Therapeutic Leukocytapheresis to relieve priapism due to leukostasis in CML patients: Our experience in a tertiary care centre.

Hyperleukocytosis in leukemic patients may cause tumour lysis syndrome, disseminated intravascular coagulopathy, and leukostasis, resulting in decreased tissue perfusion and increasing the risk of mortality. Since the myeloid blasts are larger than lymphoid blasts and are less deformable, complications of leukostasis are seen more frequently in myeloid leukemia. Priapism is a less common complication associated with leukostasis in leukaemia patients that should be treated as soon as possible to avoid ischemic injuries. Although chemotherapeutic drugs such as hydroxyurea and imatinib are used to treat hyperleukocytosis in CML patients, leukocytapheresis (LCP) can achieve rapid cytoreduction. Prophylactic LCP could not offer any advantage over aggressive chemotherapy, but therapeutic leukocyte depletion has a proven role in patients having symptomatic leukostasis due to high tumour burden. Three patients with ischaemic priapism were reported at our institute's emergency department, where detumescence could not be achieved by distal shunting or aspiration with phenylephrine instillation. The procedure of therapeutic LCP was performed in all three patients on an emergency basis, which resolved painful priapism by rapid cytoreduction.

What Is Different in Acute Hematologic Malignancy-Associated ARDS? An Overview of the Literature.

Background and Objectives: Acute hematologic malignancies are a group of heterogeneous blood diseases with a high mortality rate, mostly due to acute respiratory failure (ARF). Acute respiratory distress syndrome (ARDS) is one form of ARF which represents a challenging clinical condition. The paper aims to review current knowledge regarding the variable pathogenic mechanisms, as well as therapeutic options for ARDS in acute hematologic malignancy patients. Data collection: We provide an overview of ARDS in patients with acute hematologic malignancy, from an etiologic perspective. We searched databases such as PubMed or Google Scholar, including articles published until June 2022, using the following keywords: ARDS in hematologic malignancy, pneumonia in hematologic malignancy, drug-induced ARDS, leukostasis, pulmonary leukemic infiltration, pulmonary lysis syndrome, engraftment syndrome, diffuse alveolar hemorrhage, TRALI in hematologic malignancy, hematopoietic stem cell transplant ARDS, radiation pneumonitis. We included relevant research articles, case reports, and reviews published in the last 18 years. Results: The main causes of ARDS in acute hematologic malignancy are: pneumonia-associated ARDS, leukostasis, leukemic infiltration of the lung, pulmonary lysis syndrome, drug-induced ARDS, radiotherapy-induced ARDS, diffuse alveolar hemorrhage, peri-engraftment respiratory distress syndrome, hematopoietic stem cell transplantation-related ARDS, transfusion-related acute lung injury. Conclusions: The short-term prognosis of ARDS in acute hematologic malignancy relies on prompt diagnosis and treatment. Due to its etiological heterogeneity, precision-based strategies should be used to improve overall survival. Future studies should focus on identifying the relevance of such etiologic-based diagnostic strategies in ARDS secondary to acute hematologic malignancy.

Deletion of Tgfß signal in activated microglia prolongs hypoxia-induced retinal neovascularization enhancing Igf1 expression and retinal leukostasis.

Retinal neovascularization (NV) is the major cause of severe visual impairment in patients with ischemic eye diseases. While it is known that retinal microglia contribute to both physiological and pathological angiogenesis, the molecular mechanisms by which these glia regulate pathological NV have not been fully elucidated. In this study, we utilized a retinal microglia-specific Transforming Growth Factor-ß (Tgfß) receptor knock out mouse model and human iPSC-derived microglia to examine the role of Tgfß signaling in activated microglia during retinal NV. Using a tamoxifen-inducible, microglia-specific Tgfß receptor type 2 (Tgfßr2) knockout mouse [Tgfßr2 KO (ΔMG)] we show that Tgfß signaling in microglia actively represses leukostasis in retinal vessels. Furthermore, we show that Tgfß signaling represses expression of the pro-angiogenic factor, Insulin-like growth factor 1 (Igf1), independent of Vegf regulation. Using the mouse model of oxygen-induced retinopathy (OIR) we show that Tgfß signaling in activated microglia plays a role in hypoxia-induced NV where a loss in Tgfß signaling microglia exacerbates and prolongs retinal NV in OIR. Using human iPSC-derived microglia cells in an in vitro assay, we validate the role of Transforming Growth Factor-ß1 (Tgfß1) in regulating Igf1 expression in hypoxic conditions. Finally, we show that Tgfß signaling in microglia is essential for microglial homeostasis and that the disruption of Tgfß signaling in microglia exacerbates retinal NV in OIR by promoting leukostasis and Igf1 expression.

