SOHO Supplement 2014
Asparaginase in Acute Lymphoblastic Leukemia Jitesh D. Kawedia,1 Michael E. Rytting2 Abstract Cure rates in pediatric acute lymphoblastic leukemia have significantly improved over the past decades. Now, almost 90% of children will survive the disease. The cure rates in adolescents, young adults, and adults have not kept pace with the improvements in younger patients, even though almost an equal proportion of adult patients achieve complete remission as their pediatric counterparts. Differences in treatment regimens might be important. Intensive use of asparaginase has been a key component of successful pediatric therapy. In this review, we focus on the use of asparaginase and the potential of optimizing asparaginase use via monitoring to minimize adverse drug events and improve efficacy of the drug. Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. S3, S14-7 ª 2014 Elsevier Inc. All rights reserved. Keywords: Acute lymphoblastic leukemia, Adults, Asparaginase, Pharmacokinetics, Therapeutic drug monitoring, Toxicities
Introduction Survival in pediatric patients with acute lymphoblastic leukemia (ALL) has significantly improved over time with almost 90% of children are cured.1-6 This has been achieved by dose intensification and by extending the duration of chemotherapeutic agents.6-10 One chemotherapeutic agent, which has been central to pediatric therapies, is asparaginase. Pediatric studies support the use of asparaginase, and some groups have demonstrated that asparaginase dose intensification might improve outcome in pediatric ALL.6,10-15 However, there has been less improvement in adolescents and young adults (AYAs) or adults with ALL, and the long-term disease-free survival (DFS) in many studies is < 50%.5,16,17 In retrospective comparisons, adolescents treated with pediatric-based regimens have better outcome compared with those treated with adult-based regimens.9,18-22 There are several differences in pediatric and adult treatment regimens, including the intensive use of asparaginase in pediatric regimens.9,23,24 Studies using pediatric-based regimens in AYAs and adult patients with greater use of asparaginase have shown promising results.25-28 However, AYAs and adult patients are more prone to severe Grade 3 to 4 toxicities including thrombosis, pancreatitis, and chemical hepatitis compared with pediatric patients.29-32 Pharmacokinetic (PK) studies suggest that adult patients might have a decreased bodily clearance and consequently greater 1
Department of Pharmacy Research Division of Pediatrics The University of Texas M.D. Anderson Cancer Center, Houston, TX 2
Submitted: Feb 21, 2014; Accepted: Jun 4, 2014 Address for correspondence: Jitesh D. Kawedia, PhD, Department of Pharmacy Research, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030 Fax: þ713-563-8247; e-mail contact: [email protected]
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Clinical Lymphoma, Myeloma & Leukemia September 2014
exposure to asparaginase, which might contribute (along with other risk factors) to the increased incidence of severe adverse drug events.33,34 In this review, we discuss the effect of asparaginase on outcomes and toxicities especially in AYAs and adult patients, and the potential use of therapeutic drug monitoring to minimize adverse events, while maintaining the therapeutic efficacy of asparaginase.
Discussion Asparaginase Mechanism of Action and Its Different Preparations Asparaginase is an enzyme that catalyzes the hydrolysis of the amino acid asparagine to aspartic acid thereby depleting asparagine levels in the serum. Asparagine is a nonessential amino acid for normal tissues, because they can synthesize it via asparagine synthetase, but is an essential amino acid for malignant cells because they cannot synthesize it and rely on extracellular asparagine in the serum.35-37 Asparagine is important for synthesis of protein, DNA, and RNA. Asparaginase is derived from bacteria and the current preparations are: (1) native asparaginase (Elspar [Lundbeck], Kidrolase [Jazz Pharmaceuticals, Inc.], Crasnitin [Bayer AG], Leunase [Kyowa Hakko Kirin], Asparaginase medac [KyowaHakko]) derived from Escherichia coli; (2) pegylated form of native E. coli asparaginase (Oncaspar [Sigma-Tau Pharmaceuticals, Inc.]; pegaspargase); and (3) Erwinia asparaginase (Erwinaze, and Erwinase [Jazz Pharmaceuticals, Inc.]), which is isolated from Erwinia chrysanthemi. It is important to mention that some asparaginase preparations are discontinued and no longer available in all countries. In addition, a pegylated recombinant Erwinia asparaginase (mPEG-r-crisantaspase) is undergoing phase I evaluation (NCT015515124). There is also a preparation of asparaginase that is packaged in red blood cells.38
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.06.017
