Gemtuzumab ozogamicin, a CD33-directed antibody-drug conjugate consisting of a recombinant humanized immunoglobulin G4(IgG4) kappa monoclonal antibody (gemtuzumab) covalently linked to a cytotoxic calicheamicin derivative ( N -acetyl-γ-calicheamicin), is an antineoplastic agent.1, 14, 17, 22, 23
Gemtuzumab ozogamicin is used as monotherapy or in combination with daunorubicin and cytarabine for the treatment of newly diagnosed CD33-positive acute myeloid leukemia (AML); the drug also is used as a single agent for the treatment of relapsed or refractory AML.1, 2, 15, 23 Gemtuzumab ozogamicin has been designated an orphan drug by FDA for use in the treatment of AML.3
Gemtuzumab ozogamicin was initially approved in May 2000 under the principles and procedures of the accelerated review policy of FDA for the treatment of CD33-positive AML in first relapse in patients 60 years of age or older who were not considered candidates for other cytotoxic chemotherapy;15, 16 however, the manufacturer voluntarily withdrew the drug from the US market in October 2010 after a required postapproval study (Southwest Oncology Group [SWOG] S0106) failed to confirm clinical benefit and found that the drug was associated with an increased risk of fatal adverse events when used in combination with standard induction therapy.10, 11, 12, 13, 15 Subsequent review of exposure-response analyses suggested that use of lower or fractionated doses of gemtuzumab ozogamicin may reduce the drug's toxicity (e.g., hepatic veno-occlusive disease) without compromising efficacy (see Description),15, 21, 22, 23 and following review of several clinical trials (ALFA-0701, AML-19, MyloFrance-1) that used lower dosages of gemtuzumab ozogamicin, FDA allowed the drug to be reintroduced in the US market.1, 2, 15, 23
Newly Diagnosed Acute Myeloid Leukemia
Gemtuzumab ozogamicin is used in combination with daunorubicin and cytarabine for induction and consolidation therapy for newly diagnosed CD33-positive de novo AML.1, 15, 26 In adults with newly diagnosed CD33-positive de novo AML, the addition of gemtuzumab ozogamicin to standard induction and consolidation therapy with daunorubicin and cytarabine substantially prolonged event-free survival; however, subgroup analysis suggested an apparent lack of clinical benefit in patients with unfavorable cytogenetics.1, 15, 25 (See Decreased Efficacy in Patients with Unfavorable Cytogenetics under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Efficacy of gemtuzumab ozogamicin in combination with daunorubicin and cytarabine for newly diagnosed CD33-positive AML is based principally on the results of an open-label, randomized phase 3 trial (ALFA-0701).1, 15, 26 In this trial, 271 patients 50-70 years of age with previously untreated de novo AML were randomized in a 1:1 ratio to receive therapy with gemtuzumab ozogamicin in combination with daunorubicin and cytarabine or standard therapy with daunorubicin and cytarabine alone.1, 15 Patients in the standard therapy group received induction therapy with daunorubicin 60 mg/m2 by IV infusion on days 1-3 and cytarabine 200 mg/m2 by continuous IV infusion on days 1-7.1, 26 Patients in the gemtuzumab ozogamicin group received the same dosages of daunorubicin and cytarabine in addition to gemtuzumab ozogamicin 3 mg/m2 (up to a maximum of 4.5 mg) by IV infusion on days 1, 4, and 7.1 If complete remission (CR) was not achieved following the first induction cycle, a second induction cycle consisting of only daunorubicin and cytarabine was administered.1 If CR was achieved, consolidation therapy according to original treatment assignment was administered for 2 cycles.1 Consolidation therapy in the standard therapy group consisted of daunorubicin 60 mg/m2 by IV infusion on day 1 and cytarabine 1 g/m2 by IV infusion every 12 hours on days 1-4 of each consolidation cycle, with an additional dose of daunorubicin 60 mg/m2 administered on day 2 of the second consolidation cycle.1 For consolidation therapy in the gemtuzumab ozogamicin group, the same dosages of daunorubicin and cytarabine as in the standard therapy group were administered with the addition of gemtuzumab ozogamicin 3 mg/m2 (up to a maximum of 4.5 mg) on day 1 of each consolidation cycle.1 Allogeneic stem cell transplantation was permitted in patients who achieved CR; however, an interval of at least 2 months was recommended between the last dose of gemtuzumab ozogamicin and transplantation.1
