Skip to main content
SpringerLink
Log in

Pharmacotherapeutic Advances in the Treatment of Acute Lymphoblastic Leukaemia in Adults

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

Abstract

Acute lymphoblastic leukaemia (ALL) in adults is a challenging malignancy in that many patients will show evidence of initial chemotherapy responsiveness but will subsequently relapse. The disease is heterogeneous and outcomes vary dramatically depending on the prognostic factors present in an individual patient. An important determinant of outcome is the age of the patient. The stunning success of therapy in paediatric ALL has led to the use of intensive paediatric regimens in adolescents and young adults with what appear to be improved outcomes. For patients who relapse or have high-risk features, blood and marrow transplantation (BMT) continues to play an important role in the therapeutic armamentarium. The use of reduced-intensity conditioning regimens for allogeneic BMT suggests that outcomes may be improved by this approach. Monoclonal antibodies are showing benefit as single agents in the relapsed setting or in combination with chemotherapy in newly diagnosed patients. In recent years, several new chemotherapeutic agents have shown promise as single agents and are being incorporated into multi-agent chemotherapy. The development of tyrosine kinase inhibitors for Philadelphia chromosome-positive leukaemias has significantly improved outcomes. The molecular revolution has led to the identification of new aberrant molecular pathways in the pathogenesis of ALL, and drugs targeting these aberrancies are in various stages of development preclinically and clinically. These developments bring the hope that therapeutic outcomes in adult ALL can begin to approach those seen in the paediatric setting.

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

Table I
Table II
Fig. 1

Similar content being viewed by others

References

  1. Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet 2008; 371(9617): 1030–43

    Article  PubMed  CAS  Google Scholar 

  2. Pui C-H, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354(2): 166–78

    Article  PubMed  CAS  Google Scholar 

  3. Fielding A. The treatment of adults with acute lymphoblastic leukemia. Hematology/Am Soc Hematol Educ Program 2008: 381–9

  4. Pulte D, Gondos A, Brenner H. Improvement in survival in younger patients with acute lymphoblastic leukemia from the 1980s to the early 21st century. Blood 2009 Feb 12; 113(7): 1408–11

    Article  PubMed  CAS  Google Scholar 

  5. Moorman AV, Harrison CJ, Buck GAN, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 2007 Apr 15; 109(8): 3189–97

    Article  PubMed  CAS  Google Scholar 

  6. Mullighan CG, Goorha S, Radtke I, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007; 446(7137): 758–64

    Article  PubMed  CAS  Google Scholar 

  7. Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH 1 in human T cell acute lymphoblastic leukemia. Science 2004 Oct 8; 306(5694): 269–71

    Article  PubMed  CAS  Google Scholar 

  8. Stock W, La M, Sanford B, et al. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children’s Cancer Group and Cancer and Leukemia Group B studies. Blood 2008 Sep 1; 112(5): 1646–54

    Article  PubMed  CAS  Google Scholar 

  9. Litzow MR. Evolving paradigms in the therapy of Philadelphia chromosome-negative acute lymphoblastic leukemia in adults. Hematology 2009 Jan 1; 2009(1): 362–70

    Article  Google Scholar 

  10. Ramanujachar R, Richards S, Hann I, et al. Adolescents with acute lymphoblastic leukaemia: emerging from the shadow of paediatric and adult treatment protocols. Pediatr Blood Cancer 2006; 47(6): 748–56

    Article  PubMed  Google Scholar 

  11. Ribera JM, Oriol A. Acute lymphoblastic leukemia in adolescents and young adults. Hematol Oncol Clin North Am 2009 Oct; 23(5): 1033–42, vi

    Article  PubMed  Google Scholar 

  12. Boissel N, Auclerc M-F, 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 Mar 1; 21(5): 774–80

    Article  PubMed  Google Scholar 

  13. de Bont JM, Holt B, Dekker AW, et al. Significant difference in outcome for adolescents with acute lymphoblastic leukemia treated on pediatric vs adult protocols in the Netherlands. Leukemia 2004 Dec; 18(12): 2032–5

    Article  PubMed  Google Scholar 

  14. Testi AM, Valsecchi MG, Conter V. Difference in outcome of adolescents with acute lymphoblastic leukemia (ALL) enrolled in pediatric (AIEOP) and adult (GIMEMA) protocols [abstract no. 1954]. Blood 2004; 104: 539

    Google Scholar 

  15. Hallböök H, Gustafsson G, Smedmyr B, et al. Treatment outcome in young adults and children >10 years of age with acute lymphoblastic leukemia in Sweden: a comparison between a pediatric protocol and an adult protocol. Cancer 2006 Oct 1; 107(7): 1551–61

