Redefining hyperviscosity in acute leukemia: Potential implications for red cell transfusions in the microvasculature.

Hyperleukocytosis is an emergency of acute leukemia leading to blood hyperviscosity, potentially resulting in life-threatening microvascular obstruction, or leukostasis. Due to the high number of red cells in the circulation, hematocrit/hemoglobin levels (Hct/Hgb) are major drivers of blood viscosity, but how Hct/Hgb mediates hyperviscosity in acute leukemia remains unknown. In vivo hemorheological studies are difficult to conduct and interpret due to issues related to visualizing and manipulating the microvasculature. To that end, a multi-vessel microfluidic device recapitulating the size-scale and geometry of the microvasculature was designed to investigate how Hct/Hgb interacts with acute leukemia to induce "in vitro" leukostasis. Using patient samples and cell lines, the degree of leukostasis was different among leukemia immunophenotypes with respect to white blood cell (WBC) count and Hct/Hgb. Among lymphoid immunophenotypes, severe anemia is protective against in vitro leukostasis and Hct/Hgb thresholds became apparent above which in vitro leukostasis significantly increased, to a greater extent with B-cell acute lymphoblastic leukemia (ALL) versus T-cell ALL. In vitro leukostasis in acute myeloid leukemia was primarily driven by WBC with little interaction with Hct/Hgb. This sets the stage for prospective clinical studies assessing how red cell transfusion may affect leukostasis risk in immunophenotypically different acute leukemia patients.

A rare complication of leukostasis with AML M4 patient: Microcirculatory dysfunction of upper extremities.

BACKGROUND: In children with acute myeloid leukemia, the incidence of hyperleukocytosis is 5-33%. Patients with AML and hyperleukocytosis have a higher early mortality rate than patients with nonhyperleukocytic AML because of the increased risk of severe pulmonary and neurologic complications. Leukapheresis provides rapid cytoreduction and reduces early mortality rates. CASE PRESENTATION: In this report, we present a case with microcirculatory failure of upper extremities as a rare symptom of hyperleukocytic AML M4 at initial presentation. CONCLUSIONS: Early diagnosis and treatment of patients with AML admitted to emergency services with these symptoms is too important to prevent from loss of extremities. Most of the complications of hyperleukocytosis can be reversible with early treatment.

Priapismus as Leukostasis Manifestation in Chronic Myeloid Leukemia.

Chronic Myeloid Leukemia (CML) is a myeloproliferative disease characterized by the presence of Philadelphia chromosome or BCR-ABL oncogene fusion. Patients with CML commonly present in the chronic phase with chief complaint of abdominal pain or early satiety. Priapism as the first manifestation of CML is a rare phenomenon. Priapism as a consequence of leukostasis is a urological emergency that requires immediate intracavernosus therapy followed by systemic therapy. We report a 44-year-old male patient presenting with priapism as the first manifestation of CML.

The effect of therapeutic leukapheresis on early complications and outcomes in patients with acute leukemia and hyperleukocytosis: a propensity score-matched study.

BACKGROUND: Hyperleukocytosis in acute leukemia is associated with higher early mortality due to the major complications of leukostasis, tumor lysis syndrome (TLS), and disseminated intravascular coagulopathy (DIC). Leukapheresis remains an important modality for the management of patients with acute leukemia and hyperleukocytosis. However, the role of leukapheresis in early mortality is controversial. This study sought to evaluate the prognostic impact of leukapheresis and its beneficial effects on TLS and DIC. STUDY DESIGN AND METHODS: We conducted a propensity score-matched study of 166 patients with acute leukemia and hyperleukocytosis admitted between 2006 and 2016. The incidence of TLS and DIC was determined using well-defined Cairo-Bishop criteria for TLS and International Society of Thrombosis and Haemostasis criteria for DIC. RESULTS: Before matching, 27 of 91 patients (30%) with acute myeloid leukemia (AML) and 32 of 75 patients (43%) with acute lymphoblastic leukemia (ALL) underwent leukapheresis. Propensity score matching was performed to adjust for clinical disparities between the leukapheresis and without-leukapheresis groups and resulted in 22 matched pairs of patients with AML and 16 matched pairs of patients with ALL. After matching, we observed no significant difference in early mortality rates or in the incidence of TLS or DIC between the two groups of patients with AML and ALL. CONCLUSION: Although leukapheresis may rapidly reduce white blood cell counts and leukemic blasts, any positive influence of leukapheresis could not be demonstrated by an effect on survival outcome and the incidence of early complications, such as TLS and DIC. These results suggest that a routinely performed, prophylactic leukapheresis cannot be recommended.

