Gemtuzumab ozogamicin

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Gemtuzumab ozogamicin
Mab-ozogamicin.svg
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target CD33
Clinical data
Trade names Mylotarg
AHFS/Drugs.com Monograph
MedlinePlus a618005
License data
Pregnancy
category
Routes of
administration 		Intravenous
ATC code
Legal status
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Chemical and physical data
Molar mass 151500g·mol−1
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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. [6] [8] [9]

Contents

The most common side effects include infection, febrile neutropenia, decreased appetite, hyperglycemia, mucositis, hypoxia, hemorrhage, increased transaminase, diarrhea, nausea, and hypotension. [10] However, the addition of gemtuzumab ozogamicin to standard chemotherapy regimens does not increase infection rates. [11]

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 and for the treatment of relapsed or refractory CD33-positive AML in adults and children two years and older. [6] [10]

Mechanism

Mechanism of action of gemtuzumab ozogamicin Ijms-21-05626-g001-550.webp
Mechanism of action of gemtuzumab ozogamicin

Gemtuzumab is a monoclonal antibody to CD33 linked to a cytotoxic agent from the class of calicheamicins (ozogamicin). [6] CD33 is expressed in most leukemic blast cells but also in normal hematopoietic cells, the intensity diminishing with maturation of stem cells. [6]

History

Gemtuzumab ozogamicin was created in a collaboration between Celltech and Wyeth that began in 1991. [12] [13] The same collaboration later produced inotuzumab ozogamicin. [14] Celltech was acquired by UCB in 2004 [15] and Wyeth was acquired by Pfizer in 2009. [16]

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. [17] The accelerated approval was based on the surrogate endpoint of response rate. [18] It was the first antibody-drug conjugate to be approved. [19]

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. [20] Later the onset of VOD was shown to occur at increased frequency in gemtuzumab patients even following bone marrow transplantation. [21] The drug was discussed in a 2008 JAMA article, which criticized the inadequacy of postmarketing surveillance of biologic agents. [22]

A randomized Phase III 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. [23] 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). [18]

In June 2010, Pfizer withdrew Mylotarg from the market at the request of the US FDA. [24] [25] 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". [26]

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. [19] In September 2017, gemtuzumab ozogamicin was approved again for use in the United States [8] [27] and in the European Union. [7]

Related Research Articles

<span class="mw-page-title-main">Acute myeloid leukemia</span> Cancer of the myeloid line of blood cells

Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may include feeling tired, shortness of breath, easy bruising and bleeding, and increased risk of infection. Occasionally, spread may occur to the brain, skin, or gums. As an acute leukemia, AML progresses rapidly, and is typically fatal within weeks or months if left untreated.

<span class="mw-page-title-main">Inotuzumab ozogamicin</span> Chemical compound

Inotuzumab ozogamicin, sold under the brand name Besponsa, is an antibody-drug conjugate medication used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia. It is administered by intravenous infusion.

Lintuzumab (SGN-33) is a humanized monoclonal antibody used in the treatment of cancer. The drug had been developed by Seattle Genetics as a treatment for acute myeloid leukemia (AML), a condition which results in the deaths of 9,000 people a year in the United States. Lintuzumab targets the CD33 protein, which is expressed in AML and other myeloproliferative diseases, but does not appear in abundance on normal cells.

<span class="mw-page-title-main">CD33</span> Mammalian protein found in Homo sapiens

CD33 or Siglec-3 is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells.

<span class="mw-page-title-main">CD135</span> Protein-coding gene in the species Homo sapiens

Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3, receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the FLT3 gene. FLT3 is a cytokine receptor which belongs to the receptor tyrosine kinase class III. CD135 is the receptor for the cytokine Flt3 ligand (FLT3L).

<span class="mw-page-title-main">Mantle cell lymphoma</span> Type of blood cancer

Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma, comprising about 6% of cases. It is named for the mantle zone of the lymph nodes where it develops. The term 'mantle cell lymphoma' was first adopted by Raffeld and Jaffe in 1991.

<span class="mw-page-title-main">Antibody–drug conjugate</span> Class of biopharmaceutical drugs

Antibody–drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 pharmaceutical companies were developing ADCs.