Effect of prophylactic leukapheresis on early mortality and overall survival in acute leukemia patients with hyperleukocytosis.

Hyperleukocytosis has been associated with early mortality owing to the presence of complications including leukostasis, tumor lysis syndrome (TLS), and disseminated intravascular coagulation (DIC). Leukapheresis is a fast and effective cytoreductive procedure that removes leukocytes from the peripheral circulation. This single-center, retrospective, and observational study included 32 patients diagnosed with acute leukemia who underwent leukapheresis due to hyperleukocytosis between 2014 and 2020. This study primarily aimed to investigate the effect of prophylactic leukapheresis on early mortality and overall survival (OS). In the symptomatic group, seven and two patients died in the first and second weeks, respectively. In the prophylactic leukapheresis group, two and one patients died in the first and second weeks (p = 0.792), respectively. OS was significantly longer in the prophylactic leukapheresis group (p = 0.004). The leukapheresis procedure appears to be effective on early mortality and OS. Initiation of prophylactic leukapheresis before the appearance of leukostasis symptoms is effective on OS and possibly early mortality.

Hyperleukocytosis and Leukostasis in Acute Myeloid Leukemia: Can a Better Understanding of the Underlying Molecular Pathophysiology Lead to Novel Treatments?

Up to 18% of patients with acute myeloid leukemia (AML) present with a white blood cell (WBC) count of greater than 100,000/µL, a condition that is frequently referred to as hyperleukocytosis. Hyperleukocytosis has been associated with an adverse prognosis and a higher incidence of life-threatening complications such as leukostasis, disseminated intravascular coagulation (DIC), and tumor lysis syndrome (TLS). The molecular processes underlying hyperleukocytosis have not been fully elucidated yet. However, the interactions between leukemic blasts and endothelial cells leading to leukostasis and DIC as well as the processes in the bone marrow microenvironment leading to the massive entry of leukemic blasts into the peripheral blood are becoming increasingly understood. Leukemic blasts interact with endothelial cells via cell adhesion molecules such as various members of the selectin family which are upregulated via inflammatory cytokines released by leukemic blasts. Besides their role in the development of leukostasis, cell adhesion molecules have also been implicated in leukemic stem cell survival and chemotherapy resistance and can be therapeutically targeted with specific inhibitors such as plerixafor or GMI-1271 (uproleselan). However, in the absence of approved targeted therapies supportive treatment with the uric acid lowering agents allopurinol and rasburicase as well as aggressive intravenous fluid hydration for the treatment and prophylaxis of TLS, transfusion of blood products for the management of DIC, and cytoreduction with intensive chemotherapy, leukapheresis, or hydroxyurea remain the mainstay of therapy for AML patients with hyperleukocytosis.

Rapid Fire: Acute Blast Crisis/Hyperviscosity Syndrome.

Emergency providers are likely to encounter patients with acute and chronic leukemias. In some cases, the first presentation to the emergency department may be for symptoms related to blast crisis and leukostasis. Making a timely diagnosis and consulting a hematologist can be life saving. Presenting symptoms are caused by complications of bone marrow infiltration and hyperleukocytosis with white blood cell counts over 100,000. Presentations may include fatigue (anemia), bleeding (thrombocytopenia), shortness of breath, and/or neurologic symptoms owing to hyperleukocytosis and subsequent leukostasis. Treatment of symptomatic cases involves induction chemotherapy and/or leukapheresis. Asymptomatic hyperleukocytosis can be treated with hydroxyurea.

