Incidence Of Tumor Lysis Syndrome Research Articles

Tumor lysis syndrome (TLS) in acute myeloid leukemia (AML) patients treated with azacitidine (AZA) and venetoclax (VEN).

e19507 Background: Studies evaluating VEN with hypomethylating agents in AML patients have reported no incidence of clinical TLS. However, little is known about TLS development in a real-world setting. Here, we investigate our institutional incidence of clinical TLS and describe these patients’ presentations. Methods: This is a single-center, retrospective study of 156 adult pts treated with AZA/VEN for AML between 2015-2019. The primary outcome is the absolute incidence of clinical TLS after AZA/VEN administration per Cairo-Bishop (CB) criteria. Secondary outcomes include median time to TLS, CTCAE grade of TLS, and mortality. All patients received TLS mitigation strategies including fluids, uric acid lowering agents, and frequent lab monitoring. VEN was escalated over 3-4 days, starting at 100 mg, and given with AZA at the standard dose and schedule. Results: The median age was 70 years (22-89); 80 pts (51%) were female. 121 pts (78%) were treatment-naïve, 26 pts (17%) were relapsed, and 9 pts (6%) were refractory. Four pts (3%) developed clinical TLS per CB criteria after AZA/VEN administration. Two pts were relapsed, one pt was treatment-naïve, and one pt had mixed phenotype acute leukemia, B/myeloid. All four pts developed renal insufficiency. No seizures, cardiac arrhythmias, or mortality occurred secondary to TLS. Two pts required renal replacement therapy, and two pts required escalation of care to ICU for TLS management. Median time to TLS onset was 12 hours (10-25) after receiving the first dose of VEN. CTCAE grade 3 TLS occurred in 2 pts (1%) and grade 4 TLS occurred in 2 pts (1%). VEN was held in 2 pts (8, 10 days); no pts required permanent discontinuation of VEN. Baseline features for each patient are listed in the table. Conclusions: Though we report higher rates of clinical TLS compared to prior studies, the incidence of clinical TLS with AZA/VEN remains low. These results support close monitoring of pts, particularly in the first 24 hours of receiving VEN. [Table: see text]

Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: A Retrospective, Single-Institution Analysis Based on Risk Features and Debulking Strategy with Anti-CD20 Monoclonal Antibody