Leukostasis in Children and Adolescents with Chronic Myeloid Leukemia: Japanese Pediatric Leukemia/Lymphoma Study Group.

BACKGROUND: The details of leukostasis in children and adolescents with chronic myeloid leukemia (CML) are unknown. This study determined the characteristics of leukostasis in children and adolescents with CML. PROCEDURE: A total of 256 cases from a retrospective study of patients with CML conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group from 1996 to 2011 were analyzed, and of these, 238 cases were evaluated in this study. RESULTS: Leukostasis was diagnosed in 23 patients (9.7%). The median leukocyte count and spleen size below the left costal margin in cases with leukostasis were significantly higher and larger when compared to those in cases without leukostasis (458.5 × 10(9) /l vs. 151.8 × 10(9) /l (P < 0.01), and 13 vs. 5 cm (P < 0.01), respectively). Leukostasis occurred with ocular symptoms in 14 cases, priapism in four cases, and dyspnea, syncope, headache, knee pain, difficulty hearing, and aseptic necrosis of the femoral head in one case each. One case had two leukostasis symptoms simultaneously. Three cases were diagnosed before imatinib became available. Five cases received special treatment, and in the remaining 15 cases, all of these symptoms resolved after treatment with imatinib. CONCLUSIONS: This retrospective study represents the largest series of children and adolescents in which leukostasis of CML has been reported. Our data provide useful insight into the characteristics of leukostasis in recent cases of children and adolescents with CML.

Exchange Transfusion and Leukapheresis in Pediatric Patients with AML With High Risk of Early Death by Bleeding and Leukostasis.

BACKGROUND: The risk of early death (ED) by bleeding/leukostasis is high in patients with AML with hyperleukocytosis (>100,000/µl). Within the pediatric AML-BFM (Berlin-Frankfurt-Münster) 98/04 studies, emergency strategies for these children included exchange transfusion (ET) or leukapheresis (LPh). Risk factors for ED and interventions performed were analyzed. PATIENTS: Two hundred thirty-eight of 1,251 (19%) patients with AML presented with hyperleukocytosis; 23 of 1,251 (1.8%) patients died of bleeding/leukostasis. RESULTS: ED due to bleeding/leukostasis was highest at white blood cell (WBC) count >200,000/µl (14.3%). ED rates were even higher (20%) in patients with FAB (French-American-British) M4/M5 and hyperleukocytosis >200,000/µl. Patients with WBC >200,000/µl did slightly better with ET/LPh compared to those without ET/LPh (ED rate 7.5% vs. 21.2%, P = 0.055). Multivariate WBC >200,000/µl was of strongest prognostic significance for ED (P(χ(2) ) <0.0001). CONCLUSION: Our data confirm the high risk of bleeding/leukostasis in patients with hyperleukocytosis. ET/LPh shows a trend toward reduced ED rate due to bleeding/leukostasis and is recommended at WBC >200,000/µl, and in FAB M4/M5 even at lower WBC.

[CHRONIC MYELOID LEUKEMIA IN A YOUNG MALE PRESENTING WITH BILATERAL CALF PAIN DUE TO LEUKOSTASIS].

