Real-world incidence of venetoclax toxicities in British Columbia.

INTRODUCTION: Venetoclax is used to treat relapsed/refractory chronic lymphocytic leukemia (r/r CLL). Tumour lysis syndrome (TLS) is a serious toxicity associated with venetoclax, and real-world studies suggest that the incidence may be higher than in clinical trials. The purpose of this study is to describe the incidence of venetoclax toxicities in British Columbia (BC). METHODS: Retrospective review of electronic medical charts for patient characteristics and clinical outcomes of patients treated with venetoclax for r/r CLL in BC. Patients were classified according to their risk for developing TLS. The incidence of TLS was categorized based on laboratory metrics or clinical diagnosis. Other non-TLS toxicities were also collected. RESULTS: Of 33 patients identified, 40%, 33%, and 27% were at low, intermediate, and high risk for TLS, respectively. Laboratory TLS occurred in 1/33 patients (3%), and no clinical TLS was reported. Grade 3 or 4 toxicities occurred in 19/33 patients (58%). Of these, neutropenia was the most common, occurring in 16 patients (84%) followed by thrombocytopenia, which occurred in 8 patients (42%). CONCLUSIONS: The incidence of TLS in patients treated with venetoclax for r/r CLL in BC was lower than in other real-world studies. Findings may warrant further investigation to determine if the higher incidence of TLS in real-world reports may be mitigated through modifying TLS risk categorization and associated prophylactic measures. Neutropenia was the most common grade 3 or 4 venetoclax toxicity reported, and the incidence in BC is comparable to other centres.

Risk-based management strategy and outcomes of tumor lysis syndrome in children with leukemia/lymphoma: Analysis from a resource-limited setting.

BACKGROUND: Data from low- and middle-income countries on tumor lysis syndrome (TLS) in the pediatric population are limited. This study aims to analyze the clinical and biochemical characteristics and treatment outcomes of TLS in children with leukemia/lymphomas in a resource-limited setting. PROCEDURE: Children with intermediate risk (IRD) and high risk (HRD) for developing TLS were retrospectively studied at a tertiary cancer center in India. RESULTS: Over a three-year period, 224 children with acute leukemia/lymphoma having IRD (21.8%, n = 49) and HRD (78.1%, n = 175) were identified. TLS developed in 53.6% (n = 120) cases, of which 75% (n = 90) had laboratory TLS alone. Thirteen children had clinical TLS (C-TLS) at presentation while 17 patients progressed to develop C-TLS. TLS developed in 51% (n = 25) and 54.5% (n = 95) of children with IRD and HRD, respectively. Rasburicase was used in 8.5% (n = 19) cases and five children required hemodialysis. Two children (0.8%) expired during the course of TLS management. Multivariate analysis identified the presence of hyperuricemia as the single significant risk factor for developing TLS. When children in whom a 25% change in biochemical values from the baseline that falls within the normal range were excluded, 21.4% (48/224) cases were identified to have clinically relevant TLS (8% in IRD and 25% in HRD). CONCLUSION: With hydration, supportive care and judicious use of rasburicase, it is feasible to manage TLS efficiently in resource-limited settings. A modification of the TLS definition criteria would help to identify clinically relevant TLS.

Tumour Lysis Syndrome in children with haematological cancers: Experience at a tertiary care hospital in Karachi.

OBJECTIVE: To determine the incidence of tumour lysis syndrome and to identify associated factors and mortality rate in paediatric haematological patients. METHODS: The prospective study was conducted from April to September 2016 at Indus Children Cancer Hospital, Karachi, and collected data for all new paediatric oncology patients registered with diagnosis of haematological malignancies. Each patient was monitored for a period of three days before and seven days after the start of the treatment. SPSS 21 was used for data analysis. RESULTS: of the 232 patients, 86(37.1%) developed laboratory tumour lysis syndrome and 35(40.7%) of these patients developed the spontaneous variety. Overall, 24 (10.3%) patients progressed to clinical syndrome with 12(50%) of them developing spontaneous clinical syndrome. Mortality occurred in 17 (7.3%) patients. CONCLUSIONS: Despite preventive measures, tumour lysis syndrome remains an oncological emergency in children with haematological malignancies.