Background: The treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) has continued to evolve in recent years, offering the patients different therapeutic options. Venetoclax (ven) is a selective, small molecule inhibitor of B-cell receptor-2 (BCL-2) approved by the FDA for patients with newly diagnosed and relapsed/refractory CLL. Stratification based on tumor lysis syndrome (TLS) risk is recommended and may guide debulking strategies. Methods: We retrospectively analyzed 36 patients with relapsed/refractory (RR) CLL who received treatment with ven at the Moffitt Cancer Center between January 2016 and July 2019. Objective response to therapy was determined based on iwCLL. Progression free survival (PFS) and overall survival (OS) were evaluated via Kaplan-Meier method; overall response rate (ORR) and complete response (CR) via Fisher's exact test. Adverse events (AEs) were graded by CTCAEv5. Results: The median age was 58.5 years (28-82). Median follow up was 12.97 months. The vast majority of patients had high risk disease; Chromosomal analysis by Fluorescence In Situ Hybridization (FISH) reported Del17p and Del11q (+/- others, except Del17p) in 18 (50%) patients and 6 (16.7%) patients respectively. Twenty one (58.3%) patients had a TP53 mutation by next generation sequencing. Twenty five (80.6%) patients had unmutated IGHV status, and 24 (79.9%) patients had high or very high CLL-International prognostic Index (CLL-IPI) score. Twenty-four patients (66.7%) had been previously treated with Ibrutinib, 11 of those progressing on it. Further characteristics are described in table 1. Median OS was not reached. Median PFS was 23.93 months, figure 1a. Median duration of response was 25.97 months. The ORR (PR+CR) at the time of analysis was 63.9%, with CR rate of 33.3%, and PR rate of 30.6%. Nine patients (25%) had stable disease (SD), while four patients (11.1%) progressed on treatment. Minimal residual disease (MRD) was evaluated as part of the response assessment in 7 patients (19.4%) by flow cytometry (1 patient) and by clonoSEQ (6 patients), and 4 (11.1%) had achieved undetectable disease. Response rates were also based on risk stratification; OS and PFS were not affected by the presence of TP53 mutation (p=0.1145) as described in figure 1b, IGHV unmutated status, or NOTCH1 mutation. PFS was inferior in patients with high-very high CLL-IPI score (p=0.0414), figure 1c. The presence of bulky lymphadenopathy (≥5 cm) did not affect outcomes (p=0.5772), figure 1d. Reasons for treatment discontinuation were: progressive disease (PD) in 6 (16.7%), MD/patient preference in 5 (13.9%), Richter's transformation in 2 (5.6%), AEs in 1 (2.8%), allogeneic transplant in 1 (2.8%), and death while on treatment in 1 (2.8%) case. Twenty patients (55.6%) were considered to be at intermediate/high risk of developing TLS, of whom 15 (75%) received debulking therapy with rituximab (1), ofatumumab (11), or obinutuzumab (3) prior to ven. Based on the absolute lymphocyte count (ALC), the risk of TLS became low in 12 patients. The use of a debulking monoclonal antibody (MoAb) improved lymphocytosis, but did not impact PFS. Treatment was well tolerated, and was not dependent on the use of debulking MoAb; however, out of the 18 patients (50%) who underwent debulking therapy, 9 (25%) had grade 3/4 toxicities. Neutropenia was the most common grade 3/4 toxicity in all patients, which was seen in 7 (19.4%) patients, and diarrhea was the most common grade 3/4 non-hematologic toxicity, seen in 4 (11.1%) patients; grade 3/4 neutropenia was seen in 4 (57.1%) of those patients who received debulking therapy, while diarrhea was only seen in 1 (25%). No cases of TLS were observed. Ten patients (27.8%) were admitted for ramp up of ven as per physician preference, independent of TLS risk and comorbidities. Conclusion: Venetoclax is a very active agent for R/R CLL with an acceptable toxicity profile. Debulking strategy is a tolerable option for patients with high burden disease and may reduce the incidence of TLS and/or hospitalization. Nonetheless, based on this retrospective study, it does not seem to have a significant impact in outcomes, and it carries a higher risk for potential cumulative toxicity. Disclosures Chavez: Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals, Inc.: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Sandoval-Sus:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Shah:Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria. Bello:Celgene: Speakers Bureau. Sokol:EUSA: Consultancy. Nodzon:Pfizer: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy, Other: Speaker Fees; Abbvie: Other: Speaker Fees. Pinilla Ibarz:Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Sanofi: Speakers Bureau.

Relevant nursing measures for the adverse reactions associated with chimeric antigen receptor T cells (CAR-T) immunotherapy: a systematic review of case reports†

Abstract Objective Cytokine release syndrome (CRS) and tumor lysis syndrome (TLS) that occur after chimeric antigen receptor T (CAR-T) cells are reinfused, which severely affect the survival and prognosis of patients. Although several articles have reported on the care of CAR-T cell immunotherapy, the quality of the study and the effectiveness of holistic nursing interventions have not been systematically reviewed. The purpose of this study was to systematically evaluate the existing holistic nursing interventions of CAR-T cell immunotherapy. Methods A literature search for keywords was performed in PubMed, EMBASE, the Cochrane Library, CNKI, CBM, and Wanfang Data from its inception until January 2018. Studies were deemed eligible if they comprised patients with tumor receiving CAR-T cell immunotherapy, described the holistic nursing process, and were published in Chinese and English. Results A total of 6 articles on holistic nursing interventions of CAR-T cell immunotherapy are reported, and the nursing methods and results of each article are analyzed. The quality of the studies included was medium. All nursing measures were considered effective. Conclusions Holistic nursing programs reduce the incidence of CRS and TLS and improve the quality of life of cancer patients.

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia

AbstractThis single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10−4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.

Tumor Lysis Syndrome.

Tumor lysis syndrome (TLS) is an acute, life-threatening disease among adults and children that is associated with the initiation of cytoreductive therapy in the treatment of malignancy. A pattern of metabolic derangements occurs as a result of a massive release of intracellular contents into the systemic circulation. Characteristic findings include hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia, and uremia, all of which can lead to cardiac arrhythmia, seizures, renal failure, and sudden death. The incidence of TLS appears to be increasing because of a rapidly growing armamentarium of highly effective biologic and targeted therapies. Risk assessment and prevention are at the forefront of management and rely on clinician awareness, prophylactic measures, and vigilant laboratory monitoring. Established TLS requires early, aggressive intervention with intravenous hydration, electrolyte management, and the use of hypouricemic agents. This review highlights the central role of diagnostic laboratory criteria for TLS, and summarizes the clinical findings, pathophysiology, and evidence-based guidelines for the prevention and management of TLS.