The primary measure of efficacy was event-free survival (defined as time to occurrence of any of the following events: failure to achieve CR or CR with incomplete platelet recovery [CRp] following induction therapy, relapse, or death from any cause).1, 15, 26 CR was defined as the presence of less than 5% blasts in bone marrow, absence of circulating blasts, full recovery of peripheral blood cell counts (platelet count exceeding 100,000/mm3, absolute neutrophil count [ANC] exceeding 1000/mm3, and hemoglobin concentration exceeding 9 g/dL) and transfusion independence.15 CRp was defined as the presence of less than 5% blasts in bone marrow, absence of circulating blasts, and incomplete recovery of platelet counts to greater than 100,000/mm3.15 Event dates for patients who failed to achieve protocol-specified CR or CRp were assigned as the date of bone marrow assessment following the last induction cycle.15, 25
The median age of patients in the ALFA-0701 study was 62 years, and 88% of the patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.1 Baseline patient characteristics were generally balanced between the treatment groups; however, a larger proportion of gemtuzumab ozogamicin-treated patients were male compared with those receiving standard therapy (55 versus 44%).1 Overall, 59, 65, and 70% of patients had documented favorable/intermediate-risk cytogenetics and 33, 27, and 21% had poor/adverse-risk cytogenetics according to the National Comprehensive Cancer Network (NCCN), European LeukemiaNet (ELN), and cytogenetic risk classifications, respectively.1 Among patients with evaluable data on CD33 expression, 14% had low expression (defined as expression on less than 30% of blasts) and none had no expression of CD33 as detected by flow cytometry.1
At the time of analysis, patients receiving gemtuzumab ozogamicin in combination with daunorubicin and cytarabine had a longer median event-free survival compared with those receiving standard therapy (17.3 versus 9.5 months; hazard ratio: 0.56).1 Because CR is the preferred end point in studies with patients with newly diagnosed AML, and CR and CRp are not considered to be equivalent measures of cytotoxic activity, an exploratory analysis limiting the definition of induction response to only CR and using the date of randomization as the event date was conducted by the FDA.1, 23, 25, 28 In this exploratory analysis, median event-free survival also was prolonged in gemtuzumab ozogamicin-treated patients compared with standard therapy recipients (13.6 versus 8.8 months; hazard ratio: 0.68).1, 25 Overall survival was not substantially different between the treatment groups.1 Results of a subgroup analysis based on relevant patient and disease characteristics suggested that the effect of gemtuzumab ozogamicin combined with daunorubicin and cytarabine on event-free survival and overall survival were consistent across most subgroups with the exception of patients with unfavorable cytogenetics, who did not appear to derive a benefit from the addition of gemtuzumab ozogamicin to standard therapy (hazard ratio: 1.11 for event-free survival and 1.55 for overall survival).15, 25 (See Decreased Efficacy in Patients with Unfavorable Cytogenetics under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Gemtuzumab ozogamicin is used as a single agent for induction and continuation therapy for newly diagnosed CD33-positive AML.1, 2, 8 In adults with newly diagnosed CD33-positive AML, single-agent gemtuzumab ozogamicin therapy substantially prolonged overall survival compared with best supportive care.1, 2
