Gemtuzumab ozogamicin

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.^[5][9]

Gemtuzumab ozogamicin is a recombinant, humanized anti-CD33 monoclonal antibody (IgG4 κ antibody hP67.6) covalently attached to the cytotoxic antitumor antibiotic calicheamicin (N-acetyl-γ-calicheamicin) payload via a bifunctional linker (4-(4-acetylphenoxy)butanoic acid).

Calicheamicin (the payload) is approximately 4,000 times more active than doxorubicin, and since it also destroys the DNA of normal, healthy, cells, it cannot be used as a single agent to treat patients. However, by linking calicheamicin to a monoclonal antibody, scientists have optimized the features of both components, creating a class of targeted drugs called antibody-drug conjugates (ADC) or armed antibodies which selectively dispatch highly potent cytotoxic anticancer chemotherapies directly to cancer cells while, at the same time, leaving healthy tissue unaffected.^[11]

CD33 is expressed in most leukemic blast cells but also in normal hematopoietic cells, the intensity diminishing with maturation of stem cells.

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, gemtuzumab ozogamicin 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 gemtuzumab ozogamicin 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^[7][27] and in the European Union.^[6]