[Metabolic disorders as paraneoplastic syndromes]. / Metabolische Entgleisungen als paraneoplastische Syndrome.

Paraneoplastic syndromes are characterized by the tumor-induced release of peptide hormones and/or the initiation of immune phenomena, which elicit clinical changes and alterations in laboratory parameters independent of the tumor size and spread. In addition to neurological, endocrinal and rheumatological phenotypes, metabolic alterations play a special role in the clinical routine as they commonly present with acute symptoms in an emergency situation and necessitate immediate diagnosis and prompt initiation of treatment. Metabolic alterations within the framework of malignant diseases should be treated in a multidisciplinary team and it is often necessary to perform monitoring and treatment in an intensive care unit. This article focuses on the diagnostic and therapeutic options for metabolic disorders due to paraneoplastic syndromes, such as hypercalcemia, hypocalcemia, hyperglycemia, hypoglycemia and a special variant of tumor-induced metabolic disorders due to tumor lysis syndrome.

In-Hospital Outcomes of Tumor Lysis Syndrome: A Population-Based Study Using the National Inpatient Sample.

The epidemiology and outcomes of tumor lysis syndrome (TLS) are understudied. We used the National Inpatient Sample (NIS), a nationally representative weighted sample of all U.S. hospital discharges, to study outcomes and predictors of mortality in hospitalized patients with TLS. The NIS was queried for patients with a discharge diagnosis of TLS (ICD-9 code 277.88) from 2010-2013. Baseline characteristics and outcomes were analyzed. A multivariable logistic regression analysis was performed to identify predictors of mortality. From 2010-2013, 28,370 patients were discharged with a diagnosis of TLS. The most common malignancies were non-Hodgkin lymphoma (30%), solid tumors (20%), acute myeloid leukemia (19%), and acute lymphocytic leukemia (13%). Overall in-hospital mortality was 21%. The median length of stay was 10 days (IQR 5-22). Sixty-nine percent of patients experienced a severe complication, including sepsis (22%, 95% confidence interval [CI] 21-23), dialysis (15%, 95% CI 14-16), acute respiratory failure (23%, 95% CI 22-24), mechanical ventilation (16%, 95% CI 15-17), gastrointestinal hemorrhage (6%, 95% CI 5-7), cerebral hemorrhage (2%, 95% CI 2-3), seizures (1%, 95% CI 0.6-1), and cardiac arrest (2%, 95% CI 2-3). Predictors of mortality were derived from a multivariable logistic regression and included age, Elixhauser comorbidity score, insurance status, teaching versus nonteaching hospital, and cancer type. Predictors of increased length of stay included age, race, teaching versus nonteaching hospital, and cancer type. In the U.S., many patients with TLS develop life-threatening complications and a quarter die during hospitalization. As more cancer treatments become available, strategies to improve the supportive care of patients with TLS should be a priority.

Prognostic factors, long-term survival, and outcome of cancer patients receiving chemotherapy in the intensive care unit.

