- First Online:
- 42 Downloads
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.
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.
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.
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%.
- 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]
- 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
- 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]
- 29.Wyeth Laboratories. Mylotarg® (gemtuzumab ozogamicin for injection) [online]. Available from URL: http://www.wyeth.com/ [Accessed 2005 May 2]
- 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
- 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.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
- 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
- 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
- 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.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
- 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.National Cancer Institute. Clinical trials [online]. Available from URL: http://www.cancer.gov/clinicaltrials [Accessed 2005 May 24]
- 58.Wyeth Laboratories. Gemtuzumab ozogamicin phase 2 trials HSCT patient survival data, 2005. (Data on file)Google Scholar
- 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
- 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.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
- 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]
- 72.Kompetenznetz-leukäemien. Akute und chronisch leukämien [online]. Available from URL: http://www.kompetenznetzleukaemie.de/kn_home_en/ [Accessed 2005 May 27]