Quizartinib, sold under the brand name Vanflyta, is an anti-cancer medication used for the treatment of acute myeloid leukemia.

<span class="mw-page-title-main">Midostaurin</span> Chemical compound

Midostaurin, sold under the brand name Rydapt & Tauritmo both by Novartis, is a multi-targeted protein kinase inhibitor that has been investigated for the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and advanced systemic mastocytosis. It is a semi-synthetic derivative of staurosporine, an alkaloid from the bacterium Streptomyces staurosporeus.

<span class="mw-page-title-main">Vadastuximab talirine</span> Chemical compound

Vadastuximab talirine is an antibody-drug conjugate (ADC) directed to CD33 (siglec-3) which is a transmembrane receptor expressed on cells of myeloid lineage. The experimental drug, being developed by Seattle Genetics, was in clinical trials for the treatment of acute myeloid leukemia (AML).

Seagen Inc. is an American biotechnology company focused on developing and commercializing innovative, empowered monoclonal antibody-based therapies for the treatment of cancer. The company, headquartered in Bothell, Washington, is the industry leader in antibody-drug conjugates or ADCs, a technology designed to harness the targeting ability of monoclonal antibodies to deliver cell-killing agents directly to cancer cells. Antibody-drug conjugates are intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy, while potentially enhancing antitumor activity.

FLAG is a chemotherapy regimen used for relapsed and refractory acute myeloid leukemia (AML). The acronym incorporates the three primary ingredients of the regimen:

  1. Fludarabine: an antimetabolite that, while not active toward AML, increases formation of an active cytarabine metabolite, ara-CTP, in AML cells;
  2. Arabinofuranosyl cytidine : an antimetabolite that has been proven to be the most active toward AML among various cytotoxic drugs in single-drug trials; and
  3. Granulocyte colony-stimulating factor (G-CSF): a glycoprotein that shortens the duration and severity of neutropenia.

Avelumab, sold under the brand name Bavencio, is a fully human monoclonal antibody medication for the treatment of Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma.

<span class="mw-page-title-main">Venetoclax</span> Medication

Venetoclax, sold under the brand names Venclexta and Venclyxto, is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML).

<span class="mw-page-title-main">Glasdegib</span> Treatment for acute myeloid leukemia

Glasdegib, sold under the brand name Daurismo, is a medication for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults older than 75 years or those who have comorbidities that preclude use of intensive induction chemotherapy. It is taken by mouth and is used in combination with low-dose cytarabine.

<span class="mw-page-title-main">Enasidenib</span> Chemical compound

Enasidenib is a medication used to treat relapsed or refractory acute myeloid leukemia in people with specific mutations of the isocitrate dehydrogenase 2 (IDH2) gene, determined by an FDA-approved IDH2 companion diagnostic test. It is an inhibitor of IDH2. It was developed by Agios Pharmaceuticals and is licensed to Celgene for further development.

<span class="mw-page-title-main">Gilteritinib</span> Chemical compound

Gilteritinib, sold under the brand name Xospata, is an anti-cancer drug. It acts as an inhibitor of FLT3, hence it is a tyrosine kinase inhibitor.

<span class="mw-page-title-main">Ivosidenib</span> Anti-cancer medication

Ivosidenib, sold under the brand name Tibsovo, is an anti-cancer medication for the treatment of acute myeloid leukemia (AML) and cholangiocarcinoma. It is a small molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), which is mutated in several forms of cancer. Ivosidenib is an isocitrate dehydrogenase-1 inhibitor that works by decreasing abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to differentiation of malignant cells.

<span class="mw-page-title-main">Selinexor</span> Anti-cancer drug

Selinexor sold under the brand name Xpovio among others, is a selective inhibitor of nuclear export used as an anti-cancer medication. It works by blocking the action of exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis. It is the first drug with this mechanism of action.

<span class="mw-page-title-main">Olutasidenib</span> Chemical compound

Olutasidenib, sold under the brand name Rezlidhia, is an anticancer medication used to treat relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation. Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor. It is taken by mouth.