    Article  PubMed  CAS  Google Scholar 

  16. 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 Mar; 48(3): 254–61

    Article  PubMed  Google Scholar 

  17. Usvasalo A, Raty R, Knuutila S, et al. Acute lymphoblastic leukemia in adolescents and young adults in Finland. Haematologica 2008 Aug; 93(8): 1161–8

    Article  PubMed  CAS  Google Scholar 

  18. Thomas DA, Rytting M, O’Brien S, et al. Outcome for adolescents and young adults (AYA) with the hyper-CVAD (with or without rituximab) regimens for de novo acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma [abstract]. Blood 2009 Nov 20; 114(22): 3084

    Google Scholar 

  19. Schiffer CA. Differences in outcome in adolescents with acute lymphoblastic leukemia: a consequence of better regimens? Better doctors? Both? J Clin Oncol 2003 Mar 1; 21(5): 760–1

    Article  PubMed  Google Scholar 

  20. Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol 2009 Feb 20; 27(6): 911–8

    Article  PubMed  CAS  Google Scholar 

  21. 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(1): 76–85

    Article  PubMed  Google Scholar 

  22. Ribera J-M, Oriol A, Sanz M-A, et al. Comparison of the results of the treatment of adolescents and young adults with standard-risk acute lymphoblastic leukemia with the Programa Espanol de Tratamiento en Hematologia pediatric-based protocol ALL-96. J Clin Oncol 2008 Apr 10; 26(11): 1843–9

    Article  PubMed  CAS  Google Scholar 

  23. National Cancer Institute. Phase II study of combination chemotherapy in adolescents and young adults with newly diagnosed acute lymphoblastic leukemia [online]. Available from URL: http://www.cancer.gov/clinicaltrials/search/view?cdrid=574230&version=HealthProfessional&protocolsearchid=8797071 [Accessed 2011 Feb 17]

  24. Sebban C, Lepage E, Vernant JP, et al. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia. J Clin Oncol 1994 Dec 1; 12(12): 2580–7

    PubMed  CAS  Google Scholar 

  25. Thomas X, Boiron J-M, Huguet F, et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol 2004 Oct 15; 22(20): 4075–86

    Article  PubMed  CAS  Google Scholar 

  26. Yanada M, Matsuo K, Suzuki T, et al. Allogeneic hematopoietic stem cell transplantation as part of postremission therapy improves survival for adult patients with high-risk acute lymphoblastic leukemia. Cancer 2006; 106(12): 2657–63

    Article  PubMed  Google Scholar 

  27. Hahn T, Wall D, Camitta B, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in adults: an evidence-based review. Biol Blood Marrow Transplant 2006; 12(1): 1–30

    Article  PubMed  CAS  Google Scholar 

  28. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2008 Feb 15; 111(4): 1827–33

    Article  PubMed  CAS  Google Scholar 

  29. Ram R, Gafter-Gvili A, Vidal L, et al. Management of adult patients with acute lymphoblastic leukemia in first complete remission. Cancer 2010; 116(14): 3447–57

    Article  PubMed  Google Scholar 

  30. Mohty M, Labopin M, Tabrizzi R, et al. Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Haematologica 2008 Feb; 93(2): 303–6

    Article  PubMed  Google Scholar 

  31. Mohty M, Labopin M, Volin L, et al. Reduced-intensity versus conventional myeloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Blood 2010 Nov 25; 116(22): 4439–43

    Article  PubMed  CAS  Google Scholar 

  32. Marks DI, Wang T, Perez WS, et al. The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission. Blood 2010 Jul 22; 116(3): 366–74

    Article  PubMed  CAS  Google Scholar 

  33. Eapen M, Rocha V, Sanz G, et al. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis. Lancet Oncol 2010 Jul; 11(7): 653–60

    Article  PubMed  Google Scholar 

  34. Ciceri F, Labopin M, Aversa F, et al. A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood 2008 Nov 1; 112(9): 3574–81

    Article  PubMed  CAS  Google Scholar 

  35. Cave H, van der Werff ten Bosch J, Suciu S, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. N Engl J Med 1998; 339(9): 591–8

    Article  PubMed  CAS  Google Scholar 

  36. Coustan-Smith E, Sancho J, Behm FG, et al. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood 2002 Jun 17; 100(1): 52–8