Tumor lysis syndrome in paediatric cancer patients

Introduction: Tumor lysis syndrome (TLS) is a common complication of malignancies and can result in renal failure or death.&#x0D; Review: In paediatric tumor with a high proliferative rate and relatively large mass and a high sensitivity to cytotoxic agents, beging of therapy often results in the rapid release of intracellular metabolic products of proteins and nucleic acids into the bloodstream. Raised concentrations of uric acid, phosphates, potassium and urea can overwhelm the body’s homeostatic mechanisms to excrete these materials and result in the clinical spectrum associated with TLS. Clinical features include gastrointestinal disturbances, neuromuscular effects, cardiovascular complications, acute renal failure and death. The incidence of clinical TLS is approximately 6% for acute leukemias and 10% for lymphomas. Pediatric cancers are the leading cause of death by disease in children. The most common pediatric cancers include the leukemias, lymphoma, Wilms’ tumor and neuroblastoma. Thus, TLS prevention and treatment is a multidisciplinary approach involving the collaboration of medical oncologists/ hematologists and nephrologists has role for optimal patient outcomes. Rehydration is fundamental in the management of TLS. For hyperuricemia we may use allopurinol. Conclusion: The early diagnosis and treatment of metabolic abnormalities prevents the severe complications of tumor lysis syndrome.&#x0D; Journal of Paediatric Surgeons of Bangladesh (2016) Vol. 7 (2): 55-60

Evaluation and characterization of tumor lysis syndrome before and after chemotherapy among pediatric oncology patients in Tikur Anbessa specialized hospital, Addis Ababa, Ethiopia

BackgroundTumor lysis syndrome (TLS) is a life-threatening emergency disorder, caused by an abrupt release of intracellular metabolites after tumor cell death. It is characterized by a series of metabolic manifestations, especially hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia. The aim of this study was to evaluate and characterize the incidence of tumor lysis syndrome among pediatric oncology patients before and after treatment.MethodsHospital based prospective cohort study was conducted for 6 months on 61 newly diagnosed pediatric oncology patients. Socio-demographic data was collected by interview administered questionnaire. Patients were followed and the physical diagnosis, imaging and laboratory results were interpreted by senior physicians. Data was entered to and analyzed by SPSS version 23.ResultsAmong 61 pediatric oncology patients 39(63.9%) were males. The mean (±SD) age of the pediatric patients was 6.39 (± 3.67) years ranging from 2 months to 14 years. 29.5% of patients were found to have TLS. There were 11.5% and 18.0% of laboratory TLS (LTLS) and clinical TLS (CTLS) cases respectively. There were72.2% spontaneous and 27.8% treatment induced TLS cases with 23% and 21.3% cases of hyperuricemia and 4.9% and 6.6% cases of hyperkalemia incidence before and after treatment respectively. Only two patients died, in the study period, due to TLS.ConclusionThere was high incidence of TLS irrespective of socio-demographic variation among study participants, suggesting that children with cancer are at risk of developing TLS. As TLS is a life-threatening complication of malignancies, early identification of patients at risk and reducing morbidity and mortality is crucially important.

Effectiveness of Single-dose Rasburicase in Patients With Lymphoid Malignancies at a High Risk for Tumor Lysis Syndrome.

Tumor lysis syndrome (TLS) is a life-threatening disorder that occurs mainly in patients with high-tumor burden hemato-oncologic malignancies. It results in metabolic derangements, including hyperuricemia and acute renal failure. The powerful management for TLS is a daily dose of rasburicase for up to 5 days before chemotherapy; however, the optimal dose and duration of rasburicase for TLS prophylaxis have not been standardized for patients at high risk for TLS. Therefore, we evaluated the efficacy of single-dose rasburicase for prophylactic purposes in patients with malignant lymphoma at high risk for TLS. We retrospectively evaluated patients with malignant lymphoma at high risk for TLS treated with a prophylactic single-dose of rasburicase (0.1-0.2 mg/kg) from March 2012 to March2016. A total of 67 patients treated with a single-dose of rasburicase for prophylaxis were analyzed. A relatively large number of patients (n= 23; 34.3%) had the highly proliferative lymphoblastic lymphoma subtype (n= 14) or Burkitt lymphoma (n= 9) and were at the highest risks of tumor lysis. Two patients were newly diagnosed with TLS; the incidence of TLS after single-dose prophylaxis was 3.0%. Multivariate analysis revealed no predictable risk factors for response to prophylactic rasburicase, though increased level of serum creatinine approached statistical significance in reducing the efficacy of single-dose rasburicase to prevent TLS (odds ratio, 3.61; P= .054). Our data indicated that single-dose rasburicase effectively prevented progression of TLS, and, regardless of any risk factors, including increased creatinine, single-dose rasburicase for TLS prophylaxis was useful in patients with lymphoma at a high risk for TLS.