Effect of Asparaginase on Treatment Outcomes in Pediatric ALL Asparaginase is used during induction, consolidation, and maintenance phases of pediatric ALL therapy. In the Pediatric Oncology Group 8704 study involving T-cell ALL and lymphoblastic lymphoma patients randomized to E. coli asparaginase (25,000 IU/m2 weekly for 20 weeks) during consolidation had improved complete continuous remission compared with patients randomized to the nonasparaginase arm (71.3% vs. 57.8% at the end of 4 years).12 Similarly, in a study carried out by the Associazione Italiana Ematologia Oncologia Pediatrica, standard-risk ALL children treated with Berlin-Frankfurt-Munich (BFM)-type chemotherapy were randomized to receive asparaginase (25,000 IU/ m2 weekly for 20 weeks) or not receive asparaginase. Children who received asparaginase had a significantly increased 10-year DFS and overall survival (OS) (87.5% vs. 78.7% and 93.7% vs. 88.6%, respectively) compared with those who were not treated with asparaginase.39 In the Dana-Farber Cancer Institute (DFCI) Consortium Protocol 91-01, it was observed that prolonged asparaginase intensification significantly improved outcome in pediatric ALL, and patients who received 25 or fewer weeks of asparaginase had significantly worse outcome than those who tolerated at least 26 weeks of asparaginase treatment (5-year event-free survival [EFS] was 73% vs. 90%).6
Effect of Asparaginase on Treatment Outcomes in AYA and Adult ALL Recent retrospective comparisons indicate that young adults treated with pediatric-based protocols might have better outcomes than similar patients treated with adult regimens. This has resulted in renewed interest in asparaginase and subsequent toxicities in AYAs and adults.9,25-28,40 In their retrospective analysis, Stock and colleagues found that young adults (16-20 years of age) treated according to Children’s Cancer Group (CCG) protocols had better outcomes than similar patients treated according to adult protocols from the Cancer and Leukemia Group B (CALGB). The 7-year EFS and OS were 63% and 67% compared with 34% and 46%, respectively, in patients treated according to CCG and CALGB protocols.9 The major difference in the 2 protocols was a greater dose of dexamethasone, vincristine, L-asparaginase, and methotrexate. For asparaginase the CCG protocols used a cumulative dose of 318,000 IU/m2 compared with 50,000 IU/m2 in CALGB protocols. The French Group for Research on Adult Acute Lymphoblastic Leukemia reported an improved DFS of 56% in patients (aged 15-55 years) after an increase in the cumulative asparaginase dose from 20,000 IU/m2 in the LALA-94 (Lymphoblastic Acute Leukemia in Adults 94) trial to 132,000 IU/m2 (doses of prednisolone and vincristine were also increased).40 Similarly, the German Multicenter Study Group For Adult ALL reported a significant improvement of treatment outcome in AYAs aged 15 to 35 years treated with a pediatric-derived adult protocol.27 The 07/03 protocol intensified treatment with asparaginase and methotrexate and added targeted therapies such as rituximab and imatinib, and minimal residual disease-based stratification (it also included stem cell transplant for high-risk and very high-risk patients). The dose for pegaspargase was increased from 1000 to 2000 IU/m2 in induction, and from 500 to 2000 IU/m2 in consolidation therapy
(combined with high-dose methotrexate and mercaptopurine) for patients aged between 15 and 55 years.28 Of the 1529 AYA patients, 642 were treated according to the 05/03 protocol and 887 were treated according to the 07/03 protocol. Compared with the 05/03 protocol, complete remission and OS increased from 88% to 91% and 86% to 90%, respectively, with 73% OS in patients aged 15 to 17 years.27
Toxicities Associated With Asparaginase Although inclusion of asparaginase in treatment regimens has improved treatment outcomes, there are several dose-limiting toxicities that make the management of asparaginase therapy difficult. Because asparaginase is a foreign protein derived from bacteria, patients commonly develop allergic reactions and antibodies against the enzyme, which significantly hampers its efficacy and results in suboptimal treatment response. In the St Jude Total XV study, patients who developed antibodies to native asparaginase had a 6.5-fold greater risk of developing central nervous system relapse.41 Other notable toxicities, which in some cases can be fatal, include pancreatitis, bleeding, thrombosis, hyperglycemia, hyperlipidemia, hyperbilirubinemia, and liver dysfunction.31,42,43 In pediatric patients, asparaginase-induced allergy and silent hypersensitivity are major challenges.44-46 When patients develop allergy or silent hypersensitivity to E. coli asparaginase, they are switched to pegaspargase and then Erwinia asparaginase. Because of the greater incidence of allergic reactions to native asparaginase, pegaspargase is now used as first-line treatment in the United States and other countries.47 Although pegaspargase sometimes circumvents the problem of allergic reaction and enzyme-neutralizing antibodies, the problem might still persist. Furthermore, it is not clear whether the antipegaspargase antibody titer is capable of causing significant neutralization of pegaspargase. In contrast, the therapeutic benefits of asparaginase in AYAs and adults are less certain because of serious adverse drug toxicities which are not seen at such high frequencies in pediatric patients.29-31 In adults, no large body of data exists, but Stock and colleagues compared toxicities with intravenously (I.V.)