Skip to main content

Advertisement

SpringerLink
Log in

Novel Targets for Treatment of Adult Acute Lymphocytic Leukemia

  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

The treatment of acute lymphocytic leukemia (ALL) results in long-term disease-free survival in only 30–40% of adults. Conventional chemotherapy is toxic and woefully ineffective. Therefore, novel agents are being investigated. Among these agents are monoclonal antibodies such as rituximab, epratuzumab, and alemtuzumab and targeted therapies such as tyrosine kinase inhibitors, mTOR inhibitors, and mitogen-activated protein kinase (MEK) inhibitors. This article discusses such novel targets for the treatment of ALL.

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

Notes

  1. Being withdrawn from the market and will be available only in the setting of studies.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Fielding A: The treatment of adults with acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2008, 381–389.

  2. Fielding AK, Richards SM, Chopra R, et al.: Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 2007, 109:944–950.

    Article  CAS  PubMed  Google Scholar 

  3. Hansel TT, Kropshofer H, Singer T, et al.: The safety and side effects of monoclonal antibodies. Nat Rev Drug Discov 2010, 9:325–338.

    Article  CAS  PubMed  Google Scholar 

  4. Thomas DA, O’Brien S, Jorgensen JL, et al.: Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia. Blood 2009,113, 6330–6337.

    Article  CAS  PubMed  Google Scholar 

  5. Thomas DA, Faderl S, O’Brien S, 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):1569–1580.

    Article  CAS  PubMed  Google Scholar 

  6. Wang M, Fayad L, Cabanillas F, et al.: Phase 2 trial of rituximab plus hyper-CVAD alternating with rituximab plus methotrexate-cytarabine for relapsed or refractory aggressive mantle cell lymphoma. Cancer 2008, 113(10):2734–2741.

    Article  CAS  PubMed  Google Scholar 

  7. Johann Wolfgang Goethe University Hospitals: Trial for treatment of adult patients with standard risk acute lymphoblastic leukemia with chemotherapy and rituximab. In ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine. Available at http://clinicaltrials.gov/ct2/show/NCT00199004. Accessed July 9, 2010. NLM Identifier: NCT00199004.

  8. M.D. Anderson Cancer Center: Modified Hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, and dexamethasone) program for acute lymphoblastic leukemia. In ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine. Available at http://clinicaltrials.gov/ct2/show/NCT00671658. Accessed July 9, 2010. NLM Identifier: NCT00671658.

  9. Johann Wolfgang Goethe University Hospitals: German multicenter trial for treatment of elderly patients with newly diagnosed acute lymphoblastic leukemia. In ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine. Available at http://clinicaltrials.gov/ct2/show/NCT00198978. Accessed July 9, 2010. NLM Identifier: NCT00198978.

  10. University College London Hospitals: Standard chemotherapy with or without nelarabine or epratuzumab and/or rituximab in treating patients with newly diagnosed acute lymphoblastic leukemia. In ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine. Available at http://clinicaltrials.gov/ct2/show/NCT01085617. Accessed July 9, 2010. NLM Identifier: NCT01085617.

  11. Lajaunias F, Nitschke L, Moll T, et al.: Differentially regulated expression and function of CD22 in activated B-1 and B-2 lymphocytes. J Immunol 2002, 168, 6078–6083.

    CAS  PubMed  Google Scholar 

  12. Coleman M, Goldenberg DM, Siegel AB, et al.: Epratuzumab: targeting B-cell malignancies through CD22. Clin Cancer Res 2003, 9:3991S–3394S.

    CAS  PubMed  Google Scholar 

  13. Raetz EA, Cairo MS, Borowitz MJ, 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, 26:3756–3762.

    Article  CAS  PubMed  Google Scholar 

  14. Southwest Oncology Group; National Cancer Institute (NCI): Epratuzumab, cytarabine, and clofarabine in treating patients with relapsed or refractory acute lymphoblastic leukemia. In ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine. Available at http://clinicaltrials.gov/ct2/show/NCT00945815. Accessed July 9, 2010. NLM Identifier: NCT00945815.