Curcumolide reduces diabetic retinal vascular leukostasis and leakage partly via inhibition of the p38MAPK/NF-κ B signaling.

Retinal inflammation in a hyperglycemic condition is believed to play a crucial role in the development of diabetic retinopathy, and targeting inflammatory mediators is a promising strategy for the control of diabetic retinopathy. Curcumolide, a novel sesquiterpenoid with a unique 5/6/5 tricyclic skeleton, was isolated from Curcuma wenyujin. In this study, we demonstrate that treatment with curcumolide alleviated retinal inflammatory activities both in vitro and in vivo in a STZ-induced diabetic rat model and in TNF-α-stimulated HUVECs. Curcumolide alleviated retinal vascular permeability and leukostasis and attenuated the overexpression of TNF-α and ICAM-1 in diabetic retinas. Moreover, curcumolide also inhibited inducible p38 MAPK and NF-κB activation and the subsequent induction of proinflammatory mediators. These data suggest potential treatment strategies against diabetic retinopathy, particularly in the early stages of the disease.

[Successful induction therapy for acute myeloid leukemia complicated with brain hemorrhage and hyperleukocytosis].

Adequate management of hyperleukocytosis in patients with acute myeloid leukemia (AML) is essential for the prevention of life-threatening complications related to leukostasis and tumor lysis syndrome, but the optimal therapeutic strategy remains unclear. We report a 15-year-old girl with newly diagnosed AML who had extreme hyperleukocytosis (leukocyte count at diagnosis, 733,000/µl) leading to a brain hemorrhage. She was initially treated with hydroxyurea, but presented with brain hemorrhage due to leukostasis and underwent leukapheresis emergently with intensive care and mechanical ventilation. Full-dose standard induction chemotherapy was initiated after achieving gradual cytoreduction (leukocyte count, 465,000/µl) within five days after the initiation of therapy with hydroxyurea and leukapheresis. These treatments were successful and she experienced no complications. The patient ultimately recovered fully and was discharged with complete remission of AML. Although the effects of hydroxyurea and leukapheresis in the setting of hyperleukocytosis are still controversial, these initial treatments may contribute to successful bridging therapy followed by subsequent induction chemotherapy, especially in AML cases with extreme hyperleukocytosis or life-threatening leukostasis.

How we approach a patient with symptoms of leukostasis requiring emergent leukocytapheresis.

Hyperleukocytosis can induce leukostasis, which can lead to vascular obstructions (usually in the lungs and central nervous system), tumor lysis syndrome, and disseminated intravascular coagulation. Although it has not been conclusively shown to improve long-term outcome, leukocytapheresis may be used as part of the management of hyperleukocytosis with or without leukostasis to rapidly reduce the white blood cell (WBC) burden. Since leukocytapheresis only temporarily decreases the WBC count, early initiation of more definite therapy, such as hydroxyurea and/or chemotherapy, is essential. In this article, clinical assessment of the patient's clinical status to determine the need for leukocytapheresis as well as a general guideline for management of the technical aspects and complications of the procedure are discussed.

CD11b+ bone marrow-derived monocytes are the major leukocyte subset responsible for retinal capillary leukostasis in experimental diabetes in mouse and express high levels of CCR5 in the circulation.

We investigated the phenotype of cells involved in leukostasis in the early stages of streptozotocin-induced diabetes in mice by direct observation and by adoptive transfer of calcein-AM-labeled bone marrow-derived leukocytes from syngeneic mice. Retinal whole mounts, confocal microscopy, and flow cytometry ex vivo and scanning laser ophthalmoscopy in vivo were used. Leukostasis in vivo and ex vivo in retinal capillaries was increased after 2 weeks of diabetes (Hb A(1c), 14.2 ± 1.2) when either donor or recipient mice were diabetic. Maximum leukostasis occurred when both donor and recipient were diabetic. CD11b(+), but not Gr1(+), cells were preferentially entrapped in retinal vessels (fivefold increase compared with nondiabetic mice). In diabetic mice, circulating CD11b(+) cells expressed high levels of CCR5 (P = 0.04), whereas spleen (P = 0.0001) and retinal (P = 0.05) cells expressed increased levels of the fractalkine chemokine receptor. Rosuvastatin treatment prevented leukostasis when both recipient and donor were treated but not when donor mice only were treated. This effect was blocked by treatment with mevalonate. We conclude that leukostasis in early diabetic retinopathy involves activated CCR5(+)CD11b(+) myeloid cells (presumed monocytes). However, leukostasis also requires diabetes-induced changes in the endothelium, because statin therapy prevented leukostasis only when recipient mice were treated. The up-regulation of the HMG-CoA reductase pathway in the endothelium is the major metabolic dysregulation promoting leukostasis.