    Article  PubMed  CAS  Google Scholar 

  37. Bruggemann M, Raff T, Flohr T, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood 2006 Feb 1; 107(3): 1116–23

    Article  PubMed  CAS  Google Scholar 

  38. Bassan R, Spinelli O, Oldani E, et al. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood 2009 Apr 30; 113(18): 4153–62

    Article  PubMed  CAS  Google Scholar 

  39. Patel B, Rai L, Buck G, et al. Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993. Br J Haematol 2010; 148(1): 80–9

    Article  PubMed  CAS  Google Scholar 

  40. Pui CH, Jeha S. New therapeutic strategies for the treatment of acute lymphoblastic leukaemia. Nat Rev Drug Discov 2007 Feb; 6(2): 149–65

    Article  PubMed  CAS  Google Scholar 

  41. Kurtzberg J. The long and winding road of the clinical development of nelarabine. Leuk Lymphoma 2007; 48(1): 1–2

    Article  PubMed  CAS  Google Scholar 

  42. Kurtzberg J, Ernst TJ, Keating MJ, 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 May 20; 23(15): 3396–403

    Article  PubMed  CAS  Google Scholar 

  43. Berg SL, Blaney SM, Devidas M, et al. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory t-cell malignancies: a report from the Children’s Oncology Group. J Clin Oncol 2005 May 20; 23(15): 3376–82

    Article  PubMed  CAS  Google Scholar 

  44. Dunsmore K, Devidas M, Borowitz MJ, et al. Nelarabine can be safely incorporated into an intensive, multiagent chemotherapy regimen for the treatment of T-cell acute lymphocytic leukemia (ALL) in children: a report of the Children’s Oncology Group (COG) AALL00P2 protocol for T-cell leukemia [abstract]. Blood 2006 Nov 16; 108(11): 1864

    Google Scholar 

  45. DeAngelo DJ, Yu D, Johnson JL, et al. Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood 2007 Jun 15; 109(12): 5136–42

    Article  PubMed  CAS  Google Scholar 

  46. Vigil CE, Kantarjian H, Thomas DA, et al. Phase II study of hyper-CVAD followed by nelarabine consolidation in newly diagnosed patients with T cell acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LL) [abstract]. J Clin Oncol (Meeting Abstracts) 2010 May 20; 28 (15 Suppl.): 6524

    Google Scholar 

  47. Montgomery JA, Shortnacy-Fowler AT, Clayton SD, et al. Synthesis and biological activity of 2′-fluoro-2-halo derivatives of 9-beta-D-arabinofuranosyladenine. J Med Chem 1992; 35(2): 397–401

    Article  PubMed  CAS  Google Scholar 

  48. Kantarjian HM, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol 2003 Mar 15; 21(6): 1167–73

    Article  PubMed  CAS  Google Scholar 

  49. Jeha S, Gandhi V, Chan KW, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood 2004 Feb 1; 103(3): 784–9

    Article  PubMed  CAS  Google Scholar 

  50. Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood 2003 Oct 1; 102(7): 2379–86

    Article  PubMed  CAS  Google Scholar 

  51. Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol 2006 Apr 20; 24(12): 1917–23

    Article  PubMed  CAS  Google Scholar 

  52. Hijiya N, Gaynon PS, Fernandez M, et al. Durable remissions observed in a phase i/ii study of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute leukemia [abstract]. Blood 2008 Nov 16; 112(11): 2925

    Google Scholar 

  53. Cooper T, Alonzo TA, Gerbing RB, et al. AAML0523: a report from the children’s oncology group on the safety of clofarabine in combination with cytarabine in pediatric patients with relapsed acute leukemia [abstract]. Blood 2009 Nov 20; 114(22): 3076

    Google Scholar 

  54. Faderl S, Ravandi F, Huang X, et al. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodys-plastic syndrome. Blood 2008 Sep 1; 112(5): 1638–45

    Article  PubMed  CAS  Google Scholar 

  55. Kaasgaard T, Andresen TL. Liposomal cancer therapy: exploiting tumor characteristics. Expert Opin Drug Deliv 2010; 7(2): 225–43

    Article  PubMed  CAS  Google Scholar 

  56. Krishna R, Webb MS, St Onge G, et al. Liposomal and nonliposomal drug pharmacokinetics after administration of liposome-encapsulated vincristine and their contribution to drug tissue distribution properties. J Pharmacol Exp Ther 2001 Sep 1; 298(3): 1206–12

    PubMed  CAS  Google Scholar 

  57. Mayer LD, Bally MB, Loughrey H, et al. Liposomal vincristine preparations which exhibit decreased drug toxicity and increased activity against murine L1210 and P388 tumors. Cancer Res 1990 Feb 1; 50(3): 575–9

