Red cell exchange for rapid leukoreduction in adults with hyperleukocytosis and leukostasis.

ABSTRACT: We show that red cell exchange (RCE) treats hyperleukocytosis in acute leukemia. RCE provided similar leukoreduction to standard therapeutic leukoreduction and could be superior in patients with severe anemia or monocytic leukemias or when requiring rapid treatment.

Genetic mutations and leukapheresis in acute myeloid leukemia: is there a link?

Acute myeloid leukemia is the most common acute leukemia in adults and up to 20% of patients present with hyperleukocytosis at the onset of the disease. The therapeutic approach involves medical support, cytoreductive treatment, and/or leukapheresis. Despite WBC count greater than 100.000/µL, not all patients develop symptoms. To clarify the role of leukapheresis in the setting of hyperleukocytotic AML, we aimed to find associations between AML morphologic subtypes and molecular alterations on presence or absence of leukostasis symptoms (and hence therapeutic vs prophylactic leukapheresis) and clinical outcomes in the cohort of 41 patients at our single center who underwent leukapheresis for hyperleukocytotic AML. There was a trend for increased WBC count, 30-day mortality, M4-M5 AML subtypes, and number of leukapheresis procedures performed in symptomatic hyperleukocytotic pts. No molecular marker was significantly associated with presence or absence of leukostasis symptoms due to small sample size, though there was a trend for increased NPM1-mutated and NPM1 + FLT3-mutated AML in asymptomatic patients and a greater proportion of symptomatic patients who were negative for all assessed molecular alterations. In conclusion, leukapheresis combined with cytoreductive treatment represents a synergic and efficient approach in the management of hyperleukocytosis especially in symptomatic patients considering the higher mortality independently from the presence of specific clonal markers whose distribution among the two groups may result more considerable with a higher number of patients.

Safety and performance of the Spectra Optia apheresis system for white blood cell depletion in patients with elevated white blood cell counts.

BACKGROUND: For the past 30 years, white blood cell depletion (WBCD) or leukocytapheresis has been conducted to rapidly reduce excessive circulating white blood cell (WBC) concentrations in patients at risk for or with symptoms of leukostasis due to hyperleukocytosis. The goal of leukocytapheresis is to prevent or treat acute complications from leukostasis, thereby enabling patients to receive potentially curative chemotherapy. METHODS: This report details the results from a retrospective and a prospective clinical study conducted in the European Union and the People's Republic of China, which assessed the use of the Spectra Optia Apheresis System for leukocytapheresis in patients with hyperleukocytosis. The primary objective of both studies was to the assess the safety and performance of the WBCD procedure in patients with elevated WBC counts. RESULTS: Data were collected from 72 participants completing 87 WBCD procedures. The mean percent change in participant WBC counts post-procedure was 50.3 ± 21.2% and the collection efficiency (CE1) of the WBCD procedures was 53.7 ± 19.8%. Sixty-one participants (95.3%) experienced a total of 279 adverse events (AEs) with the majority of the AEs related to post-procedure changes in laboratory values, which is an anticipated AE in this patient population. CONCLUSION: The data collected within these studies indicate that the WBCD procedure is safe and well tolerated in patients with hyperleukocytosis as evaluated by percent decrease in WBC count, CE1, and AE incidence.

Therapeutic leukocytapheresis for leukostasis in chronic lymphocytic leukemia: A case report and literature review.

Chronic lymphocytic leukemia (CLL) is a clonal mature B-cell neoplasm with a typically indolent clinical course. Though most clinicians follow these neoplasms through observation alone, an aggressive transformation to prolymphocytic leukemia, diffuse large-B-cell lymphoma (Richter transformation) or classical Hodgkin lymphoma requires immediate attention. We present a case of extreme leukocytosis (>1 million/µL) in a previously diagnosed CLL patient. Due to symptomatic leukostasis, she was started on cytoreductive therapies including leukocytapheresis. After three rounds of leukocytapheresis (LCP) and concurrent chemotherapy, her white blood cell count decreased from a maximum 1262 × 103 /µL to 574 × 103 /µL. To our knowledge, CLL with symptomatic leukostasis that required therapeutic LCP is rarely reported in literature. We propose that therapeutic LCP is of value in such rare, yet dangerous settings like our case.

Therapeutic leukocytapheresis in infants and children with leukemia and hyperleukocytosis: A single institution experience.

