Drugs

, Volume 65, Issue 16, pp 2405–2427

Gemtuzumab Ozogamicin

A Review of its Use in Acute Myeloid Leukaemia
Adis Drug Evaluation

Summary

Abstract

Gemtuzumab ozogamicin (Mylotarg®) is a conjugate of a monoclonal antibody and calicheamicin, which targets the membrane antigen CD33 in CD33-positive acute myeloid leukaemia (AML) and, after cell internalisation, releases a derivative of the cytotoxic calicheamicin component. In the US, it is approved as monotherapy in patients aged ≥60 years with a first relapse of AML who are ineligible for other cytotoxic therapy.

Monotherapy with gemtuzumab ozogamicin results in complete remission (CR) or CR with incomplete platelet recovery (CRp) in ≈25% of adults (including those aged ≥60 years) with CD33-positive AML in first relapse. Preliminary data indicate a potential role for gemtuzumab ozogamicin as a component of induction or consolidation regimens in adults and, based on an early study, in the treatment of children with AML, although randomised, controlled studies are needed. Serious adverse events, notably hepatotoxicity, characterise its tolerability profile, but gemtuzumab ozogamicin is comparatively well tolerated by most patients. Gemtuzumab ozogamicin is a valuable new treatment option for patients aged ≥60 years with CD33-positive AML in first relapse for whom other cytotoxic chemotherapy is not considered appropriate; patients with a first CR (CR1) of >12 months are likely to have the best outcome.

Pharmacological Properties

Gemtuzumab ozogamicin is a humanised monoclonal antibody conjugated to a cytotoxic calicheamicin derivative, which targets the CD33 antigen expressed by leukaemic blasts in most patients with AML. After internalisation by the leukaemic cell, the linker between the antibody and calicheamicin is hydrolysed, calicheamicin dimethyl hydrazide is released and reduced; the reduced species binds to DNA in the minor groove, causing site-specific double-stranded breaks and cell death.

In vitro, gemtuzumab ozogamicin displays good activity against certain CD33+ AML cell lines. At low concentrations (0.01–0.025 ng/mL), in vitro sensitivity of AML cells to gemtuzumab ozogamicin correlates with CD33 expression, but at high concentrations (1–10 μg/mL), CD33-independent uptake may occur. Various gemtuzumab ozogamicin resistance mechanisms have been suggested, including cell escape because of surface antigen expression or cell cycle phase, expression of proteins causing drug efflux, altered signalling pathways, antiapoptotic expression and patient antigen load. Sensitivity to gemtuzumab ozogamicin can be enhanced in vitro by ciclosporin, an inhibitor of p-glycoprotein-mediated drug efflux. In patients, a clinical response is inversely correlated with peripheral blood antigen load and drug efflux ratios, and is not predicted by pharmacokinetic parameters.

The maximum plasma concentrations of the CD33 antibody (hP67.6) and calicheamicin occur shortly after the end of the intravenous infusion of gemtuzumab ozogamicin. Distribution is mainly within plasma and antibody distribution in bone marrow, spleen and liver occurred in radiolabelling studies. The pharmacokinetic parameters of gemtuzumab ozogamicin differ after the first and second doses and vary widely between patients, particularly after the first dose; however, they do not depend on age or gender. The calicheamicin derivative remains conjugated in plasma and hP67.6 is believed to be eliminated from plasma mainly by binding to CD33 expressed on peripheral blast cells.

Therapeutic Efficacy

The clinical efficacy of gemtuzumab ozogamicin has been evaluated in noncomparative trials in adults. In a pooled analysis of three trials, one to three doses of gemtuzumab ozogamicin 9 mg/m2 monotherapy 14–28 days apart, each administered as a 2-hour intravenous infusion, resulted in CR in 13% of 277 patients with a first relapse of primary AML and CRp in another 13%, giving an overall remission (OR) rate of 26%. CR and CRp rates in patients aged ≥60 years, representing 57% of the trial population, were 12% and 12%. The OR rate was 34% in patients with a CR1 of ≥1 year and 11 % in those with a CR1 of ≤6 m onths. Median relapse-free survival for all those in OR was 5.2 months. Median overall survival was almost 5 months for the total patient population, and was >1 year in those patients achieving CR or CRp; overall survival was longer in patients in CR or CRp who proceeded to haematopoietic stem cell transplantation (HSCT) than in those receiving no further treatment.

