Skip to main content
SpringerLink
Log in

Emerging Molecular Therapies for the Treatment of Acute Lymphoblastic Leukemia

  • Chapter
  • First Online:
Impact of Genetic Targets on Cancer Therapy

Part of the book series: Advances in Experimental Medicine and Biology ((volume 779))

Abstract

The improved molecular understanding of cancer initiation, progression, and therapeutic resistance has yielded several novel molecular events that are being targeted by emerging therapies. While the treatment of ALL is a success story in the pediatric population, achieving a sustained remission in the adult population remains an area of investigation. Nevertheless, certain therapies have significantly improved the overall survival for adult ALL patients that should continue to improve with the discovery of better molecular targets and targeted agents. Here, we discuss novel therapeutic options under clinical investigation for the treatment of Philadephia chromosome negative ALL including immunotherapy, monoclonal antibodies, and small molecules that may be used as single agent or adjuvant therapy in the management of adult ALL.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. SEER incidence and NCHS mortality statistics [database on the Internet]. 2011. Available from http://seer.cancer.gov/statfacts/html/alyl.html#survival. Contract No.: Report.

  2. Onciu M. Acute lymphoblastic leukemia. Hematol/Oncol Clin North Am. 2009;23(4):655–74. doi:10.1016/j.hoc.2009.04.009.

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  4. Nishiwaki S, Miyamura K. Allogeneic stem cell transplant for adult Philadelphia chromosome-negative acute lymphoblastic leukemia. Leuk Lymphoma. 2012 Apr;53(4):550–6.

    Article  PubMed  CAS  Google Scholar 

  5. Walshe CA, Beers SA, French RR, Chan CH, Johnson PW, Packham GK, et al. Induction of cytosolic calcium flux by CD20 is dependent upon B Cell antigen receptor signaling. J Biol Chem. 2008;283(25):16971–84. doi:10.1074/jbc.M708459200.

    Article  PubMed  CAS  Google Scholar 

  6. Borowitz MJ, Shuster J, Carroll AJ, Nash M, Look AT, Camitta B, et al. Prognostic significance of fluorescence intensity of surface marker expression in childhood B-precursor acute lymphoblastic leukemia. A Pediatric Oncology Group Study. Blood. 1997;89(11):3960–6.

    PubMed  CAS  Google Scholar 

  7. Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010;116(12):2040–5. doi:10.1182/blood-2010-03-276246.

    Article  PubMed  CAS  Google Scholar 

  8. Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24(19):3121–7. doi:10.1200/jco.2005.05.1003. Official Journal of the American Society of Clinical Oncology.

    Article  PubMed  CAS  Google Scholar 

  9. Dworzak MN, Schumich A, Printz D, Potschger U, Husak Z, Attarbaschi A, et al. CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy. Blood. 2008;112(10):3982–8. doi:10.1182/blood-2008-06-164129.

    Article  PubMed  CAS  Google Scholar 

  10. Thomas DA, O’Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, Wierda W, et al. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol. 2010;28(24):3880–9. doi:10.1200/jco.2009.26.9456. Official Journal of the American Society of Clinical Oncology.

    Article  PubMed  CAS  Google Scholar 

  11. Hoelzer D, Heuttmann A, Kaul F, et al. Immunochemotherapy with rituximab in adult CD20+ B -precursor ALL improves molecular CR rate and outcome in standard as well as in high risk patients with stem cell transplant. Haematologica. 2009;94 Suppl 2:481. Abst.

    Google Scholar 

  12. Thomas DA, Faderl S, O’Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006;106(7):1569–80. doi:10.1002/cncr.21776.

    Article  PubMed  CAS  Google Scholar 

  13. Paietta E LX, Richards S et al. Implications for the use of monoclonal antibodies in future adult ALL trials :analysis of antigen expression in 505 B-lineage all patients on the MRC UKALLXII/ECOG2993 intergroup trial. Proc ASH. 2008;112(1907).

