causaland most important treatment of DIC and should be started in allsuspicious cases even before cytological and cytogenetic or molecularproof.45

TLS

Although TLS is more common in lymphoidmalignancies andALL, itcan alsooccur inAML. In patientswith leukostasis, TLSoccurs in up to10%of cases.21 There is no evidence that low-dose cytostatic treatmentwith a slow and gradual leukocyte reduction decreases the risk of tumor

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

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.

BLOOD, 21 MAY 2015 x VOLUME 125, NUMBER 21 HOW I TREAT HYPERLEUKOCYTOSIS IN AML 3247


lysis as opposed to standard-dose intensive induction.46 In patientswitha curative treatment concept, intensive chemotherapy should thereforestart immediately and without a “prephase.” Prevention strategies in-clude hydration and prophylactic allopurinol. Close monitoring duringthe first days of treatment will reveal tumor lysis characterized by el-evation of serum potassium, phosphorus, and uric acid levels andpotentially by decline in calcium levels. Hyperuricemia can lead toacute renal damage or even failure and should be treated with allo-purinol or rasburicase depending on the uric acid levels. EstablishedTLS is managed similarly, with the addition of aggressive hydrationand 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 preventsthe synthesis of new uric acid. In cases with marked hyperuricemiaand TLS, rasburicase (urate oxidase) effectively lowers uric acidlevels by enzymatic degradation, even after a single and low-doseapplication.47-51

Leukostasis

Leukostasis refers to clinical symptoms and complications causedby HL. Whereas pathologically, the definition of leukostasis is clear(Figure 4), the clinical diagnosis is rarelymadewith high confidence.43

Leukostasis is empirically diagnosed when patients present with acuteleukemia, HL, and respiratory or neurologic symptoms. However, theclinical and radiographic manifestations of leukostasis are difficult todistinguish from those of common infections or hemorrhagic compli-cations of acute leukemia.24 Novotny et al39 developed a score for theclinical probability of leukostasis, and Piccirillo et al40 showed a cor-relation between Novotny’s score and early death in the case of a scoreof3 indicatinghighlyprobable leukostasis.Approximately 44%to50%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 leukocytosisbelow 100 000/mL.39,40 Organs most frequently affected are lung,brain, and kidneys. In a study by Porcu et al, the proportions of patientswith respective symptoms were 39%, 27%, and 14%.6 Similar fre-quencieswere reported by other investigators.9,29,52 CT scan orMRI ofthe headmay reveal intracranial hemorrhage (Figures 1 and 2). A chestradiograph or CT scan often will show bilateral interstitial or alveolarinfiltrates (Figure 1).43,53 The typical clinical symptoms of leukostasisare listed in Table 1. Apart from tissue damage caused by stasis andleukocyte infiltration, 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 arapid diagnosis cannot be made, the patient should be transferred to aspecialized hospital on the same day. Whereas there are widely agreed

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 patient’s 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.

3248 ROLLIG and EHNINGER BLOOD, 21 MAY 2015 x VOLUME 125, NUMBER 21


upon and accepted standards for the treatment of DIC and TLS, the useof leukapheresis inHLand themodeof cytoreduction are still amatter ofdebate.

Cytoreduction

Hydroxyurea is commonly used before a proper induction regimen isimplemented in order to lower the tumor burden and reduce the risk oftumor lysis. However, there are no data indicating that this approach issuperior to immediate induction or that tumor lysis can be preventedby a low-dose cytoreduction strategy. Results of a recent systematicreview 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 Thisapplies to all HL patients with AML, both with and without signs ofleukostasis. In cases with unclear HL, HU may be used short term asbridging strategy (Figure 1). If respiratory failure develops despitefalling WBC counts, pneumonia or cytarabine-induced pulmonarydamage57,58 should be considered and treated accordingly. In APL,treatment with ATRA should be initiated immediately, even if APL isonly suspected. After APL confirmation, idarubicin or arsenic trioxideshould be added for proper cytoreduction treatment.59