Analysis of the incidence of tumor lysis syndrome in patients with hematological malignancies treated with rasburicase.

The purpose of this study was to assess the incidence of tumor lysis syndrome (TLS) in patients with hematological malignancies treated with rasburicase, and to evaluate the dose and duration of rasburicase administration. A total of 52 patients were enrolled. The background of the patients, incidence of TLS and laboratory data were retrospectively examined; in addition, the dose and duration of rasburicase administration and the factors affecting the onset of TLS were evaluated and compared among TLS risk categories. During the study period, 2 (3.8%) of the patients developed clinical TLS and 24 (46.2%) developed laboratory TLS (LTLS). Although the LTLS rate was very high, there were no life-threatening cases of TLS. The median daily dose of rasburicase administered to all patients was 7.5 mg/day (interquartile range, 7.5-9.0 mg/day), and the daily weight-based dose was 0.147 mg/kg/day (range, 0.126-0.178 mg/kg/day). The administration duration was 3 days (interquartile range, 3-4 days). Additionally, there was no significant association between TLS risk classification and daily rasburicase administration dose, duration, or post-administration laboratory data. The factors affecting the onset of TLS included serum uric acid level, as well as serum creatinine and phosphate levels. Rasburicase was highly effective in the prevention and management of hyperuricemia, even at a low-dose (7.5 mg/day) and a duration that was 3 days shorter compared with that recommended by the manufacturer. Therefore, clinicians should administer rasburicase based on their clinical judgment, taking into consideration the cost-effectiveness of this therapy.

Urate oxidase for the prevention and treatment of tumour lysis syndrome in children with cancer.

Urate oxidase for the prevention and treatment of tumour lysis syndrome in children with cancer.

Prevention and treatment of tumor lysis syndrome, and the efficacy and role of rasburicase.

Tumor lysis syndrome (TLS) is a potentially life-threatening condition that occurs in oncologic and hematologic patients with large tumor burden, either due to cytotoxic therapy or, less commonly, spontaneously because of massive tumor cell lysis. TLS is clinically characterized by acute renal failure, hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. While limited options are available for treating TLS, identifying patients at high risk for developing TLS and prevention in high-risk patients remain an important aspect in the treatment of cancer patients. In general, treatment of TLS consists of intensive hydration, stimulation of diuresis, and, more specifically, in the use of allopurinol and rasburicase. Rasburicase, a recombinant urate oxidase, rapidly and effectively reduces hyperuricemia, which subsequently significantly decreases the risk of acute renal failure and other clinical manifestations of TLS. For this review, a comprehensive literature search using the term “tumor lysis syndrome” and/or “rasburicase” was performed considering articles listed in MEDLINE. Incidence, prevention, and therapy of TLS with a special focus on the role of rasburicase are discussed. We evaluated 120 relevant articles including 35 case reports, 32 clinical trials, and 14 meta-analyses.

Features and Outcome of Patients (Pts) with New Diagnosis of Acute Myeloid Leukemia (AML) with Monocytic Differentiation (AML-Mo) Following Standard Induction Therapy. Do We Need a Different Strategy?