    Google Scholar 

  14. de Vries JF, Zwaan CM, De Bie M, Voerman JS, den Boer ML, van Dongen JJ, et al. The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells. Leukemia. 2012;26(2):255–64. doi:10.1038/leu.2011.206 Official Journal of the Leukemia Society of America, Leukemia Research Fund, UK.

    Article  PubMed  Google Scholar 

  15. Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, et al. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. The Lancet Oncol. 2012;13(4):403–11. doi:10.1016/s1470-2045(11)70386-2.

    Article  CAS  Google Scholar 

  16. Raetz EA, Cairo MS, Borowitz MJ, Blaney SM, Krailo MD, Leil TA, et al. Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: a children’s oncology group pilot study. J Clin Oncol. 2008;26(22):3756–62. doi:10.1200/jco.2007.15.3528. Official Journal of the American Society of Clinical Oncology.

    Article  PubMed  CAS  Google Scholar 

  17. Raetz EA, Cairo MS, Borowitz MJ, Lu X, Devidas M, Reid JM, et al. Reinduction chemoimmunotherapy with epratuzumab in relapsed acute lymphoblastic leukemia (all) in children, adolescents and young adults: results from Children’s Oncology Group (COG) study ADVL04P2. Blood. 2011;118(573): Abst.

    Google Scholar 

  18. Portell CA, Advani AS. Antibody therapy for acute lymphoblastic leukemia. Curr Hematol Malig Rep. 2012;7(2):153–9. doi:10.1007/s11899-012-0120-7.

    Article  PubMed  Google Scholar 

  19. Kreitman RJ, Pastan I. Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox. Clin Cancer Res. 2011;17(20):6398–405. doi:10.1158/1078-0432.ccr-11-0487. An Official Journal of the American Association for Cancer Research.

    Article  PubMed  CAS  Google Scholar 

  20. Raponi S, De Propris MS, Intoppa S, Milani ML, Vitale A, Elia L, et al. Flow cytometric study of potential target antigens (CD19, CD20, CD22, CD33) for antibody-based immunotherapy in acute lymphoblastic leukemia: analysis of 552 cases. Leuk Lymphoma. 2011;52(6):1098–107. doi:10.3109/10428194.2011.559668.

    Article  PubMed  CAS  Google Scholar 

  21. Nagorsen D, Baeuerle PA. Immunomodulatory therapy of cancer with T cell-engaging Bite antibody blinatumomab. Exp Cell Res. 2011;317(9):1255–60. doi:10.1016/j.yexcr.2011.03.010.

    Article  PubMed  CAS  Google Scholar 

  22. Nagorsen D, Bargou R, Ruttinger D, Kufer P, Baeuerle PA, Zugmaier G. Immunotherapy of lymphoma and leukemia with T-cell engaging bite antibody blinatumomab. Leuk Lymphoma. 2009;50(6):886–91. doi:10.1080/10428190902943077.

    Article  PubMed  CAS  Google Scholar 

  23. Topp MS, Kufer P, Gokbuget N, Goebeler M, Klinger M, Neumann S, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011;29(18):2493–8. doi:10.1200/jco.2010.32.7270. Official Journal of the American Society of Clinical Oncology.

    Article  PubMed  CAS  Google Scholar 

  24. Handgretinger R, Zugmaier G, Henze G, Kreyenberg H, Lang P, von Stackelberg A. Complete remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post-transplant relapsed acute lymphoblastic leukemia. Leukemia. 2011;25(1):181–4. doi:10.1038/leu.2010.239. Official Journal of the Leukemia Society of America, Leukemia Research Fund, UK.

    Article  PubMed  CAS  Google Scholar 

  25. Topp M, Gokbuget N, Zugmaier G, et al. Anti-CD19 bite blinatumomab induces high complete remission rate in adult patients with relapsed B-Precursor ALL: updated results of an ongoing phase II trial. 53rd annual meeting society of Hematology, San Diego,USA. Blood. 2011;118(21):252. Abstract.