-administered pegaspargase in 76 adult patients treated at the Cleveland Clinic, the University of Texas M.D. Anderson Cancer Center, and the University of Southern California with those for 1274 pediatric patients, administered with intramuscular pegaspargase treated at member institutions of the Children’s Oncology Group.31 Older patients suffered greater incidence of Grade 3 to 4 toxicities of the pancreas and liver, such as increased transaminase level (20% vs. 36%), hyperbilirubinemia (3% vs. 14%), hypofibrinogenemia (3% vs. 14%), hyperglycemia (7% vs. 25%), and pancreatitis (2% vs. 5%), and thrombosis (3% vs. 8%). These adverse effects were further exacerbated with use of the pegaspargase, which has a longer elimination half-life. The U.K. phase III multicenter trial, UKALL 14, reported that pegaspargase was “definitely or probably” implicated in 11 of 18 induction deaths.48 The incidence of nonfatal pegaspargase toxicities during induction was 36% (n ¼ 33). Liver dysfunction was most common (24.5%) followed by coagulopathy (7.7%) and thrombosis (5.6%). Age and Philadelphia (Ph) chromosome status were independent factors for risk of induction deaths. The odds ratio for age > 40 years and > 55 years were 5.27 and 4.47, respectively, and 6.08 for Ph-positive disease. Older age
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Asparaginase in Acute Lymphoblastic Leukemia (> 40 years) was also associated with Grade 3 to 4 pegaspargaserelated liver dysfunction in this trial.48
Therapeutic Drug Monitoring for Asparaginase
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Sustained and prolonged asparagine depletion is an important factor in effectiveness of asparaginase treatment. To estimate the intensity of asparaginase therapy, asparaginase enzyme activity is monitored. Asparaginase enzyme activity > 0.1 IU/mL,49,50 and possibly > 0.05 IU/mL51,52 corresponds to asparagine depletion. Wetzler and colleagues defined asparagine depletion according to pegaspargase enzyme levels > 0.03 IU/mL for 14 consecutive days after at least 1 of 4 planned pegaspargase administrations for patients treated according to the CALGB study 9511 protocol. Of the 85 patients, 22 who did not achieve asparagine depletion had inferior DFS and OS (hazard ratio, 1.8).53 There are other studies that recommend much higher levels of enzyme activity for asparagine depletion. Based on best fit population PK and pharmacodynamic results obtained from nonlinear mixed effect modeling, Avramis and Panosyan reported that asparaginase enzyme activity < 0.4 IU/mL provided insufficient depletion, whereas > 0.4 to 0.7 IU/mL provided optimal asparagine depletion (90%).54 However, asparaginase enzyme activity > 0.1 IU/mL is considered a reasonable threshold for asparagine depletion. Two earlier studies performed pegaspargase PK evaluations in children and adolescents and in adult patients (aged 17-55 years) separately. Pediatric patients dosed I.V. at 2500 IU/m2 maintained therapeutic levels of 0.1 IU/mL or greater up to 21 days, and the adult patients dosed I.V. at 2000 IU/m2 were able to maintain 0.1 IU/mL or higher up to 25 days.33,34 Although adult patients received a lower dose (2000 IU/m2 vs. 2500 IU/m2) they maintained the therapeutic levels (> 0.1 IU/mL) for more days compared with pediatric patients (25 vs. 21 days). These studies suggest that the adult patients might have a lower bodily clearance rate for asparaginase, thus resulting in increased drug levels; this might explain the greater incidence of toxicities. Therapeutic drug monitoring has been used in different pediatric clinical trials to identify patients who are at risk of subtherapeutic asparaginase enzymatic activity due to allergic reactions or silent hypersensitivity. In the DFCI consortium protocol 00-01, one of the goals was to optimize asparaginase therapy in children and adolescents newly diagnosed with ALL. Patients who achieved complete remission were randomized to receive either a fixed dose of 25,000 IU/m2/wk of native asparaginase or pharmacokinetically-guided individualized dosing based on nadir serum asparaginase enzyme activity (NSAA) measured every 3 weeks. The starting asparaginase dose in the individualized arm was 12,500 IU/m2, after that the dose was adjusted to maintain NSAA between 0.1 and 0.14 IU/mL. Interestingly, it was observed that patients in the individualized arm received a lower median asparaginase dose (17,500 IU/m2 vs. 25,000 IU/m2) but had better outcome. The 5-year EFS in the individualized arm was 90% compared with 82% in the fixed-dose arm. The Dutch Childhood Oncology Group (DCOG) has implemented therapeutic drug monitoring to individualize pegaspargase and Erwinia asparaginase dose to detect silent inactivation in their current DCOG-ALL-1 protocol.55 So far, findings suggest that therapeutic drug monitoring helps in improving outcome, and allows a decreased asparaginase dose. AYAs and adult patients
Clinical Lymphoma, Myeloma & Leukemia September 2014
might have a lower clearance rate of asparaginase compared with younger children and would benefit from therapeutic drug monitoring to reduce the risk of toxicity while maintaining the therapeutic efficacy of asparaginase.