Background: Pts with AML-Mo, often present with leukocytosis and aggressive clinical features such as extramedullary involvement and coagulation abnormalities. Frequently the clinical presentation resembles a hyperinflammatory phenotype. This often leads to unfavorable outcomes compared to pts with other subtypes of AML regardless of pretreatment cytogenetic/molecular features. No large series have systematically assessed the characteristics of pts with AML-Mo following standard induction therapy. We conducted a retrospective case-control study of pts with AML-Mo to define disease characteristics and associate those with outcome.Methods: Sixty-one consecutive pts between January 2010 and March of 2016 with AML who met FAB criteria for acute myelomonocytic or acute monocytic leukemia or exhibited greater than 20% monocytic differentiation on flow cytometry were considered as AML-Mo, and were compared to a control cohort of 128 pts with AML without monocytic differentiation. All pts were newly diagnosed and treated on a standard intensive induction protocol. Pts were excluded for incomplete cytogenetic and molecular data.Results: There were no significant differences between the two groups with regard to age, sex, secondary AML, prior MDS, and ELN risk stratification. Pts with AML-Mo had higher median WBC (43,000/µ vs 7,000/µL, p<0.0001) and higher LDH values (1,661 U/L vs 847 U/L, p<0.0001). The treatment course of pts with AML-Mo was characterized by significantly higher incidence of tumor lysis syndrome (42%vs 6%, p<.0001), diffuse alveolar injury (10% vs 0%, p=.001) , respiratory failure with need for high flow oxygen or mechanical ventilation (31% vs 6%), p=<.0001), symptomatic leukostasis ( 7% vs 1%, p=.014), renal failure (41% vs 10%, p=<.0001), and DIC (19%vs 3%, =.0008). Induction mortality was 18% for AML-Mo and 2% for other AML pts (p=.0003). CR rate was 79% (AML-Mo) and 82% (AML), respectively (p=.65).With a median follow up of 10.7 months, 1 and 5-yr OS was 55% and 34% (AML-Mo) compared to 70% and 38% (AML) at 1 and 5 years, respectively (p=.0075, p=.034)(Figure 1). Allo HSCT in CR1 resulted in greater reduction in the risk of mortality for pts with AML-Mo compared to other AML pts (56% vs 11%, p=0.148) (Figure 2). This effect prevailed when considering ELN risk at diagnosis and HSCT into a multivariate model (p=0.032).Conclusions: Pts with AML-Mo experience higher rates of complications and death within 30 days of induction. Despite similar CR rates, overall survival was inferior. While allo HSCT benefited both pts with AML and AML-Mo, the benefit was greatest for AML-Mo pts. Besides allo HSCT in CR, other measures (eg reduction of inflammatory reactions by suppression of cytokines and other mediators) should be considered to decrease the high induction mortality and complication rate of these pts. [Display omitted] [Display omitted] DisclosuresMcCloskey:Novartis: Speakers Bureau; Incyte: Consultancy; Ariad: Consultancy, Speakers Bureau; Amgen: Speakers Bureau. Depadova:Amgen: Speakers Bureau. Koprivnikar:Alexion: Consultancy, Speakers Bureau. Stanislaus:Novartis: Consultancy, Speakers Bureau. Goldberg:Neostem: Equity Ownership; Pfizer: Honoraria; Bristol Myers Squibb, Novartis: Speakers Bureau; Novartis: Consultancy; COTA Inc: Employment.

High Risk of Tumor Lysis Syndrome in Symptomatic Patients with Multiple Myeloma with Renal Dysfunction Treated with Bortezomib.

Tumor lysis syndrome (TLS) is a life-threatening complication associated with cancer chemotherapy. We retrospectively evaluated the risk of developing TLS in patients with symptomatic multiple myeloma undergoing chemotherapy. Sixty-four patients (median age=71 years, range=48-87 years, 35 males/29 females) who were treated at our Institution between April 2006 and December 2015 were evaluated. A total of 124 chemotherapy courses were administered, of which 63 courses were bortezomib-based regimens and 34 courses were immunomodulatory drug (IMiD)-based regimens. TLS occurred in 13 (10.5%) out of 124 chemotherapy courses with five (4.0%) cases of laboratory TLS and eight (6.5%) cases of clinical TLS. The incidences of TLS were 17.5% for bortezomib-containing regimens and 3.2% for non-bortezomib-based regimens. No TLS occurred in the patients treated with IMiD-containing regimens. TLS occurred more frequently in the patients with elevated uric acid, creatinine, or beta-2-microglobulin levels at baseline. The patients with disease classified as advanced International Staging System also developed TLS more frequently. All the patients who developed clinical TLS received bortezomib-containing regimens (8/63, 12.7%). Among them, patients with elevated values of uric acid or creatinine developed clinical TLS more often than those without such elevation. The incidence of clinical TLS was 33.3% if the patients had renal dysfunction at baseline and were subsequently treated with bortezomib-based regimens (8/24 cases). Patients with renal dysfunction or a high uric acid level receiving bortezomib-based chemotherapy have a high risk of developing TLS.