In a dose-finding noncomparative trial in 29 children (median age 12 years) with relapsed or refractory AML, 14% achieved CR and 14% CRp after one or two gemtuzumab ozogamicin doses of 6–9 mg/m2, but dose-limiting toxicity occurred.

Early-phase trials of gemtuzumab ozogamicin in combination therapy regimens, usually with cytarabine and anthracyclines, resulted in CR rates of 35–83% in adults with primary and secondary AML, including those aged >60 years and, in a consolidation regimen, maintenance of remission in 32% of patients after 1 year.

Tolerability

One to three doses of gemtuzumab ozogamicin 9 mg/m2 were generally fairly well tolerated in adults with relapsed primary AML, although serious adverse events were reported. Patients receiving gemtuzumab ozogamicin monotherapy plus prior or subsequent HSCT had a 17% incidence of hepatic veno-occlusive disease (VOD) and a 10% VOD-associated fatality rate. VOD also occurred in patients who did not have HSCT; other severe hepatotoxicity has affected recipients of gemtuzumab ozogamicin.

Infusion-related events were common but generally transient and reversible. Gemtuzumab ozogamicin has, however, been associated with severe hypersensitivity reactions, including anaphylaxis, infusion reactions and pulmonary events. Almost all patients in phase II trials experienced severe neutropenia and thrombocytopenia, the latter associated with serious bleeding in 13% of patients. Other severe adverse effects had a relatively low incidence; grade 3 or 4 sepsis, pneumonia or nausea or vomiting affected 8–17% of patients. The overall incidence of early treatment-related mortality was 16%. Paediatric patients in a small dose-finding trial experienced similar adverse events, although there was less myelosuppression; VOD occurred at dosages of 6–9 mg/m2 in children and, as in adults, was more common in HSCT recipients, affecting 40%.