    PubMed  CAS  Google Scholar 

  58. Gelmon KA, Tolcher A, Diab AR, et al. Phase I study of liposomal vincristine. J Clin Oncol 1999 Feb 1; 17(2): 697–705

    PubMed  CAS  Google Scholar 

  59. Sarris AH, Hagemeister F, Romaguera J, et al. Liposomal vincristine in relapsed non-Hodgkin’s lymphomas: early results of an ongoing phase II trial. Ann Oncol 2000 Jan 1; 11(1): 69–72

    Article  PubMed  CAS  Google Scholar 

  60. Thomas DA, Sarris AH, Cortes J, et al. Phase II study of sphingosomal vincristine in patients with recurrent or refractory adult acute lymphocytic leukemia. Cancer 2006; 106(1): 120–7

    Article  PubMed  CAS  Google Scholar 

  61. O’Brien SM, Aulitzky W, Ben Yehuda D, et al. Phase II study of marqibo in adult patients with refractory or relapsed philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) [abstract]. J Clin Oncol (Meeting Abstracts) 2010 May 20; 28 (15 Suppl.): 6507

    Google Scholar 

  62. Thomas DA, Kantarjian HM, Stock W, et al. Phase 1 multicenter study of vincristine sulfate liposomes injection and dexamethasone in adults with relapsed or refractory acute lymphoblastic leukemia. Cancer 2009; 115(23): 5490–8

    Article  PubMed  CAS  Google Scholar 

  63. Glantz MJ, LaFollette S, Jaeckle KA, et al. Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 1999 Oct 1; 17(10): 3110–6

    PubMed  CAS  Google Scholar 

  64. Kim S, Kim DJ, Geyer MA, et al. Multivesicular liposomes containing 1-beta-D-arabinofuranosylcytosine for slow-release intrathecal therapy. Cancer Res 1987 Aug 1; 47(15): 3935–7

    PubMed  CAS  Google Scholar 

  65. Chamberlain MC, Kormanik P, Howell SB, et al. Pharmacokinetics of intralumbar DTC-101 for the treatment of leptomeningeal metastases. Arch Neurol 1995 Sep 1; 52(9): 912–7

    Article  PubMed  CAS  Google Scholar 

  66. Zimm S, Collins JM, Miser J, et al. Cytosine arabinoside cerebrospinal fluid kinetics. Clin Pharmacol Ther 1984 Jun; 35(6): 826–30

    Article  PubMed  CAS  Google Scholar 

  67. Bleyer WA. Intrathecal depot cytarabine therapy: a welcome addition to a limited armamentarium. Clin Cancer Res 1999 Nov; 5(11): 3349–51

    PubMed  CAS  Google Scholar 

  68. Goekbuget N, Hartog CM, Bassan R, et al. Liposomal cytarabine is effective and tolerable in the treatment of central nervous system relapse of acute lymphoblastic leukemia and very aggressive lymphoma. Haematologica 2011 Feb; 96(2): 238–44

    Article  CAS  Google Scholar 

  69. Jabbour E, O’Brien S, Kantarjian H, et al. Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia. Blood 2007 Apr 15; 109(8): 3214–8

    Article  PubMed  CAS  Google Scholar 

  70. Thomas DA, Jabbour E, Kantarjian H, et al. Neurologic toxicity of intrathecal liposomal cytarabine when used for CNS prophylaxis in conjunction with the hyper-CVAD regimen. Blood 2007 Sep 1; 110(5): 1698-1a-9

    Article  Google Scholar 

  71. Chamberlain MC, Glantz MJ. Re: neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia [letter]. Blood 2007 Sep 1; 110(5): 1698

    Article  PubMed  CAS  Google Scholar 

  72. Pui CH. Toward optimal use of intrathecal liposomal cytarabine. Leuk Lymphoma 2007; 48(9): 1672–3

    Article  PubMed  Google Scholar 

  73. Ferrando AA. The role of NOTCH1 signaling in T-ALL. Hematology 2009 Jan 1; 2009(1): 353–61

    Article  Google Scholar 

  74. Deangelo DJ, Stone RM, Silverman LB, 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 [abstract]. J Clin Oncol (Meeting Abstracts) 2006 Jun 20; 24 (18 Suppl.): 6585