Prognostic factors and outcomes of cancer patients with acute organ failure receiving chemotherapy (CT) in the intensive care unit (ICU) are still incompletely described. We therefore retrospectively studied all patients who received CT in any ICU of our institution between October 2006 and November 2013. Fifty-six patients with hematologic (n = 49; 87.5 %) or solid (n = 7; 12.5 %) malignancies, of which 20 (36 %) were diagnosed in the ICU, were analyzed [m/f ratio, 33:23; median age, 47 years (IQR 32 to 62); Charlson Comorbidity Index (CCI), 3 (2 to 5); Simplified Acute Physiology Score II (SAPS II), 50 (39 to 61)]. The main reasons for admission were acute respiratory failure, acute kidney failure, and septic shock. Mechanical ventilation and vasopressors were employed in 34 patients (61 %) respectively, hemofiltration in 22 (39 %), and extracorporeal life support in 7 (13 %). Twenty-seven patients (48 %) received their first CT in the ICU. Intention of therapy was cure in 46 patients (82 %). Tumor lysis syndrome (TLS) developed in 20 patients (36 %). ICU and hospital survival was 75 and 59 %. Hospital survivors were significantly younger; had lower CCI, SAPS II, and TLS risk scores; presented less often with septic shock; were less likely to develop TLS; and received vasopressors, hemofiltration, and thrombocyte transfusions in lower proportions. After discharge, 88 % continued CT and 69 % of 1-year survivors were in complete remission. Probability of 1- and 2-year survival was 41 and 38 %, respectively. Conclusively, administration of CT in selected ICU cancer patients was feasible and associated with considerable long-term survival as well as long-term disease-free survival.

Oncological emergencies: tumor lysis syndrome.

Tumor lysis syndrome (TLS) occurs as a result of massive lysis of malignant cells and release of intracellular contents into the systemic circulation. It can lead to hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia. TLS is most commonly present after initiation of anticancer therapy but it can also develop spontaneously (STLS--spontaneous tumor lysis syndrome). In the article, pathophysiology, classification, risk factors and recommendations of management in TLS, with a special focus on solid tumors, are discussed. The keys to the identification of high-risk patients, prevention and management of TLS are included in presented guidelines.

Tumour lysis syndrome and acute kidney injury in high-risk haematology patients in the rasburicase era. A prospective multicentre study from the Groupe de Recherche en Réanimation Respiratoire et Onco-Hématologique.

In tumour lysis syndrome (TLS), metabolic alterations caused by the destruction of malignant cells manifest as laboratory abnormalities with (clinical TLS) or without (laboratory TLS) organ dysfunction. This prospective multicentre cohort study included 153 consecutive patients with malignancies at high risk for TLS (median age 54 years (interquartile range, 38-66). Underlying malignancies were acute leukaemia (58%), aggressive non-Hodgkin lymphoma (29.5%), and Burkitt leukaemia/lymphoma (12.5%). Laboratory TLS developed in 17 (11.1%) patients and clinical TLS with acute kidney injury (AKI) in 30 (19.6%) patients. After adjustment for confounders, admission phosphates level (odds ratio [OR] per mmol/l, 5.3; 95% confidence interval [95% CI], 1.5-18.3), lactic dehydrogenase (OR per x normal, 1.1; 95%CI, 1.005-1.25), and disseminated intravascular coagulation (OR, 4.1; 95%CI, 1.4-12.3) were associated with clinical TLS; and TLS was associated with day-90 mortality (OR, 2.45; 95%CI, 1.09-5.50; P = 0.03). In this study, TLS occurred in 30.7% of high-risk patients. One third of all patients experienced AKI, for which TLS was an independent risk factor. TLS was associated with increased mortality, indicating a need for interventional studies aimed at decreasing early TLS-related deaths in this setting.

The clinical management of tumour lysis syndrome in haematological malignancies.

Tumour lysis syndrome (TLS) is caused by the disintegration of malignant cells, usually following the instigation of chemotherapy, although it may already be established at the time of initial presentation in a minority of cases. As a direct consequence of malignant cell breakdown, intracellular ions, proteins, nucleic acids and their metabolites are released into the plasma causing the characteristic metabolic abnormalities of TLS; hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia. In many cases the release of large amounts intracellular contents is so abrupt that the normal homeostatic mechanisms are rapidly overwhelmed and without prompt, effective management, the clinical effects of TLS soon become apparent.

[Tumor lysis syndrome in intensive therapy: diagnostic and therapeutic encare]. / Síndrome de lisis tumoral en terapia intensiva: encare diagnóstico y terapéutico.