Conclusion Asparaginase is a chemotherapeutic agent, which has helped to improve treatment outcomes in pediatric ALL. Studies show better treatment outcomes in patients who have received a high percentage of planned asparaginase courses designed in their respective trials as opposed to those who had to discontinue or miss therapy because of adverse events. Pediatric-inspired regimens that include administration and dose intensification of asparaginase have resulted in significant improvements of treatment outcomes in AYAs and adult patients in published trials. Although asparaginase use is feasible in AYAs and adults, there are severe adverse effects, most commonly hepatotoxicity. Asparaginase PK studies suggest that older patients might a have lower rate of asparaginase clearance, hence greater drug exposure, which can lead to a greater rate of toxicities. Therapeutic drug monitoring has been implemented to individualize pegaspargase and Erwinia asparaginase dosing in pediatric ALL to monitor asparaginase efficacy or change formulation in patients who have lower than desired asparaginase trough levels. In contrast, for older patients who might have higher asparaginase levels, therapeutic drug monitoring can be used so that treatment can start with a lower asparaginase dose. Then, asparaginase activity can be managed to maintain therapeutic levels while perhaps reducing the adverse events associated with asparaginase. Further studies are needed to investigate the benefit of therapeutic drug monitoring in AYAs and adults treated with asparaginase.
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Jitesh D. Kawedia, Michael E. Rytting 13. Abshire TC, Pollock BH, Billett AL, Bradley P, Buchanan GR. Weekly polyethylene glycol conjugated L-asparaginase compared with biweekly dosing produces superior induction remission rates in childhood relapsed acute lymphoblastic leukemia: a Pediatric Oncology Group Study. Blood 2000; 96: 1709-15. 14. Avramis VI, Sencer S, Periclou AP, et al. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children’s Cancer Group study. Blood 2002; 99:1986-94. 15. Asselin BL, Ryan D, Frantz CN, et al. In vitro and in vivo killing of acute lymphoblastic-leukemia cells by L-asparaginase. Cancer Res 1989; 49:4363-8. 16. Smith M, Arthur D, Camitta B, et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol 1996; 14:18-24. 17. Weiss MA, Lamanna N. In adult ALL, less is now more. Blood 2006; 107:852-3. 18. de Bont JM, Holt B, Dekker AW, van der Does-van den Berg A, Sonneveld P, Pieters R. Significant difference in outcome for adolescents with acute lymphoblastic leukemia treated on pediatric vs adult protocols in the Netherlands. Leukemia 2004; 18:2032-5. 19. de Bont JM, van der Holt B, Dekker AW, van der Does-van den Berg A, Sonneveld P, Pieters R. Adolescents with acute lymphatic leukaemia achieve significantly better results when treated following Dutch paediatric oncology protocols than with adult protocols [in Dutch]. Ned Tijdschr Geneeskd 2005; 149: 400-6. 20. Testi A. Difference in outcome of adolescents (14-17 years) with acute lymphoblastic leukemia (ALL) enrolled in the Italian pediatric (AIEOP) and adult (GIMEMA) multicenter protocols. J Clin Oncol 2006; 24:508s. 21. Ramanujachar R, Richards S, Hann I, et al. Adolescents with acute lymphoblastic leukaemia: Outcome on UK national paediatric (ALL97) and adult (UKALLXII/ E2993) trials. Pediatr Blood Cancer 2007; 48:254-61. 22. Barry E, DeAngelo DJ, Neuberg D, et al. Favorable outcome for adolescents with acute lymphoblastic leukemia treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols. J Clin Oncol 2007; 25: 813-9. 23. Ramanujachar R, Richards S, Hann I, Webb D. Adolescents with acute lymphoblastic leukaemia: Emerging from the shadow of paediatric and adult treatment Protocols. Pediatr Blood Cancer 2006; 47:748-56. 24. Boissel N, Auclerc MF, Lheritier V, et al. Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol 2003; 21:774-80. 25. DeAngelo DJ. The treatment of adolescents and young adults with acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2005:123-30. 26. Storring JM, Minden MD, Kao S, et al. Treatment of adults with BCR-ABL negative acute lymphoblastic leukaemia with a modified paediatric regimen. Br J Haematol 2009; 146:76-85. 27. Beck J, Brandt K, Brüggemann M, et al. Significant improvement of outcome in adolescents and young adults (AYAs) aged 15-35 years with acute lymphoblastic leukemia (ALL) with a pediatric derived adult ALL protocol; results of 1529 AYAs in 2 consecutive trials of the German Multicenter Study Group For Adult ALL (GMALL) (abstract). Blood 2013; 122:839. 28. Goekbuget N, Baumann A, Beck J, et al. PEG-asparaginase intensification in adult acute lymphoblastic leukemia (ALL): significant improvement of outcome with moderate increase of liver toxicity in the German Multicenter Study Group for Adult ALL (GMALL) Study 07/2003. Blood 2010; 116:219-20. 29. Advani A, Earl M, Bleyer A, Douer D, Rytting M, Bleyer A. Toxicities of intravenous (IV) pegasparaginase (ONCASPAR (R)) in adults with acute lymphoblastic leukemia (ALL) (abstract). Blood 2007; 110:827a. 30. Rytting M, Earl M, Douer D, Muriera B, Advani A, Bleyer A. Toxicities in adults with acute lymphoblastic leukemia (ALL) treated with regimens using pegasparaginase (abstract). Blood 2008; 112:672. 31. Stock W, Douer D, DeAngelo DJ, et al. Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma 2011; 52:2237-53. 32. Aldoss I, Lunning MA, Avramis VI, et al. High-grade pegylated asparaginaserelated hepatotoxicity occurrence in a pediatric-inspired adult acute lymphoblastic leukemia regimen does not necessarily predict recurrent hepatotoxicity in subsequent cycles (abstract). Blood 2013; 122:2671.
