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The New England Journal of Medicine Aug 2011We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T...
We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×10(5) cells per kilogram of body weight) of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect.
Topics: Agammaglobulinemia; Antigens, CD19; B-Lymphocytes; Bone Marrow; Chimera; Cytokines; Humans; Immunotherapy; Lentivirus; Leukemia, Lymphoid; Male; Receptors, Antigen, T-Cell; Remission Induction; T-Lymphocytes; Tumor Lysis Syndrome
PubMed: 21830940
DOI: 10.1056/NEJMoa1103849 -
Journal of Community Hospital Internal... Jun 2020Tumor lysis syndrome (TLS) is an oncological emergency characterized by a classic tetrad of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. Risk... (Review)
Review
Tumor lysis syndrome (TLS) is an oncological emergency characterized by a classic tetrad of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. Risk assessment and prophylactic therapy is critical in preventing this oncological emergency. Treatment of established TLS involves aggressive hydration, electrolyte management, and the use of hypouricemic agents.
PubMed: 32850076
DOI: 10.1080/20009666.2020.1761185 -
Archives of Pathology & Laboratory... Mar 2019Tumor lysis syndrome (TLS) is an acute, life-threatening disease among adults and children that is associated with the initiation of cytoreductive therapy in the... (Review)
Review
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.
Topics: Adult; Child; Female; Humans; Male; Tumor Lysis Syndrome
PubMed: 30499695
DOI: 10.5858/arpa.2017-0278-RS -
Cureus Sep 2021Background Tumor lysis syndrome (TLS) is a known oncologic emergency characterized by severe metabolic derangements. TLS has been well documented in patients with...
Background Tumor lysis syndrome (TLS) is a known oncologic emergency characterized by severe metabolic derangements. TLS has been well documented in patients with hematologic malignancies, but rarely with metastatic melanoma. The objective of this study was to investigate the clinical characteristics and outcomes of TLS with metastatic melanoma. Methods Retrospective literature review and analysis. Results Eighteen cases of TLS were identified with metastatic melanoma from published literature. The median age of patients was 63 years (36-79 years). All patients have stage IV disease. Seven cases (39%) of TLS were associated with multiple treatment regimes, including nivolumab (22%), ipilimumab (16%), and dacarbazine (22%). The time from treatment to diagnosis was 3.5 days (8 hours-21 days) in treatment-related TLS. Three cases (17%) were due to spontaneous TLS. The majority of cases have a high tumor burden (77.5%) and liver metastasis (83%). Seven cases were treated with rasburicase (39%). The mortality rate was 100% for the patients with spontaneous TLS and 73% for patients with treatment-related TLS. Three cases utilized traditional chemotherapy and the six most recent cases of treatment-associated TLS utilized immunotherapy and targeted therapy. Conclusion TLS in metastatic melanoma, due to either spontaneous or treatment-related causes, is associated with a very high mortality rate. This study highlights the importance of awareness, early intervention, and risk assessment of this underdiagnosed emergency.
PubMed: 34692319
DOI: 10.7759/cureus.18108 -
Advances in Chronic Kidney Disease Jan 2014Tumor lysis syndrome (TLS) is an oncologic emergency triggered by the rapid release of intracellular material from lysing malignant cells. Most common in rapidly growing... (Review)
Review
Tumor lysis syndrome (TLS) is an oncologic emergency triggered by the rapid release of intracellular material from lysing malignant cells. Most common in rapidly growing hematologic malignancies, TLS has been reported in virtually every cancer type. Central to its pathogenesis is the rapid accumulation of uric acid derived from the breakdown of nucleic acids, which leads to kidney failure by various mechanisms. Kidney failure then limits the clearance of potassium, phosphorus, and uric acid leading to hyperkalemia, hyperphosphatemia, and secondary hypocalcemia, which can be fatal. Prevention of TLS may be more effective than treatment, and identification of at-risk individuals in whom to target preventative efforts remains a key research area. Herein, we discuss the pathophysiology, epidemiology, and treatment of TLS with an emphasis on the kidney manifestations of the disease.