  15. Hu Y, Turner MJ, Shields J, et al.: Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 2009, 128, 260–270.

    Article  CAS  PubMed  Google Scholar 

  16. Robak T: Alemtuzumab for B-cell chronic lymphocytic leukemia. Expert Rev Anticancer Ther 2008, 8:1033–1051.

    Article  CAS  PubMed  Google Scholar 

  17. Weidmann E, Hess G, Chow KU, et al.: A phase II study of alemtuzumab, fludarabine, cyclophosphamide, and doxorubicin (Campath-FCD) in peripheral T-cell lymphomas. Leuk Lymphoma 2010, 51:447–455.

    Article  CAS  PubMed  Google Scholar 

  18. ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine. Available at http://clinicaltrials.gov/.

  19. Nabhan C, Patton D, Gordon LI, et al.: A pilot trial of rituximab and alemtuzumab combination therapy in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL). Leuk Lymphoma 2004, 45:2269–2273.

    Article  CAS  PubMed  Google Scholar 

  20. 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) [abstract]. Blood (ASH Annual Meeting Abstracts) 2009, 114: Abstract 838.

  21. Horton HM, Bernett MJ, Pong E, et al.: Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia. Cancer Res 2008, 68:8049–8057.

    Article  CAS  PubMed  Google Scholar 

  22. Scott and White Hospital & Clinic; National Cancer Institute (NCI): DT2219ARL immunotoxin in treating patients with B-cell leukemia or lymphoma that has relapsed or not responded to treatment. In ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine. Available at http://clinicaltrials.gov/ct2/show/NCT00889408. Accessed July 9, 2010. NLM Identifier: NCT00889408.

  23. Masonic Cancer Center, University of Minnesota: Yttrium Y 90 anti-CD19 antibody BU-12 in patients with advanced relapsed or refractory acute lymphoblastic leukemia or chronic lymphocytic leukemia. In ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine. Available at http://clinicaltrials.gov/ct2/show/NCT00643240. Accessed July 9, 2010. NLM Identifier: NCT00643240.

  24. Papayannidis C, Derenzini E, Iacobucci I, et al.: Successful combination treatment of clofarabine, cytarabine, and gemtuzumab-ozogamicin in adult refractory B-acute lymphoblastic leukemia. Am J Hematol 2009, 84:849–850.

    Article  CAS  PubMed  Google Scholar 

  25. • Armstrong F, Brunet de la Grange P, Gerby B, et al.: NOTCH is a key regulator of human T-cell acute leukemia initiating cell activity. Blood 2009, 113:1730–1740. This paper reviews the role of NOTCH and further elucidates the mechanisms of its pathogenesis in T-cell ALL.

  26. Tanigaki K, Honjo T: Regulation of lymphocyte development by Notch signaling. Nat Immunol 2007, 8:451–456.

    Article  CAS  PubMed  Google Scholar 

  27. Weng AP, Ferrando AA, Lee W, et al.: Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004, 306:269–271.

    Article  CAS  PubMed  Google Scholar 

  28. Palomero T, Ferrando A: Therapeutic targeting of NOTCH1 signaling in T-cell acute lymphoblastic leukemia. Clin Lymphoma Myeloma 2009, 9(Suppl 3):S205–S210.

    CAS  PubMed  Google Scholar 

  29. Real PJ, Ferrando AA: NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia 2009, 23:1374–1377.

    Article  CAS  PubMed  Google Scholar 

  30. Real PJ, Tosello V, Palomero T, et al.: Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med 2009, 15:50–58.

    Article  CAS  PubMed  Google Scholar 

  31. Cullion K, Draheim KM, Hermance N, et al.: Targeting the Notch1 and mTOR pathways in a mouse T-ALL model. Blood 2009, 113:6172–6181.