Chronic myeloid Leukemia (CML) is a chronic myeloproliferative disorder, caused by the unregulated proliferation of granulocytes at different stages of development and maturation. Leukostasis is one of the complications of CML, causing partial or total occlusion of microvasculature with a variety of clinical manifestations, mostly ophthalmic, neurologic or respiratory. Recently, we encountered a 21-year old soldier, who complained of severe bilateral calf pain which began a few months earlier during training. He underwent complete ambulatory orthopedic evaluation which was unrevealing, and finally presented to the hospital casualty department where CML was diagnosed on the basis of an elevated WBC count and morphologic findings. Bilateral retinal hemorrhages due to leukostasis were noticed at fundoscopy. The calf pain resolved completely after leukapheresis and initial cytoreductive therapy and was in retrospect attributed to peripheral leukostasis. To the best of our knowledge this is the first report of CML presenting with bilateral calf pain due to Leukocytosis and possible leukostasis. This case report highlights the importance of differential diagnosis in cases of calf pain and the awareness of this rare manifestation of CML.

[Leukostasis during Chronic Myelogenous Leukemia Resolved Following Leukapheresis].

Patients with hyperleucocytic leukemia (WBC count>10×10(4) mL) are at high risk of early mortality owing to pulmonary or cerebral leukostasis. Several researchers have reported the efficacy of immediate leukapheresis. Here, we report of a patient with chronic myelogenous leukemia in blast crisis and with pulmonary failure due to leukostasis who recovered after a combination therapy of leukapheresis and imatinib treatment.

Vascular cell-adhesion molecule-1 plays a central role in the proangiogenic effects of oxidative stress.

Oxidative stress exacerbates neovascularization (NV) in many disease processes. In this study we investigated the mechanism of that effect. Mice deficient in superoxide dismutase 1 (Sod1(-/-) mice) have increased oxidative stress and show severe ocular NV that is reduced to baseline by antioxidants. Compared with wild-type mice with ischemic retinopathy, Sod1(-/-) mice with ischemic retinopathy had increased expression of several NF-κB-responsive genes, but expression of vascular cell-adhesion molecule-1 (Vcam1) was particularly high. Intraocular injection of anti-VCAM-1 antibody eliminated the excessive ischemia-induced retinal NV. Elements that contributed to oxidative stress-induced worsening of retinal NV that were abrogated by blockade of VCAM-1 included increases in leukostasis, influx of bone marrow-derived cells, and capillary closure. Compared with ischemia alone, ischemia plus oxidative stress resulted in increased expression of several HIF-1-responsive genes caused in part by VCAM-1-induced worsening of nonperfusion and, hence, ischemia, because anti-VCAM-1 significantly reduced the increased expression of all but one of the genes. These data explain why oxidative stress worsens ischemia-induced retinal NV and may be relevant to other neovascular diseases in which oxidative stress has been implicated. The data also suggest that antagonism of VCAM-1 provides a potential therapy to combat worsening of neovascular diseases by oxidative stress.

[Leukostasis and tumor lysis: important complications of hyperleukocytosis]. / Leukostase und Tumorlyse: Wichtige Komplikationen der Hyperleukozytose.

The occurrence of hyperleukocytosis (leukocytes > 100.000/µl) is associated with complications such as leukostasis, tumor lysis and consumption coagulopathy in patients with acute leukemia much more often than in patients with chronic malignant hematological diseases. To manage these situations may be complex as organ failure is often imminent or manifest, infectious complications arise and indications for induction chemotherapy are usually urgent. Prophylaxis and therapy of the tumor lysis syndrome consists of hydration, lowering of uric acid and the management of electrolyte disturbances. Leukostasis requires immediate reduction of the leukocyte count by leukapheresis, administration of hydroxycarbamide and, ultimately, by causative and specific treatment of the underlying disease itself. In patients with curable diseases or favorable long-term prognosis, transfer to the intensive care unit must be evaluated early in the course of impending organ dysfunction, especially in cases of acute respiratory failure.

Leukapheresis in management hyperleucocytosis induced complications in two pediatric patients with chronic myelogenous leukemia.