33. Silverman LB, Supko JG, Stevenson KE, et al. Intravenous PEG-asparaginase during remission induction in children and adolescents with newly diagnosed acute lymphoblastic leukemia. Blood 2010; 115:1351-3. 34. Douer D, Yampolsky H, Cohen LJ, et al. Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia. Blood 2007; 109: 2744-50. 35. Ho DH, Whitecar JP Jr, Luce JK, Frei E 3rd. L-asparagine requirement and the effect of L-asparaginase on the normal and leukemic human bone marrow. Cancer Res 1970; 30:466-72. 36. Capizzi RL, Bertino JR, Skeel RT, et al. L-asparaginase: clinical, biochemical, pharmacological, and immunological studies. Ann Intern Med 1971; 74:893-901. 37. Fu CH, Sakamoto KM. PEG-asparaginase. Expert Opin Pharmacother 2007; 8: 1977-84. 38. Domenech C, Thomas X, Chabaud S, et al. L-asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: results of the GRASPALL 2005-01 randomized trial. Br J Haematol 2011; 153:58-65. 39. Pession A, Valsecchi MG, Masera G, et al. Long-term results of a randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia. J Clin Oncol 2005; 23:7161-7. 40. Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL2003 study. J Clin Oncol 2009; 27:911-8. 41. Kawedia JD, Liu C, Pei D, et al. Dexamethasone exposure and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia. Blood 2012; 119: 1658-64. 42. Rytting M. Peg-asparaginase for acute lymphoblastic leukemia. Expert Opin Biol Ther 2010; 10:833-9. 43. Parsons SK, Skapek SX, Neufeld EJ, et al. Asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia. Blood 1997; 89:1886-95. 44. Killander D, Dohlwitz A, Engstedt L, et al. Hypersensitive reactions and antibodyformation during L-asparaginase treatment of children and adults with acute leukemia. Cancer 1976; 37:220-8. 45. Evans WE, Tsiatis A, Rivera G, et al. Anaphylactoid reactions to Escherichia coli and Erwinia asparaginase in children with leukemia and lymphoma. Cancer 1982; 49:1378-83. 46. Woo MH, Hak LJ, Storm MC, et al. Anti-asparaginase antibodies following E. coli asparaginase therapy in pediatric acute lymphoblastic leukemia. Leukemia 1998; 12:1527-33. 47. Dinndorf PA, Gootenberg J, Cohen MH, Keegan P, Pazdur R. FDA drug approval summary: pegaspargase (oncaspar) for the first-line treatment of children with acute lymphoblastic leukemia (ALL). Oncologist 2007; 12:991-8. 48. Kirkwood A, Dey A, Rowntree C, et al. Feasibility of pegylated-asparaginase (PEG-ASP) during induction in adults with acute lymphoblastic leukaemia (ALL): results from the UK phase 3 multicentre trial UKALL 14 (abstract). Blood 2013; 122:3900. 49. Riccardi R, Holcenberg JS, Glaubiger DL, Wood JH, Poplack DG. L-asparaginase pharmacokinetics and asparagine levels in cerebrospinal fluid of rhesus monkeys and humans. Cancer Res 1981; 41:4554-8. 50. Albertsen BK, Schroder H, Jakobsen P, Muller HJ, Carlsen NT, Schmiegelow K. Monitoring of Erwinia asparaginase therapy in childhood ALL in the Nordic countries. Br J Clin Pharmacol 2001; 52:433-7. 51. Rizzari C, Zucchetti M, Conter V, et al. L-asparagine depletion and L-asparaginase activity in children with acute lymphoblastic leukemia receiving i.m. or i.v. Erwinia C. or E. coli L-asparaginase as first exposure. Ann Oncol 2000; 11:189-93. 52. Tsurusawa M, Chin M, Iwai A, et al. L-asparagine depletion levels and L-asparaginase activity in plasma of children with acute lymphoblastic leukemia under asparaginase treatment. Cancer Chemother Pharmacol 2004; 53:204-8. 53. Wetzler M, Sanford BL, Kurtzberg J, 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; 109:4164-7. 54. Avramis VI, Panosyan EH. Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations: the past, the present and recommendations for the future. Clin Pharmacokinet 2005; 44:367-93. 55. Pieters R, Kaspers G, te Loo MD, et al. A prospective study on drug monitoring of pegasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia (abstract). Blood 2013; 122:2634.