Topics: Acute Kidney Injury; Allopurinol; Bicarbonates; Buffers; Calcium; Diuretics; Enzyme Inhibitors; Febuxostat; Fluid Therapy; Humans; Hyperkalemia; Hyperphosphatemia; Hyperuricemia; Hypocalcemia; Renal Dialysis; Thiazoles; Tumor Lysis Syndrome; Urate Oxidase
PubMed: 24359983
DOI: 10.1053/j.ackd.2013.07.001 -
Open Access Emergency Medicine : OAEM 2015Tumor lysis syndrome (TLS) is the most common oncologic emergency. It is caused by rapid tumor cell destruction and the resulting nucleic acid degradation during or days... (Review)
Review
Tumor lysis syndrome (TLS) is the most common oncologic emergency. It is caused by rapid tumor cell destruction and the resulting nucleic acid degradation during or days after initiation of cytotoxic therapy. Also, a spontaneous form exists. The metabolic abnormalities associated with this syndrome include hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, and acute kidney injury. These abnormalities can lead to life-threatening complications, such as heart rhythm abnormalities and neurologic manifestations. The emergency management of overt TLS involves proper fluid resuscitation with crystalloids in order to improve the intravascular volume and the urinary output and to increase the renal excretion of potassium, phosphorus, and uric acid. With this therapeutic strategy, prevention of calcium phosphate and uric acid crystal deposition within renal tubules is achieved. Other measures in the management of overt TLS are prescription of hypouricemic agents, renal replacement therapy, and correction of electrolyte imbalances. Hyperkalemia should be treated quickly and aggressively as its presence is the most hazardous acute complication that can cause sudden death from cardiac arrhythmias. Treatment of hypocalcemia is reserved for patients with electrocardiographic changes or symptoms of neuromuscular irritability. In patients who are refractory to medical management of electrolyte abnormalities or with severe cardiac and neurologic manifestations, early dialysis is recommended.
PubMed: 27147889
DOI: 10.2147/OAEM.S73684 -
Cureus Mar 2021Tumor lysis syndrome, an oncological emergency, is characterized by laboratory parameters such as hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia, as... (Review)
Review
Tumor lysis syndrome, an oncological emergency, is characterized by laboratory parameters such as hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia, as well as renal injury with an elevated creatinine. Tumor lysis syndrome is seen in patients with aggressive malignancies and high tumor burden. More frequently, it occurs in individuals with hematologic malignancies such as high-grade lymphomas (such as Burkitt lymphoma) and leukemia (such as acute lymphocytic leukemia). It also, albeit less commonly, can be seen in patients with widespread solid tumors that are rapidly proliferating and are markedly sensitivity to antineoplastic therapy. Tumor lysis syndrome is usually preceded by cancer-directed therapy; however, the syndrome can present spontaneously prior to the individual receiving malignancy-directed treatment. We reported a man with metastatic salivary duct carcinoma who had cutaneous metastases that presented as carcinoma hemorrhagiectoides. Microscopic examination demonstrated that the metastatic tumor cells had infiltrated and replaced the entire dermis. After the patient received his first dose of antineoplastic therapy, he had an excellent response and the cutaneous metastases developed into ulcers; we hypothesize that most of the dermis, which had been replaced by tumor cells, disappeared as a result of the therapeutic response, and the overlying epidermis became necrotic and shed, leaving an ulcer. His dramatic response to treatment prompted us to propose a new classification of tumor lysis syndrome, which should include the systemic form of the condition as well as the new variant: cutaneous tumor lysis syndrome. We anticipate that, with improvement in targeted therapies, there may be an increase in therapy-associated cutaneous tumor lysis syndrome.
PubMed: 33859885
DOI: 10.7759/cureus.13816 -
The New England Journal of Medicine Jan 2016New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct...
BACKGROUND
New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells.
METHODS
We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day.
RESULTS
The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%.
CONCLUSIONS
Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Recurrence; Remission Induction; Sulfonamides; Tumor Lysis Syndrome
PubMed: 26639348
DOI: 10.1056/NEJMoa1513257