Complications caused by elevated white blood cell count in pediatric patients with CML could be a presenting feature of the disease. Here, we present two adolescents, aged 16 and 17years, who were admitted for investigation of extremely elevated leukocytes and complications of leucostasis. Initial manifestations were priapism and blurred vision, respectively. Diagnosis of chronic phase of chronic myeloid leukemia is established, and conventional measures for leucoreduction began. However, since there were no improvements, a leukapheresis procedure was initiated. After undergoing 3 daily procedures the leukocyte count declined for each patient, with resolution of pripaism and ophtalmological disturbances. Leukapheresis is safe and effective therapeutic option for patients with complications of hyperleucocytosis. If started in a timely manner, permanent organ damage or death could be avoided.

Hyperleukocytosis and leukostasis in acute and chronic leukemias.

Leukostasis is a life-threatening complication of high concentrations of circulating leukemic cells, most often myeloblasts. Effective care of patients with leukostasis involves early recognition and treatment, and aggressive management of concurrent complications of the underlying leukemia. The relatively poor prognosis in patients with leukostasis underscores the importance of the timely and effective care of this hematologic emergency. While cytoreductive measures such as hydroxyurea, corticosteroids, intravenous chemotherapy, and leukapheresis are available to urgently reduce high cell counts, characterization of the leukemia and initiation of tailored, definitive treatment is a parallel priority. However, data supporting any specific cytoreductive approach are limited, making clinical practice guided primarily by expert opinion. In this review, we discuss the pathophysiology, clinical manifestations, diagnosis, and management of leukemic hyperleukocytosis and leukostasis, with an emphasis on how to acutely manage this oncologic emergency in patients with acute myeloid leukemia, which is the most common cause of symptomatic leukostasis.

Pazopanib, a multitargeted tyrosine kinase inhibitor, reduces diabetic retinal vascular leukostasis and leakage.

OBJECTIVE: To determine the efficacy of pazopanib eye drops in the streptozotocin induced diabetic retinopathy rat model. METHODS: A 0.5% w/v pazopanib suspension was prepared in phosphate buffered saline (PBS, pH 7.4) in the presence of 0.5% w/v sodium carboxymethyl cellulose. Brown Norway rats were divided into three groups (n=4) - (1) healthy, (2) diabetic, and (3) diabetic with treatment. The drug suspension was administered twice daily as eye drops to group 3 for 30 days. Efficacy parameters including the number of adherent leukocytes in the retinal vasculature (leukostasis), blood-retinal FITC-dextran leakage, and vitreous-to-plasma protein ratio were measured. RESULTS: Pazopanib suspension in the form of eye drops significantly reduced leukostasis (32%), FITC-dextran leakage (39%), and the vitreous-to-plasma protein ratio (64%) in diabetic animals compared to untreated diabetic group. CONCLUSION: Pazopanib eye drops can alleviate retinal complications of diabetic retinopathy.

Adiponectin suppresses pathological microvessel formation in retina through modulation of tumor necrosis factor-alpha expression.

The fat-derived hormone adiponectin has been shown to have a protective role in macrovascular disorders. However, nothing is known about the function of adiponectin in retinal microvessel disease. Here, we investigated the causal role of adiponectin in retinal vessel formation and inflammation under conditions of hypoxia. When neonatal mice were subjected to ischemia-induced retinopathy, pathological retinal neovascularization during ischemia was exacerbated in adiponectin-knockout (APN-KO) mice compared with wild-type mice (neovascular area: 17.0+/-1.0% versus 11.7+/-0.6%, respectively). APN-KO mice also exhibited increased leukocyte adhesion (2.3+/-0.4-fold) and tumor necrosis factor (TNF)-alpha expression (2.6+/-0.2-fold) in hypoxic retina. Adenovirus-mediated overexpression of adiponectin attenuated hypoxia-induced pathological retinal neovascularization by 35% in wild-type mice and by 40% in APN-KO mice and leukostasis by 64% in wild-type mice and by 75% in APN-KO mice, which were associated with reduced TNF-alpha production. TNF-alpha blockade diminished the enhanced pathological neovascularization in APN-KO mice by 34%, and the inhibitory effects of adiponectin overexpression on retinal neovascularization and leukocyte adhesion were abolished in mice lacking TNF-alpha. These data provide evidence that adiponectin protects against retinal vessel injury following pathological stimuli through modulation of TNF-alpha inflammatory responses.