Leukapheresis

The term leukapheresis stems from the Greek “to take away” or “toremove.”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 routinelyavailable in many hematologic treatment centers. If apheresis equipment

is not available, judicious phlebotomies with concurrent blood and/orplasma replacement may be used as an alternative strategy to reduceHL.43 In modern apheresis devices (blood cell separators), WBCs andtheir precursors are separated from patients’ blood by centrifugation.During a single leukapheresis, theWBC count can be reduced by 10%to 70%.60 The efficacy of leukapheresis to reduce the number ofWBCshas 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 bonemarrow.61 These cells are rapidly mobilized into the peripheral bloodshortly after a successful leukapheresis.24 The second and more im-portant reason is that a beneficial clinical effect on early clinical out-comes could not be shown consistently in clinical trials. Fromwhat weknow from all clinical trials employing leukapheresis in HL patients,long-term prognosis cannot be changed (ie, relapse risk is higher andOS is shorter in AML patients with initial HL). Concerning the pre-vention of early complications and early death, several clinical trialsdelivered heterogeneous results. In a systematic review, Oberoi et al46

identified 14 studies using leukapheresis systematically or occasionallyin 420 children and adult patients with HLAML. One additional studywith 45 patients generally not using leukapheresis was added forcomparison.The resultsof the trials couldnot be synthesizedbecauseofheterogeneity, but there was neither a trend for higher or lower earlydeath in patients with andwithout leukapheresis nor did the early deathrates differ depending on the leukapheresis strategy used (systemat-ically vs occasionally vs not). In a comparison between institutionswithleukapheresis in all HL patients and institutions using a “never” or“sometimes” policy, no beneficial effect could be shown. Similarly, theinvestigators of this comprehensive review did not observe an inverserelationship between the percentage of patients receiving a leukaphe-resis and the incidence of early death.46 Pastore et al9 analyzed an HL

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

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.



patient population based on a score correcting for disease-related riskfactors in order to separate the leukapheresis effect on early death. Ac-cording to their analysis, leukapheresis had no beneficial effect on earlydeath, irrespective of the individual early death risk.9 All trials wereretrospective and not randomized, and it is unlikely that such studieswill ever be feasible given the rarity of the condition, urgency for de-cision making, and strong physician preferences.

As part of a discussion, the efficient reduction of WBCs and thestandardized and generally well-tolerated procedure are brought for-ward as arguments for using leukapheresis,whereas hypercalcemia, theuse of anticoagulants, aggravation of preexisting thrombopenia,24 andthe potential need for a central venous access43,46,61,62 may put patientsat procedural risk on top of their unstable condition. Last but not least,infrastructural requirements and costs linked to leukapheresis have tobetaken into account.

In conclusion, leukapheresis may be beneficial in patients present-ing with a manifest leukostasis syndrome because leukapheresis re-presents a causal therapeutic principle. Based on a grading score forthe probability of leukostasis in leukemia patients with HL and a vali-dation analysis, patients with distinct symptoms have a high risk ofleukostasis-related early death (Table 1).39,40 Contraindications suchas cardiovascular comorbidities, hemodynamic instability, and coag-ulation disturbances should be evaluated carefully in order to avoid anextra procedural risk for the patient. Patientswith amanifest leukostasisin relation to HL and without contraindications should receive dailyleukapheresis. The blood volume to process should be between 2 and 4times the patient’s 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 thepatient’s bloodvolumehas been collected,fluid replacementwithcolloids or human albumin is recommended. Red cell transfusionsshould be given only if inevitable and only at the end of leukapheresisin order to avoid further increase of blood viscosity.63 Leukapheresiscan be repeated daily until symptoms of leukostasis have disappearedor theWBCcount isbelow1003109/mL.60,63Cytoreductive treatmentshould 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 beneficial effect of leukapheresis in HLpatients without clinical symptoms of leukostasis. Prophylactic leu-kapheresis offers no advantage over intensive induction chemotherapyand supportive care, including those patients with TLS.46,63 Based onthe pros and cons of the procedure, a routinely performed prophylacticleukapheresis cannot be recommended. In APL, leukapheresis mightworsen the coagulopathy and increase the rate of complications and istherefore not recommended.64