References

  1. 1.
    Ferrara F. Unanswered questions in acute myeloid leukaemia. Lancet Oncol 2004; 5(7): 443–50PubMedCrossRefGoogle Scholar
  2. 2.
    National Cancer Institute. SEER (Surveillance, Epidemiology, and End Results) Cancer Statistics Review 1975–2002 [online]. Available from URL: http://seer.cancer.gov [Accessed 2005 May 19]
  3. 3.
    Stone RM. The difficult problem of acute myeloid leukemia in the older adult. CA Cancer J Clin 2002; 52(6): 363–71PubMedCrossRefGoogle Scholar
  4. 4.
    Rowe JM, Neuberg D, Friedenberg W, et al. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood 2004; 103(2): 479–85PubMedCrossRefGoogle Scholar
  5. 5.
    Wedding U, Bokemeyer C, Meran JG. Elderly patients with acute myeloid leukaemia: characteristics in biology, patients and treatment. Ontologie 2004; 27(1): 72–82CrossRefGoogle Scholar
  6. 6.
    Bross PF, Beitz J, Chen G, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 2001 Jun; 7(6): 1490–6PubMedGoogle Scholar
  7. 7.
    Tallman MS, Gilliland DG, Rowe JM. Drug therapy of acute myeloid leukemia. Blood 2005 Aug 15; 106(4): 1154–63PubMedCrossRefGoogle Scholar
  8. 8.
    Ferrara F, Palmieri S, Mele G. Prognostic factors and therapeutic options for relapsed or refractory acute myeloid leukemia. Haematologica 2004; 89(8): 998–1008PubMedGoogle Scholar
  9. 9.
    Sekeres MA, Stone RM. The challenge of acute myeloid leukemia in older patients. Curr Opin Oncol 2002; 14(1): 24–30PubMedCrossRefGoogle Scholar
  10. 10.
    Ferrara F, Morabito F, Latagliata R, et al. Aggressive salvage treatment is not appropriate for the majority of elderly patients with acute myeloid leukemia relapsing after first complete remission. Haematologica 2001; 86: 814–20PubMedGoogle Scholar
  11. 11.
    Jackson GH, Taylor PRA. Acute myeloid leukaemia: optimising treatment in elderly patients. Drugs Aging 2002; 19(8): 571–81PubMedCrossRefGoogle Scholar
  12. 12.
    Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Eng J Med 1994; 331: 896–903CrossRefGoogle Scholar
  13. 13.
    Wheatley K, Burnett AK, Goldstone AH, et al. A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. United Kingdom Medical Research Council’s Adult and Childhood Leukaemia Working Parties. Br J Haematol 1999 Oct; 107(1): 69–79Google Scholar
  14. 14.
    Appelbaum FR. New targets for therapy in acute myeloid leukemia. Leukemia 2003; 17(3): 492–5PubMedCrossRefGoogle Scholar
  15. 15.
    Linenberger ML. CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance. Leukemia 2005 Feb; 19(2): 176–82PubMedCrossRefGoogle Scholar
  16. 16.
    Baer MR, Stewart CC, Dodge RK, et al. High frequency of immunophenotype changes in acute myeloid leukemia at relapse: implications for residual disease detection (Cancer and Leukemia Group B Study 8361). Blood 2001; 97: 3574–80PubMedCrossRefGoogle Scholar
  17. 17.
    Medical Research Council Working Parties on Leukaemia in Adults and Children. Acute Myeloid Leukaemia Trial 15 [online]. Available from URL: http://www.aml15.bham.ac.uk [Accessed 2005 Aug 17]
  18. 18.
    McGavin JK, Spencer CM. Gemtuzumab ozogamicin. Drugs 2001; 61(9): 1317–22; discussion 1323-4PubMedCrossRefGoogle Scholar
  19. 19.
    Jedema I, Barge RMY, van der Velden VHJ, et al. Internalization and cell cycle-dependent killing of leukemic cells by gemtuzumab ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity. Leukemia 2004 Feb; 18(2): 316–25PubMedCrossRefGoogle Scholar
  20. 20.
    Linenberger ML, Hong T, Flowers D, et al. Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin. Blood 2001 Aug 15; 98: 988–94PubMedCrossRefGoogle Scholar
  21. 21.
    Walter RB, Raden BW, Cronk MR, et al. The peripheral benzodiazepine receptor ligand PK11195 overcomes different resistance mechanisms to sensitize AML cells to gemtuzumab ozogamicin. Blood 2004 Jun 1; 103(11): 4276–84PubMedCrossRefGoogle Scholar
  22. 22.
    Hamann PR, Hinman LM, Hollander I, et al. Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjugate Chem 2002; 13: 47–58CrossRefGoogle Scholar