The tumor lysis syndrome (TLS) is a life-threatening complication caused by the massive release of nucleic acids, potassium and phosphate into the blood. This complication is the result of tumor cell lysis, which may occur due to treatment of drug sensitive and is characterized by rapid capacity of proliferation, that is often hematological origin. Moreover, the TLS can be observed before starting the treatment due to spontaneous tumor cell death, and frequently worsens when chemotherapy is initiated. TLS has high mortality, so that its prevention continues to be the most important therapeutic measure. In the intensive care unit (ICU), physicians should be aware of the clinical characteristics of TLS, which results in severe electrolyte metabolism disorders, especially hyperkalemia, hyperphosphatemia and hypocalcemia, and acute kidney injury which is a major cause of ICU mortality. An adequate strategy for the management of the TLS, combining hydration, urate oxidase, and an early admission to ICU can control this complication in most patients. The aim of this review is to provide diagnostic tools that allow to the ICU physician to recognize the population at high risk for developing the TLS, and outline a proper strategy for treating and preventing this serious complication.

Predictors of laboratory spontaneous tumour lysis syndrome in children with high-grade tumours in Uganda.

High-grade malignancy is endemic in sub-Saharan Africa and is prone to the spontaneous tumour lysis syndrome. However, data on spontaneous tumour lysis syndrome remain scanty in our setting. We sought to determine the prevalence and factors associated with laboratory spontaneous tumour lysis syndrome in children in Uganda. We conducted a cross-sectional study among children <18 years old with histologically confirmed high-grade malignancy between October 2013 and April 2014. Laboratory spontaneous tumour lysis syndrome was defined as the presence of ≥2 of each of hyperkalaemia, hypocalcaemia, hyperuricaemia and hyperphosphatemia prior to administration of chemotherapy when alternative diagnoses had been excluded. A p < 0.05 was considered statistically significant. Of 108 children, of median age 7.7 years, where boys outnumbered girls 2:1, high-grade, malignancy included Burkitt's lymphoma, acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, acute myeloid leukaemia and Burkitt's leukaemia, with 14 suffering with laboratory spontaneous tumour lysis syndrome. Hypocalcaemia was its most common electrolyte imbalance; and four children died prior to commencement of chemotherapy. Bulky disease, lactate dehydrogenase levels ≥500 iu/l and serum creatinine levels >1.2 mg/dl were associated with laboratory spontaneous tumour lysis syndrome. However, only bulky disease was significantly predictive of laboratory spontaneous tumour lysis syndrome. Such children would benefit from routine screening.

Incidence and risk of tumor lysis syndrome in patients with relapsed chronic lymphocytic leukemia (CLL) treated with venetoclax in routine clinical practice.

The risk of TLS in patients with relapsed CLL treated outside of clinical trials is not well described. Using the Mayo Clinic CLL Database, 48 patients treated with venetoclax for relapsed CLL in routine practice were identified; chart review determined baseline risk for TLS and laboratory abnormalities during venetoclax ramp-up. Overall, 6 (13%) patients developed laboratory TLS, 3 of whom demonstrated clinical TLS. The majority of patients who developed TLS were stratified as low or medium risk by the package insert. Of the 42 patients who did not meet Howard criteria for TLS, isolated hyperphosphatemia occurred in 19 patients (45%), hyperkalemia in 13 patients (31%), hyperuricemia in 2 patients (5%), and hypocalcemia in 1 patient (2%). In routine practice, the incidence of TLS appears higher than reported in clinical trials (3-6%). Half of patients who did not meet criteria for TLS developed clinically significant electrolyte abnormalities that required medical intervention.

Determining relative importance of variables in developing and validating predictive models.