    Google Scholar 

  75. Real PJ, Tosello V, Palomero T, et al. Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med 2009; 15(1): 50–8

    Article  PubMed  CAS  Google Scholar 

  76. Wei P, Walls M, Qiu M, et al. Evaluation of selective γ-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Mol Cancer Ther 2010 Jun 1; 9(6): 1618–28

    Article  PubMed  CAS  Google Scholar 

  77. Furman R, Hoelzer DH. Purine nucleoside phosphorylase inhibition as a novel therapeutic approach for B-cell lymphoid malignancies. Semin Oncol 2007; 34 (6 Suppl. 5): S29–34

    Article  PubMed  CAS  Google Scholar 

  78. Furman RR, 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) [abstract]. Blood 2006 Nov 16; 108(11): 1851

    Google Scholar 

  79. Bueso-Ramos C, Xu Y, McDonnell TJ, et al. Protein expression of a triad of frequently methylated genes, p73, p57Kip2, and p15, has prognostic value in adult acute lymphocytic leukemia independently of its methylation status. J Clin Oncol 2005 Jun 10; 23(17): 3932–9

    Article  PubMed  CAS  Google Scholar 

  80. Zheng S, Ma X, Zhang L, et al. Hypermethylation of the 5’ CpG island of the FHIT gene is associated with hyper-diploid and translocation-negative subtypes of pediatric leukemia. Cancer Res 2004 Mar 15; 64(6): 2000–6

    Article  PubMed  CAS  Google Scholar 

  81. Hui Y, Koyu H, Blanca S-G, et al. Antileukemia activity of the combination of 5-aza-2’-deoxycytidine with valproic acid. Leuk Res 2005; 29(7): 739–48

    Article  CAS  Google Scholar 

  82. Yanez L, Bermudez A, Richard C, et al. Successful induction therapy with decitabine in refractory childhood acute lymphoblastic leukemia. Leukemia 2009; 23(7): 1342–3

    Article  PubMed  CAS  Google Scholar 

  83. Garcia-Manero G, Thomas D, Rytting M, et al. A phase 1 study of dose-dense 5-aza-2’-deoxycitidine (decitabine) in relapse refractory acute lymphocytic leukemia (ALL) [abstract]. Blood 2009 Nov 20; 114(22): 2030

    Google Scholar 

  84. Borowitz MJ, Shuster J, Carroll AJ, 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 Jun 1; 89(11): 3960–6

    PubMed  CAS  Google Scholar 

  85. Jeha S, Behm F, Pei D, et al. Prognostic significance of CD20 expression in childhood B-cell precursor acute lymphoblastic leukemia. Blood 2006 Nov 15; 108(10): 3302–4

    Article  PubMed  CAS  Google Scholar 

  86. 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 Jun 18; 113(25): 6330–7

    Article  PubMed  CAS  Google Scholar 

  87. Maury S, Huguet F, Leguay T, et al. Adverse prognostic significance of CD20 expression in adults with Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia. Haematologica 2009 Feb 1, 2010; 95(2): 324–8

    Article  PubMed  Google Scholar 

  88. Maloney DG, Smith B, Rose A. Rituximab: mechanism of action and resistance. Semin Oncol 2002 Feb; 29 (1 Suppl. 2): 2–9

    Article  PubMed  CAS  Google Scholar 

  89. Coiffier B, Lepage E, Brie`re J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346(4): 235–42

    Article  PubMed  CAS  Google Scholar 

  90. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006 Jul 1; 24(19): 3121–7

    Article  PubMed  CAS  Google Scholar 

  91. 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 Apr 1; 106(7): 1569–80

    Article  PubMed  CAS  Google Scholar 

  92. Thomas DA, O’Brien S, Faderl S, 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 Aug 20; 28(24): 3880–9

    Article  PubMed  CAS  Google Scholar 

  93. Hoelzer DH, Huettmann AM, Kaul FK, et al. Immunochemotherapy with rituximab in adult CD20+ B-precursor ALL improves molecular CR rate and outcome in standard-risk as well as in high-risk patients with SCT [abstract no. 0481]. Haematologica 2009; 94(2): 195

    Article  CAS  Google Scholar 

  94. Dworzak MN, Schumich A, Printz D, 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 Nov 15; 112(10): 3982–8

    Article  PubMed  CAS  Google Scholar 

  95. Coleman M, Goldenberg DM, Siegel AB, et al. Epratuzumab. Clin Cancer Res 2003 Sep 1; 9(10): 3991–4s

    Google Scholar 

  96. Carnahan J, Stein R, Qu Z, et al. Epratuzumab, a CD22-targeting recombinant humanized antibody with a different mode of action from rituximab. Mol Immunol 2007 Feb; 44(6): 1331–41