  23. 23.
    Matsui H, Takeshita A, Naito K, et al. Reduced effect of gemtuzumab ozogamicin (CMA-676) on P-glycoprotein and/ or CD34-positive leukemia cells and its restoration by multidrug resistance modifiers. Leukemia 2002 May; 16(5): 813–9PubMedCrossRefGoogle Scholar
  24. 24.
    Walter RB, Raden BW, Kamikura DM, et al. Influence of CD33 expression levels and ITIM-dependent internalization on gemtuzumab ozogamicin-induced cytotoxicity. Blood 2005 Feb 1; 105(3): 1295–302PubMedCrossRefGoogle Scholar
  25. 25.
    Walter RB, Raden BW, Hong TC, et al. Multidrug resistance protein attenuates gemtuzumab ozogamicin-induced cytotoxicity in acute myeloid leukemia cells. Blood 2003 Aug 15; 102(4): 1466–73PubMedCrossRefGoogle Scholar
  26. 26.
    Takeshita A, Shinjo K, Naito K, et al. Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells. Leukemia 2005; 19: 1306–11PubMedCrossRefGoogle Scholar
  27. 27.
    Arceci RJ, Sande J, Lange B, et al. Safety and efficacy of gemtuzumab ozogamicin (Mylotarg®) in pediatric patients with advanced CD33-positive acute myeloid leukemia. Blood 2005 Aug 15; 106(4): 1183–8PubMedCrossRefGoogle Scholar
  28. 28.
    van der Velden VHJ, Boeckx N, Jedema I, et al. High CD33-antigen loads in peripheral blood limit the efficacy of gemtuzumab ozogamicin (Mylotarg®) treatment in acute myeloid leukemia patients. Leukemia 2004 May; 18(5): 983–8PubMedCrossRefGoogle Scholar
  29. 29.
    Wyeth Laboratories. Mylotarg® (gemtuzumab ozogamicin for injection) [online]. Available from URL: http://www.wyeth.com/ [Accessed 2005 May 2]
  30. 30.
    Dowell JA, Korth-Bradley J, Liu H, et al. Pharmacokinetics of gemtuzumab ozogamicin, an antibody-targeted chemotherapy agent for the treatment of patients with acute myeloid leukemia in first relapse. J Clin Pharmacol 2001 Nov; 41(11): 1206–14PubMedCrossRefGoogle Scholar
  31. 31.
    Lee MD, Dunne TS, Siegel MM, et al. Calichemicins, a novel family of antitumour antibiotics. 1. Chemistry and partial structure of calichemicin γ-1 I. J Am Chem Soc 1987; 109: 3464–6CrossRefGoogle Scholar
  32. 32.
    Amico D, Barbui AM, Erba E, et al. Differential response of human acute myeloid leukemia cells to gemtuzumab ozogamicin in vitro: role of Chk1 and Chk2 phosphorylation and caspase 3. Blood 2003 Jun 1; 101: 4589–97PubMedCrossRefGoogle Scholar
  33. 33.
    Buckwalter M, Dowell JA, Korth-Bradley J, et al. Pharmacokinetics of gemtuzumab ozogamicin as a single-agent treatment of pediatric patients with refractory or relapsed acute myeloid leukemia. J Clin Pharmacol 2004 Aug; 44(8): 873–80PubMedCrossRefGoogle Scholar
  34. 34.
    Korth-Bradley JM, Dowell JA, King SP, et al. Impact of age and gender on the pharmacokinetics of gemtuzumab ozogamicin. Pharmacotherapy 2001 Oct; 21: 1175–80PubMedCrossRefGoogle Scholar
  35. 35.
    Larson RA, Sievers EL, Stadtmauer E.A., et al. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer 2005 Oct 1; 104(7): 1442–52PubMedCrossRefGoogle Scholar
  36. 36.
    Roboz GJ, Knovich MA, Bayer RL, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with poor-prognosis acute myeloid leukemia. Leuk Lymphoma 2002 Oct; 43: 1951–5PubMedCrossRefGoogle Scholar
  37. 37.
    Lo-Coco F, Cimino G, Breccia M, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 2004 Oct 1; 104(7): 1995–9PubMedCrossRefGoogle Scholar
  38. 38.
    Amadori S, Suciu S, Stasi R, et al. Gemtuzumab ozogamicin (Mylotarg®) as single-agent treatment for frail patients 61 years of age and older with acute myeloid leukemia: final results of AML-15B, a phase II study of the European Organisation for Research and Treatment of Cancer and Gruppo Italiano Malattie Ematologiche dell’Adulto Leukemia Groups. Leukemia 2005 Oct; 19(10): 1768–73PubMedCrossRefGoogle Scholar
  39. 39.
    Nabhan C, Rundhaugen LM, Riley MB, et al. Phase II pilot trial of gemtuzumab ozogamicin (GO) as first line therapy in acute myeloid leukemia patients age 65 or older. Leuk Res 2005 Jan; 29(1): 53–7PubMedCrossRefGoogle Scholar
