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.

Too many white cells-TAM, JMML, or something else?

Leukocytosis is a common finding in pediatric patients, and the differential diagnosis can be broad, including benign reactive leukocytosis and malignant myeloproliferative disorders. Transient abnormal myelopoiesis is a myeloproliferative disorder that occurs in young infants with constitutional trisomy 21 and somatic GATA1 mutations. Most patients are observed, but outcomes span the spectrum from spontaneous resolution to life-threatening complications. Juvenile myelomonocytic leukemia is a highly aggressive myeloproliferative disorder associated with altered RAS-pathway signaling that occurs in infants and young children. Treatment typically involves hematopoietic stem cell transplantation, but certain patients can be observed. Early recognition of these and other myeloproliferative disorders is important and requires a clinician to be aware of these diagnoses and have a clear understanding of their presentations. This paper discusses the presentation and evaluation of leukocytosis when myeloproliferative disorders are part of the differential and reviews different concepts regarding treatment strategies.

Effectiveness of leukapheresis on early survival in acute myeloid leukemia: An observational propensity score matching cohort study.

BACKGROUND: The association between leukapheresis (LK) as a treatment option for hyperleukocytosis (HL) in patients with acute myeloid leukemia (AML) remains controversial. METHODS: Data were extracted from the electronic medical record for 2801 patients with AML between April 2009 and December 2019. LK was performed when the leukocyte count was ≥100 × 109 /L at the time initial bone marrow examination. RESULTS: A comparison between the patients with HL in the non-LK (n = 1579) and LK (n = 208) groups revealed survival probabilities (%) of 93.2% and 90.4% (P = .130) for day 30 (D30), 85.4% and 84.2% (P = .196) for D60, and 83.6% and 80.8% (P = .258) for D90, respectively. After propensity score matching, a comparison between the patients with HL in the non-LK (n = 192) and LK (n = 192) groups revealed survival probabilities (%) of 83.9% and 91.2% (P = .030) for D30, 75.0% and 84.9% (P = .015) for day 60 (D60), and 62.4% and 81.3% (P = .034) for day 90 (D90), respectively. After D150, the observed effect of LK appeared to be mitigated without a survival benefit. DISCUSSION: LK was associated with improved early survival outcomes at D30, D60, and D90 among patients with AML exhibiting HL. Thus, it may be considered a treatment option for reducing cell mass in such patients.

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.

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.

The effect of the time from diagnosis to induction therapy on prognosis in patients with acute leukemia undergoing leukapheresis for symptomatic hyperleukocytosis.

INTRODUCTION: Our study investigated leukapheresis's effect on delayed induction therapy outcomes in patients with acute leukemia presenting with symptomatic hyperleukocytosis. METHODS: This retrospective cohort study included 30 adult patients diagnosed with acute leukemia who underwent leukapheresis for leukostasis. The patients were divided into the first 24 h and >24 h groups, according to the time from diagnosis to induction therapy (TDT). RESULTS: There was no significant difference between the TDT groups regarding complete remission (CR), 4-week mortality, and overall survival (OS) at a median follow-up of 409 days. Tumor lysis syndrome, disseminated intravascular coagulation, and hemoglobin levels were significant in early mortality. In univariate analysis, age, hemoglobin levels, patients' eligibility for intensive chemotherapy, and achieving CR were critical factors for OS. CONCLUSION: The study findings suggest that waiting for the clinical and laboratory results may be a safe and reasonable approach before assigning patients the best treatment option with leukapheresis.

Clinical characteristics and outcomes of children with newly diagnosed acute myeloid leukemia and hyperleukocytosis managed with different cytoreductive methods.

