How I Treat How I Treat Hyperleukocytosis in Acute Myeloid Leukemia

From www.bloodjournal.org by guest on January 2, 2016. For personal use only. How I Treat

How I treat hyperleukocytosis in acute myeloid leukemia

Christoph R¨olligand Gerhard Ehninger

Medizinische Klinik und Poliklinik I, Universit¨atsklinikumder Technischen Universit¨at Dresden, Germany

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

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

3246 BLOOD, 21 MAY 2015 x VOLUME 125, NUMBER 21 From www.bloodjournal.org by guest on January 2, 2016. For personal use only.

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

without HL and ranges from 8% in the first 24 hours9 to ;20% during the first week,9,38,39,40 the main causes of death being bleeding, thromboembolic events, and neurologic and pulmonary complications. In AML without HL, the early death rate is significantly lower, ranging from ;3% to 9%.41 However, also in long-term follow-up, HL is a negative prognostic factor as indicated by significantly shorter overall survival (OS)1,5,42 In our Study Alliance Leukemia study group data- base capturing 3510 intensively treated patients with an age range between 15 and 87 years, early death in HL vs all other AMLs was 6% vs 1% (P , .001) after 1 week and 13% vs 7% after 30 days (P , .001). The 5-year OS was 28% vs 31% indicating a small but significant prognostic difference (P 5 .004). When early death patients were ex- cluded 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 5 .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, lactate dehydrogenase, and ECOG, HL retained its significant impact on prognosis (C.R. and G.E., unpublished data). Because of excessive early mortality, HL in AML is a medical emergency, and treatment should start immediately.

DIC

DIC is a coagulopathy induced by the formation of small clots con- suming coagulation proteins and platelets, resulting in disruption of normal coagulation and severe bleeding tendency.43 Acute DIC is 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% to 40% of HL-AML.24 Platelet transfusions and standard measures to restore normal coagulation such as substitution of fresh frozen plasma or ﬁbrinogen44 should be initiated immediately in these patients because 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, platelet counts should be ;20 000 to 30 000/mL; in patients with full heparin anticoagulation, ;50 000/mL. In the sub- Figure 1. Clinical case 1. A 42-year-old woman presented to her general group of acute promyelocytic leukemia (APL), induction of differen- practitioner with general weakness and tooth pain. Laboratory assessment showed tiation by administration of all-trans retinoid acid (ATRA) is the causal 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 and most important treatment of DIC and should be started in all a differential blood count revealed 56% myeloid blasts. By that time, the patient suspicious cases even before cytological and cytogenetic or molecular was in stable clinical condition with a minimally elevated C-reactive protein of proof.45 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 TLS down to 19 000/mL, but the patient developed respiratory failure requiring mechanical ventilation. The computed tomography (CT) scan result was highly suggestive for Although TLS is more common in lymphoid malignancies and ALL, it leukostasis of the lungs (A), and cranial CT showed multiple focal supratentorial can also occur in AML. In patients with leukostasis, TLS occurs in up to hemorrhages (B). During the next few days, respiratory indices improved, and the 21 patient could be extubated. Early bone marrow response assessment showed 10% of cases. There is no evidence that low-dose cytostatic treatment a good response with leukemia-free hypoplastic marrow, and after regeneration with a slow and gradual leukocyte reduction decreases the risk of tumor 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 Figure 1 (continued) pleural effusions. Respiratory failure required mechanical blasts11; (2) cytarabine alone led to a profound and rapid WBC reduction; and (3) the ventilation support as indicated by the endotracheal tube. A central venous catheter patient recovered from mechanical ventilation because the underlying leuko- in the right brachiocephalic vein and nasogastric tube in the esophagus can be seen. stasis could be treated successfully. (A) Contrast-enhanced CT image (lung (B) Horizontal plane of native cranial CT scan demonstrating multiple hyperdense window) through the upper fields of the lungs demonstrates parenchymal lesions in both brain hemispheres indicating hemorrhagic lesions. Accompanying infiltrates as well as diffuse ground-glass opacities suggestive for leukostasis cerebral edema is characterized by loss of gray-white matter differentiation, com- and myeloblast infiltration. There is sparing of the lung periphery. Note also bilateral pression of lateral ventricles, and effacement of sulcal spaces. From www.bloodjournal.org by guest on January 2, 2016. For personal use only.