  40. 40.
    Amadori S, Suciu S, Willemze R, et al. Sequential administration of gemtuzumab ozogamicin and conventional chemotherapy as first line therapy in elderly patients with acute myeloid leukemia: a phase II study (AML-15) of the EORTC and GIMEMA leukemia groups. Haematologica 2004 Aug; 89(8): 950–6PubMedGoogle Scholar
  41. 41.
    DeAngelo DJ, Stone RM, Durrant S, et al. Gemtuzumab ozogamicin (Mylotarg®) in combination with induction chemotherapy for the treatment of patients with de novo acute myeloid leukemia: two age-specific phase 2 trials [abstract no. 341]. Blood 2003 Nov 16; 102 (11 Part 1): 100.Google Scholar
  42. 42.
    Kell WJ, Burnett AK, Chopra R, et al. A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia. Blood 2003 Dec 15; 102(13): 4277–83PubMedCrossRefGoogle Scholar
  43. 43.
    Stone RM, Moser B, Schulman P, et al. A dose escalation and phase II study of gemtuzumab ozogamicin (GO) with high-dose cytarabine (HiDAC) for patients (pts) with refractory or relapsed acute myeloid leukemia (AML): CALGB 19902 [abstract no. 873]. Blood 2004; 104 (11 Pt 1): 249.CrossRefGoogle Scholar
  44. 44.
    Tsimberidou A, Estey E, Cortes J, et al. Gemtuzumab, fludarabine, cytarabine, and cyclosporine in patients with newly diagnosed acute myelogenous leukemia or high-risk myelodysplastic syndromes. Cancer 2003 Mar 15; 97: 1481–7PubMedCrossRefGoogle Scholar
  45. 45.
    Tsimberidou A, Cortes J, Thomas D, et al. Gemtuzumab ozogamicin, fludarabine, cytarabine and cyclosporine combination regimen in patients with CD33+ primary resistant or relapsed acute myeloid leukemia. Leuk Res 2003 Oct; 27(10): 893–7PubMedCrossRefGoogle Scholar
  46. 46.
    Moore JO, Seiter K, Kolitz JE, et al. Phase 2 study of oblimersen sodium (G3139; Bcl-2 antisense; Genasense®) plus gemtuzumab ozogamcin (Mylotarg®) in elderly patients with relapsed acute myeloid leukemia (AML) [abstract no. 865]. Blood 2004; 104 (11 Pt 1): 247.Google Scholar
  47. 47.
    Tsimberidou AM, Estey E, Cortes JE, et al. Mylotarg, fludarabine, cytarabine (ara-C), and cyclosporine (MFAC) regimen as post-remission therapy in acute myelogenous leukemia. Cancer Chemother Pharmacol 2003 Dec; 52(6): 449–52PubMedCrossRefGoogle Scholar
  48. 48.
    Alvarado Y, Tsimberidou A, Kantarjian H, et al. Pilot study of Mylotarg, idarubicin and cytarabine combination regimen in patients with primary resistant or relapsed acute myeloid leukemia. Cancer Chemother Pharmacol 2003 Jan; 51: 87–90PubMedCrossRefGoogle Scholar
  49. 49.
    Estey EH, Giles FJ, Beran M, et al. Experience with gemtuzumab ozogamycin (‘mylotarg’) and all-trans retinoic acid in untreated acute promyelocytic leukemia. Blood 2002 Jun 1; 99: 4222–4PubMedCrossRefGoogle Scholar
  50. 50.
    Chevallier P, Rolland V, Garand R, et al. Mylotarg 9 mg/m2 combined with intermediate dose aracytin and mitoxantrone (MIDAM) in relapsed/refractory CD33+ acute myeloid leukemia: a single center phase II experience [abstract no. 1811]. Blood 2004; 104(11): 501–2Google Scholar
  51. 51.
    Venugopal P, Gregory SA, Raza A, et al. Phase II study of gemtuzumab ozogamycin (Mylotarg) combined with intensive induction chemotherapy using high dose ara-C and mitoxantrone followed by amifostine in poor prognosis acute myeloid leukemia: preliminary results [abstract no. 1323]. Blood 2002; 100 (11 Pt 1): 341aCrossRefGoogle Scholar
  52. 52.
    Sievers EL, Larson RA, Stadtmauer EA, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 2001 Jul 1; 19(13): 3244–54PubMedGoogle Scholar
  53. 53.
    Larson RA, Boogaerts M, Estey E, et al. Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin). Leukemia 2002 Sep; 16: 1627–36PubMedCrossRefGoogle Scholar
  54. 54.
    Zwaan CM, Reinhardt D, Corbacioglu S, et al. Gemtuzumab ozogamicin: first clinical experiences in children with relapsed/refractory acute myeloid leukemia treated on compassionate-use basis. Blood 2003 May 15; 101(10): 3868–71PubMedCrossRefGoogle Scholar