Tumor Lysis Syndrome in Multiple Myeloma: An Increasingly Recognized Risk-A Report of Seven Cases.

Tumor lysis syndrome is a constellation of metabolic disturbances commonly seen during therapy of bulky, rapidly proliferative tumors. Multiple myeloma is a low proliferation tumor with rare incidence of tumor lysis syndrome in the pre-Bortezomib era. Post Bortezomib use, a rise in the incidence of tumor lysis has been noted. We present seven cases of tumor lysis syndrome with three patients in spontaneous tumor lysis and four developing the same after chemotherapy. In the previous studies, elevated LDH and deletion of chromosome 13 has been associated with risk of TLS. In our study, we noted several abnormal karyotpes including del 9p13, del 17 and monosomy 13 were more frequently found but larger studies are needed to explore the causative nature of these associations. Prognosis in these patients is relatively poor reflecting the higher tumor burden. However, further studies are needed to learn about other poor prognostic markers.

Risk and prevention strategies can help avert tumor lysis syndrome

Risk and prevention strategies can help avert tumor lysis syndrome

Tumor lysis syndrome in the era of novel and targeted agents in patients with hematologic malignancies: a systematic review.

Effective new treatments are now available for patients with hematologic malignancies. However, their propensity to cause tumor lysis syndrome (TLS) has not been systematically examined. A literature search identified published Phase I-III clinical trials of monoclonal antibodies (otlertuzumab, brentuximab, obinutuzumab, ibritumomab, ofatumumab); tyrosine kinase inhibitors (alvocidib [flavopiridol], dinaciclib, ibrutinib, nilotinib, dasatinib, idelalisib, venetoclax [ABT-199]); proteasome inhibitors (oprozomib, carfilzomib); chimeric antigen receptor (CAR) T cells; and the proapoptotic agent lenalidomide. Abstracts from major congresses were also reviewed. Idelalisib and ofatumumab had no reported TLS. TLS incidence was ≤5% with brentuximab vedotin (for anaplastic large-cell lymphoma), carfilzomib and lenalidomide (for multiple myeloma), dasatinib (for acute lymphoblastic leukemia), and oprozomib (for various hematologic malignancies). TLS incidences were 8.3 and 8.9% in two trials of venetoclax (for chronic lymphocytic leukemia [CLL]) and 10% in trials of CAR T cells (for B-cell malignancies) and obinutuzumab (for non-Hodgkin lymphoma). TLS rates of 15% with dinaciclib and 42 and 53% with alvocidib (with sequential cytarabine and mitoxantrone) were seen in trials of acute leukemias. TLS mitigation was employed routinely in clinical trials of alvocidib and lenalidomide. However, TLS mitigation strategies were not mentioned or stated only in general terms for many studies of other agents. The risk of TLS persists in the current era of novel and targeted therapy for hematologic malignancies and was seen to some extent with most agents. Our findings underscore the importance of continued awareness, risk assessment, and prevention to reduce this serious potential complication of effective anticancer therapy.

Inferior Outcomes with Intensive AML Induction Therapy in Patients Age 70 or Greater Compared to Age 60-69