BACKGROUND: Multiple regression models are used in a wide range of scientific disciplines and automated model selection procedures are frequently used to identify independent predictors. However, determination of relative importance of potential predictors and validating the fitted models for their stability, predictive accuracy and generalizability are often overlooked or not done thoroughly. METHODS: Using a case study aimed at predicting children with acute lymphoblastic leukemia (ALL) who are at low risk of Tumor Lysis Syndrome (TLS), we propose and compare two strategies, bootstrapping and random split of data, for ordering potential predictors according to their relative importance with respect to model stability and generalizability. We also propose an approach based on relative increase in percentage of explained variation and area under the Receiver Operating Characteristic (ROC) curve for developing models where variables from our ordered list enter the model according to their importance. An additional data set aimed at identifying predictors of prostate cancer penetration is also used for illustrative purposes. RESULTS: Age is chosen to be the most important predictor of TLS. It is selected 100% of the time using the bootstrapping approach. Using the random split method, it is selected 99% of the time in the training data and is significant (at 5% level) 98% of the time in the validation data set. This indicates that age is a stable predictor of TLS with good generalizability. The second most important variable is white blood cell count (WBC). Our methods also identified an important predictor of TLS that was otherwise omitted if relying on any of the automated model selection procedures alone. A group at low risk of TLS consists of children younger than 10 years of age, without T-cell immunophenotype, whose baseline WBC is < 20 x 10(9)/L and palpable spleen is < 2 cm. For the prostate cancer data set, the Gleason score and digital rectal exam are identified to be the most important indicators of whether tumor has penetrated the prostate capsule. CONCLUSION: Our model selection procedures based on bootstrap re-sampling and repeated random split techniques can be used to assess the strength of evidence that a variable is truly an independent and reproducible predictor. Our methods, therefore, can be used for developing stable and reproducible models with good performances. Moreover, our methods can serve as a good tool for validating a predictive model. Previous biological and clinical studies support the findings based on our selection and validation strategies. However, extensive simulations may be required to assess the performance of our methods under different scenarios as well as check their sensitivity to a random fluctuation in the data.

Decreasing Inappropriate Use of Rasburicase to Promote Cost-Effective Care.

BACKGROUND: Rasburicase is a recommended treatment of tumor lysis syndrome and patients at high-risk for developing tumor lysis syndrome. Unfortunately, it is expensive, and unnecessary use raises costs of care. METHODS: Plan, Do, Study, Act methodology was used to decrease the inappropriate use of rasburicase. In the Plan phase, a multidisciplinary quality improvement team reviewed the rasburicase ordering process and its prescription patterns at Parkland Health and Hospital System between October 2015 and September 2017 to determine appropriate interventions for improvement. In the Do phase, interventions were deployed to improve rasburicase prescriptions. In the Study phase, the team reviewed the rasburicase orders and appropriateness from February 2018 to October 2018. During the Act phase, the interventions were found to be successful, and the process changes were solidified. RESULTS: At baseline, 65 doses of rasburicase were administered during the 2-year baseline period, 21 of these (32.3%) were inappropriate. Review of the ordering process identified pitfalls: one-click ready-to-sign order, fixed default dose, no hard-stop alert requiring physicians to review and confirm appropriate indications, and lack of secondary pharmacy review. We aimed to reduce the percentage of inappropriate rasburicase orders from a baseline of 32.3% to 10% over 3 months. In February 2018, we implemented the interventions, which resulted in reduction in inappropriate rasburicase use, with only a single inappropriate order placed in 7 months postintervention. CONCLUSION: A multidisciplinary approach and classic quality improvement methodology enabled us to reduce inappropriate rasburicase use. Straightforward electronic medical record interventions and secondary pharmacy review are effective in addressing overuse.

Impact of early rasburicase on incidence of clinical tumor lysis syndrome in lymphoma.

Early administration of rasburicase to enhance uric acid (UA) elimination has been adopted without robust evidence in support of its impact on clinical outcomes in tumor lysis syndrome (TLS), specifically, the prevention of acute kidney injury (AKI). This was a retrospective cohort study of adult lymphoma patients at intermediate or high risk for TLS. Excluded patients had AKI or were on dialysis at hospital admission. The incidence of new AKI in the setting of TLS was described along with predictors of its development, including early rasburicase use. In 383 included patients, the incidence of new-onset AKI during hospitalization was 6%. Predictors included age, history of renal or cardiovascular disease, and UA >8 mg/dL. Rasburicase use did not significantly impact the risk of developing AKI (HR 2.3; p = .11). The UA level at the time of administration did not modify the effect of rasburicase on prevention of AKI (p = .36 for the interaction term).