Therapeutic leukapheresis in patients with leukostasis secondary to acute myelogenous leukemia.

Leukostasis is a relatively uncommon but potentially catastrophic complication of acute myelogenous leukemia (AML). Prompt leukoreduction is considered imperative to reduce the high mortality rate in this condition. Leukapheresis, usually associated with chemotherapy, is an established approach to diminish blast cell counts. We report a single center experience in managing leukostasis with leukapheresis. Fifteen patients with leukostasis of 187 patients with AML (8.02%) followed at our institution were treated with leukapheresis associated with chemotherapy. The procedures were scheduled to be performed on a daily basis until clinical improvement was achieved and WBC counts were significantly reduced. Overall and early mortalities, defined as that occurred in the first 7 days from diagnosis, were reported. A high proportion of our patients with leukostasis (46.66%) had a monocytic subtype AML (M4/M5, according to French-American-British classification). The median overall survival was 10 days, despite a significant WBC reduction after the first apheresis procedure (from 200.7 × 109/L to 150.3 × 109/L). Almost half of patients (7/15) had an early death. Therapeutic leukapheresis, associated or not to chemotherapy, is an effective approach to reduce WBC counts in patients with AML and leukostasis; however, this therapeutic procedure does not appear to change significantly the sombre prognosis observed in the majority of patients with this complication. Other forms of treatment must be found to reduce the high mortality rate related to leukostasis.

Rapid treatment of leukostasis in leukemic mantle cell lymphoma using therapeutic leukapheresis: a case report.

We describe a case of severe leukocytosis caused by leukemic mantle cell lymphoma (MCL), complicated by leukostasis with myocardial infarction in which leukapheresis was used in the initial management. A 73-year-old male presented to the emergency department because of fatigue and thoracic pain. Blood count revealed 630 × 10(9)/L WBC (white blood cells). The electrocardiogram showed ST-elevation with an increase of troponin and creatinine kinase. The diagnosis was ST-elevation myocardial infarction (STEMI) induced and complicated by leukostasis. Immunophenotyping, morphology, cytogenetic and fluorescence-in-situ-hybridization analysis revealed the diagnosis of a blastoid variant of MCL. To remove leukocytes rapidly, leukapheresis was performed in the intensive care unit. Based on the differential blood count with 95% blasts, which were assigned to the lymphocyte population by the automatic hematology analyzer, leukapheresis procedures were then performed with the mononuclear cell standard program on the Spectra cell separator. The patient was treated with daily leukapheresis for 3 days. The WBC count decreased to 174 × 10(9)/L after the third leukapheresis, with a 72% reduction. After the second apheresis, treatment with vincristine, cyclophosphamide, and prednisolone was started. The patient fully recovered in the further course of the treatment. To the best of our knowledge, this is the first report on blastoid MCL with leukostasis associated with a STEMI that was successfully treated by leukapheresis. Effective harvest of circulating lymphoma cells by leukapheresis requires adaptation of instrument settings based on the results of the differential blood count prior to apheresis.

High dose cyclophosphamide for cytoreduction in patients with acute myeloid leukemia with hyperleukocytosis or leukostasis.