Background: The median age of diagnosis for acute myeloid leukemia (AML) is between age 65 and 70. While advances in therapy and supportive care in the past several decades has significantly improved outcomes in younger patients, the prognosis in elderly AML patients, defined as age 60 or greater, remains dismal. In addition, many elderly patients are unable to receive such aggressive therapy due to increased treatment-related mortality and poorer clinical response. There remains great interest in identifying factors that are associated with both beneficial and detrimental outcomes in this patient population.Methods: This was a retrospective analysis conducted at Moffitt Cancer Center. The primary study objective was to compare the incidence of 30-day mortality of patients aged 60-69 years vs. patients 70 years or older with newly diagnosed AML who received intensive remission induction chemotherapy. Secondary endpoints included 60-day mortality, overall survival (OS), complete response rate (CR), receipt of allogeneic hematopoietic stem cell transplant, rate of infection, cardiac complications, major organ failure, ICU transfer, and any other treatment-related complications. Baseline patient characteristics at diagnosis were summarized using descriptive statistics including mean, median, standard deviation, and range for continuous measures and proportions and frequencies for categorical measures. The primary outcome was assessed via chi-squared analysis. Assuming treatment-related mortality is 5% in the younger patients and 15% in patients > 70 years old, with a 2-sided p-value of 0.05, a sample size of 300 would provide a power of 0.83 to detect this 10% difference in mortality. Overall survival was estimated using the Kaplan-Meier method, and compared using a log-rank test. Univariate and multivariate analyses using Cox-Regression models were conducted to identify factors affecting OS.Results: A total of 246 patients with newly diagnosed AML between age 60-69 (n=132) and 70 or greater (n=114) who underwent initial remission-induction chemotherapy between July 2009 and July 2014 were identified and included in this analysis. Background characteristics and known factors that affect CR and OS such as overall risk category and performance status were well matched between groups. Sixty-four (56%) patients in the older and 62 (47%) patients in the younger group received 7+3 induction chemotherapy, whereas 41 (36%) in the older and 50 (38%) in the younger group received cladribine-based regimens. The remainder of patients received clinical trial induction chemotherapy. Twenty-three (17.4%) of patients in the younger patient group underwent immediate re-induction chemotherapy, compared to 8 (7%) patients in the older group (p=0.02).Thirty day mortality rate was 6.8% (9) in the younger group and 14% (16) in the older group (p=0.062). By day 60 after initiation of induction chemotherapy, 13.6% (18) and 23.7% (27) of patients in the younger and older cohorts, respectively, were deceased (p=0.031). No difference was noted in infection rate, ICU transfer, major organ failure, percentage of patients intubated, incidence of tumor lysis syndrome, or initiation of parenteral nutrition.Seventy-nine (59.8%) patients in the younger arm achieved CR, compared to 51 (44.7%) patients in the older arm (p=0.003). Median OS was 10.4 months and 8.3 months in the younger and older group respectively (p=0.002). Significantly more patients in the younger group went on to receive stem cell transplant. Multivariate analysis of the composite group revealed age >75, risk category, prior therapy with hypomethylating agents, and number of comorbidities were predictors of poorer survival.Conclusions: The presented study demonstrates that intensively-treated patients age ≥70 have an increased early treatment-related mortality, similar treatment-related morbidity, and a lower incidence of CR and OS compared to patients age 60-69. Additionally, prior hypomethylator use, risk category and comorbidities contribute to poorer survival. These observations give further insight into the role of intensive remission chemotherapy in an elderly AML patient population.Table 1Multivariable Analysis Overall Survival (p = <0.05)Hazard Ratio95% CIAge >751.51.06-2.20Risk Category1.11.01-1.16Prior Hypomethylator1.61.17-2.12No. of Comorbidities1.11.04-1.20 [Display omitted] DisclosuresOff Label Use: Cladribine for use in acute myeloid leukemia.

FLORENCE: a randomized, double-blind, phase III pivotal study of febuxostat versus allopurinol for the prevention of tumor lysis syndrome (TLS) in patients with hematologic malignancies at intermediate to high TLS risk

BackgroundSerum uric acid (sUA) control is of key relevance in tumor lysis syndrome (TLS) prevention as it correlates with both TLS and renal event risk. We sought to determine whether febuxostat fixed dose achieves a better sUA control than allopurinol while preserving renal function in TLS prevention. Patients and methodsPatients with hematologic malignancies at intermediate to high TLS risk grade were randomized to receive febuxostat or allopurinol, starting 2 days before induction chemotherapy, for 7–9 days. Study treatment was blinded, whereas daily dose (low/standard/high containing allopurinol 200/300/600 mg, respectively, or fixed febuxostat 120 mg) depended on the investigator's choice. The co-primary end points, sUA area under curve (AUC sUA1–8) and serum creatinine change, were assessed from baseline to day 8 and analyzed through analysis of covariance with two-sided overall significance level of 5%. Secondary end points included treatment responder rate, laboratory and clinical TLS incidence and safety. ResultsA total of 346 patients (82.1% intermediate TLS risk; 82.7% assigned to standard dose) were randomized. Mean AUC sUA1–8 was 514.0±225.71 versus 708.0±234.42 mgxh/dl (P < 0.0001) in favor of febuxostat. Mean serum creatinine change was -0.83 ± 26.98% and -4.92 ± 16.70% for febuxostat and allopurinol, respectively (P = 0.0903). No differences among secondary efficacy end points were detected. Drug-related adverse events occurred in 6.4% of patients in both arms. ConclusionIn the largest adult trial carried out in TLS prevention, febuxostat achieved a significant superior sUA control with one fixed dose in comparison to allopurinol with comparable renal function preservation and safety profile. Clinical trial registrationNCT01724528.

