Skip to main content
SpringerLink
Log in

Asparaginase-Associated Pancreatitis in Pediatric Patients with Acute Lymphoblastic Leukemia: Current Perspectives

  • Review Article
  • Published:
Pediatric Drugs Aims and scope Submit manuscript

Abstract

Asparaginase therapy is a vital agent in the treatment of acute lymphoblastic leukemia (ALL), with increasing evidence of its high importance in high-risk ALL populations. However, despite the clear clinical and biological benefits of asparaginase therapy, many patients experience toxicities. A well-known treatment-limiting toxicity is asparaginase-associated pancreatitis (AAP). If severe, it necessitates discontinuation of asparaginase therapy, which can lead to a higher risk of relapse in patients with ALL. New protocols for ALL therapy have increased overall total doses of asparaginase therapy in select high-risk populations and have incorporated longer half-life formulations of pegylated asparaginase. Treatment drug monitoring has also allowed assurance of adequate levels of asparagine depletion throughout treatment. It is currently unknown if these changes will increase rates of AAP. Interestingly, important pharmacogenomics data, such as single nucleotide polymorphisms, can identify patients at the highest risk for severe AAP. The incidence of AAP in recent trials, current pharmacogenomic data that could further our understanding of the disease, and the importance of cautiously re-exposing patients to further asparaginase treatment after an initial episode of AAP are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet. 2008;371(9617):1030–43. https://doi.org/10.1016/s0140-6736(08)60457-2.

    Article  CAS  PubMed  Google Scholar 

  2. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006;354(2):166–78. https://doi.org/10.1056/NEJMra052603.

    Article  CAS  PubMed  Google Scholar 

  3. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405. https://doi.org/10.1182/blood-2016-03-643544.

    Article  CAS  PubMed  Google Scholar 

  4. Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. 2015;373(16):1541–52. https://doi.org/10.1056/NEJMra1400972.

    Article  CAS  PubMed  Google Scholar 

  5. Pession A, Valsecchi MG, Masera G, Kamps WA, Magyarosy E, Rizzari C, 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(28):7161–7. https://doi.org/10.1200/jco.2005.11.411.

    Article  CAS  PubMed  Google Scholar 

  6. Jaffe N, Traggis D, Das L, Moloney WC, Hann HW, Kim BS, et al. l-Asparaginase in the treatment of neoplastic diseases in children. Cancer Res. 1971;31(7):942–9.

    CAS  PubMed  Google Scholar 

  7. Silverman LB, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell LA, et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91–01. Blood. 2001;97(5):1211–8. https://doi.org/10.1182/blood.v97.5.1211.

    Article  CAS  PubMed  Google Scholar 

  8. Silverman LB, Stevenson KE, O’Brien JE, Asselin BL, Barr RD, Clavell L, et al. Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985–2000). Leukemia. 2010;24(2):320–34. https://doi.org/10.1038/leu.2009.253.

    Article  CAS  PubMed  Google Scholar 

  9. Amylon MD, Shuster J, Pullen J, Berard C, Link MP, Wharam M, et al. Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study. Leukemia. 1999;13(3):335–42. https://doi.org/10.1038/sj.leu.2401310.

    Article  CAS  PubMed  Google Scholar 

  10. Egler RA, Ahuja SP, Matloub Y. l-Asparaginase in the treatment of patients with acute lymphoblastic leukemia. J Pharmacol Pharmacother. 2016;7(2):62–71. https://doi.org/10.4103/0976-500x.184769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kearney SL, Dahlberg SE, Levy DE, Voss SD, Sallan SE, Silverman LB. Clinical course and outcome in children with acute lymphoblastic leukemia and asparaginase-associated pancreatitis. Pediatr Blood Cancer. 2009;53(2):162–7. https://doi.org/10.1002/pbc.22076.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Jarrar M, Gaynon PS, Periclou AP, Fu C, Harris RE, Stram D, et al. Asparagine depletion after pegylated E. coli asparaginase treatment and induction outcome in children with acute lymphoblastic leukemia in first bone marrow relapse: a Children’s Oncology Group study (CCG-1941). Pediatr Blood Cancer. 2006;47(2):141–6. https://doi.org/10.1002/pbc.20713.

    Article  PubMed  Google Scholar 

  13. Kidd JG. 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;98(6):565–82. https://doi.org/10.1084/jem.98.6.565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Müller HJ, Boos J. Use of l-asparaginase in childhood ALL. Crit Rev Oncol Hematol. 1998;28(2):97–113. https://doi.org/10.1016/s1040-8428(98)00015-8.