BACKGROUND: Hyperleukocytosis, defined as white blood cell (WBC) count above 100 × 109 /L, has high early morbidity and mortality from leukostasis-related complications, namely intracranial hemorrhage and pulmonary distress. Initiating chemotherapy without prior leukocytoreduction may lead to tumor lysis syndrome (TLS). Therapeutic leukocytapheresis (TL) is used as one leukocytoreductive intervention; however, its safety and efficacy in pediatric leukemia has not been established. The purpose of this study is to evaluate safety of TL in pediatric patients and assess the efficacy of TL in reducing WBC count in pediatric leukemia. METHODS: Retrospective chart review was conducted on 14 patients with acute lymphoblastic leukemia (ALL) and 5 with acute myeloid leukemia (AML) who underwent TL during the period 2000-2014 at a single institution. RESULTS: Mean WBC count of 19 patients who received TL was 483.2 × 109 /L (547.1 in ALL, 304.3 in AML); a portion of patients presented with central nervous system symptoms (15%), respiratory symptoms (10%), or both (10%). TL reduced WBC count (mean 50.7% reduction after a single TL procedure; additional 17.1% reduction after a second TL procedure in 6 patients). Short-term survival immediately following TL was 100% without any major procedural complication. Mean survival time in patients with AML was 1.5 years and with ALL was 6.5 years. CONCLUSIONS: TL significantly reduces WBC number in pediatric leukemia patients as young as 22 days old. In our retrospective study, TL was not associated with any significant complications and suggests that TL is a safe initial procedure in pediatric leukemia.

Comparing leukapheresis protocols for an AML patient with symptomatic leukostasis.

BACKGROUND: Acute myeloid leukemia (AML) is a malignancy characterized by rapid clonal proliferation of myeloid precursors, which can result in hyperleukocytosis. Leukapheresis can be used to rapidly reduce the white blood cell count (WBC). However, the only FDA cleared device for WBC depletion, the COBE Spectra, will no longer be supported by the manufacturer in 2017, and there are few studies comparing different methods of leukapheresis. CASE REPORT: A 68-year-old African American female was admitted to the hospital for relapse of her AML. Laboratory data demonstrated a WBC count of 291 600/µL and flow cytometry of the peripheral blood demonstrated 85% myeloid blasts. Leukapheresis was ordered to help treat the leukostasis. METHODS: Three different apheresis protocols were used to achieve cytoreduction: Spectra Optia mononuclear collection (MNC) protocol, Spectra Optia granulocyte collection (PMN) protocol, and Therakos CELLEX buffy coat collection without return. Due to different inlet flow rates, the procedures were evaluated based on the number of WBCs collected and volume of blood processed (VBP). RESULTS: The Spectra Optia PMN collected the most WBCs and collected nearly as many WBCs per VBP as the Therakos CELLEX, which had the highest value. CONCLUSION: To our knowledge, we are reporting the first use of Therakos CELLEX and Spectra Optia PMN protocol for WBC depletion. While the Spectra Optia granulocyte protocol showed the best performance for this AML patient, further studies will be needed to compare the Spectra Optia PMN protocol to the MNC protocol for AML patients.

miR-15a/16 reduces retinal leukostasis through decreased pro-inflammatory signaling.

BACKGROUND: Hyperglycemia is a significant risk factor for diabetic retinopathy and induces increased inflammatory responses and retinal leukostasis, as well as vascular damage. Although there is an increasing amount of evidence that miRNA may be involved in the regulation in the pathology of diabetic retinopathy, the mechanisms by which miRNA mediate cellular responses to control onset and progression of diabetic retinopathy are still unclear. The purpose of our study was to investigate the hypothesis that miR-15a/16 inhibit pro-inflammatory signaling to reduce retinal leukostasis. METHODS: We generated conditional knockout mice in which miR-15a/16 are eliminated in vascular endothelial cells. For the in vitro work, human retinal endothelial cells (REC) were cultured in normal (5 mM) glucose or transferred to high glucose medium (25 mM) for 3 days. Transfection was performed on REC in high glucose with miRNA mimic (hsa-miR-15a-5p, hsa-miR-16-5p). Statistical analyses were done using unpaired Student t test with two-tailed p value. p < 0.05 was considered significant. Data are presented as mean ± SEM. RESULTS: We demonstrated that high glucose conditions decreased expression of miR-15a/16 in cultured REC. Overexpression of miR-15a/16 with the mimic significantly decreased pro-inflammatory signaling of IL-1ß, TNFα, and NF-κB in REC. In vivo data demonstrated that the loss of miR-15a/16 in vascular cells led to increased retinal leukostasis and CD45 levels, together with upregulated levels of IL-1ß, TNFα, and NF-κB. CONCLUSIONS: The data indicate that miR-15a/16 play significant roles in reducing retinal leukostasis, potentially through inhibition of inflammatory cellular signaling. Therefore, we suggest that miR-15a/16 offer a novel potential target for the inhibition of inflammatory mediators in diabetic retinopathy.

Leukostasis in adult acute hyperleukocytic leukemia: a clinician's digest.

Leukostasis is a poorly understood and life-threatening complication of acute hyperleukocytic leukemia. The incidence of hyperleukocytosis and leukostasis differs among various subtypes of leukemias. While the pathophysiology of leukostasis is not fully understood, recent research has elucidated many novel pathways that may have therapeutic implications in the future. Respiratory and neurological compromise represents the classical clinical manifestations of leukostasis. If it is not diagnosed and treated rapidly, the one-week mortality rate is approximately 40%. Targeted induction chemotherapy is an important component of the successful treatment of leukostasis, although other modalities of cytoreduction are being used and investigated. Copyright © 2016 John Wiley & Sons, Ltd.