    Article  PubMed  CAS  Google Scholar 

  97. Leonard JP, Coleman M, Ketas JC, et al. Epratuzumab, a humanized anti-CD22 antibody, in aggressive non-Hodgkin’s lymphoma. Clin Cancer Res 2004 Aug 15; 10(16): 5327–34

    Article  PubMed  CAS  Google Scholar 

  98. Micallef IN, Maurer MJ, Nikcevich DA, et al. A phase II study of epratuzumab and rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy (ER-CHOP) in patients with previously untreated diffuse large B-cell lymphoma [abstract]. J Clin Oncol (Meeting Abstracts) 2008 May 20; 26 (15 Suppl.): 8500

    Google Scholar 

  99. 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 Aug 1; 26(22): 3756–62

    Article  PubMed  CAS  Google Scholar 

  100. Wayne AS, Kreitman RJ, Findley HW, et al. Anti-CD22 immunotoxin RFB4(dsFv)-PE38 (BL22) for CD22-positive hematologic malignancies of childhood: preclinical studies and phase I clinical trial. Clin Cancer Res 2010 Mar 15; 16(6): 1894–903

    Article  PubMed  CAS  Google Scholar 

  101. Wayne AS, Bhojwani D, Jeha S, et al. Phase I clinical trial of the anti-CD22 immunotoxin CAT-8015 (HA22) for pediatric acute lymphoblastic leukemia (ALL) [abstract]. Blood 2009 Nov 20; 114(22): 839

    Google Scholar 

  102. Wong BY, Dang NH. Inotuzumab ozogamicin as novel therapy in lymphomas. Expert Opin Biol Ther 2010; 10(8): 1251–8

    Article  PubMed  CAS  Google Scholar 

  103. Dang NH, Smith MR, Offner F, et al. Anti-CD22 immunoconjugate inotuzumab ozogamicin (CMC-544)+ rituximab: clinical activity including survival in patients with recurrent/refractory follicular or ‘aggressive’ lymphoma [abstract]. Blood 2009 Nov 20; 114(22): 584

    Google Scholar 

  104. Vallera D, Hua C, Andrew RS, et al. Genetic alteration of a bispecific ligand-directed toxin targeting human CD19 and CD22 receptors resulting in improved efficacy against systemic B cell malignancy. Leuk Res 2009; 33(9): 1233–42

    Article  PubMed  CAS  Google Scholar 

  105. Keating MJ, O’Brien S, Ferrajoli A. Alemtuzumab: a novel monoclonal antibody. Expert Opin Biol Ther 2001; 1(6): 1059–65

    Article  PubMed  Google Scholar 

  106. Tibes R, Keating MJ, Ferrajoli A, et al. Activity of alemtuzumab in patients with CD52-positive acute leukemia. Cancer 2006; 106(12): 2645–51

    Article  PubMed  CAS  Google Scholar 

  107. 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

    Article  PubMed  CAS  Google Scholar 

  108. 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 2009 Nov 20; 114(22): 838

    Google Scholar 

  109. Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res 2009 Jun 15; 69(12): 4941–4

    Article  PubMed  CAS  Google Scholar 

  110. Nagorsen D, Bargou R, Ruttinger D, et al. Immunotherapy of lymphoma and leukemia with T-cell engaging BiTE antibody blinatumomab. Leuk Lymphoma 2009 Jun; 50(6): 886–91

    Article  PubMed  CAS  Google Scholar 

  111. Nagorsen D, Zugmaier G, Viardot A, et al. Confirmation of safety, efficacy and response duration in non-Hodgkin lymphoma patients treated with 60 mcg/m2/d of BiTE(R) antibody blinatumomab [abstract]. Blood 2009 Nov 20; 114(22): 2723

    Google Scholar 

  112. Topp MS, Zugmaier G, Goekbuget N, et al. Report of a phase II trial of single-agent BiTE(R) antibody blinatumomab in patients with minimal residual disease (MRD) positive B-precursor acute lymphoblastic leukemia (ALL) [abstract]. Blood 2009 Nov 20; 114(22): 840

    Google Scholar 

  113. Stock W. Current treatment options for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Leuk Lymphoma 2010; 51(2): 188–98

    Article  PubMed  CAS  Google Scholar 

  114. Fielding AK, Rowe JM, Richards SM, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood 2009 May 7; 113(19): 4489–96

    Article  PubMed  CAS  Google Scholar 

  115. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001 Apr 5; 344(14): 1038–42