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

Figure 2. Clinical case 2. A 68-year-old man sought medical help at the emergency unit of his local hospital because of weakness, bone pain, and night sweats over several weeks. He was admitted because of HL of ;170 000/mL, anemia, and thrombocytopenia. After the diagnosis of AML M4 was made, HU and cytarabine were started, and the patient was transferred to our hospital, presenting with a WBC count 70 000/mL and central neurologic deficits with speech impairment. A magnetic resonance imaging (MRI) scan showed several meningeal lesions, but the cerebrospinal fluid cell count was normal, and infection parameters were negative. In order to avoid cerebrospinal fluid contamination with leukemic blasts, lumbar puncture was postponed until peripheral blast clearance. We continued cytarabine induction and added daunorubicin for 3 days. WBC counts declined rapidly after initiation of cytarabine; the 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-Grünwald and Giemsa stain, 3400) showing numerous myeloid blasts with wide cytoplasm and large euchromatin-containing nuclei with 1 or more nucleoli. lysis as opposed to standard-dose intensive induction.46 In patients with Leukostasis is empirically diagnosed when patients present with acute a curative treatment concept, intensive chemotherapy should therefore leukemia, HL, and respiratory or neurologic symptoms. However, the start immediately and without a “prephase.” Prevention strategies in- clinical and radiographic manifestations of leukostasis are difficult to clude hydration and prophylactic allopurinol. Close monitoring during distinguish from those of common infections or hemorrhagic compli- the first days of treatment will reveal tumor lysis characterized by el- cations of acute leukemia.24 Novotny et al39 developed a score for the evation of serum potassium, phosphorus, and uric acid levels and clinical probability of leukostasis, and Piccirillo et al40 showed a cor- potentially by decline in calcium levels. Hyperuricemia can lead to relation between Novotny’sscoreandearlydeathinthecaseofascore acute renal damage or even failure and should be treated with allo- of 3 indicating highly probable leukostasis. Approximately 44% to 50% purinol or rasburicase depending on the uric acid levels. Established of AML patients with a WBC count .100 000/mLhaveahighprob- TLS is managed similarly, with the addition of aggressive hydration ability of leukostasis based on clinical symptoms. Although less fre- and diuresis, plus allopurinol or rasburicase for hyperuricemia. Addi- quently, typical symptoms can also occur in patients with leukocytosis tionally, electrolyte imbalances should be corrected. Whereas allopu- below 100 000/mL.39,40 Organs most frequently affected are lung, rinol is the less expensive therapy for hyperuricemia, it only prevents brain, and kidneys. In a study by Porcu et al, the proportions of patients the synthesis of new uric acid. In cases with marked hyperuricemia with respective symptoms were 39%, 27%, and 14%.6 Similar fre- and TLS, rasburicase (urate oxidase) effectively lowers uric acid quencies were reported by other investigators.9,29,52 CT scan or MRI of levels by enzymatic degradation, even after a single and low-dose the head may reveal intracranial hemorrhage (Figures 1 and 2). A chest 47-51 application. radiograph or CT scan often will show bilateral interstitial or alveolar infiltrates (Figure 1).43,53 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 fre- Leukostasis quent and relevant complications of leukostasis. 9,19,43 Immediate initiation of cytoreductive treatment in this chemosen- Leukostasis refers to clinical symptoms and complications caused sitive disease is mandatory and should not be delayed.43,54 In case a by HL. Whereas pathologically, the definition of leukostasis is clear rapid diagnosis cannot be made, the patient should be transferred to a (Figure 4), the clinical diagnosis is rarely made with high confidence.43 specialized hospital on the same day. Whereas there are widely agreed From www.bloodjournal.org by guest on January 2, 2016. For personal use only.

BLOOD, 21 MAY 2015 x VOLUME 125, NUMBER 21 HOW I TREAT HYPERLEUKOCYTOSIS IN AML 3249

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

Cytoreduction

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

Leukapheresis

The term leukapheresis stems from the Greek “to take away” or “to Figure 4. Histopathological finding in leukostasis. Specimen from the leptome- remove.”43 Leukapheresis in HL is based on the principle of rapidly re- ninges of an AML patient postmortem stained with hematoxylin and eosin (3200). (A) moving excessive leukocytes by mechanical separation. The mechan- 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 ical removal of leukocytes by leukapheresis has become routinely cells (RBCs), and WBCs. (B) Numerous myeloid blasts and some RBCs are present in available in many hematologic treatment centers. If apheresis equipment the extravascular space, infiltrating the leptomeningeal tissue. From www.bloodjournal.org by guest on January 2, 2016. For personal use only.