Incidence of chemotherapy-related tumour lysis syndrome at Kenyatta National Hospital, Nairobi.

OBJECTIVES: To estimate the magnitude of laboratory defined Tumour Lysis Syndrome (TLS) at Kenyatta National Hospital (KNH), identify its pattern of presentation, resolution, and determine the biochemical outcome of affected patients. DESIGN: Prospective patient-treatment cohort study. SETTING: Kenyatta National Referral and Teaching Hospital, between November 2004 and April 2005. SUBJECTS: One hundred and forty two patients receiving first course chemotherapy. MAIN OUTCOME MEASURE: Laboratory defined Tumour Lysis Syndrome (TLS). RESULTS: One hundred and eleven patients completed the study protocol. Forty two patients (37.8%) developed TLS. The incidence in haematological malignancies was 75.5% while in non-haematological malignancies was 3.6%. Hyperphosphataemia and hyperkalaemia were the most consistent diagnostic parameters while hyperuricaemia occurred in only one patient. No patient developed hypocalcaemia. Ninety five percent of patients developed TLS within the first three days of receiving chemotherapy while 55% resolved in the first week. Two TLS case mortalities occurred. CONCLUSIONS: The incidence of TLS in this cohort study was 38%, and was highest among haematological malignancies. No cases occurred in breast cancer patients. Majority of the cases were diagnosed on the basis of increase in serum phosphate and potassium; uric acid did not rise predominantly due to prophylactic uricosuric therapy. A majority (95%) developed within three days of commencing chemotherapy.

[Analysis of the 2015 British guidelines on the prevention and management of tumor lysis syndrome]. / Analyse des recommandations britanniques 2015 sur la prévention et la prise en charge du syndrome de lyse tumorale.

Whether it appears spontaneously or is induced by therapy, the tumor lysis syndrome is responsible for a massive release of ions and puric bases degradation of products in the circulation exceeding the renal excretion capacity. Some, such as uric acid, xanthine, and calcium phosphate, can precipitate in the renal tubules or parenchyma. It must be known to any practitioner supporting patients with hematologic malignancies, mainly high-grade but also some solid tumors. The 2015 publication of the British recommendations pertaining to patients suffering from hematological diseases should be broadcast. The main goal of treatment is to prevent the occurrence of renal dysfunction associated with heavy morbidity and mortality, either for his own conduct or consequences on obtaining a good tumor response. Some items proposed for the care, whether curative or preventive, should be discussed or detailed, which is the subject of this paper.

Tumor lysis syndrome in children with non-Hodgkin lymphoma.

This study was designed to evaluate the incidence of tumor lysis syndrome (TLS) among children with non-Hodgkin lymphoma and to define whether renal involvement can be associated with higher incidence of TLS after chemotherapy. Medical charts of 59 patients were reviewed. TLS was diagnosed using laboratory and clinical criteria. Renal involvement was diagnosed based on ultrasound and CT scan findings. Laboratory TLS occurred in 7 patients (11.85%) and clinical TLS was observed in 7 patients (11.85%) as well. In 5 out of 14 TLS patients, hemodialysis was required to correct electrolyte abnormalities and TLS related death was reported overall in 3 patients. Sex, age, pretreatment LDH, and initial WBC count were not associated with higher incidence of TLS after chemotherapy, but a significant correlation was found between pretreatment renal involvement at imaging studies and development of TLS after chemotherapy (p = .027). The results indicate that despite all preventive measures, tumor lysis syndrome still occurs in children with non-Hodgkin lymphoma following chemotherapy. Patients who have evidence of renal involvement at imaging studies are more likely to develop TLS after chemotherapy.