Future research evaluating therapies targeting cytokines and adhe-sion molecules involved in myeloblast-endothelium interactions maybe worth exploring.46

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 assesseligibility for intensive treatment. Treatment-eligible patients start withstandard induction treatment combining standard-dose cytarabine plusdaunorubicin (7 1 3). In parallel, we provide intravenous hydrationto ensure adequate urine flow, use allopurinol or rasburicase to reduceserum uric acid levels, and check for signs of DIC or tumor lysis twicedaily until the WBC count has fallen below upper normal limits.Patients with suspected APL should receive ATRA immediately andadditionally idarubicin after cytological or genetic APL confirmation.In addition to idarubicin, the WBC count is further reduced by HUuntil normal levels have been reached. DIC and TLS are treated withstandard 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 to30 000/mL or 50 000/mL in case of full heparin anticoagulationuntil the WBC count has been reduced and the clinical situation hasbeen 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 asAPL, coagulation disorders, cardiovascular comorbidities, or instablecirculation. Patients without contraindications are scheduled to receiveleukapheresis with a target WBC count below 100 000/mL or the dis-appearance of clinical symptoms. In patients with contraindications forimmediate intensive induction treatment such as severe metabolic dis-turbances or renal insufficiency, we use HU for cytoreduction.

Once CR has been achieved, we make a decision on consolidationtreatment depending on donor availability and cytogenetic risk. If thestandard induction does not lead toCR,we use a salvage regimen basedon high-dose cytarabine, possibly including novel investigationaldrugs. Infirst CR,we recommend apatientwith intermediate or adversecytogenetic risk and an available matched donor to undergo allogeneicstem cell transplantation in first remission based on the high relapseprobability of hyperleukocytotic AML after conventional chemother-apy consolidation. In all other cases including core binding factor leu-kemiaswithout c-kitmutations, standard chemotherapywith 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.

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



cytarabine will be used as consolidation. Whenever possible, treat-ment should be part of a clinical trial or registry in order to gainmoreknowledge and to improve treatment options in the future.

Acknowledgments

The authors thankMichael 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) forproviding radiographic material for Figures 1 and 2A. The authorsalso thank Gustavo Baretton, Christian Zietz, and Friederike Kuithan(Institut fur Pathologie, Universitatsklinikum TU Dresden) for tissue

sections and their interpretation in Figure 4, andChristianeKulper andMarika Erler (Medizinische Klinik und Poliklinik I, Universitatskli-nikum TUDresden) for technical assistance on cytological specimensin Figure 2C.

Authorship

Contribution: G.E. and C.R. wrote the manuscript.Conflict-of-interest disclosure: The authors declare no competing

financial interests.Correspondence:ChristophRollig,UniversitatsklinikumTUDresden,

Fetscherstrasse 74, 01307 Dresden, Germany; e-mail: [email protected].

References

1. Dutcher JP, Schiffer CA, Wiernik PH.Hyperleukocytosis in adult acute nonlymphocyticleukemia: impact on remission rate and duration,and survival. J Clin Oncol. 1987;5(9):1364-1372.

2. Vaughan WP, Kimball AW, Karp JE, Dragon LH,Burke PJ. Factors affecting survival of patientswith acute myelocytic leukemia presenting withhigh wbc counts. Cancer Treat Rep. 1981;65(11-12):1007-1013.

3. Cuttner J, Holland JF, Norton L, Ambinder E,Button G, Meyer RJ. Therapeutic leukapheresisfor hyperleukocytosis in acute myelocyticleukemia. Med Pediatr Oncol. 1983;11(2):76-78.