    Google Scholar 

  26. Blanc V, Bousseau A, Caron A, Carrez C, Lutz RJ, Lambert JM. SAR3419: an anti-CD19-Maytansinoid Immunoconjugate for the treatment of B-cell malignancies. Clin Cancer Res. 2011;17(20):6448–58. doi:10.1158/1078-0432.ccr-11-0485. An Official Journal of the American Association for Cancer Research.

    Article  PubMed  CAS  Google Scholar 

  27. Watanabe T, Masuyama J, Sohma Y, Inazawa H, Horie K, Kojima K, et al. CD52 is a novel costimulatory molecule for induction of CD4+ regulatory T cells. Clin Immunol (Orlando). 2006;120(3):247–59. doi:10.1016/j.clim.2006.05.006.

    Article  CAS  Google Scholar 

  28. Angiolillo AL, Yu AL, Reaman G, Ingle AM, Secola R, Adamson PC. A phase II study of Campath-1H in children with relapsed or refractory acute lymphoblastic leukemia: a Children’s Oncology Group report. Pediatr Blood Cancer. 2009;53(6):978–83. doi:10.1002/pbc.22209.

    Article  PubMed  Google Scholar 

  29. Parnes A, Bifulco C, Vanasse GJ. A novel regimen incorporating the concomitant administration of fludarabine and alemtuzumab for the treatment of refractory adult acute lymphoblastic leukaemia: a report of three cases. Br J Haematol. 2007;139(1):164–5. doi:10.1111/j.1365-2141.2007.06760.x.

    Article  PubMed  CAS  Google Scholar 

  30. Stock W, Sanford B, Lozanski G, et al. Alemtuzumab can be incorporated into front-line therapy of adult Acute Lymphoblastic Leukemia (ALL): final phase I results of a Cancer and Leukemia Group B study (CALGB 10102). Proc ASH. 2009;114(838): Abstract.

    Google Scholar 

  31. Porter DL, Kalos M, Zheng Z, Levine B, June C. Chimeric antigen receptor therapy for B-cell malignancies. J Cancer. 2011;2:331–2.

    Article  PubMed  Google Scholar 

  32. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33. doi:10.1056/NEJMoa1103849.

    Article  PubMed  CAS  Google Scholar 

  33. Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Translat Med. 2012;4(132):132ra53. doi:10.1126/scitranslmed.3003761.

    Article  Google Scholar 

  34. Maillard I, Weng AP, Carpenter AC, Rodriguez CG, Sai H, Xu L, et al. Mastermind critically regulates Notch-mediated lymphoid cell fate decisions. Blood. 2004;104(6):1696–702. doi:10.1182/blood-2004-02-0514.

    Article  PubMed  CAS  Google Scholar 

  35. Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science (New York, NY). 2004;306(5694):269–71. doi:10.1126/science.1102160.

    Article  CAS  Google Scholar 

  36. Deangelo D, Stone R, Silverman L, et al. A phase I clinical trial of the Notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. J Clin Oncol. 2006;24(18S):6585. ASCO Annual Meeting Proceeding, June 20 Supplement.

    Google Scholar 

  37. Elyaman W, Bradshaw EM, Wang Y, Oukka M, Kivisakk P, Chiba S, et al. JAGGED1 and delta1 differentially regulate the outcome of experimental autoimmune encephalomyelitis. J Immunol. 2007;179(9):5990–8. Baltimore, MD: 1950.

    PubMed  CAS  Google Scholar 

  38. Real PJ, Tosello V, Palomero T, Castillo M, Hernando E, de Stanchina E, et al. Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med. 2009;15(1):50–8. doi:10.1038/nm.1900.

    Article  PubMed  CAS  Google Scholar 

  39. Andrews PD, Knatko E, Moore WJ, Swedlow JR. Mitotic mechanics: the auroras come into view. Curr Opin Cell Biol. 2003;15(6):672–83.