References

  1. 1 2 "Mylotarg Australian prescription medicine decision summary". Therapeutic Goods Administration (TGA). 17 April 2020. Retrieved 17 August 2020.
  2. ↑ AusPAR: Gemtuzumab ozogamicin. Therapeutic Goods Administration (TGA) (Report). October 2020.
  3. ↑ "Summary Basis of Decision (SBD) for Mylotarg". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  4. ↑ "Mylotarg 5mg powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC)". (emc). 29 October 2019. Retrieved 17 August 2020.
  5. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  6. 1 2 3 4 5 "Mylotarg- gemtuzumab ozogamicin injection, powder, lyophilized, for solution". DailyMed. 29 June 2020. Retrieved 17 August 2020.
  7. 1 2 "Mylotarg EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 28 February 2020.
  8. 1 2 "FDA approves Mylotarg for treatment of acute myeloid leukemia". U.S. Food and Drug Administration (FDA) (Press release). 1 September 2017. Retrieved 16 August 2020.
  9. ↑ "FDA Approves Gemtuzumab Ozogamicin for CD33-positive AML". U.S. Food and Drug Administration (FDA) (Press release). 1 September 2017. Retrieved 6 September 2017.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  10. 1 2 "FDA approves gemtuzumab ozogamicin for CD33-positive AML in pediatric patients". U.S. Food and Drug Administration (FDA) (Press release). 16 June 2020. Retrieved 16 June 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  11. ↑ Kyriakidis I, Mantadakis E, Stiakaki E, Groll AH, Tragiannidis A (October 2022). "Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas". Cancers. 14 (20): 5022. doi: 10.3390/cancers14205022 . PMC   9599435 . PMID   36291806.
  12. ↑ "Mylotarg". Informa Biomedtracker. Archived from the original on 19 August 2017. Retrieved 19 August 2017.
  13. ↑ Niculescu-Duvaz I (December 2000). "Technology evaluation: gemtuzumab ozogamicin, Celltech Group". Current Opinion in Molecular Therapeutics. 2 (6): 691–696. PMID   11249747.
  14. ↑ Damle NK, Frost P (August 2003). "Antibody-targeted chemotherapy with immunoconjugates of calicheamicin". Current Opinion in Pharmacology. 3 (4): 386–390. doi:10.1016/S1471-4892(03)00083-3. PMID   12901947.
  15. ↑ "Celltech sold to Belgian firm in £1.5bn deal". The Guardian. 18 May 2004.
  16. ↑ Sorkin AR, Wilson D (25 January 2009). "Pfizer Agrees to Pay $68 Billion for Rival Drug Maker Wyeth". The New York Times .
  17. ↑ Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, et al. (June 2001). "Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia". Clinical Cancer Research. 7 (6): 1490–1496. PMID   11410481.
  18. 1 2 Gemtuzumab Voluntarily Withdrawn From US Market. June 2010
  19. 1 2 Stanton D (1 February 2017). "Pfizer resubmits US and EU application for withdrawn ADC Mylotarg". BioPharma Reporter.
  20. ↑ Giles FJ, Kantarjian HM, Kornblau SM, Thomas DA, Garcia-Manero G, Waddelow TA, et al. (July 2001). "Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation". Cancer. 92 (2): 406–413. doi:10.1002/1097-0142(20010715)92:2<406::AID-CNCR1336>3.0.CO;2-U. PMID   11466696. S2CID   28510415.
  21. ↑ Wadleigh M, Richardson PG, Zahrieh D, Lee SJ, Cutler C, Ho V, et al. (September 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): 1578–1582. doi: 10.1182/blood-2003-01-0255 . PMID   12738663.
  22. ↑ The Research on Adverse Drug Events and Reports (RADAR) Project, JAMA
  23. ↑ Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, et al. (June 2013). "A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia". Blood. 121 (24): 4854–4860. doi:10.1182/blood-2013-01-466706. PMC   3682338 . PMID   23591789.
  24. ↑ Mylotarg (gemtuzumab ozogamicin): Market Withdrawal, US FDA
  25. ↑ Pfizer pulls leukemia drug from U.S. market, Reuters
  26. ↑ 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.
  27. ↑ "Drug Approval Package: Mylotarg (gemtuzumab ozogamicin)". U.S. Food and Drug Administration (FDA). 7 June 2018. Retrieved 16 August 2020.
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