    Article  PubMed  Google Scholar 

  15. Oparaji JA, Rose F, Okafor D, Howard A, Turner RL, Orabi AI, et al. Risk factors for asparaginase-associated pancreatitis: a systematic review. J Clin Gastroenterol. 2017;51(10):907–13. https://doi.org/10.1097/mcg.0000000000000827.

    Article  CAS  PubMed  Google Scholar 

  16. Wolthers BO, Frandsen TL, Baruchel A, Attarbaschi A, Barzilai S, Colombini A, et al. Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study. Lancet Oncol. 2017;18(9):1238–48. https://doi.org/10.1016/s1470-2045(17)30424-2.

    Article  CAS  PubMed  Google Scholar 

  17. Raja RA, Schmiegelow K, Frandsen TL. Asparaginase-associated pancreatitis in children. Br J Haematol. 2012;159(1):18–27. https://doi.org/10.1111/bjh.12016.

    Article  CAS  PubMed  Google Scholar 

  18. Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, O’Brien JE, et al. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli l-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015;16(16):1677–90. https://doi.org/10.1016/s1470-2045(15)00363-0.

    Article  CAS  PubMed  Google Scholar 

  19. Salzer W, Seibel N, Smith M. Erwinia asparaginase in pediatric acute lymphoblastic leukemia. Expert Opin Biol Ther. 2012;12(10):1407–14. https://doi.org/10.1517/14712598.2012.718327.

    Article  CAS  PubMed  Google Scholar 

  20. Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, et al. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli l-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children’s Oncology Group Study AALL07P4. J Clin Oncol. 2014;32(34):3874–82. https://doi.org/10.1200/jco.2014.55.5763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Vrooman LM, Kirov II, Dreyer ZE, Kelly M, Hijiya N, Brown P, et al. Activity and toxicity of intravenous erwinia asparaginase following allergy to E. coli-derived asparaginase in children and adolescents with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2016;63(2):228–33. https://doi.org/10.1002/pbc.25757.

    Article  CAS  PubMed  Google Scholar 

  22. Finch ER, Smith CA, Yang W, Liu Y, Kornegay NM, Panetta JC, et al. Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia. Pediatr Blood Cancer. 2020;67(1): e28040. https://doi.org/10.1002/pbc.28040.

    Article  CAS  PubMed  Google Scholar 

  23. Haskell CM, Canellos GP, Leventhal BG, Carbone PP, Block JB, Serpick AA, et al. l-Asparaginase: therapeutic and toxic effects in patients with neoplastic disease. N Engl J Med. 1969;281(19):1028–34. https://doi.org/10.1056/nejm196911062811902.

    Article  CAS  PubMed  Google Scholar 

  24. Pemmaraju N, Rytting ME. Questions on asparaginase-associated pancreatitis. Lancet Oncol. 2017;18(9):1148–9. https://doi.org/10.1016/s1470-2045(17)30610-1.

    Article  PubMed  Google Scholar 

  25. Samarasinghe S, Dhir S, Slack J, Iyer P, Wade R, Clack R, et al. Incidence and outcome of pancreatitis in children and young adults with acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003. Br J Haematol. 2013;162(5):710–3. https://doi.org/10.1111/bjh.12407.

    Article  CAS  PubMed  Google Scholar 

  26. Raja RA, Schmiegelow K, Albertsen BK, Prunsild K, Zeller B, Vaitkeviciene G, et al. Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol. Br J Haematol. 2014;165(1):126–33. https://doi.org/10.1111/bjh.12733.

    Article  CAS  PubMed  Google Scholar 

  27. Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62(1):102–11. https://doi.org/10.1136/gutjnl-2012-302779.

    Article  PubMed  Google Scholar 

  28. Bollen TL, Singh VK, Maurer R, Repas K, van Es HW, Banks PA, et al. A comparative evaluation of radiologic and clinical scoring systems in the early prediction of severity in acute pancreatitis. Am J Gastroenterol. 2012;107(4):612–9. https://doi.org/10.1038/ajg.2011.438.

    Article  PubMed  Google Scholar 

  29. Schmiegelow K, Attarbaschi A, Barzilai S, Escherich G, Frandsen TL, Halsey C, et al. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus. Lancet Oncol. 2016;17(6):e231–9. https://doi.org/10.1016/s1470-2045(16)30035-3.

    Article  PubMed  Google Scholar 

  30. Knoderer HM, Robarge J, Flockhart DA. Predicting asparaginase-associated pancreatitis. Pediatr Blood Cancer. 2007;49(5):634–9. https://doi.org/10.1002/pbc.21037.