Leukapheresis treatment in elderly acute leukemia patients with hyperleukocytosis: A single center experience.

AIM: Leukapheresis is an invasive treatment modality used for hyperleukocytosis. Various drugs and fluids are used during the leukapheresis. Aging itself and associated factors such as increased comorbidity, decreased tolerance to drugs, increased drug toxicity give rise to the application of other treatment modalities in elderly patients. Treatment of acute leukemia in the elderly differs from young patients. Consequently, we assumed that outcome, effectiveness, and side effects of leukapheresis treatment used for acute leukemia patients with hyperleukocytosis may be different in elderly compared to younger patients. METHODS: We retrospectively evaluated a total of 39 patients. Eighteen patients were 65 years and older. Indications for leukapheresis were determined as symptoms of leukostasis and prophylaxis. Acid citrate dextrose-A, calcium gluconate, and plasma were used during the leukapheresis. Age, sex, diagnosis, count, and indications of leukapheresis procedures, leukocyte count, and lactate dehydrogenase level were analyzed at the onset of and after leukapheresis; side effects, causes of death, early and total mortality rates were also analyzed. We compared the two groups with regard to effectiveness, clinical outcomes, and side effects. RESULTS: There were no statistically significant differences between the two groups with respect to sex, diagnosis, initial leukocyte count, lactate dehydrogenase level, number of leukapheresis procedures, rates of side effects, or early and total mortality (P > 0.05). Leukapheresis treatment was effective in both groups (P < 0.05) and no significant difference was found in its effectiveness between two groups (P > 0.05). CONCLUSION: Leukapheresis is an effective and safe treatment modality in elderly acute leukemia patients with hyperleukocytosis.

[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.

[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.

A safe therapeutic apheresis protocol in paediatric patients weighing 11 to 25 kg.

BACKGROUND AND OBJECTIVES: Erythrocytapheresis and leukapheresis (LPE) of small children are logistically complex and many centres are reluctant to perform these procedures. In children, both sickle cell and leukaemic emergencies demand prompt action to prevent additional morbidity but detailed protocols for small children are lacking, and often are performed using guidelines shown to work in larger patients. We report a 3-year experience with children weighing 11-25 kg at a large academic medical centre. MATERIALS AND METHODS: All patients were treated with the COBE® Spectra apheresis system; circuit was primed with blood not adjusted for haematocrit and anticoagulant citrate dextrose A was used as anticoagulation. Procedures were performed in the paediatric intensive care unit by apheresis nursing staff. RESULTS: Twenty-five apheresis procedures in 19 patients were performed; 17 of 19 patients presented with sickle cell-related acute complications and two (2/19) with newly diagnosed acute leukaemia and hyperleucocytosis. None of the patients required medications during the procedures. Vital signs and clinical condition remained stable and did not worsen during or postapheresis. One patient had a delayed haemolytic transfusion reaction 1 week posterythrocytapheresis as he developed alloantibodies as a result of the procedure. All sickle cell patients achieved a target haematocrit of 21-30% and Haemoglobin A of ≥68%. Both leukaemia patients who underwent LPE had no further signs of leukostasis and achieved marked reductions in leucocyte counts. CONCLUSIONS: Apheresis of children weighing 11-25 kg can be safely performed without increased morbidity. We outline a protocol that can be used to perform apheresis with minimal complications.

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.

Leucodepletion for hyperleucocytosis--first report on a novel technology featuring electronic interphase management.

BACKGROUND AND OBJECTIVES: Therapeutic leucodepletion plays an established role in the initial treatment of patients with acute myeloid leukaemia (AML) and possibly other leukaemias presenting with leucostasis. Recently, a new leucodepletion technology, Spectra Optia IDL, has become available that differs from its predecessor, COBE Spectra MNC, by a variety of electronic supports, including by electronic adjustment of buffy coat positioning at the collection port. Given the paucity of patients in need of leucodepletions and marked differences in clinical presentation as well as blast properties (e.g. size, density), formal clinical trials comparing leucodepletion technologies have never been executed. MATERIALS AND METHODS: Here, we present aggregate data from eight leucodepletions performed in AML patients with clinical signs of leucostasis between 11/2011 and 07/2012 with the new device and compare the apheresis outcomes with those from fifteen leucodepletions performed with the old technology between 06/2010 and 10/2011. RESULTS: Patients did not differ with respect to epidemiological data. Pre-apheresis leucocyte count (WBC) was significantly higher in Spectra Optia IDL patients. Tolerability was excellent with both devices. Basic apheresis denominators such as duration, processed volume, inlet pump rate, ACD-A consumption and product volume were very similar. A negative correlation between pre-apheresis WBC and collection efficiency was noted. Mean collection efficiency for leucocytes with Spectra Optia IDL (47·3%) was similar to that with COBE Spectra MNC (50·5%). Platelet attrition was similar with both devices, approximately 30%. CONCLUSION: The novel, electronically guided leukapheresis system is suitable for leucodepletion.

[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.

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.