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The Role of L-Asparaginase in the Treatment of ADULT ALL Melissa Rooney, MD NO FINANCIAL DISCLOSURES

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The Role of L-Asparaginase in the Treatment of ADULT ALL Melissa Rooney, MD NO FINANCIAL DISCLOSURES

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    1. The Role of L-Asparaginase in the Treatment of ADULT ALL Melissa Rooney, MD NO FINANCIAL DISCLOSURES

    2. Outline History of L-Asparaginase L-Asparaginase Mechanism of Action Common Regimens Used in Adult ALL Importance of Asparagine Depletion in ALL Toxicities Associated with L-Asparaginase

    5. Formulations of L-Asparaginase

    6. Sources of Asparagine Non-essential amino acid Dietary sources of asparagine

    7. Mechanism of Action of Asparaginase

    8. Clinical Studies

    15. Of the 43 patients who received less than 25 weeks of therapy, 37 (86%) experienced an asparaginase related dose limiting toxicity Pancreatitis (39%) Allergy (19%) CNS Thrombosis (12%) Non CNS DVT (7%) Asparaginase intolerance was also associated with older age (p <0.01) 9-18 years old, 18 (24%) received <25 weeks <9 years old, 25 (9%) received > 26 weeks

    16. Goal to explore differences in OS and DFS in patients who achieve asparagine depletion versus those who do not Followed protocol of CALGB 8811 Pegasparagase given days 5 and 22 of induction and days 15 and 43 of intensification Blood samples collected at various time points and asparagine depletion was defined as an asparaginase level of >0.03 U/mL 14 consecutive days after 1 of 4 administrations of pegasparagase

    20. L-Asparaginase Toxicities Advantages: Not myelosuppressive Not cross-resistant with other anti-neoplastic agents Very distinct toxicity profile Primary immune mediated hypersensitivity reactions Adverse events related to decreased protein synthesis

    21. Toxicities

    22. Hypersensitivity Reactions Heterogeneous presentation The incidence in children is 15% (Silverman et al.) and 10-15% in adults (Stock et al.) The incidence is dependent upon: Number of prior exposures to asparaginase Type of asparaginase used Concomitant corticosteroid therapy Host immunocompetence

    23. Silent Hypersensitivity Neutralizing anti-asparaginase antibody can form with or without a clinical allergic reaction. Antibody formation can alter the ability to obtain maximum asparagine depletion. In children the frequency of developing antibodies to native E. coli asparaginase is as high as 50% (Zalewska-Szewczyk B et al.) Difference in formulations: Native E. coli compared to pegasparagase (26% v. 2%) (Avramis et al.) in children In CALGB 9511 10% of adults who were given 4 doses of pegasparaginase developed neutralizing antibodies (Wetzler et al.) If silent hypersensitivity occurs, may be continued unknowingly without the benefit of ASNase continued risk of toxicity If silent hypersensitivity occurs, may be continued unknowingly without the benefit of ASNase continued risk of toxicity

    24. Management and Recommendations Goal is to minimize incidence of hypersensitivity reactions and allow for maximal exposure to L-asparaginase. Role of corticosteroids Post-administration monitoring For life threatening reactions, further treatment with that particular formulation is contraindicated, however may be challenged with another formulation

    25. Thrombosis and Bleeding Effects the production of procoagulant and thrombolytic proteins Asparagine depletion leads to decreased synthesis of fibrinogen, plasminogen and the anti-coagulation factors antithrombin III, protein C and protein S Cranial venous sinus thrombosis is associated with thrombin generation as a consequence CVST is often associated with hemorrhage likely secondary to hypofibrinogenemia

    26. Thrombosis and Bleeding Age dependent, Dana Farber Cancer Institute reported 5% of pediatric patients, and 42% of adults 30 years of age and older (Grace, Brit J of Haem 2011). The majority of thromboses occur in the induction phase (Grace, Brit J of Haem 2011).

    27. Management and Recommendations PT/INR, aPTT, antithrombin level and fibrinogen should be measured prior to asparaginase therapy and then as clinically warranted Prophylaxis: Anticoagulant: LMWH and then AT replacement when level is <60% Bleeding: use cryoprecipitate when fibrinogen <100 For intracranial thrombohemorrhagic complications, the use of AT III concentrates and/or cryoprecipitate Use caution with FFP Anti-coagulate patients with thrombotic events

    28. Pancreatic and Hepatic Toxicities High rates of protein synthesis is the liver and pancreas >50% of adults develop transaminitis or hyperbilirubinemia, however this is usually not dose limiting 15% of patients develop pancreatitis and in up to 2% of children and 5% of adults can be life-threatening Endocrine function of the pancreas can be affected leading to hyperglycemia

    29. Conclusions L-Asparaginase is an established anti-leukemic agent L-Asparaginase has contributed to the successful treatment protocols in children Adult ALL protocols not incorporating L-asparaginase produce similar outcomes Asparagine depletion appears to have impact on survival Dose, duration, and toxicities associated with L-Asparaginase need to be further defined in adults and adult patients need to be enrolled in clinical trials

    30. References Broome JD. et al. Evidence that the L-asparaginase of guinea pig serum is responsible for its antilymphoma effects. I. Properties of the L-asparaginase of guinea pig serum in relation to those of the antilymphoma substance. J Exp Med.1963 Jul;118:99-120. Douer, D. Is asparaginase a critical component in the treatment of acute lymphoblastic leukemia? Best Pract Res Clin Haematol. 2008 Dec;21(4):647-58. Review. Hill JM, et al. L-asparaginase therapy for leukemia and other malignant neoplasms. Remission in human leukemia. JAMA. 1967 Nov 27;202(9):882-8. Kantarjian H et al.Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer 2004 Dec 15;101(12):2788-801 Kidd, JK. Regression of transplanted lymphomas induced in vivo by means of normal guinea pig serum. I. Course of transplanted cancers of various kinds in mice and rats given guinea pig serum, horse serum, or rabbit serum. J Exp Med.1953 Dec;98(6):565-82. Larson, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group b study 8811. Blood. 1995 Apri 15; 85 (8): 2025-2037. Mashburn LT and Wriston JC. Tumor inhibitory effect of L-asparaginase from escherichia coli. Arch Biochem Biophys.1964 May;105:450-2. Ortega JA et al. L-asparaginase, vincristine, and prednisone for induction of first remission in acute lymphocytic leukemia. Cancer Res.1977 Feb;37(2):535-40. Rowe, J and A Goldstone. How I treat acute lymphocytic leukemia in adults. Blood 2007 Oct; 110 (7): 2268-2275. Silverman LB et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 2001 Mar 1; 97(5):1211-1218. Stock et al. Prevention and management of asparaginase/pegasparagase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma. 2011 Aug 10. [Epub ahead of print] Wetzler et al. Effective asparagine depletion with pegylated asparaginase results in improved outcomes in adult acute lymphoblastic leukemia: Cancer and Leukemia Group B Study 9511. Blood. 2007 May 15; 109 (10): 4164-4167.

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