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Asparaginase in Acute Lymphoblastic Leukemia Jitesh D. Kawedia,1 Michael E. Rytting2 Abstract Cure rates in pediatric acute lymphoblastic leukemia have significantly improved over the past decades. Now, almost 90% of children will survive the disease. The cure rates in adolescents, young adults, and adults have not kept pace with the improvements in younger patients, even though almost an equal proportion of adult patients achieve complete remission as their pediatric counterparts. Differences in treatment regimens might be important. Intensive use of asparaginase has been a key component of successful pediatric therapy. In this review, we focus on the use of asparaginase and the potential of optimizing asparaginase use via monitoring to minimize adverse drug events and improve efficacy of the drug. Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. S3, S14-7 ª 2014 Elsevier Inc. All rights reserved. Keywords: Acute lymphoblastic leukemia, Adults, Asparaginase, Pharmacokinetics, Therapeutic drug monitoring, Toxicities
Introduction Survival in pediatric patients with acute lymphoblastic leukemia (ALL) has significantly improved over time with almost 90% of children are cured.1-6 This has been achieved by dose intensification and by extending the duration of chemotherapeutic agents.6-10 One chemotherapeutic agent, which has been central to pediatric therapies, is asparaginase. Pediatric studies support the use of asparaginase, and some groups have demonstrated that asparaginase dose intensification might improve outcome in pediatric ALL.6,10-15 However, there has been less improvement in adolescents and young adults (AYAs) or adults with ALL, and the long-term disease-free survival (DFS) in many studies is < 50%.5,16,17 In retrospective comparisons, adolescents treated with pediatric-based regimens have better outcome compared with those treated with adult-based regimens.9,18-22 There are several differences in pediatric and adult treatment regimens, including the intensive use of asparaginase in pediatric regimens.9,23,24 Studies using pediatric-based regimens in AYAs and adult patients with greater use of asparaginase have shown promising results.25-28 However, AYAs and adult patients are more prone to severe Grade 3 to 4 toxicities including thrombosis, pancreatitis, and chemical hepatitis compared with pediatric patients.29-32 Pharmacokinetic (PK) studies suggest that adult patients might have a decreased bodily clearance and consequently greater 1
Department of Pharmacy Research Division of Pediatrics The University of Texas M.D. Anderson Cancer Center, Houston, TX 2
Submitted: Feb 21, 2014; Accepted: Jun 4, 2014 Address for correspondence: Jitesh D. Kawedia, PhD, Department of Pharmacy Research, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030 Fax: þ713-563-8247; e-mail contact: [email protected]
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Clinical Lymphoma, Myeloma & Leukemia September 2014
exposure to asparaginase, which might contribute (along with other risk factors) to the increased incidence of severe adverse drug events.33,34 In this review, we discuss the effect of asparaginase on outcomes and toxicities especially in AYAs and adult patients, and the potential use of therapeutic drug monitoring to minimize adverse events, while maintaining the therapeutic efficacy of asparaginase.
Discussion Asparaginase Mechanism of Action and Its Different Preparations Asparaginase is an enzyme that catalyzes the hydrolysis of the amino acid asparagine to aspartic acid thereby depleting asparagine levels in the serum. Asparagine is a nonessential amino acid for normal tissues, because they can synthesize it via asparagine synthetase, but is an essential amino acid for malignant cells because they cannot synthesize it and rely on extracellular asparagine in the serum.35-37 Asparagine is important for synthesis of protein, DNA, and RNA. Asparaginase is derived from bacteria and the current preparations are: (1) native asparaginase (Elspar [Lundbeck], Kidrolase [Jazz Pharmaceuticals, Inc.], Crasnitin [Bayer AG], Leunase [Kyowa Hakko Kirin], Asparaginase medac [KyowaHakko]) derived from Escherichia coli; (2) pegylated form of native E. coli asparaginase (Oncaspar [Sigma-Tau Pharmaceuticals, Inc.]; pegaspargase); and (3) Erwinia asparaginase (Erwinaze, and Erwinase [Jazz Pharmaceuticals, Inc.]), which is isolated from Erwinia chrysanthemi. It is important to mention that some asparaginase preparations are discontinued and no longer available in all countries. In addition, a pegylated recombinant Erwinia asparaginase (mPEG-r-crisantaspase) is undergoing phase I evaluation (NCT015515124). There is also a preparation of asparaginase that is packaged in red blood cells.38
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.06.017
Effect of Asparaginase on Treatment Outcomes in Pediatric ALL Asparaginase is used during induction, consolidation, and maintenance phases of pediatric ALL therapy. In the Pediatric Oncology Group 8704 study involving T-cell ALL and lymphoblastic lymphoma patients randomized to E. coli asparaginase (25,000 IU/m2 weekly for 20 weeks) during consolidation had improved complete continuous remission compared with patients randomized to the nonasparaginase arm (71.3% vs. 57.8% at the end of 4 years).12 Similarly, in a study carried out by the Associazione Italiana Ematologia Oncologia Pediatrica, standard-risk ALL children treated with Berlin-Frankfurt-Munich (BFM)-type chemotherapy were randomized to receive asparaginase (25,000 IU/ m2 weekly for 20 weeks) or not receive asparaginase. Children who received asparaginase had a significantly increased 10-year DFS and overall survival (OS) (87.5% vs. 78.7% and 93.7% vs. 88.6%, respectively) compared with those who were not treated with asparaginase.39 In the Dana-Farber Cancer Institute (DFCI) Consortium Protocol 91-01, it was observed that prolonged asparaginase intensification significantly improved outcome in pediatric ALL, and patients who received 25 or fewer weeks of asparaginase had significantly worse outcome than those who tolerated at least 26 weeks of asparaginase treatment (5-year event-free survival [EFS] was 73% vs. 90%).6
