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Here We GO Again: The Reapproval of Gemtuzumab Ozogamicin

Tracy Krause, PharmD BCOP
Oncology Clinical Pharmacy Specialist
Hospital of the University of Pennsylvania
Philadelphia, PA

Induction therapy with 7+3 has been the hallmark of chemotherapy for newly diagnosed acute myeloid leukemia (ND-AML) for several decades. The year 2017 resulted in several U.S. Food and Drug Administration (FDA) approvals for AML, increasing the therapeutic armamentarium. The fourth AML therapy approved in 2017, gemtuzumab ozogamicin (GO), was previously approved for CD33-positive AML but was withdrawn from the market in 2010. Given the return of GO to our treatment options, it is important that we understand differences between the past and present approvals and the data that emerged in the interim and allowed the reapproval.

CD33 is expressed on myeloid precursors, maturing myeloid cells, and monocytes. CD33 is present on at least some leukemia blasts in almost all patients with AML, with about 50% of patients expressing CD33 on more than 75% of blasts.1 Despite CD33’s status as a common marker in AML, early studies of CD33 antibodies had shown limited clinical benefit.2 However, because antibody binding to CD33 results in rapid internalization of the antigen and antibody, conjugation of other molecules to enhance efficacy of therapy was considered. Calicheamicins are potent antitumor antibiotics that bind into the minor groove of DNA, resulting in single- and double-strand breaks. Because of the potency and toxicity of calicheamicins, it is not clinically feasible to give them in their conventional form. Binding of a calicheamicin derivative to the CD33 antibody with an acid-labile linker allows for cytotoxicity against CD33-positive leukemia cells, while decreasing off-target toxicity.3

Clinical Trials

The initial FDA approval of GO in 2000 was as a single agent, for the treatment of CD33-positive AML in patients age 60 or older in first relapse who were deemed not to be candidates for other cytotoxic chemotherapy. This approval was based on two uncontrolled phase-2 studies, where GO-treated patients in first relapse achieved a complete response (CR) in 16.2% of cases and CR with incomplete platelet recovery (CRp) in 13.4%.4,5 This approval made GO the first FDA-approved antibody-drug conjugate.6 On the basis of these early studies showing complete or nearly complete CD33-binding saturation with a dose of 9 mg/m2, this became the recommended dose, with administration separated by 2 weeks.3

As part of postapproval investigation, Southwest Oncology Group study S0106 was conducted to confirm the therapeutic benefit of GO. S0106 was a prospective trial of patients up to age 60 with de novo AML randomized to receive standard induction with or without GO 6 mg/m2 given on day 4. Patients receiving GO were given a reduced dose of daunorubicin (45 mg/m2) compared to the control group (60 mg/m2). The results of this study showed that GO-treated patients had increased treatment-related mortality (TRM) (5.5% vs. 1.4%, p = .0062), including fatal hemorrhage, without any improvement in CR or overall survival (OS) compared to patients receiving standard induction alone.7 Because of the results of S0106, as well as a higher rate of sinusoidal obstruction syndrome (SOS) following approval, GO was withdrawn from the commercial market in 2010, pending additional clinical trial review.

Subsequent trials such as NCRI AML-17 showed that GO given at a dose of 6 mg/m2 showed no improvement in CR, relapse, or OS compared to 3 mg/m2 but did confer higher TRM and SOS risk.8 Further analysis showed that the risk of SOS correlated with higher Cmax with the first dose of GO.9 Levels of CD33 molecules are downregulated following GO exposure but return to baseline after 72 hours.10 This data led to the hypothesis that lower, fractionated doses of 3 mg/m2 on days 1, 4, and 7 may be safer and equally efficacious compared to higher doses of 6 or 9 mg/m2 separated by 2 weeks.

A meta-analysis of five randomized controlled trials adding GO to induction therapy showed a reduced risk of relapse and improved 5-year OS, along with fewer early deaths in patients receiving 3 mg/m2 compared to 6 mg/m2. In these studies, survival benefit was seen in patients with favorable cytogenetics (odds ratio [OR] .47, .31–.73; p = .0006) and intermediate cytogenetics (OR .84, .75–.95; p = .005), but not in patients with adverse cytogenetics (OR .99, .83–1.18; p = .9). In comparison with studies using higher single doses, the use of lower fractionated doses of GO did not increase TRM.11 On the basis of the data supporting the efficacy and safety of lower fractionated doses, this dosing schedule was accepted for the pivotal trial ALFA-0701.12

ALFA-0701 was a multicenter open-label randomized phase-3 trial of conventional induction chemotherapy with or without GO for induction and consolidation in 271 patients 50–70 years old with ND-AML. In the induction regimen of both treatment arms, patients received 60 mg/m2 of daunorubicin as part of the 7+3 regimen. The primary end point of event-free survival (EFS) was extended with the addition of GO to 7+3 versus 7+3 alone (17.3 vs. 9.5 months, p < .001). OS was also increased in GO-treated patients (19.2 vs. 34 months, p = .0368). Persistent grade 3 and 4 thrombocytopenia was reported in 4 (3%) patients in the control group and in 22 (16%) in the GO group (p < .001).12

GO was also studied as first-line monotherapy for older patients unable to receive intensive chemotherapy. Patients were randomized to receive either GO 6 mg/m2 on day 1 and 3 mg/m2 on day 8 or best supportive care (BSC). Patients receiving GO had a median OS of 4.9 months versus 3.6 months for BSC.13 Thirty-day all-cause mortality was similar for the groups, suggesting that the fractionated schedule limited the additional TRM observed in previous high-dose studies.14