4. Ventura GJ, Hester JP, Smith TL,Keating MJ. Acute myeloblastic leukemia withhyperleukocytosis: risk factors for early mortalityin induction. Am J Hematol. 1988;27(1):34-37.

5. Hug V, Keating M, McCredie K, Hester J, BodeyGP, Freireich EJ. Clinical course and response totreatment of patients with acute myelogenousleukemia presenting with a high leukocyte count.Cancer. 1983;52(5):773-779.

6. Porcu P, Danielson CF, Orazi A, Heerema NA,Gabig TG, McCarthy LJ. Therapeuticleukapheresis in hyperleucocytic leukaemias: lackof correlation between degree of cytoreductionand early mortality rate. Br J Haematol. 1997;98(2):433-436.

7. Creutzig U, Ritter J, Budde M, Sutor A, SchellongG. Early deaths due to hemorrhage andleukostasis in childhood acute myelogenousleukemia. Associations with hyperleukocytosisand acute monocytic leukemia. Cancer. 1987;60(12):3071-3079.

8. Bunin NJ, Pui CH. Differing complicationsof hyperleukocytosis in children with acutelymphoblastic or acute nonlymphoblasticleukemia. J Clin Oncol. 1985;3(12):1590-1595.

9. Pastore F, Pastore A, Wittmann G, HiddemannW, Spiekermann K. The role of therapeuticleukapheresis in hyperleukocytotic AML. PLoSONE. 2014;9(4):e95062.

10. Byrd JC, Mrozek K, Dodge RK, et al; Cancer andLeukemia Group B (CALGB 8461). Pretreatmentcytogenetic abnormalities are predictive ofinduction success, cumulative incidence ofrelapse, and overall survival in adult patients withde novo acute myeloid leukemia: results fromCancer and Leukemia Group B (CALGB 8461).Blood. 2002;100(13):4325-4336.

11. Zuckerman T, Ganzel C, Tallman MS, Rowe JM.How I treat hematologic emergencies in adultswith acute leukemia. Blood. 2012;120(10):1993-2002.

12. Cuttner J, Conjalka MS, Reilly M, et al.Association of monocytic leukemia in patients with

extreme leukocytosis. Am J Med. 1980;69(4):555-558.

13. Scott CS, Stark AN, Limbert HJ, Master PS, HeadC, Roberts BE. Diagnostic and prognostic factorsin acute monocytic leukaemia: an analysis of 51cases. Br J Haematol. 1988;69(2):247-252.

14. Kaneko Y, Maseki N, Takasaki N, et al. Clinicaland hematologic characteristics in acute leukemiawith 11q23 translocations. Blood. 1986;67(2):484-491.

15. Frohling S, Schlenk RF, Breitruck J, et al; AMLStudy Group Ulm. Prognostic significance ofactivating FLT3 mutations in younger adults (16 to60 years) with acute myeloid leukemia and normalcytogenetics: a study of the AML Study GroupUlm. Blood. 2002;100(13):4372-4380.

16. Thiede C, Steudel C, Mohr B, et al. Analysis ofFLT3-activating mutations in 979 patients withacute myelogenous leukemia: association withFAB subtypes and identification of subgroupswith poor prognosis. Blood. 2002;99(12):4326-4335.

17. Reuss-Borst MA, Klein G, Waller HD, Muller CA.Differential expression of adhesion molecules inacute leukemia. Leukemia. 1995;9(5):869-874.

18. Dixit A, Chatterjee T, Mishra P, et al.Disseminated intravascular coagulation in acuteleukemia at presentation and during inductiontherapy. Clin Appl Thromb Hemost. 2007;13(3):292-298.

19. McKee LC Jr, Collins RD. Intravascular leukocytethrombi and aggregates as a cause of morbidityand mortality in leukemia. Medicine (Baltimore).1974;53(6):463-478.

