Overview of TLS What is tumor lysis syndrome ? When does TLS arise? Which tumors are associated with TLS ? What is the pathophysiology of TLS? What is the pathogenesis of hyperuricemia in TLS ? Which patients are at the highest risk for TLS ? What is the classification of cancers for the risk of TLS ? Which agents may cause tumor lysis syndrome TLS ? Which clinical conditions are rare causes of TLS ? What is the global incidence of tumor lysis syndrome (TLS)?

definition metabolic derangement resulting from abrupt and massive breakdown of malignant cells and the release of intracellular contents into the circulation which overwhelms the patient’sexcretory ability. Characteristic LABORATORY findings of Tumor lysis syndrome include: Hyperuricemia Hyperkalemia Hyperphosphatemia Hypocalcemia

Guidelines for the Prevention of Tumour Lysis SyndromeVersion Document Type: Clinical Practice GuidelineApproved on 2016-09-28 Next Review Date: 2019-09-28 Guidelines for the Prevention of Tumour Lysis SyndromeVersion

Although tumor lysis syndrome has been reported with virtually every type of tumor, it is typically associated with bulky, rapidly proliferating, treatment-responsive tumors —typically, acute leukemias and high-grade non-Hodgkin lymphomas such as Burkitt lymphoma. The syndrome has also been reported with other hematologic malignancies and with solid tumors such as hepatoblastoma and stage IV neuroblastoma.

Because tumor lysis syndrome is potentially lethal, the main principles of management are (1) identification of high-risk patients with initiation of preventive therapy (2) early recognition of metabolic and renal complications and the prompt administration of supportive care, including hemodialysis.

Agents reported to cause tumor lysis syndrome include the following: Paclitaxel Fludarabine Etoposide Thalidomide Bortezomib Zoledronic acid Hydroxyurea The development of tumor lysis syndrome is not limited to the systemic administration of agents; it can occur with intrathecal administration of chemotherapy and with chemo-embolization

TLS Incidence Today Criscuolo M, et al. Expert Review of Hematology 2016; 9(2):197-208

Risk Factors for the Tumor Lysis Syndrome. 1. Cancer mass:- Risk Factor Comment Bulky tumor or extensive metastasis The larger the cancer mass have higher risk of clinical TLS Organ infiltration by cancer cells Hepatomegaly, splenomegaly, and nephromegaly generally represent tumor infiltration into these organs and a larger tumor burden Bone marrow involvement Healthy adults have 1.4 kg of bone marrow A marrow that has been replaced by leukemic cells contains a cancer mass greater than 1 kg and represents bulky disease. Renal infiltration or outflow-tract obstruction Decreased urine flow predispose to nephropathy from other causes, such as the tumor lysis syndrome.

Risk Factors for the Tumor Lysis Syndrome. 2. Cell lysis potential:- Risk Factor Comment High rate of proliferation of cancer cells LDH is a surrogate for tumor proliferation. The higher level is a risk of TLS Cancer-cell sensitivity to anticancer therapy Cancers that are more sensitive to therapy have a higher rate of TLS Intensity of initial anticancer therapy Preexisting nephropathy from hypertension, diabetes or or other causes has a greater risk for acute kidney injury and TLS

Risk Factors for the Tumor Lysis Syndrome. 3. Features on patient presentation:- Risk Factor Comment Nephropathy before diagnosis of cancer Predisposes to TLS Dehydration or volume depletion Dehydration decreases the rate of urine flow through renal tubules and increases the level of solutes Acidic urine Uric acid has a lower solubility in acidic urine and therefore crystallizes more rapidly Hypotension Hypotension decreases urine flow and increases the level of solutes that can crystallize. Hypotension can also independently cause acute kidney injury. Exposure to nephrotoxins Vancomycin, aminoglycosides, contrast agents for diagnostic imaging, and other potential nephrotoxins increase the risk of acute kidney injury from lysis of cancer cells.

Comment Risk Factor Risk Factors for the Tumor Lysis Syndrome. 4. Supportive care Risk Factor Comment Inadequate hydration Increases the risk of crystallization inside tubules Exogenous potassium potassium should not be included in the intravenous fluids, and potassium from food or medications should be minimized until the risk of TLS has passed.

Risk Factors for the Tumor Lysis Syndrome. 4. Supportive care:- Risk Factor Comment Exogenous phosphate Restricting dietary phosphate and adding a phosphate binder reduce the exogenous load of phosphate so that the kidneys need only excrete the endogenous load of phosphate released by cancer-cell lysis. Delayed uric acid removal Allopurinol prevents formation of new uric acid by inhibiting xanthine oxidase and preventing conversion of xanthine to uric acid. Allopurinol does not remove existing uric acid and increases urinary excretion of xanthine, which can crystallize and cause “xanthine nephropathy“ Rasburicase rapidly removes uric acid by converting it to allantoin,which is highly soluble and readily excreted in the urine.

Timing of developing TLS TLS occurs mainly after conventional chemotherapy. However, corticosteroids, radiation, or monoclonal Abs may also cause a significant TLS. Less frequent, spontaneous TLS can develop prior to initiation of anticancer therapy. Even invasive procedures like biopsy, embolization and tumor surgery could lead to TLS.

ALL with > 100,000 or LDH of 2 ULN AML with WBC > 100,000 High-Risk Tumors newly diagnosed/relapsed with Burkitt’s lymphoma newly diagnosed with lymphoblastic lymphoma with advanced or bulky disease ALL with > 100,000 or LDH of 2 ULN AML with WBC > 100,000 DLBCL and bulky disease with an elevated LDH of 2 ULN pre-existing renal impairment Intermediate-Risk Tumors AML with WBC between 25,000 and 100,000 ALL with WBC < 100,000 and a LDH of less than 2 ULN DLBCL and LDH of 2 ULN but non-bulky disease Early stage Burkitt lymphoma or leukemia with a LDH < 2 ULN Highly chemotherapy sensitive solid tumours (e.g. neuroblastoma, germ cell tumour) with advanced or bulky disease Low-Risk Tumors Solid cancers Indolent lymphomas CML AML with a WBC < 25,000 and LDH elevated to less than 2 ULN