    Article  PubMed  CAS  Google Scholar 

  116. O’Brien SG, Guilhot Fo, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348(11): 994–1004

    Article  PubMed  Google Scholar 

  117. Ottmann OG, Druker BJ, Sawyers CL, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 2002 Aug 28; 100(6): 1965–71

    Article  PubMed  CAS  Google Scholar 

  118. Vignetti M, Fazi P, Cimino G, et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B protocol. Blood 2007 May 1; 109(9): 3676–8

    Article  PubMed  CAS  Google Scholar 

  119. Ottmann OG, Wassmann B, Pfeifer H, et al. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Cancer 2007; 109(10): 2068–76

    Article  PubMed  CAS  Google Scholar 

  120. Yanada M, Takeuchi J, Sugiura I, et al. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 2006 Jan 20; 24(3): 460–6

    Article  PubMed  CAS  Google Scholar 

  121. Hatta Y, Mizuta S, Ohtake S, et al. Promising outcome of imatinib-combined chemotherapy followed by allogeneic hematopoietic stem cell transplantation for philadelphia chromosome-positive acute lymphoblastic leukemia: results of the Japan Adult Leukemia Study Group (JALSG) Ph+ALL202 regimen [abstract]. Blood 2009 Nov 20; 114(22): 3090

    Google Scholar 

  122. Thomas DA, O’Brien SM, Faderl S, et al. Long-term outcome after hyper-CVAD and imatinib (IM) for de novo or minimally treated Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL) [abstract]. J Clin Oncol (Meeting Abstracts) 2010 May 20; 28 (15 Suppl.): 6506

    Google Scholar 

  123. Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a Children’s Oncology Group Study. J Clin Oncol 2009 Nov 1; 27(31): 5175–81

    Article  PubMed  CAS  Google Scholar 

  124. Dombret H, Gabert J, Boiron J-M, et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 trial. Blood 2002 Sep 18; 100(7): 2357–66

    Article  PubMed  CAS  Google Scholar 

  125. Yanada M, Sugiura I, Takeuchi J, et al. Prospective monitoring of BCR-ABL1 transcript levels in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia undergoing imatinib-combined chemotherapy. Br J Haematol 2008; 143(4): 503–10

    PubMed  Google Scholar 

  126. Carpenter PA, Snyder DS, Flowers MED, et al. Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood 2007 Apr 1; 109(7): 2791–3

    PubMed  CAS  Google Scholar 

  127. Wassmann B, Pfeifer H, Stadler M, et al. Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 2005 Jul 15; 106(2): 458–63

    Article  PubMed  CAS  Google Scholar 

  128. Ribera J-M, Oriol A, Gonzalez M, et al. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: final results of the CSTIBES02 trial. Haematologica 2010 Jan 1; 95(1): 87–95

    Article  PubMed  CAS  Google Scholar 

  129. Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004 Jul 16; 305(5682): 399–401

    Article  PubMed  CAS  Google Scholar 

  130. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in im-atinib-resistant Philadelphia chromosome-positive leuke-mias. N Engl J Med 2006; 354(24): 2531–41

    Article  PubMed  CAS  Google Scholar 

  131. Ottmann O, Dombret H, Martinelli G, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood 2007 Oct 1; 110(7): 2309–15

    Article  PubMed  CAS  Google Scholar 

  132. Porkka K, Koskenvesa P, Lundan T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood 2008 Aug 15; 112(4): 1005–12

    Article  PubMed  CAS  Google Scholar 

  133. Foa R, Vitale A, Guarini A, et al. Line treatment of adult Ph+ acute lymphoblastic leukemia (ALL) patients: final results of the GIMEMA LAL1205 study [abstract]. Blood 2008 Nov 16; 112(11): 305

    Google Scholar 

  134. Ravandi F, O’Brien S, Thomas D, et al. First report of phase II study of dasatinib with hyperCVAD for the frontline treatment of patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Blood 2010 Sep; 116(12): 2070–7

    Article  PubMed  CAS  Google Scholar 

  135. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005 Feb; 7(2): 129–41

    Article  PubMed  CAS  Google Scholar 

  136. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006; 354(24): 2542–51

    Article  PubMed  Google Scholar 

  137. Larson R, Ottman O, Kantarjian H, et al. A phase II study of nilotinib administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL) [abstract]. J Clin Oncol (Meeting Abstracts) 2007 Jun 20; 25 (18 Suppl.): 7040

    Google Scholar 

  138. Naka K, Hoshii T, Hirao A. Novel therapeutic approach to eradicate tyrosine kinase inhibitor resistant chronic myeloid leukemia stem cells. Cancer Sci 2010; 101(7): 1577–81

