Incidence and Management of Toxicity Associated with L-Asparaginase in the Treatment of ALL and NK/T-Cell Lymphoma: an Observational Study

  • Yeang, Shu Hui (Department of Pharmacy, Singapore General Hospital) ;
  • Chan, Alexandre (Department of Pharmacy, National Cancer Centre Singapore) ;
  • Tan, Chuen Wen (Department of Haematology, Singapore General Hospital) ;
  • Lim, Soon Thye (Department of Pharmacy, National Cancer Centre Singapore) ;
  • Ng, HengJoo (Department of Haematology, Singapore General Hospital)
  • Published : 2016.07.01


Background: L-asparaginase (ASNase) is commonly used in the treatment of acute lymphoblastic leukemia (ALL) and natural killer (NK)/T-cell lymphoma. This study was designed to describe the incidence of toxicity associated with ASNase in Asian adults. Secondary objectives were to investigate the management and impact of toxicity on subsequent ASNase use, and to compare the actual management against current recommendations. Materials and Methods: In this retrospective, multi-center, observational study, Asian patients ${\geq}18$ years old who received ${\geq}1$ dose of the native E. coli ASNase from 2008 to 2013 were included. Patients were excluded if they did not receive ASNase. Endpoints of this study were development of specific toxicities, whether ASNase was discontinued or re-challenged, and developmentg of recurrent toxicity. All data analyses were performed using SPSS version 20.0. Results: A total of 56 patients were analyzed. Mean (${\pm}SD$) age was 36.2 (${\pm}15.2$) years old, with 62.5% being males, 55.4% with ALL and 28.6% with NK/T-cell lymphoma. Hypersensitivity (12.5%) was associated with the highest incidence of toxicity (6 out of 7 patients had Grade 3 and 4 toxicity), followed by 10.7% for hepatic transaminitis, 3.6% for non-CNS thrombosis and 1.8% each for hyperbilirubinemia and pancreatitis. Hypersensitivity recurred in the 3 patients who were re-challenged with E. coli ASNase. Conclusions: ASNase is associated with a wide range of toxicities, with hypersensitivity being the most commonly observed among Asian adult patients.


L-Asparaginase;ALL;NK/T cell lymphoma;treatment;toxicity;hypersensitivity


  1. Alvarnas JC, Brown PA, Aoun P, et al (2012). Acute lymphoblastic leukemia. J Natl Compr Canc Netw, 10, 858-914.
  2. Alvarnas JC, Brown PA, Aoun P, et al (2015). Acute lymphoblastic leukemia. J Natl Compr Canc Netw, 13, 1240-79.
  3. Asselin BL, Ryan D, Frantz CN, et al (1989). In vitro and in vivo killing of acute lymphoblastic leukemia cells by L-asparaginase. Cancer Res, 49, 4363-8.
  4. Earl M (2009). Incidence and management of asparaginaseassociated adverse events in patients with acute lymphoblastic leukemia. Clin Adv Hematol Oncol, 7, 600-6.
  5. Grace RF, Dahlberg SE, Neuberg D, et al (2011). The frequency and management of asparaginase-related thrombosis in paediatric and adult patients with acute lymphoblastic leukaemia treated on dana-farber cancer institute consortium protocols. Br J Haematol, 152, 452-9.
  6. Kafkewitz D and Bendich A (1983). Enzyme-induced asparagine and glutamine depletion and immune system function. Am J Clin Nutr, 37, 1025-30.
  7. Kfoury-Baz EM, Nassar RA, Tanios RF, et al (2008). Plasmapheresis in asparaginase-induced hypertriglyceridemia. Transfusion, 48, 1227-30.
  8. Liu C, Kawedia JD, Cheng C, et al (2012). Clinical utility and implications of asparaginase antibodies in acute lymphoblastic leukemia. Leukemia, 26, 2303-9.
  9. Nakagawa M, Kimura S, Fujimoto K, et al (2008). A case report of an adult with severe hyperlipidemia during acute lymphocytic leukemia induction therapy successfully treated with plasmapheresis. Ther Apher Dial, 12, 509-13.
  10. Narta UK, Kanwar SS and Azmi W (2007). Pharmacological and clinical evaluation of L-asparaginase in the treatment of leukemia. Crit Rev Oncol Hematol, 61, 208-21.
  11. National Cancer Institute (2009). Common Terminology Criteria for Adverse Events v4.0. NIH publication # 09-7473.
  12. Oettgen HF, Stephenson PA, Schwartz MK, et al (1970). Toxicity of E. coli L-asparaginase in man. Cancer, 25, 253-78.<253::AID-CNCR2820250204>3.0.CO;2-U
  13. Parsons SK, Skapek SX, Neufeld EJ, et al (1997). Asparaginaseassociated lipid abnormalities in children with acute lymphoblastic leukemia. Blood, 89, 1886-95.
  14. Seah J, Lin K, Tai D, et al (2012). Conservative management of L-asparaginase-induced hypertriglyceridemia in an adult patient: a case report and review of the literature. Onkologie, 35, 596-8.
  15. Steinherz PG (1994). Transient, severe hyperlipidemia in patients with acute lymphoblastic leukemia treated with prednisone and asparaginase. Cancer, 74, 3234-9.<3234::AID-CNCR2820741224>3.0.CO;2-1
  16. Stock W, Douer D, DeAngelo DJ, et al (2011). Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma, 52, 2237-53.
  17. Truelove E, Fielding AK and Hunt BJ (2013). The coagulopathy and thrombotic risk associated with L-asparaginase treatment in adults with acute lymphoblastic leukaemia. Leukemia, 27, 553-559.
  18. Wang B, Relling MV, Storm MC, et al (2003). Evaluation of immunologic crossreaction of antiasparaginase antibodies in acute lymphoblastic leukemia (ALL) and lymphoma patients. Leukemia, 17, 1583-8.
  19. Yamaguchi M, Suzuki R, Kwong YL, et al (2008). Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia. Cancer Sci, 99, 1016-20.
  20. Yamaguchi M, Suzuki R, Kim WS, et al (2011). Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study. J Clin Oncol, 29, 4410-6.
  21. Yong W, Zheng W, Zhang Y, et al (2003). L-asparaginase-based regimen in the treatment of refractory midline nasal/nasal-type T/NK-cell lymphoma. Int J Hematol, 78, 163-7.
  22. Zalewska-Szewczyk B, Gach A, Wyka K, et al (2009). The crossreactivity of anti-asparaginase antibodies against different L-asparaginase preparations. Clin Exp Med, 9, 113-6.