Efficacy of gemtuzumab ozogamicin as single-agent therapy for newly diagnosed CD33-positive AML is based principally on the results of an open-label, randomized phase 3 study (AML-19) in adults with previously untreated AML (de novo or secondary to myelodysplasia).1, 2 Patients were enrolled in this study if they were older than 75 years of a however, patients 61-75 years of age who were unwilling to receive standard chemotherapy or had a World Health Organization (WHO) performance status of greater than 2 also were eligible for inclusion.1, 2 A total of 237 adults were randomized (stratified by age, CD33 expression, baseline leukocyte count, WHO performance status, and treatment center) in a 1:1 ratio to receive gemtuzumab ozogamicin plus best supportive care or best supportive care alone.1, 2 Patients in the gemtuzumab ozogamicin group received a single course of induction therapy with gemtuzumab ozogamicin 6 mg/m2 by IV infusion on day 1 followed by 3 mg/m2 by IV infusion on day 8.1, 2, 8 If patients were considered to be deriving clinical benefit (i.e., stable disease or better response)8 and were not experiencing substantial toxicity, gemtuzumab ozogamicin therapy was continued at a dosage of 2 mg/m2 on day 1 of each 4-week cycle for up to 8 cycles until disease progression, relapse, or substantial toxicity occurred.1, 2, 8 The primary measure of efficacy was overall survival.1, 2 The median age of patients in the study was 77 years (range: 62-88 years of age), and 65% of patients had a WHO performance status of 0 or 1.1 Baseline patient characteristics were generally balanced between the treatment groups; however, a larger proportion of gemtuzumab ozogamicin-treated patients were female (52 versus 39%) or had favorable/intermediate risk cytogenetics (50 versus 38%) compared with those receiving best supportive care.1, 2 Among patients with evaluable data on CD33 expression, 10% had CD33 expression on less than 20% of blasts as detected by flow cytometry.1
At the time of analysis, median overall survival was prolonged in gemtuzumab ozogamicin-treated patients compared with those who received best supportive care (4.9 versus 3.6 months; hazard ratio: 0.69).1, 2 Results of a subgroup analysis based on relevant patient and disease characteristics suggested that the effect of gemtuzumab ozogamicin on overall survival was consistent across most subgroups; however, survival benefit for the drug versus best supportive care was not apparent in men (hazard ratio: 0.9) and those with CD33 expression on less than 20% of blasts (hazard ratio: 1.52).2
Relapsed or Refractory Acute Myeloid Leukemia
Gemtuzumab ozogamicin is used as a single agent for the treatment of relapsed or refractory CD33-positive AML in adults and pediatric patients 2 years of age or older.1 Use of gemtuzumab ozogamicin for this indication is based on CR rate and duration of response.1
Efficacy of gemtuzumab ozogamicin as single-agent therapy for relapsed or refractory CD33-positive AML is based principally on the results of an open-label, noncomparative phase 2 trial (MyloFrance-1).1 In this trial, 57 patients with CD33-positive AML in first relapse received a single course of gemtuzumab ozogamicin 3 mg/m2 by IV infusion on days 1, 4, and 7 followed by consolidation therapy with cytarabine (3 g/m2 for patients younger than 55 years of age or 1 g/m2 for patients 55 years of age or older and/or those with creatinine clearance less than 50 mL/minute) by IV infusion every 12 hours for 3 days.1 Hematopoietic stem cell transplantation (HSCT) was permitted following therapy with gemtuzumab ozogamicin; however, an interval of at least 90 days was recommended between gemtuzumab ozogamicin therapy and transplantation.1 The primary measures of efficacy were CR and duration of response.1 The median age of patients was 64 years (range: 22-80 years of age); 78% had intermediate-risk cytogenetics and 22% had poor-risk cytogenetics.1 The median duration of first remission following prior therapy was 10 months.1 This study excluded patients with therapy-related AML and those who had previously undergone autologous or allogeneic stem cell transplantation.1