GO has shown benefit in AML patients with relapsed disease. In the Mylofrance-1 trial, 57 patients in first relapse following a remission of 3–18 months received fractionated GO 3 mg/m2 on days 1, 4, and 7. By day 43, 15 patients achieved CR, and 4 patients achieved CRp. In this study, no significant difference in remission based on age, cytogenetic risk, or duration of first remission was seen.15


Although fractionated dosing of GO has decreased TRM risk, hepatotoxicity, including SOS, remains a concern. In the ALFA-0701 study, 6 patients (4.6%) developed SOS, either during GO treatment or after hematopoietic stem cell transplant (HSCT). The median time of onset of SOS after GO was 9 days (range: 2–298 days), with most events occurring within 4 weeks of GO administration.12,16 Rates of SOS increase in patients with baseline hepatic impairment, and GO should be delayed until hepatic function normalizes in this population. Because of the risk of SOS in GO patients receiving HSCT, the ALFA-0701 study recommended at least 2 months between the last GO dose and HSCT.12,16 Because of the risk of high mortality of SOS, close monitoring for signs of SOS and prompt management are warranted. Further analysis of prophylactic strategies to prevent SOS following GO may be useful, though previous reports assessing ursodiol did not show a benefit when GO was given at higher doses.17

Infusion reactions, including dyspnea, hypotension, and anaphylaxis, have been seen with GO. Because patients with higher pretreatment peripheral blast counts may be at higher risk of severe infusion reactions, cytoreduction is currently recommended in patients with white blood cell counts above 30,000/mm3. Premedication with acetaminophen, diphenhydramine, and corticosteroids is currently recommended prior to the administration of GO.16

GO-treated patients can develop myelosuppression, including thrombocytopenia. Persistent thrombocytopenia occurred in 16% of the patients treated with GO in the AML-0701 trial, leading to an increased need for platelet transfusions compared to patients treated with standard induction chemotherapy. Fatal bleeding events occurred in 3% of patients receiving GO.12,16 The study protocol was also amended to omit GO in the consolidation regimen in patients who did not achieve platelet recovery after induction.12 Therefore, patients treated with GO should be monitored closely during and after therapy for need for transfusions as well as for signs of bleeding.

Other calicheamicin-containing therapies have been observed to cause QT interval prolongation. Current labeling recommends monitoring for QTc prolongation during GO therapy, in particular when GO is administered with known QTc-prolonging medications and in patients with a history of QTc prolongation.16

Preparation and Administration

Prior to reconstitution, the drug product vials should be allowed to reach ambient temperature for approximately 5 minutes. The reconstituted solution should be used immediately or within an hour if refrigerated. The reconstituted solution should be added to normal saline (NS) to make a total volume of 50 ml or 100 ml, depending on the dose.16 According to the manufacturer (Pfizer, e-mail communication, October 2017), the stability data for GO infusions was based on a concentration range of .075–.234 mg/ml. Following dilution into NS, the solution can be stored at room temperature for up to 6 hours or refrigerated for up to 12 hours. GO should be infused over 2 hours using an in-line .2-micron polyethersulfone (PES) filter. During infusion, the intravenous bag should be protected from light with the use of a light-blocking cover. The infusion line does not need to be protected from light.16

Future Directions

Calicheamicin is a substrate of ATP-binding cassette (ABC) transporters, including P-glycoprotein (Pgp). One characteristic of some AMLs with adverse cytogenetics is high expression of Pgp, which may explain why this patient subgroup does not show significant improvement with GO therapy.3 Coadministration of inhibitors of ABC transporters with GO may help to increase the intracellular concentration of free calicheamicin and improve calicheamicin-induced cytotoxicity. Further experience with fractionated dosing with GO may also lead to improved tolerability and enhanced response.10

Because of the high density of CD33 expression in patients with acute promyelocytic leukemia (APML), the addition of GO to all-trans retinoic acid (ATRA) has been shown to be effective for both newly diagnosed and relapsed disease. In one study where GO could be given in addition to ATRA and arsenic trioxide in high-risk APML, 4-year OS was 89% (95% confidence interval [CI] 70%–96%) in those patients receiving GO.18 Further comparisons to idarubicin-containing regimens may be warranted.

The induction and consolidation regimens used concurrently with GO could warrant further review. In S0106, daunorubicin doses in the GO group were decreased to 45 mg/m2 to prevent toxicity. In ALFA-0701, induction daunorubicin doses were 60 mg/m2, and the study included a population of patients 50–60 years of age. With the current data showing that treatment-related toxicity is significantly improved with lower fractionated doses of GO, research into higher daunorubicin doses of 90 mg/m2 in younger patients with good cytogenetics to further enhance response and survival may be useful.

The recent reapproval of GO comes at a time when several other new treatments have arisen for patients with AML. Evaluating patients for GO-containing therapy compared to other new regimens is important prior to initiation of treatment. In comparison to the time when 7+3 was the standard of care for all patients, initiation of therapy may now be delayed in order to confirm cytogenetics and molecular status so that the most appropriate induction regimen is chosen. Studies evaluating the combination of GO with other recently approved therapies may also be useful in developing more effective AML treatment regimens in the future. 


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