    Article  PubMed  Google Scholar 

  31. Albertsen BK, Grell K, Abrahamsson J, Lund B, Vettenranta K, Jónsson ÓG, et al. Intermittent versus continuous PEG-asparaginase to reduce asparaginase-associated toxicities: a NOPHO ALL2008 randomized study. J Clin Oncol. 2019;37(19):1638–46. https://doi.org/10.1200/jco.18.01877.

    Article  CAS  PubMed  Google Scholar 

  32. Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, et al. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from children’s oncology group study AALL0232. J Clin Oncol. 2016;34(20):2380–8. https://doi.org/10.1200/jco.2015.62.4544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Denton CC, Rawlins YA, Oberley MJ, Bhojwani D, Orgel E. Predictors of hepatotoxicity and pancreatitis in children and adolescents with acute lymphoblastic leukemia treated according to contemporary regimens. Pediatr Blood Cancer. 2018. https://doi.org/10.1002/pbc.26891.

    Article  PubMed  Google Scholar 

  34. Stock W, Douer D, DeAngelo DJ, Arellano M, Advani A, Damon L, et al. Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma. 2011;52(12):2237–53. https://doi.org/10.3109/10428194.2011.596963.

    Article  CAS  PubMed  Google Scholar 

  35. Lebovic R, Pearce N, Lacey L, Xenakis J, Faircloth CB, Thompson P. Adverse effects of pegaspargase in pediatric patients receiving doses greater than 3,750 IU. Pediatr Blood Cancer. 2017. https://doi.org/10.1002/pbc.26555.

    Article  PubMed  Google Scholar 

  36. Liu C, Yang W, Devidas M, Cheng C, Pei D, Smith C, et al. Clinical and genetic risk factors for acute pancreatitis in patients with acute lymphoblastic leukemia. J Clin Oncol. 2016;34(18):2133–40. https://doi.org/10.1200/jco.2015.64.5812.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Gupta S, Wang C, Raetz EA, Schore R, Salzer WL, Larsen EC, et al. Impact of asparaginase discontinuation on outcome in childhood acute lymphoblastic leukemia: a report from the children’s oncology group. J Clin Oncol. 2020;38(17):1897–905. https://doi.org/10.1200/jco.19.03024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hayashi RJ, Winter SS, Dunsmore KP, Devidas M, Chen Z, Wood BL, et al. Successful outcomes of newly diagnosed T lymphoblastic lymphoma: results from Children’s Oncology Group AALL0434. J Clin Oncol. 2020;38(26):3062–70. https://doi.org/10.1200/jco.20.00531.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, et al. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children’s Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018;36(29):2926–34. https://doi.org/10.1200/jco.2018.77.7250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Curran E, Stock W. How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood. 2015;125(24):3702–10. https://doi.org/10.1182/blood-2014-11-551481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Abaji R, Gagné V, Xu CJ, Spinella JF, Ceppi F, Laverdière C, et al. Whole-exome sequencing identified genetic risk factors for asparaginase-related complications in childhood ALL patients. Oncotarget. 2017;8(27):43752–67. https://doi.org/10.18632/oncotarget.17959.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Wolthers BO, Frandsen TL, Abrahamsson J, Albertsen BK, Helt LR, Heyman M, et al. Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol. Leukemia. 2017;31(2):325–32. https://doi.org/10.1038/leu.2016.203.

    Article  CAS  PubMed  Google Scholar 

  43. Ben Tanfous M, Sharif-Askari B, Ceppi F, Laaribi H, Gagné V, Rousseau J, et al. Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia. Clin Cancer Res. 2015;21(2):329–34. https://doi.org/10.1158/1078-0432.Ccr-14-0508.

    Article  CAS  PubMed  Google Scholar 

  44. Wolthers BO, Frandsen TL, Patel CJ, Abaji R, Attarbaschi A, Barzilai S, et al. Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report. Haematologica. 2019;104(3):556–63. https://doi.org/10.3324/haematol.2018.199356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Grimes AC, Chen Y, Bansal H, Aguilar C, Perez Prado L, Quezada G, et al. Genetic markers for treatment-related pancreatitis in a cohort of Hispanic children with acute lymphoblastic leukemia. Support Care Cancer. 2021;29(2):725–31. https://doi.org/10.1007/s00520-020-05530-w.

    Article  PubMed  Google Scholar 

  46. Liu Y, Smith CA, Panetta JC, Yang W, Thompson LE, Counts JP, et al. Antibodies predict pegaspargase allergic reactions and failure of rechallenge. J Clin Oncol. 2019;37(23):2051–61. https://doi.org/10.1200/jco.18.02439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Asselin B, Rizzari C. Asparaginase pharmacokinetics and implications of therapeutic drug monitoring. Leuk Lymphoma. 2015;56(8):2273–80. https://doi.org/10.3109/10428194.2014.1003056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ, 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(6):1986–94. https://doi.org/10.1182/blood.v99.6.1986.