BACKGROUND: Hyperleukocytosis in patients with acute myeloid leukemia (AML) has been associated with worse outcomes. For cytoreduction, leukapheresis has been used but its clinical utility is unknown, and low-dose cytarabine (LD-cytarabine) is used as an alternative method. METHODS: Children with newly diagnosed AML treated between 1997 and 2017 in institutional protocols were studied. Hyperleukocytosis was defined as a leukocyte count of ≥100 × 109 /L at diagnosis. Clinical characteristics, early complications, survival data, and effects of cytoreductive methods were reviewed. Among 324 children with newly diagnosed AML, 49 (15.1%) presented with hyperleukocytosis. Initial management of hyperleukocytosis included leukapheresis or exchange transfusion (n = 16, considered as one group), LD-cytarabine (n = 18), hydroxyurea (n = 1), and no leukoreduction (n = 14). RESULTS: Compared with patients who received leukapheresis, the percentage decrease in leukocyte counts following intervention was greater among those who received LD-cytarabine (48% vs. 75%; p = .02), with longer median time from diagnosis to initiation of protocol therapy (28.1 vs. 95.2 hours; p < .001). The incidence of infection was higher in patients (38%) who had leukapheresis than those who receive LD-cytarabine (0%) or leukoreduction with protocol therapy (14%) (p = .008). No differences were noted in the outcomes among the intervention groups. Although patients with hyperleukocytosis had higher incidences of pulmonary and metabolic complications than did those without, no early deaths occurred, and the complete remission, event-free survival, overall survival rates, and outcomes of both groups were similar. CONCLUSION: LD-cytarabine treatment appears to be a safe and effective means of cytoreduction for children with AML and hyperleukocytosis.

Effectiveness and safety of leukapheresis in hyperleukocytic leukemias: a retrospective multicenter study.

Leukapheresis is an effective adjuvant therapy for leukemia patients with hyperleukocytosis, but few studies have reported recent data with modern modalities and comparisons among different leukemia types. We conducted a retrospective study on leukapheresis among 420 patients with AML, ALL and CML in four local centers. WBC counts decreased significantly (p < 0.001) postleukapheresis in all three cohorts. Clearance efficiency was higher in acute leukemia patients than CML patients (p < 0.01). Concomitant leukocytoreduction drugs improved WBC reduction only in AML patients (p < 0.05). Leukocyte, hemoglobin and platelet levels preleukapheresis might affect the clearance efficiency in AML and/or ALL patients. Hematological toxicities were the major concerns, but most of them were mild, and only 11 patients died of all causes within one week postleukapheresis. In conclusion, leukapheresis can safely reduce the leukemic burden, especially for patients with acute leukemias.

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.

Comparison of early mortality between leukapheresis and non-leukapheresis in adult acute myeloid leukemia patients with hyperleukocytosis: a systematic review and meta-analysis.

OBJECTIVES: One of the treatment modalities that can be used for hyperleukocytosis is leukapheresis. However, the result of studies showing the benefit of early mortality through the use of leukapheresis versus no leukapheresis is still inconclusive. Hence, we aimed to conduct a systematic review with meta-analysis to determine the effect of leukapheresis on early mortality in AML patients with hyperleukocytosis. METHODS: We conducted a literature search on five databases (PubMed, EBSCOhost, Scopus, Clinicalkey, and JSTOR) up to October 2021 for studies comparing early mortality outcomes between hyperleukocytosis AML patients treated with leukapheresis versus no leukapheresis. Summary odds ratios (OR) and 95% confidence intervals (CI) were calculated using random-effects models. Heterogeneity tests were presented in I2 value and publication bias was analyzed using a funnel plot. RESULTS: Eleven retrospective cohort studies were eligible based on the inclusion and exclusion criteria. Pooled analysis showed that there was no significant difference in early mortality between patients receiving leukapheresis and not receiving leukapheresis in studies using hyperleukocytosis cutoff of 95,000/mm3 or 100,000/mm3 (OR: 1.17; 95% CI: 0.74-1.86; p: 0.50; I2: 0%). Similarly, studies using hyperleukocytosis cutoff of 50,000/mm3 also showed no benefits of early mortality (OR: 0.67; 95% CI: 0.43-1.05; p: 0.08; I2: 0%). Most of the studies used had a moderate risk of bias due to being observational studies. Funnel plot showed an indication of publication bias on studies using hyperleukocytosis cutoff of ≥50,000/mm3. CONCLUSION: The use of leukapheresis does not provide early mortality benefit in adult AML patients with hyperleukocytosis.

Intracranial Hemorrhage Associated With T-Cell Acute Lymphoblastic Leukemia With Hyperleukocytosis: A Case Report.

Acute leukemia in children may present with hyperleukocytosis. Symptomatic hyperleukocytosis is a medical emergency that necessitates rapid stabilization of the patient and prompt lowering of the leukocyte count. We report on a patient with intracranial hemorrhage associated with T-cell acute lymphoblastic leukemia with hyperleukocytosis, which is a rare occurrence. A 16-year-old boy with hyperleukocytosis (total white cell count; 398×103/µL) underwent repeated leukapheresis and received supportive treatment until a definite diagnosis of T-cell acute lymphoblastic leukemia was made and chemotherapy was started at 10% of the usual dose. On day 2 of treatment, he had headache, vomiting, and was agitated. Brain magnetic resonance imaging showed bilateral extensive hemispheric and cerebellar punctate areas of hemorrhage and perilesional edema. Chemotherapy intensified to a maximum dose on day 3. If supportive care for tumor lysis syndrome can be promptly provided, initial chemotherapy regimen can immediately be begun at an optimal dose.