    Article  PubMed  CAS  Google Scholar 

  40. Scapin SM, Carneiro FR, Alves AC, Medrano FJ, Guimaraes BG, Zanchin NI. The crystal structure of the small GTPase Rab11b reveals critical differences relative to the Rab11a isoform. J Struct Biol. 2006;154(3):260–8. doi:10.1016/j.jsb.2006.01.007.

    Article  PubMed  CAS  Google Scholar 

  41. Quintas-Cardama A, Kantarjian H, Cortes J. Flying under the radar: the new wave of BCR-ABL inhibitors. Nat Rev Drug Discov. 2007;6(10):834–48. doi:10.1038/nrd2324.

    Article  PubMed  CAS  Google Scholar 

  42. Okabe S, Tauchi T, Ohyashiki K. Efficacy of MK-0457 and in combination with vorinostat against Philadelphia chromosome positive acute lymphoblastic leukemia cells. Ann Hematol. 2010;89(11):1081–7. doi:10.1007/s00277-010-0998-x.

    Article  PubMed  CAS  Google Scholar 

  43. Cortes-Franco J, Dombret H, Schafhausen P, Brummendorf TH, Boissel N, Latini FC, et al Danusertib hydrochloride (PHA-739358), a multi-kinase Aurora inhibitor, elicits clinical benefit in advanced chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia. 51st Annual Meeting American Society of Hematology,New Orleans,USA. Blood. 2009;114(22): Abstract 864.

    Google Scholar 

  44. Evangelisti C, Ricci F, Tazzari P, Tabellini G, Battistelli M, Falcieri E, et al. Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia. Leukemia. 2011;25(5):781–91. doi:10.1038/leu.2011.20. Official Journal of the Leukemia Society of America, Leukemia Research Fund, UK.

    Article  PubMed  CAS  Google Scholar 

  45. Grimaldi C, Chiarini F, Tabellini G, Ricci F, Tazzari PL, Battistelli M, et al. AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications. Leukemia. 2012;26(1):91–100. doi:10.1038/leu.2011.269. Official Journal of the Leukemia Society of America, Leukemia Research Fund, UK.

    Article  PubMed  CAS  Google Scholar 

  46. Uckun FM, Ozer Z, Qazi S, Tuel-Ahlgren L, Mao C. Polo-like-kinase 1 (PLK1) as a molecular target to overcome SYK-mediated resistance of B-lineage acute lymphoblastic leukaemia cells to oxidative stress. Br J Haematol. 2010;148(5):714–25. doi:10.1111/j.1365-2141.2009.07983.x.

    Article  PubMed  CAS  Google Scholar 

  47. Hasegawa H, Yamada Y, Iha H, Tsukasaki K, Nagai K, Atogami S, et al. Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells. Leukemia. 2009;23(11):2090–101. doi:10.1038/leu.2009.171. Official Journal of the Leukemia Society of America, Leukemia Research Fund, UK.

    Article  PubMed  CAS  Google Scholar 

  48. Rambal AA, Panaguiton ZL, Kramer L, Grant S, Harada H. MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM. Leukemia. 2009;23(10):1744–54. doi:10.1038/leu.2009.80. Official Journal of the Leukemia Society of America, Leukemia Research Fund, UK.

    Article  PubMed  CAS  Google Scholar 

  49. Hu X, Xu J, Sun A, Shen Y, He G, Guo F. Successful T-cell acute lymphoblastic leukemia treatment with proteasome inhibitor bortezomib based on evaluation of nuclear factor-kappaB activity. Leuk Lymphoma. 2011;52(12):2393–5. doi:10.3109/10428194.2011.593271.

    Article  PubMed  CAS  Google Scholar 

  50. Cortes J, Thomas D, Koller C, Giles F, Estey E, Faderl S, et al. Phase I study of bortezomib in refractory or relapsed acute leukemias. Clin Cancer Res. 2004;10(10):3371–6. doi:10.1158/1078-0432.ccr-03-0508. An Official Journal of the American Association for Cancer Research.