Effect of Asparaginase on Treatment Outcomes in AYA and Adult ALL Recent retrospective comparisons indicate that young adults treated with pediatric-based protocols might have better outcomes than similar patients treated with adult regimens. This has resulted in renewed interest in asparaginase and subsequent toxicities in AYAs and adults.9,25-28,40 In their retrospective analysis, Stock and colleagues found that young adults (16-20 years of age) treated according to Children’s Cancer Group (CCG) protocols had better outcomes than similar patients treated according to adult protocols from the Cancer and Leukemia Group B (CALGB). The 7-year EFS and OS were 63% and 67% compared with 34% and 46%, respectively, in patients treated according to CCG and CALGB protocols.9 The major difference in the 2 protocols was a greater dose of dexamethasone, vincristine, L-asparaginase, and methotrexate. For asparaginase the CCG protocols used a cumulative dose of 318,000 IU/m2 compared with 50,000 IU/m2 in CALGB protocols. The French Group for Research on Adult Acute Lymphoblastic Leukemia reported an improved DFS of 56% in patients (aged 15-55 years) after an increase in the cumulative asparaginase dose from 20,000 IU/m2 in the LALA-94 (Lymphoblastic Acute Leukemia in Adults 94) trial to 132,000 IU/m2 (doses of prednisolone and vincristine were also increased).40 Similarly, the German Multicenter Study Group For Adult ALL reported a significant improvement of treatment outcome in AYAs aged 15 to 35 years treated with a pediatric-derived adult protocol.27 The 07/03 protocol intensified treatment with asparaginase and methotrexate and added targeted therapies such as rituximab and imatinib, and minimal residual disease-based stratification (it also included stem cell transplant for high-risk and very high-risk patients). The dose for pegaspargase was increased from 1000 to 2000 IU/m2 in induction, and from 500 to 2000 IU/m2 in consolidation therapy
(combined with high-dose methotrexate and mercaptopurine) for patients aged between 15 and 55 years.28 Of the 1529 AYA patients, 642 were treated according to the 05/03 protocol and 887 were treated according to the 07/03 protocol. Compared with the 05/03 protocol, complete remission and OS increased from 88% to 91% and 86% to 90%, respectively, with 73% OS in patients aged 15 to 17 years.27
Toxicities Associated With Asparaginase Although inclusion of asparaginase in treatment regimens has improved treatment outcomes, there are several dose-limiting toxicities that make the management of asparaginase therapy difficult. Because asparaginase is a foreign protein derived from bacteria, patients commonly develop allergic reactions and antibodies against the enzyme, which significantly hampers its efficacy and results in suboptimal treatment response. In the St Jude Total XV study, patients who developed antibodies to native asparaginase had a 6.5-fold greater risk of developing central nervous system relapse.41 Other notable toxicities, which in some cases can be fatal, include pancreatitis, bleeding, thrombosis, hyperglycemia, hyperlipidemia, hyperbilirubinemia, and liver dysfunction.31,42,43 In pediatric patients, asparaginase-induced allergy and silent hypersensitivity are major challenges.44-46 When patients develop allergy or silent hypersensitivity to E. coli asparaginase, they are switched to pegaspargase and then Erwinia asparaginase. Because of the greater incidence of allergic reactions to native asparaginase, pegaspargase is now used as first-line treatment in the United States and other countries.47 Although pegaspargase sometimes circumvents the problem of allergic reaction and enzyme-neutralizing antibodies, the problem might still persist. Furthermore, it is not clear whether the antipegaspargase antibody titer is capable of causing significant neutralization of pegaspargase. In contrast, the therapeutic benefits of asparaginase in AYAs and adults are less certain because of serious adverse drug toxicities which are not seen at such high frequencies in pediatric patients.29-31 In adults, no large body of data exists, but Stock and colleagues compared toxicities with intravenously (I.V.)-administered pegaspargase in 76 adult patients treated at the Cleveland Clinic, the University of Texas M.D. Anderson Cancer Center, and the University of Southern California with those for 1274 pediatric patients, administered with intramuscular pegaspargase treated at member institutions of the Children’s Oncology Group.31 Older patients suffered greater incidence of Grade 3 to 4 toxicities of the pancreas and liver, such as increased transaminase level (20% vs. 36%), hyperbilirubinemia (3% vs. 14%), hypofibrinogenemia (3% vs. 14%), hyperglycemia (7% vs. 25%), and pancreatitis (2% vs. 5%), and thrombosis (3% vs. 8%). These adverse effects were further exacerbated with use of the pegaspargase, which has a longer elimination half-life. The U.K. phase III multicenter trial, UKALL 14, reported that pegaspargase was “definitely or probably” implicated in 11 of 18 induction deaths.48 The incidence of nonfatal pegaspargase toxicities during induction was 36% (n ¼ 33). Liver dysfunction was most common (24.5%) followed by coagulopathy (7.7%) and thrombosis (5.6%). Age and Philadelphia (Ph) chromosome status were independent factors for risk of induction deaths. The odds ratio for age > 40 years and > 55 years were 5.27 and 4.47, respectively, and 6.08 for Ph-positive disease. Older age
