Gemtuzumab ozogamicin

Gemtuzumab ozogamicin, sold under the brand name Mylotarg, is an antibody-drug conjugate (a drug-linked monoclonal antibody) that is used to treat acute myeloid leukemia.[2]

Gemtuzumab ozogamicin
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetCD33
Clinical data
Trade namesMylotarg
AHFS/Drugs.comMonograph
MedlinePlusa618005
License data
Pregnancy
category
  • US: N (Not classified yet) [1]
    Routes of
    administration    		Intravenous
    ATC code
    Legal status
    Legal status
    Identifiers
    CAS Number
    DrugBank
    ChemSpider
    • none
    UNII
    KEGG
    ChEMBL
    Chemical and physical data
    Molar mass151500 g·mol−1
     NY (what is this?)  (verify)

    The most common grade 3 and higher adverse reactions that occurred during Induction 1 and Intensification 2 in ≥ 5% of people who received gemtuzumab ozogamicin were infection, febrile neutropenia, decreased appetite, hyperglycemia, mucositis, hypoxia, hemorrhage, increased transaminase, diarrhea, nausea, and hypotension.[3]

    Medical uses

    In the United States, gemtuzumab ozogamicin is indicated for newly diagnosed CD33-positive acute myeloid leukemia (AML) for adults and children one month and older.[3]

    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.

    History

    Gemtuzumab ozogamicin was created in a collaboration between Celltech and Wyeth that began in 1991.[4][5] The same collaboration later produced inotuzumab ozogamicin.[6] Celltech was acquired by UCB in 2004[7] and Wyeth was acquired by Pfizer in 2009.[8]

    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.[9] The accelerated approval was based on the surrogate endpoint of response rate.[10] It was the first antibody-drug conjugate to be approved.[11]

    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.[12] Later the onset of VOD was shown to occur at increased frequency in gemtuzumab patients even following bone marrow transplantation.[13] The drug was discussed in a 2008 JAMA article, which criticized the inadequacy of postmarketing surveillance of biologic agents.[14]

    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 on August 20, 2009 prior to completion due to worrisome outcomes [15]. 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).[10]

    In June 2010, Pfizer withdrew Mylotarg from the market at the request of the US FDA.[16][17] 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".[18]

    In 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.[11] In April 2018, gemtuzumab ozogamicin was approved again for use in the United States[19] and in the European Union.[20]

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    See also

    References
    1. "Gemtuzumab (Mylotarg) Use During Pregnancy". Drugs.com. 30 September 2019. Retrieved 28 February 2020.
    2. "FDA Approves Gemtuzumab Ozogamicin for CD33-positive AML". fda.gov (Press release). U.S. Food and Drug Administration (FDA). 1 September 2017. Retrieved 6 September 2017. This article incorporates text from this source, which is in the public domain.
    3. "FDA approves gemtuzumab ozogamicin for CD33-positive AML in pediatric". U.S. Food and Drug Administration (FDA). 16 June 2020. Retrieved 16 June 2020. This article incorporates text from this source, which is in the public domain.
    4. "Mylotarg". Informa Biomedtracker. Retrieved 19 August 2017.
    5. Niculescu-Duvaz, I (December 2000). "Technology evaluation: gemtuzumab ozogamicin, Celltech Group". Current Opinion in Molecular Therapeutics. 2 (6): 691–6. PMID 11249747.
    6. 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.
    7. "Celltech sold to Belgian firm in £1.5bn deal". The Guardian. 18 May 2004.
    8. Sorkin, Andrew Ross; Wilson, Duff (25 January 2009). "Pfizer Agrees to Pay $68 Billion for Rival Drug Maker Wyeth". The New York Times.
    9. 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.
    10. Gemtuzumab Voluntarily Withdrawn From US Market. June 2010
    11. Stanton, Dan (1 February 2017). "Pfizer resubmits US and EU application for withdrawn ADC Mylotarg". BioPharma Reporter.
    12. 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.
    13. 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.
    14. The Research on Adverse Drug Events and Reports (RADAR) Project, JAMA
    16. Mylotarg (gemtuzumab ozogamicin): Market Withdrawal, US FDA
    17. Pfizer pulls leukemia drug from U.S. market, Reuters
    18. Pharmaceuticals and Medical Devices Safety Information, No. 277, February 2011 (PDF) (Technical report). Pharmaceuticals and Medical Devices Agency of Japan. 2011. Archived from the original (PDF) on 20 January 2013. Retrieved 6 July 2013.
    19. "Gemtuzumab ozogamicin: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 28 February 2020.
    20. "Mylotarg EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 28 February 2020.
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