At the time of analysis, CR following a single course of gemtuzumab ozogamicin was achieved in 26% of the patients.1 Median relapse-free survival (defined as initial documentation of CR to date of relapse or death) was 11.6 months.1
To minimize the risk of infusion-related reactions, a premedication regimen consisting of acetaminophen, an antihistamine (e.g., diphenhydramine), and a corticosteroid should be administered prior to administration of gemtuzumab ozogamicin.1 (See Infusion-related Effects under Warnings: Other Warnings and Precautions, in Cautions.) In adults , premedication with acetaminophen 650 mg and diphenhydramine hydrochloride 50 mg is recommended 1 hour prior to each gemtuzumab ozogamicin infusion, followed by methylprednisolone 1 mg/kg (or equivalent) within 30 minutes prior to infusion.1 In pediatric patients , premedication with acetaminophen 15 mg/kg (up to a maximum dose of 650 mg), diphenhydramine hydrochloride 1 mg/kg (up to a maximum dose of 50 mg), and methylprednisolone 1 mg/kg (or equivalent) is recommended 1 hour prior to each gemtuzumab ozogamicin infusion; additional doses of acetaminophen and diphenhydramine hydrochloride may be repeated at 4-hour intervals.1 If manifestations of an infusion-related reaction (e.g., pyrexia, chills, hypotension, dyspnea) occur during or within 4 hours of the infusion, methylprednisolone 1 mg/kg (or equivalent) may be administered.1
Cytoreduction is recommended prior to administration of gemtuzumab ozogamicin in patients with hyperleukocytosis (leukocyte counts of 30,000/mm3 or greater).1
Appropriate measures must be taken to prevent tumor lysis syndrome.1
Reconstitution and Administration
The usual precautions for handling and preparing solutions of cytotoxic drugs should be observed with gemtuzumab ozogamicin.1
Gemtuzumab ozogamicin is administered by IV infusion over 2 hours using a 0.2-µm polyethersulfone inline filter.1 Prior to administration, commercially available gemtuzumab ozogamicin powder for injection must be reconstituted and diluted using proper aseptic technique.1
Unopened vials of gemtuzumab ozogamicin powder for injection should be stored at 2-8°C until use; vials should not be frozen.1 The drug should be protected from light during storage and administration.1 During the infusion, only the infusion container (bag or syringe) must be protected from light.1, 24
Prior to reconstitution, gemtuzumab ozogamicin powder for injection should be brought to room temperature (approximately 5 minutes).1 The powder is reconstituted by adding 5 mL of sterile water for injection to a vial labeled as containing 4.5 mg of the drug to provide a solution containing 1 mg/mL.1 The vial should be gently swirled (not shaken) until the powder is dissolved, and the resulting solution should be inspected visually for particulate matter and discoloration.1 The reconstituted solution may contain small white to off-white, opaque to translucent, and amorphous to fiber-like particulates.1 If the reconstituted gemtuzumab ozogamicin solution is not diluted immediately, the solution may be stored under refrigeration at 2-8°C for up to 1 hour and should be protected from light; the solution should not be frozen.1
To prepare the final diluted solution for infusion, the appropriate volume of reconstituted drug should be withdrawn and diluted with 0.9% sodium chloride injection to a final concentration of 0.075-0.234 mg/mL.1 The final diluted solution should be prepared in a syringe or IV bag depending on the dose.1 For doses of 3.9 mg or greater, the infusion solution may be prepared in either a syringe or infusion bag; for doses less than 3.9 mg, the infusion solution must be prepared in a syringe to minimize the potential for drug adsorption.1, 24 The final diluted gemtuzumab ozogamicin solution for infusion should be mixed by gentle inversion and should not be shaken.1
The manufacturer recommends immediate administration of diluted solutions of the drug.1 If immediate administration is not possible, the diluted solution may be stored under refrigeration (2-8°C) for up to 12 hours (including 1-hour storage of reconstituted solution in refrigerator, if needed, prior to dilution) and at room temperature for up to 6 hours (including 2-hour infusion time and an additional 1 hour, if needed, to allow refrigerated diluted solution to reach room temperature prior to administration).1, 24 Diluted solutions of the drug should not be frozen and should be protected from light.1