Management of tumor lysis syndrome in patients with multiple myeloma during bortezomib treatment.

Tumor lysis syndrome (TLS) is a severe, life-threatening complication that typically occurs in highly proliferative malignancies. Although TLS is unusual in multiple myeloma (MM), it is still associated with significant morbidity. Bortezomib has been widely used for the treatment of MM with encouraging results, but TLS seems to occur more frequently in patients with MM receiving bortezomib than in patients receiving other conventional agents. The purpose of this article is to present and examine several significant risk factors for the development of TLS, based on the results of a study involving patients with MM who developed TLS during bortezomib treatment. Patients with MM were treated with bortezomib-containing regimens. The early identification and intervention of high-risk patients with MM is imperative. Timely and efficient management could decrease TLS incidence rates and improve the efficacy of treatment outcomes.

Restrospective Review of Incidence, Complications and Management of Tumor Lysis Syndrome in High Risk Patients with Hematologic Malignancies

Background: The tumor lysis syndrome (TLS) has been reported to be common in hematologic malignancies, particularly those associated with a high proliferative index, high tumor burden, and highly effective therapy. The classification proposed by Cairo and Bishop (Cairo MS, Bishop M. Br J Haematol 2004; 127:3-11) provides criteria that define laboratory TLS (hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia) and clinical TLS (e.g., cardiac dysrhythmias, neuromuscular irritability, signs or symptoms clearly associated with hypocalcemia, seizures, sudden death, oliguria, elevations of creatinine above baseline). Patients with laboratory manifestations of TLS are considered to be at high risk for developing clinical TLS. It has been recommended that these patients receive rasburicase as part of initial management. The purpose of this restrospective study was to survey the incidence of laboratory/clinical TLS and to attempt to evaluate the role of allopurinol vs rasburicase for TLS prophylaxis and treatment at our institution.Methods: We reviewed a series of consecutive patients presenting to our institution for initial inpatient therapy who were considered to be at high risk for tumor lysis by virtue of their hematologic diagnosis and need for aggressive chemotherapy. ICD9 codes were used to identify patients at 19 years of age or greater with Burkitt lymphoma, high tumor burden diffuse large B cell lymphoma (DLBCL)/mantle cell lymphoma (MCL), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)/lymphoma receiving their initial inpatient chemotherapy between 2007 and 2011. Electronic medical records were used to document demographic data, laboratory and clinical course information, including TLS prophylaxis/treatment strategies, from 3 days prior to 10 days post chemotherapy. Exclusion criteria were hypersensitivity to allopurinol or rasburicase or known glucose-6-phosphate dehydrogenase (G6PD) deficiency. Clinical and laboratory TLS was defined according to the method described by Cairo and Bishop.Results: A total of 149 patients met the inclusion criteria. One hundred thirty seven (92%) patients had no presenting clinical or laboratory manifestations of TLS (“prophylaxis group”) and 12 (8%) patients with manifestations of TLS at presentation were considered as the “treatment group”. In the prophylaxis group, 128 (93%) patients received allopurinol alone, 3 (2%) received rasburicase alone and 6 (5%) received both allopurinol and rasburicase. In the treatment group, all 12 patients received both rasburicase and allopurinol. Four patients in the prophylaxis group that received allopurinol alone (4/128, 3%) eventually developed TLS which was managed successfully without the addition of rasburicase. The median total dose of rasburicase in the treatment group was 12 mg (range 6-18) and repeated doses were administered on only 3 occasions. In this group, arrhythmias due to TLS were observed in 1 (8%), acute kidney injury in 8 (67%) and hyperkalemia in 3 (25%) patients. Two patients (17%) required nephrology consult and 1 (8%) received hemodialysis. Three patients (25%) in this group died - 2 from acute respiratory distress syndrome and 1 from acute subdural hematoma with herniation and pneumonia. The highest incidence of TLS was in patients with AML, in whom 11 out of 81 (13.5%) patients developed TLS.Conclusions: The incidence of TLS was approximately 11% in this high risk patient population. This study suggests that allopurinol as monotherapy can be effective as a prophylaxis strategy against TLS in a high risk patient population receiving initial chemotherapy. With appropriate monitoring, rasburicase may be added quickly in patients who develop progressive hyperuricemia during induction chemotherapy. DisclosuresNo relevant conflicts of interest to declare.