    Article  CAS  PubMed  Google Scholar 

  49. Hawkins DS, Park JR, Thomson BG, Felgenhauer JL, Holcenberg JS, Panosyan EH, et al. Asparaginase pharmacokinetics after intensive polyethylene glycol-conjugated l-asparaginase therapy for children with relapsed acute lymphoblastic leukemia. Clin Cancer Res. 2004;10(16):5335–41. https://doi.org/10.1158/1078-0432.Ccr-04-0222.

    Article  CAS  PubMed  Google Scholar 

  50. Tong WH, Pieters R, Kaspers GJ, te Loo DM, Bierings MB, van den Bos C, et al. A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia. Blood. 2014;123(13):2026–33. https://doi.org/10.1182/blood-2013-10-534347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. van der Sluis IM, Vrooman LM, Pieters R, Baruchel A, Escherich G, Goulden N, et al. Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica. 2016;101(3):279–85. https://doi.org/10.3324/haematol.2015.137380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Thu Huynh V, Bergeron S. Asparaginase toxicities: identification and management in patients with acute lymphoblastic leukemia. Clin J Oncol Nurs. 2017;21(5):E248–59. https://doi.org/10.1188/17.Cjon.E248-e259.

    Article  PubMed  Google Scholar 

  53. Treepongkaruna S, Thongpak N, Pakakasama S, Pienvichit P, Sirachainan N, Hongeng S. Acute pancreatitis in children with acute lymphoblastic leukemia after chemotherapy. J Pediatr Hematol Oncol. 2009;31(11):812–5. https://doi.org/10.1097/MPH.0b013e3181b87035.

    Article  PubMed  Google Scholar 

  54. Top PC, Tissing WJ, Kuiper JW, Pieters R, van Eijck CH. l-Asparaginase-induced severe necrotizing pancreatitis successfully treated with percutaneous drainage. Pediatr Blood Cancer. 2005;44(1):95–7. https://doi.org/10.1002/pbc.20187.

    Article  CAS  PubMed  Google Scholar 

  55. Wu SF, Chen AC, Peng CT, Wu KH. Octreotide therapy in asparaginase-associated pancreatitis in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2008;51(6):824–5. https://doi.org/10.1002/pbc.21721.

    Article  PubMed  Google Scholar 

  56. Peng S, Gerasimenko JV, Tsugorka TM, Gryshchenko O, Samarasinghe S, Petersen OH, et al. Galactose protects against cell damage in mouse models of acute pancreatitis. J Clin Invest. 2018;128(9):3769–78. https://doi.org/10.1172/jci94714.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Hijiya N, van der Sluis IM. Asparaginase-associated toxicity in children with acute lymphoblastic leukemia. Leuk Lymphoma. 2016;57(4):748–57. https://doi.org/10.3109/10428194.2015.1101098.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Editing Services, MD Anderson Medical Research Library; the authors would like to acknowledge Laura Russell for providing editorial comments on the manuscript.

Author information

Author notes

  1. Amber Gibson and Carlos Hernandez: Co-first authors and contributed equally.

Authors and Affiliations

  1. Department of Pediatrics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Amber Gibson, Carlos Hernandez, Fiorela N. Hernandez Tejada & Branko Cuglievan

  2. Department of Pharmacy Clinical Programs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jitesh Kawedia

  3. Department of Pediatrics and Internal Medicine, Holland Hospital, Holland, MI, USA

    Michael Rytting

Authors
  1. Amber Gibson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carlos Hernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fiorela N. Hernandez Tejada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jitesh Kawedia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Rytting
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Branko Cuglievan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Branko Cuglievan.

Ethics declarations

Funding

No external funding was used in the preparation of this manuscript.

Conflict of interest

Amber Gibson, Carlos Hernandez, Fiorela N. Hernandez Tejada, Jitesh Kawedia, Branko Cuglievan, and Michael Rytting declare that they have no conflicts of interest that might be relevant to the contents of this article.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

Not applicable.

Code availability

Not applicable.

Author contributions

CH and AG wrote the manuscript. FT edited the manuscript. JK edited the manuscript and provided pharmacological expertise. BC and MR edited and assisted in the writing of the manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gibson, A., Hernandez, C., Tejada, F.N.H. et al. Asparaginase-Associated Pancreatitis in Pediatric Patients with Acute Lymphoblastic Leukemia: Current Perspectives. Pediatr Drugs 23, 457–463 (2021). https://doi.org/10.1007/s40272-021-00463-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40272-021-00463-1

Search

Navigation