Gemtuzumab ozogamicin should not be admixed with or infused simultaneously through the same IV line with any other drug.1 Commercially available gemtuzumab ozogamicin powder for injection contains no preservatives and is intended for single use; any partially used vial should be discarded.1
Combination Therapy for Newly Diagnosed CD33-positive Acute Myeloid Leukemia
When used in combination with daunorubicin and cytarabine for induction therapy in patients with newly diagnosed CD33-positive de novo acute myeloid leukemia (AML), the recommended adult dosage of gemtuzumab ozogamicin is 3 mg/m2 (up to a maximum dose of 4.5 mg) on days 1, 4, and 7.1 If complete remission is not achieved after the first induction cycle, a second cycle consisting of only daunorubicin and cytarabine may be administered.1
Induction therapy should be followed by 2 cycles of consolidation therapy.1 Consolidation therapy should be administered 14 days after complete blood cell (CBC) counts have recovered following the prior cycle.1 For consolidation therapy, the recommended adult dosage of gemtuzumab ozogamicin is 3 mg/m2 (up to a maximum dose of 4.5 mg) on day 1 in combination with daunorubicin and cytarabine.1
If absolute neutrophil count (ANC) and platelet counts do not recover to greater than 500/mm3 and greater than 100,000/mm3, respectively, within 14 days after the planned start date of consolidation therapy, gemtuzumab ozogamicin should be omitted from the consolidation cycles.1
Single-agent Therapy for Newly Diagnosed CD33-positive Acute Myeloid Leukemia
For induction therapy as a single agent in patients with newly diagnosed CD33-positive AML, the recommended adult dosage of gemtuzumab ozogamicin is 6 mg/m2 on day 1 followed by 3 mg/m2 on day 8 for one cycle.1 Induction therapy should be followed by up to 8 additional cycles of continuation therapy.1
For continuation therapy, the recommended adult dosage of gemtuzumab ozogamicin is 2 mg/m2 on day 1 of each 4-week cycle.1
Single-agent Therapy for Relapsed or Refractory CD33-positive Acute Myeloid Leukemia
Gemtuzumab ozogamicin therapy for relapsed or refractory CD33-positive AML consists of a single course of treatment.1
The recommended dosage of gemtuzumab ozogamicin in adults and pediatric patients 2 years of age or older with relapsed or refractory CD33-positive AML is 3 mg/m2 (up to a maximum dose of 4.5 mg) on days 1, 4, and 7 for one cycle.1
Dosage Modification for Toxicity
If treatment-related toxicities occur, the manufacturer states that CBCs and blood chemistries should be monitored at least 3 times per week until resolution of the toxicity.1
If thrombocytopenia or neutropenia occurs in patients receiving gemtuzumab ozogamicin in combination with daunorubicin and cytarabine, discontinuance of gemtuzumab ozogamicin during consolidation therapy may be necessary.1 (See Combination Therapy for Newly Diagnosed CD33-positive Acute Myeloid Leukemia under Dosage: Acute Myeloid Leukemia, in Dosage and Administration.)
If serum aminotransferase (ALT and/or AST) elevations exceed 2.5 times the upper limit of normal (ULN) or total bilirubin concentrations exceed 2 times the ULN, therapy with gemtuzumab ozogamicin should be temporarily interrupted until ALT and AST recover to no more than 2.5 times the ULN and total bilirubin concentrations recover to no more than 2 times the ULN.1 If therapy is withheld for more than 2 days between sequential doses, the scheduled dose should be omitted.1
If hepatic veno-occlusive disease occurs, gemtuzumab ozogamicin therapy should be discontinued.1
If infusion-related reactions occur, gemtuzumab ozogamicin infusion should be interrupted and appropriate treatment (acetaminophen, diphenhydramine hydrochloride, and/or methylprednisolone) and supportive care should be provided.1 (See Dosage and Administration: General.)