CIN or not: An approach to the evaluation and management of chronic idiopathic neutrophilia.

Neutrophilia refers to an increase in the number of circulating neutrophils in the peripheral blood. Some common etiologies include infection, inflammatory conditions, myeloproliferative disorders, malignancies, endocrinopathies, drugs, and anemia. Rare disorders such as leukocyte adhesion deficiency can also cause neutrophilia. In many cases, there is an elevation of neutrophil count that persists for months or even years with no clear underlying cause in an otherwise asymptomatic patient. This is referred to as chronic idiopathic neutrophilia (CIN). Despite being a condition encountered by many physicians, there is a paucity of literature addressing CIN. Certain conditions such as stress, exercise, smoking, obesity, and obstructive sleep apnea have been associated with CIN and may provide explanations for neutrophilia previously thought to be idiopathic. Herein, we present a review of the literature on CIN and propose a systematic approach to this commonly encountered clinical condition.

Leukapheresis for the management of hyperleukocytosis in acute myeloid leukemia-A systematic review and meta-analysis.

BACKGROUND: Up to 20% of patients with acute myeloid leukemia (AML) present with hyperleukocytosis, usually defined as a white blood cell (WBC) count greater than 100 × 109 /L. Given the high early mortality rate, emergent cytoreduction with either leukapheresis, hydroxyurea, or chemotherapy is indicated, but the optimal strategy is unknown. STUDY DESIGN AND METHODS: For this systematic review and meta-analysis we searched MEDLINE and EMBASE via Ovid, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science from inception through March 2020 for multiarm studies comparing early mortality rates of patients with AML treated with leukapheresis and those who were not. The risk ratio (RR) of early death for patients who received leukapheresis vs patients who did not was estimated using a sum of the log-ratio of individual study estimates weighted by sample size. RESULTS: Among 13 two-arm, retrospective studies with 1743 patients (486 leukapheresis and 1257 nonleukapheresis patients), leukapheresis did not improve the primary outcome of early mortality compared to treatment strategies in which leukapheresis was not used (RR, 0.88; 95% confidence interval [CI], 0.69-1.13; P = .321) without statistically significant heterogeneity between studies (Cochran's Q, 18; P = .115; I2 , 33.4%). Patients presenting with clinical leukostasis tended to be more likely to undergo leukapheresis (odds ratio, 2.01; 95% CI, 0.99-4.08; P = .052). CONCLUSION: As we did not find evidence of a short-term mortality benefit and considering the associated complications and logistic burden, our results argue against the routine use of leukapheresis for hyperleukocytosis among patients with AML.

Clinical features in 52 patients with COVID-19 who have increased leukocyte count: a retrospective analysis.

Recent reports have showed that a proportion of patients with Coronavirus Disease 2019 (COVID-19) presented elevated leukocyte count. Clinical data about these patients is scarce. We aimed to evaluate the clinical findings of patients with COVID-19 who have increased leukocyte at admission. We retrospectively collected the clinical data on the 52 patients who have increased leukocyte count at admission from the 619 patients with confirmed COVID-19 who had pneumonia with abnormal features on chest CT scan in Renmin Hospital of Wuhan University in Wuhan, China, from February 3 to March 3, 2020. The mean age of the 52 patients with increased leukocyte count was 64.7 (SD 11.4) years, 32 (61.5%) were men and 47 (90.4%) had fever. Compared with the patients with non-increased leukocyte count, the patients with increased leukocyte count were significantly older (P < 0.01), were more likely to have underlying chronic diseases (P < 0.01), more likely to develop critically illness (P < 0.01), more likely to admit to an ICU (P < 0.01), more likely to receive mechanical ventilation (P < 0.01), had higher rate of death (P < 0.01) and the blood levels of neutrophil count and the serum concentrations of CRP and IL-6 were significantly increased, (P < 0.01). The older patients with COVID-19 who had underlying chronic disorders are more likely to develop leukocytosis. These patients are more likely to develop critical illness, with a high admission to an ICU and a high mortality rate.