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Table 1. Symptoms of leukostasis Organ Symptoms Conclusion: how I treat HL in AML Lung Dyspnea, hypoxemia, diffuse alveolar hemorrhage, respiratory failure Based on these facts and considerations, we follow the treatment al- Central nervous system Confusion, somnolence, dizziness, headache, gorithm shown in Figure 5. In patients with AML and HL, we assess delirium, coma, focal neurologic deficits eligibility for intensive treatment. Treatment-eligible patients start with Eye Impaired vision, retinal hemorrhage standard induction treatment combining standard-dose cytarabine plus Ear Tinnitus daunorubicin (7 1 3). In parallel, we provide intravenous hydration Heart Myocardial ischemia/infarction to ensure adequate urine flow, use allopurinol or rasburicase to reduce Vascular system Limb ischemia, renal vein thrombosis, priapism serum uric acid levels, and check for signs of DIC or tumor lysis twice For patients presenting with 1 or more of these symptoms not attributable to daily until the WBC count has fallen below upper normal limits. 39,40,60 preexisting or coexisting medical conditions, leukostasis is highly probable. Patients with suspected APL should receive ATRA immediately and additionally idarubicin after cytological or genetic APL confirmation. In addition to idarubicin, the WBC count is further reduced by HU patient population based on a score correcting for disease-related risk until normal levels have been reached. DIC and TLS are treated with factors in order to separate the leukapheresis effect on early death. Ac- standard supportive measures as mentioned previously. RBC transfu- cording to their analysis, leukapheresis had no beneficial effect on early sions are withheld whenever possible until the WBC count is reduced. 9 death, irrespective of the individual early death risk. All trials were If a transfusion is necessary, it is administered slowly. We give pro- retrospective and not randomized, anditisunlikelythatsuchstudies phylactic platelet transfusions to maintain a count of .20 000 to will ever be feasible given the rarity of the condition, urgency for de- 30 000/mL or 50 000/mL in case of full heparin anticoagulation cision making, and strong physician preferences. until the WBC count has been reduced and the clinical situation has As part of a discussion, the efficient reduction of WBCs and the been stabilized. Patients without leukostasis symptoms are not sched- standardized and generally well-tolerated procedure are brought for- uled for leukapheresis. Patients with a clinically high likelihood of leu- ward as arguments for using leukapheresis, whereas hypercalcemia, the kostasis are checked for contraindications for leukapheresis such as use of anticoagulants, aggravation of preexisting thrombopenia,24 and APL, coagulation disorders, cardiovascular comorbidities, or instable the potential need for a central venous access43,46,61,62 may put patients circulation. Patients without contraindications are scheduled to receive at procedural risk on top of their unstable condition. Last but not least, leukapheresis with a target WBC count below 100 000/mL or the dis- infrastructural requirements and costs linked to leukapheresis have to be appearance of clinical symptoms. In patients with contraindications for taken into account. immediate intensive induction treatment such as severe metabolic dis- In conclusion, leukapheresis may be beneficial in patients present- turbances or renal insufficiency, we use HU for cytoreduction. ing with a manifest leukostasis syndrome because leukapheresis re- Once CR has been achieved, we make a decision on consolidation presents a causal therapeutic principle. Based on a grading score for treatment depending on donor availability and cytogenetic risk. If the the probability of leukostasis in leukemia patients with HL and a vali- standard induction does not lead to CR, we use a salvage regimen based dation analysis, patients with distinct symptoms have a high risk of on high-dose cytarabine, possibly including novel investigational leukostasis-related early death (Table 1).39,40 Contraindications such drugs. In first CR, we recommend a patient with intermediate or adverse as cardiovascular comorbidities, hemodynamic instability, and coag- cytogenetic risk and an available matched donor to undergo allogeneic ulation disturbances should be evaluated carefully in order to avoid an stem cell transplantation in first remission based on the high relapse extra procedural risk for the patient. Patients with a manifest leukostasis probability of hyperleukocytotic AML after conventional chemother- in relation to HL and without contraindications should receive daily apy consolidation. In all other cases including core binding factor leu- leukapheresis. The blood volume to process should be between 2 and 4 kemias without c-kit mutations, standard chemotherapy with high-dose times 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 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.63 Leukapheresis can be repeated daily until symptoms of leukostasis have disappeared or the WBC count is below 100 3109/mL.60,63 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.46,63 Based on the pros and cons of the procedure, a routinely performed prophylactic leukapheresis cannot be recommended. In APL, leukapheresis might worsen the coagulopathy and increase the rate of complications and is therefore not recommended.64 Future research evaluating therapies targeting cytokines and adhe- Figure 5. Treatment algorithm for AML with hyperleukocytosis. Supportive therapy such as hydration, prophylaxis of TLS, and anti-infective treatment is necessary for all sion molecules involved in myeloblast-endothelium interactions may patients. The asterisk indicates that the algorithm also applies to patients with leu- 46 be worth exploring. kocytosis ,100 Gpt/L who present with symptoms suggestive for leukostasis. From www.bloodjournal.org by guest on January 2, 2016. For personal use only.

BLOOD, 21 MAY 2015 x VOLUME 125, NUMBER 21 HOW I TREAT HYPERLEUKOCYTOSIS IN AML 3251 cytarabine will be used as consolidation. Whenever possible, treat- sections and their interpretation in Figure 4, and Christiane Kulper¨ and ment should be part of a clinical trial or registry in order to gain more Marika Erler (Medizinische Klinik und Poliklinik I, Universitatskli-¨ knowledge and to improve treatment options in the future. nikum TU Dresden) for technical assistance on cytological specimens in Figure 2C.

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

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2015 125: 3246-3252 doi:10.1182/blood-2014-10-551507 originally published online March 16, 2015

How I treat hyperleukocytosis in acute myeloid leukemia

Christoph Röllig and Gerhard Ehninger

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