20. Lichtman MA. Rheology of leukocytes, leukocytesuspensions, and blood in leukemia. Possiblerelationship to clinical manifestations. J ClinInvest. 1973;52(2):350-358.

21. Porcu P, Cripe LD, Ng EW, et al. Hyperleukocyticleukemias and leukostasis: a review ofpathophysiology, clinical presentation andmanagement. Leuk Lymphoma. 2000;39(1-2):1-18.

22. Lichtman MA, Weed RI. Peripheral cytoplasmiccharacteristics of leukocytes in monocyticleukemia: relationship to clinical manifestations.Blood. 1972;40(1):52-61.

23. Lichtman MA, Rowe JM. Hyperleukocyticleukemias: rheological, clinical, and therapeuticconsiderations. Blood. 1982;60(2):279-283.

24. Porcu P, Farag S, Marcucci G, Cataland SR,Kennedy MS, Bissell M. Leukocytoreduction foracute leukemia. Ther Apher. 2002;6(1):15-23.

25. Soares FA, Landell GA, Cardoso MC.Pulmonary leukostasis without hyperleukocytosis:

a clinicopathologic study of 16 cases. Am JHematol. 1992;40(1):28-32.

26. Cavenagh JD, Gordon-Smith EC, Gibson FM,Gordon MY. Acute myeloid leukaemia blast cellsbind to human endothelium in vitro utilizing E-selectin and vascular cell adhesion molecule-1(VCAM-1). Br J Haematol. 1993;85(2):285-291.

27. van Buchem MA, Hogendoorn PC, Levelt CN,et al. Development of pulmonary leukostasis inexperimental myelocytic leukemia in the Brown-Norway rat. Leukemia. 1992;6(2):142-149.

28. De Waele M, Renmans W, Jochmans K, et al.Different expression of adhesion molecules onCD341 cells in AML and B-lineage ALL and theirnormal bone marrow counterparts. Eur JHaematol. 1999;63(3):192-201.

29. Bug G, Anargyrou K, Tonn T, et al. Impactof leukapheresis on early death rate in adultacute myeloid leukemia presenting withhyperleukocytosis. Transfusion. 2007;47(10):1843-1850.

30. Stucki A, Rivier AS, Gikic M, Monai N, SchapiraM, Spertini O. Endothelial cell activation bymyeloblasts: molecular mechanisms ofleukostasis and leukemic cell dissemination.Blood. 2001;97(7):2121-2129.

31. Hatfield KJ, Reikvam H, Bruserud Ø. Thecrosstalk between the matrix metalloproteasesystem and the chemokine network in acutemyeloid leukemia. Curr Med Chem. 2010;17(36):4448-4461.

32. Hatfield KJ, Bedringsaas SL, Ryningen A, GjertsenBT, Bruserud O. Hypoxia increases HIF-1aexpression and constitutive cytokine release byprimary human acute myeloid leukaemia cells.Eur Cytokine Netw. 2010;21(3):154-164.

33. Reikvam H, Hatfield KJ, Oyan AM, Kalland KH,Kittang AO, Bruserud O. Primary human acutemyelogenous leukemia cells release matrixmetalloproteases and their inhibitors: releaseprofile and pharmacological modulation. Eur JHaematol. 2010;84(3):239-251.

34. Paupert J, Mansat-De Mas V, Demur C, Salles B,Muller C. Cell-surface MMP-9 regulates theinvasive capacity of leukemia blast cells withmonocytic features. Cell Cycle. 2008;7(8):1047-1053.

35. Hunt BJ, Jurd KM. Endothelial cell activation.A central pathophysiological process. BMJ. 1998;316(7141):1328-1329.

36. Mantovani A, Sozzani S, Vecchi A, Introna M,Allavena P. Cytokine activation of endothelialcells: new molecules for an old paradigm. ThrombHaemost. 1997;78(1):406-414.

37. Stefanidakis M, Karjalainen K, Jaalouk DE,et al. Role of leukemia cell invadosome in



extramedullary infiltration. Blood. 2009;114(14):3008-3017.