Leukocytapheresis for patients with acute myeloid leukemia presenting with hyperleukocytosis and leukostasis: a contemporary appraisal of outcomes and benefits.

Introduction: Hyperleukocytosis, defined as a total white blood cell count (WBC) >50 or more commonly >100 × 109 cells/L, is a presenting feature of acute myeloid leukemia (AML) in about 6-20% of cases and is associated with a higher risk of tumor lysis syndrome (TLS), disseminated intravascular coagulation (DIC), clinical leukostasis with end organ damage, and mortality.Areas covered: In this review, authors discuss the implications of hyperleukocytosis in AML and the current understanding of cytoreductive strategies with a focus on the use of leukocytapheresis.Expert commentary: Efforts to rapidly reduce peripheral myeloblasts have included the use of leukocytapheresis. Early studies demonstrated feasibility in reducing peripheral WBC and blast counts as well as clinically relevant patient outcomes which prompted its common use for many years. However, more recent data have directly challenged the previously touted reports of reduced TLS and DIC incidence as well as survival benefit, even in patients with clinical leukostasis. The use of leukocytapheresis remains highly controversial with wide practice variations among physicians, institutions, and countries given the lack of high-quality data, risks associated with leukocytapheresis itself, associated high costs, resource utilization, and lack of evidence-based clinical guidelines.

Management of hyperleukocytosis and impact of leukapheresis among patients with acute myeloid leukemia (AML) on short- and long-term clinical outcomes: a large, retrospective, multicenter, international study.

Hyperleukocytosis in acute myeloid leukemia (AML) is associated with inferior outcomes. There is limited high quality evidence to support the benefits of leukapheresis. We retrospectively collected data from patients with newly-diagnosed AML who presented with a white cell count (WBC) >50 × 109/L to 12 centers in the United States and Europe from 2006 to 2017 and received intensive chemotherapy. Logistic regression models estimated odds ratios for 30-day mortality and achievement of composite complete remission (CRc). Cox proportional hazard models estimated hazard ratios for overall survival (OS). Among 779 patients, clinical leukostasis was reported in 27%, and leukapheresis was used in 113 patients (15%). Thirty-day mortality was 16.7% (95% CI: 13.9-19.3%). Median OS was 12.6 months (95% CI: 11.5-14.9) among all patients, and 4.5 months (95% CI: 2.7-7.1) among those ≥65 years. Use of leukapheresis did not significantly impact 30-day mortality, achievement of CRc, or OS in multivariate analysis based on available data or in analysis based on multiple imputation. Among patients with investigator-adjudicated clinical leukostasis, there were statistically significant improvements in 30-day mortality and OS with leukapheresis in unadjusted analysis, but not in multivariate analysis. Given the significant resource use, cost, and potential complications of leukapheresis, randomized studies are needed to evaluate its value.

Treatment Outcome in Pediatric Acute Lymphoblastic Leukemia With Hyperleukocytosis in the Yeungnam Region of Korea: A Multicenter Retrospective Study.

Acute lymphoblastic leukemia (ALL) with hyperleukocytosis at diagnosis is associated with early morbidity and mortality due to complications of leukostasis. Of 535 pediatric ALL patients (January 2004 to December 2016 from the Yeungnam region of Korea), 72 (13.5%) patients with an initial white blood cell (WBC) count of ≥100×10/L were included in this study, of whom 38 patients had extreme hyperleukocytosis (WBC>200×10/L) at diagnosis. Fourteen patients (19.4%) had ≥1 early respiratory and neurologic complications during induction therapy. Relapse occurred in 8 patients (24.2%) with extreme hyperleukocytosis and in 1 patient (3.0%) with an initial WBC count of 100 to 200×10/L (P=0.012). Estimated 10-year event-free survival rate (EFS) and overall survival rate were 78.3%±8.4% and 82.6%±7.7%, respectively. The 10-year EFS was significantly lower in patients with an initial WBC count of >200×10/L than in those with an initial WBC count of 100 to 200×10/L (65.7%±13.4% vs. 91.2%±7.9%; P=0.011). The 10-year EFS and overall survival rate did not differ significantly between patients with extreme hyperleukocytosis who received hematopoietic stem cell transplantation and those who received chemotherapy. In conclusion, pediatric ALL with hyperleukocytosis can lead to early complications and mortality. Patients with initial extreme hyperleukocytosis showed significantly poorer prognosis than those with WBC counts of 100 to 200×10/L.