    Article  PubMed  CAS  Google Scholar 

  139. Schenone S, Brullo C, Musumeci F, et al. Novel dual Src/Abl inhibitors for hematologic and solid malignancies. Expert Opin Investig Drugs 2010; 19(8): 931–45

    Article  PubMed  CAS  Google Scholar 

  140. Martinelli G, Iacobucci I, Papayannidis C, et al. New targets for Ph+ leukaemia therapy. Best Pract Res Clin Haematol 2009 Sep; 22(3): 445–54

    Article  PubMed  CAS  Google Scholar 

  141. Fielding AK. How I treat Philadelphia chromosome positive acute lymphoblastic leukaemia. Blood 2010 Nov 4; 116(18): 3409–17

    Article  PubMed  CAS  Google Scholar 

  142. Abdel-Karim I, Plunkett W, O’Brien S, et al. A phase I study of pemetrexed in patients with relapsed or refractory acute leukemia. Invest New Drugs 2011 Apr; 29(2): 323–31

    Article  PubMed  CAS  Google Scholar 

  143. Giles F, Rizzieri DA, George S, et al. A phase I study of Talvesta(R) (talotrexin) in relapsed or refractory leukemia or myelodysplastic syndrome [abstract]. Blood 2006 Nov 16; 108(11): 1968

    Google Scholar 

  144. Blum W, Phelps MA, Klisovic RB, et al. Phase I clinical and pharmacokinetic study of a novel schedule of flavo-piridol in relapsed or refractory acute leukemias. Haematologica 2010 Jul 1; 95(7): 1098–105

    Article  PubMed  CAS  Google Scholar 

  145. Karp JE, Passaniti A, Gojo I, et al. Phase I and pharmacokinetic study of flavopiridol followed by 1-beta-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias. Clin Cancer Res 2005 Dec 1; 11(23): 8403–12

    Article  PubMed  CAS  Google Scholar 

  146. Houghton PJ, Morton CL, Kolb EA, et al. Initial testing (stage 1) of the proteasome inhibitor bortezomib by the pediatric preclinical testing program. Pediatr Blood Cancer 2008; 50(1): 37–45

    Article  PubMed  Google Scholar 

  147. Cortes J, Thomas D, Koller C, et al. Phase I study of bortezomib in refractory or relapsed acute leukemias. Clin Cancer Res 2004 May 15; 10(10): 3371–6

    Article  PubMed  CAS  Google Scholar 

  148. Horton TM, Pati D, Plon SE, 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 Mar 1; 13(5): 1516–22

    Article  PubMed  CAS  Google Scholar 

  149. Messinger Y, Gaynon P, Raetz E, et al. Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): a report from the Therapeutic Advances in Childhood Leukemia (TACL) consortium. Pediatr Blood Cancer 2010; 55(2): 254–9

    Article  PubMed  Google Scholar 

  150. 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 Dec 9; 100(25): 15113–8

    Article  PubMed  CAS  Google Scholar 

  151. Crazzolara R, Bradstock KF, Bendall LJ. RAD001 (everolimus) induces autophagy in acute lymphoblastic leukemia. Autophagy 2009 Jul; 5(5): 727–8

    Article  PubMed  CAS  Google Scholar 

  152. Hasegawa H, Yamada Y, Iha H, 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

    Article  PubMed  CAS  Google Scholar 

  153. Rambal AA, Panaguiton ZLG, Kramer L, et al. MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM. Leukemia 2009; 23(10): 1744–54

    Article  PubMed  CAS  Google Scholar 

  154. Lin Y-W, Beharry ZM, Hill EG, et al. A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. Blood 2010 Jan 28; 115(4): 824–33

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

No sources of funding were used to assist in the preparation of this review. The author has received consulting fees from Talon Therapeutics, the makers of vincristine sulfate liposomes injection. The author gratefully acknowledges Ms Denise Chase for transcription of the manuscript.

Author information

Authors and Affiliations

  1. Department of Hematology, Mayo Clinic, 200 First St. SW, Rochester, Minnesota, 55905, USA

    Mark R. Litzow

Authors
  1. Mark R. Litzow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark R. Litzow.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Litzow, M.R. Pharmacotherapeutic Advances in the Treatment of Acute Lymphoblastic Leukaemia in Adults. Drugs 71, 415–442 (2011). https://doi.org/10.2165/11588950-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11588950-000000000-00000

Keywords

Search

Navigation