38. Marbello L, Ricci F, Nosari AM, et al. Outcome ofhyperleukocytic adult acute myeloid leukaemia:a single-center retrospective study and review ofliterature. Leuk Res. 2008;32(8):1221-1227.

39. Novotny JR, Muller-Beissenhirtz H, Herget-Rosenthal S, Kribben A, Duhrsen U. Grading ofsymptoms in hyperleukocytic leukaemia: a clinicalmodel for the role of different blast types andpromyelocytes in the development of leukostasissyndrome. Eur J Haematol. 2005;74(6):501-510.

40. Piccirillo N, Laurenti L, Chiusolo P, et al. Reliabilityof leukostasis grading score to identify patientswith high-risk hyperleukocytosis. Am J Hematol.2009;84(6):381-382.

41. Atallah E, Cortes J, O’Brien S, et al.Establishment of baseline toxicity expectationswith standard frontline chemotherapy in acutemyelogenous leukemia. Blood. 2007;110(10):3547-3551.

42. Lowenberg B, Suciu S, Archimbaud E, et al.Use of recombinant GM-CSF during and afterremission induction chemotherapy in patientsaged 61 years and older with acute myeloidleukemia: final report of AML-11, a phase IIIrandomized study of the Leukemia CooperativeGroup of European Organisation for the Researchand Treatment of Cancer and the Dutch BelgianHemato-Oncology Cooperative Group. Blood.1997;90(8):2952-2961.

43. Ganzel C, Becker J, Mintz PD, Lazarus HM,Rowe JM. Hyperleukocytosis, leukostasis andleukapheresis: practice management. Blood Rev.2012;26(3):117-122.

44. Levi M, Toh CH, Thachil J, Watson HG; BritishCommittee for Standards in Haematology.Guidelines for the diagnosis and management ofdisseminated intravascular coagulation. Br JHaematol. 2009;145(1):24-33.

45. Avvisati G, Tallman MS. All-trans retinoic acid inacute promyelocytic leukaemia. Best Pract ResClin Haematol. 2003;16(3):419-432.

46. Oberoi S, Lehrnbecher T, Phillips B, et al.Leukapheresis and low-dose chemotherapy do notreduce early mortality in acute myeloid leukemiahyperleukocytosis: a systematic review and meta-analysis. Leuk Res. 2014;38(4):460-468.

47. Coiffier B, Altman A, Pui CH, Younes A, CairoMS. Guidelines for the management of pediatricand adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26(16):2767-2778.

48. Vadhan-Raj S, Fayad LE, Fanale MA, et al.A randomized trial of a single-dose rasburicaseversus five-daily doses in patients at risk for tumorlysis syndrome. Ann Oncol. 2012;23(6):1640-1645.

49. Feng X, Dong K, Pham D, Pence S, Inciardi J,Bhutada NS. Efficacy and cost of single-doserasburicase in prevention and treatment of adulttumour lysis syndrome: a meta-analysis. J ClinPharm Ther. 2013;38(4):301-308.

50. Coutsouvelis J, Wiseman M, Hui L, et al.Effectiveness of a single fixed dose of rasburicase3 mg in the management of tumour lysissyndrome. Br J Clin Pharmacol. 2013;75(2):550-553.

51. Darmon M, Guichard I, Vincent F. Rasburicaseand tumor lysis syndrome: lower dosage,consideration of indications, and hyperhydration.J Clin Oncol. 2011;29(3):e67-e68, author replye69.

52. Chang MC, Chen TY, Tang JL, et al.Leukapheresis and cranial irradiation in patientswith hyperleukocytic acute myeloid leukemia:no impact on early mortality and intracranialhemorrhage. Am J Hematol. 2007;82(11):976-980.

53. Piro E, Carillio G, Levato L, Kropp M, Molica S.Reversal of leukostasis-related pulmonarydistress syndrome after leukapheresis and low-dose chemotherapy in acute myeloid leukemia.J Clin Oncol. 2011;29(26):e725-e726.