Beneficial effects of a novel RAGE inhibitor on early diabetic retinopathy and tactile allodynia.

PURPOSE: The receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of numerous complications of diabetes. We assessed the effect of a novel RAGE fusion protein inhibitor on retinal histopathology and nerve function, and on retinal inflammation and oxidative stress. METHODS: C57BL/6J mice were made diabetic with streptozotocin, and some were given a RAGE fusion protein (10, 100, or 300 µg per mouse 3 times per week). Mice were sacrificed at 2 months and 10 months into the study to assess retinal vascular histopathology, accumulation of albumin in the neural retina, cell loss in the ganglion cell layer, and biochemical and physiologic abnormalities in the retina. Tactile allodynia (light touch) was measured on a paw of each animal at 2 months. RESULTS: Leukostasis, expression of the intercellular adhesion molecule-1 (ICAM-1), accumulation of albumin in the neural retina, and nitration of retinal proteins were significantly increased in the retinas of mice diabetic for 2 months. The number of degenerate retinal capillaries was significantly increased in mice diabetic for 10 months, compared to the nondiabetic controls. Diabetes also enhanced sensitivity of peripheral nerves to tactile allodynia. All three doses of the RAGE fusion protein inhibited capillary degeneration, accumulation of albumin in the neural retina, nitration of retinal proteins, and tactile allodynia, demonstrating that biologically meaningful levels of the drug reached the retina. RAGE inhibition did tend to inhibit diabetes-induced retinal leukostasis and ICAM-1 expression (previously postulated to be important in the pathogenesis of retinopathy), but these effects were not statistically significant for the use of the lower doses of the drug that normalized the vascular histopathology. CONCLUSIONS: Inhibition of RAGE blocked the development of important lesions of diabetic retinopathy, but these beneficial effects seemed not to be mediated via leukostasis. RAGE inhibition also blocked the development of sensory allodynia in diabetes. RAGE is an important therapeutic target to inhibit the development of vascular and neural complications of diabetes.

[Chronic myeloid leukemia complicated with cerebellar hemorrhage and acute hydrocephalus successfully treated with imatinib and intensive supportive care].

We report a case of a 46-year-old female demonstrating general fatigue and visual disturbances with retinal bleeding. She had a white blood cell count of 419,300/mm. Thereafter, she developed vomiting associated with vertigo caused by cerebellar hemorrhage, deteriorating to acute hydrocephalus secondary to obstruction of the cerebral aqueduct. Emergency procedures for cerebral protection, such as hyperventilation, administration of mannitol, and barbiturate coma, were performed. Bone marrow examination showed a positive BCR-ABL/t(9;22)(q34;q11) chromosomal translocation detected by FISH and RT-PCR (masked Ph) and she was diagnosed as having chronic myeloid leukemia (CML) in the chronic phase (CP). She was administered Ara-C, together with imatinib 600 mg/d through a nasogastric tube. Eight days later, she underwent successful extubation and recovered without any neurological defect. She was maintained on imatinib 400 mg/d and demonstrated a major molecular response at 15 months. Physicians need to be aware that brain hemorrhage may develop as an initial symptom of CML patients in CP.

Targeting leukostasis for the treatment of early diabetic retinopathy.