    Article  CAS  PubMed  Google Scholar 

  32. De Keersmaecker K, Lahortiga I, Mentens N, et al.: In vitro validation of gamma-secretase inhibitors alone or in combination with other anti-cancer drugs for the treatment of T-cell acute lymphoblastic leukemia. Haematologica 2008, 93:533–542.

    Article  PubMed  Google Scholar 

  33. Frémin C, Meloche S: From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J Hematol Oncol 2010, 3:8.

    Article  PubMed  Google Scholar 

  34. Bhalla S, Gartenhaus R, Dai B, et al.: The novel 2nd generation small molecule MEK inhibitor, AZD-6244, induces cell death in lymphoma cells lines, primary cells, and in a human lymphoma xenograft model [abstract]. Blood (ASH Annual Meeting Abstracts) 2009, 114:Abstract 285.

  35. Gokbuget N, Hoelzer D: Treatment of adult acute lymphoblastic leukemia. Semin Hematol 2009, 46:64–75.

    Article  PubMed  Google Scholar 

  36. Gautschi O, Heighway J, Mack PC, et al.: Aurora kinases as anticancer drug targets. Clin Cancer Res 2008, 14:1639–1648.

    Article  CAS  PubMed  Google Scholar 

  37. Ansell SM, Inwards DJ, Rowland KM Jr, et al.: Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: a phase 2 trial in the North Central Cancer Treatment Group. Cancer 2008, 113:508–514.

    Article  CAS  PubMed  Google Scholar 

  38. Atkins MB, Hidalgo M, Stadler WM, et al.: Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004, 22:909–918.

    Article  CAS  PubMed  Google Scholar 

  39. Bjornsti MA, Houghton PJ: The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004, 4:335–348.

    Article  CAS  PubMed  Google Scholar 

  40. Beuvink I, Boulay A, Fumagalli S, et al.: The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 2005, 120:747–759.

    Article  CAS  PubMed  Google Scholar 

  41. Brown VI, Fang J, Alcorn K, et al.: Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc Natl Acad Sci U S A 2003, 100:15113–15118.

    Article  CAS  PubMed  Google Scholar 

  42. Majewski M, Korecka M, Kossev P, et al.: The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo: A potential approach to prevention and treatment of posttransplant lymphoproliferative disorders. Proc Natl Acad Sci U S A 2000, 97:4285–4290.

    Article  CAS  PubMed  Google Scholar 

  43. Xu Q, Simpson SE, Scialla TJ, et al.: Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 2003, 102:972–980.

    Article  CAS  PubMed  Google Scholar 

  44. Teachey DT, Obzut DA, Cooperman J, et al.: The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood 2006, 107:1149–1155.

    Article  CAS  PubMed  Google Scholar 

  45. • Teachey DT, Sheen C, Hall J, et al.: mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia. Blood 2008, 112:2020–2023. This paper demonstrates the synergy between MTIs and chemotherapy. It is the basis for ongoing trials assessing this combination in patients with ALL.

    Google Scholar 

  46. Perl AE, Kasner MT, Tsai DE, et al.: A phase I study of the mammalian target of rapamycin inhibitor sirolimus and MEC chemotherapy in relapsed and refractory acute myelogenous leukemia. Clin Cancer Res 2009, 15:6732–6739.

    Article  CAS  PubMed  Google Scholar 

  47. Elit L: CCI-779 Wyeth. Curr Opin Investig Drugs 2002, 3:1249–1253.

    CAS  PubMed  Google Scholar 

  48. Punt CJ, Boni J, Bruntsch U, et al.: Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors. Ann Oncol 2003, 14(6):931–937.

    Article  CAS  PubMed  Google Scholar 

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Thomas Jefferson University, 834 Chestnut Street, Suite 315, Philadelphia, PA, 19107, USA

    Margaret T. Kasner

Authors
  1. Margaret T. Kasner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Margaret T. Kasner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kasner, M.T. Novel Targets for Treatment of Adult Acute Lymphocytic Leukemia. Curr Hematol Malig Rep 5, 207–212 (2010). https://doi.org/10.1007/s11899-010-0064-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-010-0064-8

Keywords

Search

Navigation