Hyperleukocytosis may lead to multiple medical emergencies. Hydroxyurea, intensive chemotherapy, and leukapheresis are used for cytoreduction. However, there is little data regarding the best approach. Here, we report on the efficacy and safety of high dose cyclophosphamide (HDCy; 60 mg/kg). 27 patients with acute myeloid leukemia or blast phase chronic myeloid leukemia who presented with white blood cell count (WBC) of ≥50x109/L or symptoms of leukostasis were treated with HDCy. Primary endpoint was early mortality (death within seven days of admission). Median WBC was 107 × 109/L at time of HDCy; 74% had leukostasis symptoms at presentation. Eight (29.6%) patients died within seven days of admission. Sustained WBC reduction was achieved in 18/24 (75%) evaluable patients with median nadir of 0.25 × 109/L. Adverse effects attributed to HDCy included tumor lysis syndrome (n = 7; 25.9%), disseminated intravascular coagulopathy (n = 5; 18.5%), and hemorrhagic cystitis (n = 1; 3.7%). HDCy was effective for cytoreduction and adverse effects were acceptable.

Leukostasis retinopathy with leukemic infiltrates as onset manifestation of chronic myeloid leukemia: a case report.

PURPOSE: To describe a case of retinopathy as onset manifestation of chronic myeloid leukemia (CML), successfully treated with leukapheresis and medical therapy. METHODS: A 28-year-old male patient presented complaining painless acute visual impairment in his right eye (RE). He reported moderate asthenia and episodes of night sweats during the previous month. His past medical history was unremarkable. BCVA at presentation was 20/80 in RE and 20/32 in left eye (LE). Fundus examination revealed venous congestion, diffuse Roth spots, and whitish macular infiltrates in both eyes. OCT showed hyperreflective foveal infiltrates, in both eyes. Blood test showed markedly elevated white blood cells (WBCs) count (430 × 103/mm3). Clinical-instrumental examination revealed hepatosplenomegaly. These features were consistent with CML. The patient was treated with leukapheresis and nilotinib. RESULTS: After 2 weeks of treatment, the WBCs count dropped (71 × 103/mm3), and the patient reported subjective improvement of symptoms. At 1-month follow-up, BCVA and retinopathy signs were improved in both eyes. OCT showed the almost complete resolution of foveal infiltrates with ellipsoid zone focal defects. At 4-months follow-up, we observed complete resolution of retinopathy. BCVA was 20/32 in RE and 20/25 in LE. OCT showed the persistence of ellipsoid zone focal defects in RE and complete anatomical restoration in LE. At 6-months follow-up, the patient was clinically well and his WBCs count was normal. CONCLUSION: In our case, the CML-related retinopathy represented the onset sign of the underlying systemic pathology, leading to proper management and treatment, with hematological normalization and resolution of the retinopathy.

Leukostasis in Chronic Lymphocytic Leukemia.

BACKGROUND Chronic lymphocytic leukemia (CLL) is a mature B cell lymphocytic neoplasm that has an indolent clinical course. Therefore, not all patients with CLL require treatment at the time of diagnosis. Hyperleukocytosis (white blood cell count, >100×109/L) is present in a large proportion of patients with CLL. However, symptomatic hyperleukocytosis (leukostasis) is an extremely uncommon presentation of CLL. Leukostasis frequently presents with the clinical manifestation of respiratory, neurological, or renal system problems. This is secondary to the decreased tissue perfusion due to the intravascular accumulation of large aggregates of leukemic cells. Leukostasis is a medical emergency requiring intensive care unit (ICU) admission and its management includes aggressive hydration, prevention and treatment of tumor lysis syndrome, cytoreduction, and leukapheresis. CASE REPORT We report a case of a 77-year-old woman with a long history of untreated CLL who presented with respiratory symptoms with hyperleukocytosis. Her condition rapidly deteriorated, requiring intubation. She required induction chemotherapy with chlorambucil as well as 2 sessions of leukapheresis, to which she responded well. In most reported leukostasis cases in the literature, the white blood cell (WBC) count was >1000×109/L. We present a case of a patient with leukostasis with WBC count 524×109/L who responded to chlorambucil and leukapheresis, with good recovery. CONCLUSIONS Leukostasis, although extremely rare, is a life-threatening complication in patients with CLL. It should be strongly considered in the differential diagnosis of patients with CLL who present with hyperleukocytosis and acute pulmonary symptoms. Clinicians should be aware of this medical emergency, as delayed treatment can increase morbidity and mortality.