Leukocyte-endothelial interaction plays an important role in the early phase of the development of diabetic retinopathy. It has been studied extensively linking inflammatory processes to its development conducted to date in rats and mice, and have focused on insulin-deficient models. The molecular and functional changes that are characteristics of inflammation have been detected in retinas from diabetic animals and humans with involvement of multiple pathways that results in the final sequelae of increased permeability of the blood retinal barrier and finally ischemia that drives angiogenesis. Increased expression of Intracellular adhesion molecules heralds the onset of changes that results in attraction of leucocytes such as neutrophils. The consequent release of cytokines and growth factors such as vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha, and interleukin 1-Beta results in increased permeability and retinal edema. Other indirect mediators involved include pathways such as the protein kinase C (PKC), renin-angiotensin system, enzymes such as the poly ADP-ribose polymerase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, nitric oxide synthetase and finally advanced glycation products. Therapy for early diabetic retinopathy may inhibit one or more of these pathways using drugs that can be given systemically, with local ocular applications having a more direct effect as in other eye diseases.

Central nervous system complications of blastic hyperleukocytosis in childhood acute lymphoblastic leukemia: diagnostic and prognostic implications.

Intracranial hemorrhage during blastic crisis is a rare but critically important occurrence in children with acute lymphoblastic leukemia. This form of hemorrhage has not been described since the advent of magnetic resonance imaging (MRI), leaving radiologists and clinicians unfamiliar with its unique imaging features. The authors describe 2 boys with severe intracranial pathology secondary to blastic hyperleukocytosis. Both patients were followed with serial MRI. Imaging findings in relation to the pathophysiology of white matter leukostasis are discussed and implications for treatment and prognosis are considered.

Analyzing cell mechanics in hematologic diseases with microfluidic biophysical flow cytometry.

Pathological processes in hematologic diseases originate at the single-cell level, often making measurements on individual cells more clinically relevant than population averages from bulk analysis. For this reason, flow cytometry has been an effective tool for single-cell analysis of properties using light scattering and fluorescence labeling. However, conventional flow cytometry cannot measure cell mechanical properties, alterations of which contribute to the pathophysiology of hematologic diseases such as sepsis, diabetic retinopathy, and sickle cell anemia. Here we present a high-throughput microfluidics-based 'biophysical' flow cytometry technique that measures single-cell transit times of blood cell populations passing through in vitro capillary networks. To demonstrate clinical relevance, we use this technique to characterize biophysical changes in two model disease states in which mechanical properties of cells are thought to lead to microvascular obstruction: (i) sepsis, a process in which inflammatory mediators in the bloodstream activate neutrophils and (ii) leukostasis, an often fatal and poorly understood complication of acute leukemia. Using patient samples, we show that cell transit time through and occlusion of microfluidic channels is increased for both disease states compared to control samples, and we find that mechanical heterogeneity of blood cell populations is a better predictor of microvascular obstruction than average properties. Inflammatory mediators involved in sepsis were observed to significantly affect the shape and magnitude of the neutrophil transit time population distribution. Altered properties of leukemia cell subpopulations, rather than of the population as a whole, were found to correlate with symptoms of leukostasis in patients-a new result that may be useful for guiding leukemia therapy. By treating cells with drugs that affect the cytoskeleton, we also demonstrate that their transit times could be significantly reduced. Biophysical flow cytometry offers a low-cost and high-throughput diagnostic and drug discovery platform for hematologic diseases that affect microcirculatory flow.

Long-term global retinal microvascular changes in a transgenic vascular endothelial growth factor mouse model.

