|Source||Humanized (from mouse)|
|Chemical and physical data|
|Molar mass||151–153 kg/mol|
|(what is this?)|
Mechanism and side effects
Gemtuzumab is a monoclonal antibody to CD33 linked to a cytotoxic agent from the class of calicheamicins. CD33 is expressed in most leukemic blast cells but also in normal hematopoietic cells, the intensity diminishing with maturation of stem cells.
Common side effects of administration included shivering, fever, nausea and vomiting. Serious side effects included severe myelosuppression (suppressed activity of bone marrow, which is involved in formation of various blood cells [found in 98% of patients]), disorder of the respiratory system, tumor lysis syndrome, Type III hypersensitivity, venous occlusion, and death.
Gemtuzumab ozogamicin was created in a collaboration between Celltech and Wyeth that began in 1991. The same collaboration later produced inotuzumab ozogamicin. Celltech was acquired by UCB in 2004 and Wyeth was acquired by Pfizer in 2009.
In the United States, it was approved under an accelerated-approval process by the FDA in 2000 for use in patients over the age of 60 with relapsed acute myelogenous leukemia (AML); or those who are not considered candidates for standard chemotherapy. The accelerated approval was based on the surrogate endpoint of response rate. It was the first antibody-drug conjugate to be approved.
Within the first year after approval, the FDA required a black box warning be added to gemtuzumab packaging. The drug was noted to increase the risk of veno-occlusive disease in the absence of bone marrow transplantation. Later the onset of VOD was shown to occur at increased frequency in gemtuzumab patients even following bone marrow transplantation. The drug was discussed in a 2008 JAMA article, which criticized the inadequacy of postmarketing surveillance of biologic agents.
A randomized phase 3 comparative controlled trial (SWOG S0106) was initiated in 2004 by Wyeth in accordance with the FDA accelerated-approval process. The study was stopped[when?] prior to completion due to worrisome outcomes. Among the patients evaluated for early toxicity, fatal toxicity rate was significantly higher in the gemtuzumab combination therapy group vs the standard therapy group. Mortality was 5.7% with gemtuzumab and 1.4% without the agent (16/283 = 5.7% vs 4/281 = 1.4%; P = .01).
In June 2010, Pfizer withdrew Mylotarg from the market at the request of the US FDA. However, some other regulatory authorities did not agree with the FDA decision, with Japan's Pharmaceuticals and Medical Devices Agency stating in 2011 that the "risk-benefit balance of gemtuzumab ozogamicin has not changed from its state at the time of approval".
In early 2017 Pfizer reapplied for US and EU approval, based on a meta-analysis of prior trials and results of the ALFA-0701 clinical trial, an open-label Phase III trial in 280 older people with AML.
- "Approved Drugs > FDA Approves Gemtuzumab Ozogamicin for CD33-positive AML". fda.gov. Silver Spring, USA: U.S. Food and Drug Administration. 1 September 2017. Retrieved 6 September 2017.
- "Mylotarg". Informa Biomedtracker. Retrieved 19 August 2017.
- Niculescu-Duvaz, I (December 2000). "Technology evaluation: gemtuzumab ozogamicin, Celltech Group". Current Opinion in Molecular Therapeutics. 2 (6): 691–6. PMID 11249747.
- Damle, NK; Frost, P (August 2003). "Antibody-targeted chemotherapy with immunoconjugates of calicheamicin". Current Opinion in Pharmacology. 3 (4): 386–90. doi:10.1016/S1471-4892(03)00083-3. PMID 12901947.
- "Celltech sold to Belgian firm in £1.5bn deal". The Guardian. 18 May 2004.
- Sorkin, Andrew Ross; Wilson, Duff (25 January 2009). "Pfizer Agrees to Pay $68 Billion for Rival Drug Maker Wyeth". The New York Times.
- Bross PF, Beitz J, Chewn G, Chen XH, Duffy E, Kieffer L, Roy S, Sridhara R, Rahman A, Williams G, Pazdur R (2001). "Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia". Clin Cancer Res. 7 (6): 1490–6. PMID 11410481.
- Gemtuzumab Voluntarily Withdrawn From US Market. June 2010
- Stanton, Dan (February 1, 2017). "Pfizer resubmits US and EU application for withdrawn ADC Mylotarg". BioPharma Reporter.
- Giles FJ, Kantarjian HM, Kornblau SM, Thomas DA, Garcia-Manero G, Waddelow TA, David CL, Phan AT, Colburn DE, Rashid A, Estey EH (2001). "Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation". Cancer. 92 (2): 406–13. doi:10.1002/1097-0142(20010715)92:2<406::AID-CNCR1336>3.0.CO;2-U. PMID 11466696.
- Wadleigh M, Richardson PG, Zahrieh D, Lee SJ, Cutler C, Ho V, Alyea EP, Antin JH, Stone RM, Soiffer RJ, DeAngelo DJ (2003). "Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation". Blood. 102 (5): 1578–82. doi:10.1182/blood-2003-01-0255. PMID 12738663.
- The Research on Adverse Drug Events and Reports (RADAR) Project, JAMA
- Mylotarg (gemtuzumab ozogamicin): Market Withdrawal, US FDA
- Pfizer pulls leukemia drug from U.S. market, Reuters
- Pharmaceuticals and Medical Devices Safety Information, No. 277, February 2011 (PDF) (Technical report). Pharmaceuticals and Medical Devices Agency of Japan. 2011.