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Asparaginase in Acute Lymphoblastic Leukemia (> 40 years) was also associated with Grade 3 to 4 pegaspargaserelated liver dysfunction in this trial.48
Therapeutic Drug Monitoring for Asparaginase
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Sustained and prolonged asparagine depletion is an important factor in effectiveness of asparaginase treatment. To estimate the intensity of asparaginase therapy, asparaginase enzyme activity is monitored. Asparaginase enzyme activity > 0.1 IU/mL,49,50 and possibly > 0.05 IU/mL51,52 corresponds to asparagine depletion. Wetzler and colleagues defined asparagine depletion according to pegaspargase enzyme levels > 0.03 IU/mL for 14 consecutive days after at least 1 of 4 planned pegaspargase administrations for patients treated according to the CALGB study 9511 protocol. Of the 85 patients, 22 who did not achieve asparagine depletion had inferior DFS and OS (hazard ratio, 1.8).53 There are other studies that recommend much higher levels of enzyme activity for asparagine depletion. Based on best fit population PK and pharmacodynamic results obtained from nonlinear mixed effect modeling, Avramis and Panosyan reported that asparaginase enzyme activity < 0.4 IU/mL provided insufficient depletion, whereas > 0.4 to 0.7 IU/mL provided optimal asparagine depletion (90%).54 However, asparaginase enzyme activity > 0.1 IU/mL is considered a reasonable threshold for asparagine depletion. Two earlier studies performed pegaspargase PK evaluations in children and adolescents and in adult patients (aged 17-55 years) separately. Pediatric patients dosed I.V. at 2500 IU/m2 maintained therapeutic levels of 0.1 IU/mL or greater up to 21 days, and the adult patients dosed I.V. at 2000 IU/m2 were able to maintain 0.1 IU/mL or higher up to 25 days.33,34 Although adult patients received a lower dose (2000 IU/m2 vs. 2500 IU/m2) they maintained the therapeutic levels (> 0.1 IU/mL) for more days compared with pediatric patients (25 vs. 21 days). These studies suggest that the adult patients might have a lower bodily clearance rate for asparaginase, thus resulting in increased drug levels; this might explain the greater incidence of toxicities. Therapeutic drug monitoring has been used in different pediatric clinical trials to identify patients who are at risk of subtherapeutic asparaginase enzymatic activity due to allergic reactions or silent hypersensitivity. In the DFCI consortium protocol 00-01, one of the goals was to optimize asparaginase therapy in children and adolescents newly diagnosed with ALL. Patients who achieved complete remission were randomized to receive either a fixed dose of 25,000 IU/m2/wk of native asparaginase or pharmacokinetically-guided individualized dosing based on nadir serum asparaginase enzyme activity (NSAA) measured every 3 weeks. The starting asparaginase dose in the individualized arm was 12,500 IU/m2, after that the dose was adjusted to maintain NSAA between 0.1 and 0.14 IU/mL. Interestingly, it was observed that patients in the individualized arm received a lower median asparaginase dose (17,500 IU/m2 vs. 25,000 IU/m2) but had better outcome. The 5-year EFS in the individualized arm was 90% compared with 82% in the fixed-dose arm. The Dutch Childhood Oncology Group (DCOG) has implemented therapeutic drug monitoring to individualize pegaspargase and Erwinia asparaginase dose to detect silent inactivation in their current DCOG-ALL-1 protocol.55 So far, findings suggest that therapeutic drug monitoring helps in improving outcome, and allows a decreased asparaginase dose. AYAs and adult patients
Clinical Lymphoma, Myeloma & Leukemia September 2014
might have a lower clearance rate of asparaginase compared with younger children and would benefit from therapeutic drug monitoring to reduce the risk of toxicity while maintaining the therapeutic efficacy of asparaginase.
Conclusion Asparaginase is a chemotherapeutic agent, which has helped to improve treatment outcomes in pediatric ALL. Studies show better treatment outcomes in patients who have received a high percentage of planned asparaginase courses designed in their respective trials as opposed to those who had to discontinue or miss therapy because of adverse events. Pediatric-inspired regimens that include administration and dose intensification of asparaginase have resulted in significant improvements of treatment outcomes in AYAs and adult patients in published trials. Although asparaginase use is feasible in AYAs and adults, there are severe adverse effects, most commonly hepatotoxicity. Asparaginase PK studies suggest that older patients might a have lower rate of asparaginase clearance, hence greater drug exposure, which can lead to a greater rate of toxicities. Therapeutic drug monitoring has been implemented to individualize pegaspargase and Erwinia asparaginase dosing in pediatric ALL to monitor asparaginase efficacy or change formulation in patients who have lower than desired asparaginase trough levels. In contrast, for older patients who might have higher asparaginase levels, therapeutic drug monitoring can be used so that treatment can start with a lower asparaginase dose. Then, asparaginase activity can be managed to maintain therapeutic levels while perhaps reducing the adverse events associated with asparaginase. Further studies are needed to investigate the benefit of therapeutic drug monitoring in AYAs and adults treated with asparaginase.
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