AIMS/HYPOTHESIS: Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of diabetic retinopathy. We investigated whether transgenic mice with moderate VEGF expression in photoreceptors (trVEGF029) developed changes similar to diabetic retinopathy and whether retinopathy progressed with time. MATERIALS AND METHODS: Human VEGF(165) (hVEGF(165)) expression was analysed using ELISA and quantitative RT-PCR; serum glucose levels were also measured. Fundus fluorescein angiography (FA) was used to screen the degree of retinopathy from 6 weeks. Dynamic changes in the density of retinal microvasculature, as well as other changes similar to diabetic retinopathy, including retinal leucostasis, capillary endothelial cell and pericyte loss, and numbers of acellular capillaries, were quantified. RESULTS: trVEGF029 mice were normoglycaemic and showed a moderate, short-term hVEGF(165) upregulation for up to 3 weeks. Changes in the retinal microvasculature not only mimicked those seen in diabetic retinopathy, but also showed similar pathological progression with time. FA at 6 weeks identified two phenotypes, mild and moderate, which were distinguished by the extent of vascular leakage. Quantitative analysis of diabetic retinopathy-like changes revealed that these parameters were tightly correlated with the initial degree of vascular leakage; low levels reflected slow and limited retinal microvascular changes in mild cases and high levels reflected more rapid and extensive changes in moderate cases. CONCLUSIONS/INTERPRETATION: The data suggest that even an early short-term elevation in hVEGF(165) expression might set a train of events that lead to progressive retinopathy. Induction of many features characteristic of diabetic retinopathy in trVEGF029 enables mechanisms leading to the disease state to be examined, and provides a relevant animal model for testing novel therapeutics.

Correlation between expression of CD56/NCAM and severe leukostasis in hyperleukocytic acute myelomonocytic leukaemia.

OBJECTIVE: The possible contribution of surface molecules to the development of leukostasis syndrome in hyperleukocytic acute myeloid leukaemia (AML) was assessed by routine immunophenotyping and grading of the probability of clinical leukostasis. METHODS: Fifty-three patients (23 women, 30 men, median age 59 yr) with hyperleukocytic AML [white blood count (WBC) above 50 x 10(9)/L] were graded for the probability of clinical leukostasis according to the severity of neurologic, pulmonary and other symptoms possibly caused by leukostasis using a recently published scoring system. Age, WBC, absolute blast count, haemoglobin, cytogenetic risk group, infection, relative CD56 expression and absolute count of CD56 positive blasts were analyzed in multivariate stepwise backward logistic regression analysis. RESULTS: In patients with acute monocytic leukaemia (AML M4/M5) the absolute count of leukaemic blasts expressing CD56/NCAM was highly associated with the development of symptoms graded as highly probable leukostasis and all three patients succumbing to early death were CD56 positive. Only the absolute count of CD56 positive blasts was a significant predictor of risk of severe leukostasis (P = 0.020). This was not found in AML without monocytic involvement (AML M1, M2, M3v). CONCLUSIONS: The expression of CD56/NCAM, a surface marker used in routine immunophenotyping of AML, may help to predict severe and potentially fatal leukostasis in hyperleukocytic acute myelomonocytic leukaemia. These results emphasize the usefulness of this four-stage clinical grading scale for analysing the factors, which lead to severe leukostasis in hyperleukocytic patients. We extend previous findings that the mechanisms of leukostasis are different depending on the involvement of the monocytic lineage.

Therapeutic leukapheresis in hyperleukocytic leukaemias--the experience of a tertiary institution in Singapore.

INTRODUCTION: Hyperleukocytic leukaemias are associated with early mortality due to respiratory or neurological complications. They result from endothelial damage secondary to leukostasis. Leukapheresis, which aims to lower the white blood cell (WBC) count, has been used in certain patients to reduce the threat from leukostasis. However, there are very few published clinical investigations on the most appropriate use of leukapheresis in hyperleukocytosis. MATERIALS AND METHODS: We performed a retrospective analysis of 14 patients with hyperleukocytic leukaemia who presented to our institution and underwent therapeutic leukapheresis. We compare their clinical and biological characteristics and investigate the impact of leukapheresis on early mortality and long-term prognosis. RESULTS: The median presenting WBC count was 439 x 10(3)/mm(3). Although patients with acute myeloid leukaemia (AML) had the lowest median presenting WBC counts, they constituted the largest group of patients with symptomatic hyperleukocytosis. Leukapheresis was highly effective, with the mean absolute and percentage reduction in WBC after each cycle being 126 x 10(3)/mm(3) and 31.9% respectively. Four patients with AML died within 2 weeks of presentation despite prompt and effective leukapheresis. CONCLUSION: The interaction between the leukaemic cells and the vascular environment, a mechanism that none of the current therapies directly address, is probably more important in causing leukostasis than the absolute cell count itself.