    Article  PubMed  CAS  Google Scholar 

  51. Horton TM, Pati D, Plon SE, Thompson PA, Bomgaars LR, Adamson PC, et al. A phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with refractory leukemia: a Children’s Oncology Group study. Clin Cancer Res. 2007;13(5):1516–22. doi:10.1158/1078-0432.ccr-06-2173. An Official Journal of the American Association for Cancer Research.

    Article  PubMed  CAS  Google Scholar 

  52. Mazumder A, Vesole DH, Jagannath S. Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: a case series illustrating utility in clinical practice. Clin Lymphoma Myeloma Leuk. 2010;10(2):149–51. doi:10.3816/CLML.2010.n.022.

    Article  PubMed  CAS  Google Scholar 

  53. Furman R, Gore L, Ravandi F, et al. Forodesine IV (Bcx-1777) is clinically active in relapsed/refractory T-cell leukemia: results of a phase II study (interim report). Blood. 2006;108:1851.

    Google Scholar 

  54. Kurtzberg J, Ernst TJ, Keating MJ, Gandhi V, Hodge JP, Kisor DF, et al. Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol. 2005;23(15):3396–403. doi:10.1200/jco.2005.03.199. Official Journal of the American Society of Clinical Oncology.

    Article  PubMed  CAS  Google Scholar 

  55. Gokbuget N, Basara N, Baurmann H, Beck J, Bruggemann M, Diedrich H, et al. High single-drug activity of nelarabine in relapsed T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation. Blood. 2011;118(13):3504–11. doi:10.1182/blood-2011-01-329441.

    Article  PubMed  Google Scholar 

  56. Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003;102(7):2379–86.

    Article  PubMed  CAS  Google Scholar 

  57. Barba P, Sampol A, Calbacho M, Gonzalez J, Serrano J, Martinez-Sanchez P, et al. Clofarabine-based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience. Am J Hematol. 2012;87(6):631–4. doi:10.1002/ajh.23167.

    Article  PubMed  Google Scholar 

  58. Tong WG, Wierda WG, Lin E, Kuang SQ, Bekele BN, Estrov Z, et al. Genome-wide DNA methylation profiling of chronic lymphocytic leukemia allows identification of epigenetically repressed molecular pathways with clinical impact. Epigenetics. 2010;5(6):499–508. Official Journal of the DNA Methylation Society Official Journal of the DNA Methylation Society.

    Article  PubMed  CAS  Google Scholar 

  59. Garcia-Manero G, Thomas D, Rytting M, et al. Final report of a phase I trial of decitabine with or without hyperCVAD in relapsed acute lymphocytic leukemia (ALL). Blood. 2010;116(21):867. Abstract.

    Google Scholar 

  60. Marks PA, Xu WS. Histone deacetylase inhibitors: potential in cancer therapy. J Cell Biochem. 2009;107(4):600–8. doi:10.1002/jcb.22185.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute and Penn State Hershey Medical Center, Hershey, PA, 17033, USA

    Monali Vasekar, Joshua E. Allen & David Claxton M.D. (Professor of Medicine)

  2. Penn State Hershey Medical Center, Hershey, PA, 17033, USA

    Jamal Joudeh

Authors
  1. Monali Vasekar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joshua E. Allen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jamal Joudeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Claxton M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Claxton M.D. .

Editor information

Editors and Affiliations

  1. University Drive 500, Hershey, 17033, Pennsylvania, USA

    Wafik S El-Deiry

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Vasekar, M., Allen, J.E., Joudeh, J., Claxton, D. (2013). Emerging Molecular Therapies for the Treatment of Acute Lymphoblastic Leukemia. In: El-Deiry, W. (eds) Impact of Genetic Targets on Cancer Therapy. Advances in Experimental Medicine and Biology, vol 779. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6176-0_16

Download citation

Publish with us

Policies and ethics

Search

Navigation