54. Giles FJ, Shen Y, Kantarjian HM, et al.Leukapheresis reduces early mortality in patientswith acute myeloid leukemia with high white cellcounts but does not improve long- term survival.Leuk Lymphoma. 2001;42(1-2):67-73.

55. Dohner H, Estey EH, Amadori S, et al;European LeukemiaNet. Diagnosis andmanagement of acute myeloid leukemia in adults:recommendations from an international expertpanel, on behalf of the European LeukemiaNet.Blood. 2010;115(3):453-474.

56. Ferrara F, Schiffer CA. Acute myeloid leukaemiain adults. Lancet. 2013;381(9865):484-495.

57. Jehn U, Goldel N, Rienmuller R, Wilmanns W.Non-cardiogenic pulmonary edema complicatingintermediate and high-dose Ara C treatment forrelapsed acute leukemia. Med Oncol TumorPharmacother. 1988;5(1):41-47.

58. Andersson BS, Luna MA, Yee C, Hui KK, KeatingMJ, McCredie KB. Fatal pulmonary failurecomplicating high-dose cytosine arabinosidetherapy in acute leukemia. Cancer. 1990;65(5):1079-1084.

59. Lo-Coco F, Avvisati G, Vignetti M, et al; ItalianGIMEMA Cooperative Group. Front-line treatmentof acute promyelocytic leukemia with AIDAinduction followed by risk-adapted consolidationfor adults younger than 61 years: results of theAIDA-2000 trial of the GIMEMA Group. Blood.2010;116(17):3171-3179.

60. Holig K, Moog R. Leukocyte depletion bytherapeutic leukocytapheresis in patients withleukemia. Transfus Med Hemother. 2012;39(4):241-245.

61. Bruserud Ø, Liseth K, Stamnesfet S, et al.Hyperleukocytosis and leukocytapheresis in acuteleukaemias: experience from a single centre andreview of the literature of leukocytapheresis inacute myeloid leukaemia. Transfus Med. 2013;23(6):397-406.

62. Blum W, Porcu P. Therapeutic apheresis inhyperleukocytosis and hyperviscosity syndrome.Semin Thromb Hemost. 2007;33(4):350-354.

63. Szczepiorkowski ZM, Winters JL, Bandarenko N,et al; Apheresis Applications Committee of theAmerican Society for Apheresis. Guidelines onthe use of therapeutic apheresis in clinicalpractice—evidence-based approach from theApheresis Applications Committee of theAmerican Society for Apheresis. J Clin Apher.2010;25(3):83-177.

64. Vahdat L, Maslak P, Miller WH Jr, et al. Earlymortality and the retinoic acid syndrome in acutepromyelocytic leukemia: impact of leukocytosis,low-dose chemotherapy, PMN/RAR-alphaisoform, and CD13 expression in patients treatedwith all-trans retinoic acid. Blood. 1994;84(11):3843-3849.



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

2015 125: 3246-3252

Christoph Röllig and Gerhard Ehninger How I treat hyperleukocytosis in acute myeloid leukemia

http://www.bloodjournal.org/content/125/21/3246.full.htmlUpdated information and services can be found at:

(1436 articles)Myeloid Neoplasia (169 articles)How I Treat

(3517 articles)Free Research Articles Articles on similar topics can be found in the following Blood collections

http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requestsInformation about reproducing this article in parts or in its entirety may be found online at:

http://www.bloodjournal.org/site/misc/rights.xhtml#reprintsInformation about ordering reprints may be found online at:

http://www.bloodjournal.org/site/subscriptions/index.xhtmlInformation about subscriptions and ASH membership may be found online at:

Copyright 2011 by The American Society of Hematology; all rights reserved.of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society


from how i treat · a white blood cell count>100000/ml, caused by leukemic cell proliferation....

Documents