Abstract
The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of gemtuzumab ozogamicin (GO) in patients with relapsed and/or refractory CD33-positive acute myeloid leukemia (AML). Patients received 2-h infusions of GO twice with an interval of approximately 14 days. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria Version 2.0. Samples for pharmacokinetics were taken on day 1 and day 8 of the first treatment cycle. The dose was increased stepwise and, in each cohort, patients were treated at the same dose. Forty patients, median age 58 years (range 28–68) were treated; 20 and 20 patients were enrolled to the phase I and II parts, respectively. In the phase I part, dose-limiting toxicities (DLTs) were hepatotoxicities, and the recommended dose was established as 9 mg/m2 given as two intravenous infusions separated by approximately 14 days. The pharmacokinetic study revealed that C max and AUC were equivalent to those of non-Japanese patients. In the phase II part, complete remission was observed in 5 patients, and one patient had complete remission without platelet recovery. Four of these 6 in remission and one in the phase I are long-term survivors (alive for at least 44 months). GO is safe and effective as a single agent among Japanese CD33-positive AML patients. Remission lasted longer in a subset of patients than in non-Japanese patients in earlier studies. Further studies of this agent are warranted to establish standard therapy.
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Hamann P, Hinman L, Hollander I. Gemutuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjug Chem. 2002;13:47–58. doi:10.1021/bc010021y.
Zein N, Poncin M, Nilakantan R. Calichemicin gamma 1I and DNA: molecular recognition process responsible for site-specificity. Science. 1989;244:697–9. doi:10.1126/science.2717946.
van der Jagt RH, Badger CC, Appelbaum FR, et al. Localization of radiolabeled antimyeloid antibodies in a human acute leukemia xenograft tumor model. Cancer Res. 1992;52:89–94.
van der Velden VH, teMarvelde JG, Hoogeveen PG, et al. Targeting of the CD33-calicheamicin immunoconjugate Mylotarg (CMA676) in acute myeloid leukemia: in vivo and in vitro saturation and internalization by leukemia and normal myeloid cells. Blood. 2001;97:3197–204. doi:10.1182/blood.V97.10.3197.
Sievers EL, Apelbaum FR, Spielberger RT, et al. Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin imunoconjugate. Blood. 1999;93:3678–84.
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;19:3244–54.
Dowell JA, Korth-Bradley J, Liu H, King SP, Berger MS. 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;41:1206–14. doi:10.1177/00912700122012751.
Bross PF, Beitz J, Chen G, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001;7:1490–6.
Leopold LH, Berger MS, Feingold J. Acute and long-term toxicities associated with gemtuzumab ozogamicin (Mylotarg) therapy of acute myeloid leukemia. Clin Lymphoma. 2002;2(Suppl 1):S29–34. doi:10.3816/CLM.2002.s.006.
Nabhan C, Rundhaugen L, Jatoi M, et al. Gemtuzumab ozogamicin (MylotargTM) is infrequently associated with sinusoidal obstructive syndrome/veno-occlusive disease. Ann Oncol. 2004;15:1231–6. doi:10.1093/annonc/mdh324.
Korth-Bradley JM, Dowell JA, King SP, Liu H, Berger MS. Impact of age and gender on the pharmacokinetics of gemtuzumab ozogamicin. Pharmacotherapy. 2001;21:1175–80. doi:10.1592/phco.21.15.1175.33890.
Stadtmauer E, Sievers E, Larson R, et al. Final report of the effects of cytogenetic risk group on outcome of patients with acute myeloid leukemia in first relapse treated with Gemtuzumab Ozogamicin (Mylotarg). Blood. 2002;100:197a.
Lo Coco F, Ammatuna E, Noguera N. Treatment of acute promyelocytic leukemia with gemtuzumab ozogamicin. Clin Adv Hematol Oncol. 2006;4:57–62, 76–77.
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This study was supported by research funding from Wyeth Japan Pharmaceuticals, Tokyo, Japan.
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S. Furusawa: deceased.
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Kobayashi, Y., Tobinai, K., Takeshita, A. et al. Phase I/II study of humanized anti-CD33 antibody conjugated with calicheamicin, gemtuzumab ozogamicin, in relapsed or refractory acute myeloid leukemia: final results of Japanese multicenter cooperative study. Int J Hematol 89, 460–469 (2009). https://doi.org/10.1007/s12185-009-0298-1
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DOI: https://doi.org/10.1007/s12185-009-0298-1