  55. 55.
    Reinhardt D, Diekamp S, Fleischhack G, et al. Gemtuzumab ozogamicin (Mylotarg®) in children with refractory or relapsed acute myeloid leukemia. Onkologie 2004 Jun; 27(3): 269–72PubMedCrossRefGoogle Scholar
  56. 56.
    HOVON Stichting Hemato-Oncologie voor Volwassenen Nederland (Dutch hemato-oncology association). HOVON 43 AML [online]. Available from URL: http://www.hovon.nl [Accessed 2005 Aug 18]
  57. 57.
    National Cancer Institute. Clinical trials [online]. Available from URL: http://www.cancer.gov/clinicaltrials [Accessed 2005 May 24]
  58. 58.
    Wyeth Laboratories. Gemtuzumab ozogamicin phase 2 trials HSCT patient survival data, 2005. (Data on file)Google Scholar
  59. 59.
    Sievers EL, Spielberger R, Brunvand MW, et al. Gemtuzumab ozogamicin (Mylotarg®) as a single agent to evaluate safety and determine maximum tolerated dose in post hemopoeitic stem cell transplant patients with relapsed, CD33+ acute myeloid leukemia (AML) [abstract no. 1304]. Blood 2002 Nov 16; 100 (11 Pt 1): 336.Google Scholar
  60. 60.
    Sievers EL, Linenberger M. Mylotarg: antibody-targeted chemotherapy comes of age. Curr Opin Oncol 2001 Nov; 13(6): 522–7PubMedCrossRefGoogle Scholar
  61. 61.
    Larson RA. Current use and future development of gemtuzumab ozogamicin. Semin Hematol 2001 Jul; 38 (3 Suppl. 6): 24–31PubMedCrossRefGoogle Scholar
  62. 62.
    Erba HP, Stadtmauer EA, Larson RA, et al. Risk assessment for hepatic veno-occlusive disease in patients treated with gemtuzumab ozogamicin (Mylotarg®) with or without hematopoietic stem cell transplantation [abstract no. 3241]. Blood 2003; 102: 871aGoogle Scholar
  63. 63.
    Erba HP, Stadtmauer EA, Larson RA, et al. Final results of a multivariate logistic regression analysis to determine factors contributing to the risk of developing hepatic veno-occlusive disease after treatment with gemtuzumab ozogamicin [abstract no. 1313]. Blood 2002; 100: 339aGoogle Scholar
  64. 64.
    Wadleigh M, Richardson PG, Zahrieh D, et al. Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood 2003 Sep 1; 102(5): 1578–82PubMedCrossRefGoogle Scholar
  65. 65.
    National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology-Acute Myeloid Leukemia Version 2.2005 [online]. Available from URL: http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf [Accessed 2005 Mar 24]
  66. 66.
    European Society for Medical Oncology. ESMO minimum clinical recommendations for the diagnosis, treatment and follow-up of acute myeloblastic leukemia (AML) in adult patients. Ann Oncol 2005; 16 Suppl. 1: i48–9CrossRefGoogle Scholar
  67. 67.
    Ferrara F, Venditti A, Carellajr AM, et al. Autologous stem-cell transplantation for patients with acute myeloid leukemia aged over 60 yr. Eur J Haematol 2002; 69: 200–4PubMedCrossRefGoogle Scholar
  68. 68.
    Kimby E, Nygren P, Glimelius B. A systematic overview of chemotherapy effects in acute myeloid leukaemia: SBUgroup. Acta Oncol 2001; 40(2/3): 231–52PubMedCrossRefGoogle Scholar
  69. 69.
    Kern W, Aul C, Maschmeyer G, et al. Superiority of high-dose over intermediate-dose cytosine arabinoside in the treatment of patients with high-risk acute myeloid leukemia: results of an age-adjusted prospective randomized comparison. Leukemia 1998 Jul; 12(7): 1049–55PubMedCrossRefGoogle Scholar
  70. 70.
    Archimbaud E, Anglaret B, Thomas X, et al. Continuous-infusion daunorubicin and carboplatin for high-risk acute myeloid leukemia in the elderly. Leukemia 1992 Aug; 6(8): 776–9PubMedGoogle Scholar
  71. 71.
    Rajvanshi P, Shulman HM, Sievers EL, et al. Hepatic sinusoidal obstruction after gemtuzumab ozogamicin (Mylotarg) therapy. Blood 2002 Apr 1; 99: 2310–4PubMedCrossRefGoogle Scholar
  72. 72.
    Kompetenznetz-leukäemien. Akute und chronisch leukämien [online]. Available from URL: http://www.kompetenznetzleukaemie.de/kn_home_en/ [Accessed 2005 May 27]

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, AucklandNew Zealand

Personalised recommendations