Upon resolution of a mild or moderate infusion-related reaction, the infusion may be resumed but consideration should be given to reducing the rate of infusion by at least 50%.1 If the infusion-related reaction recurs, the infusion should be interrupted again and the same recommendations followed.1
If severe or life-threatening infusion-related reactions (i.e., anaphylaxis, severe respiratory symptoms, clinically important hypotension) occur, therapy with gemtuzumab ozogamicin should be permanently discontinued.1
If other severe or life-threatening nonhematologic toxicity occurs, therapy with gemtuzumab ozogamicin should be temporarily interrupted until the toxicity has improved to no more than mild in severity.1 If therapy is withheld for more than 2 days between sequential doses, the scheduled dose should be omitted.1
The manufacturer makes no special dosage recommendations for patients with hepatic or renal impairment or for geriatric patients.1 (See Specific Populations under Cautions: Warnings/Precautions.)
Known hypersensitivity to gemtuzumab ozogamicin or any ingredient in the formulation.1
Hepatotoxicity, including severe and potentially fatal hepatic veno-occlusive disease (VOD; also known as sinusoidal obstruction syndrome), has been reported in patients receiving gemtuzumab ozogamicin therapy (either as monotherapy or as part of a combination chemotherapy regimen).1, 5, 7, 20, 27 Patients with underlying hepatic disease, those receiving higher dosages of gemtuzumab ozogamicin, and those receiving the drug before or after hematopoietic stem cell transplantation (HSCT) appear to be at greater risk of VOD.1, 20 In the ALFA-0701 trial, VOD occurred in 6 of 131 gemtuzumab ozogamicin-treated patients (5%) during or following combination therapy with daunorubicin and cytarabine, or following subsequent HSCT; 3 of these cases were fatal.1 In this trial, the median time to onset of VOD following combination therapy with gemtuzumab ozogamicin, daunorubicin, and cytarabine was 9 days (range: 2-298 days); 1 patient developed VOD more than 28 days following the last dose of gemtuzumab ozogamicin, while the other 5 patients developed the condition within 28 days of receiving any dose of the drug.1 Hepatic VOD also was reported in 2 patients who received gemtuzumab ozogamicin for relapsed disease following therapy with daunorubicin and cytarabine during the randomized trial.1 In the MyloFrance-1 study, VOD was not observed during or following gemtuzumab ozogamicin monotherapy or following subsequent HSCT for relapsed or refractory acute myeloid leukemia (AML).1 In this study, none of the patients underwent HSCT within 3.5 months of gemtuzumab ozogamicin therapy.1 In a prospective observational study conducted to assess the safety of gemtuzumab ozogamicin during routine clinical practice, hepatic VOD was reported in 9.1% of the 482 patients who were evaluated.27
In clinical trials, the risk of developing hepatic VOD was higher in adults receiving a higher dosage (9 mg/m2 for 2 doses administered 14 days apart) of gemtuzumab ozogamicin monotherapy (see Description),1, 5 those with preexisting moderate or severe hepatic impairment, and those receiving gemtuzumab ozogamicin before or after HSCT.1 The risk of developing VOD was increased by 8.7-fold in patients with preexisting moderate or severe hepatic impairment compared with those without such impairment.1 In addition, the risk was increased by 2.9-fold in patients who received gemtuzumab ozogamicin prior to HSCT and by 2.6-fold in those who received the drug after HSCT compared with those who received the drug but did not undergo HSCT.1 Although a relationship between development of hepatic VOD and timing of HSCT prior to or following higher dosages of gemtuzumab ozogamicin monotherapy has not been established, some clinicians recommend that patients wait at least 2-3.5 months after the last dose of gemtuzumab ozogamicin before undergoing HSCT because of evidence suggesting that intervals less than this time period may increase the risk of VOD.1, 5
Liver function test abnormalities, including elevations in serum aminotransferase (e.g., ALT and AST) and bilirubin concentrations, also have been reported in patients receiving gemtuzumab ozogamicin either in combination with daunorubicin and cytarabine or as monotherapy.1
Patients receiving gemtuzumab ozogamicin should be closely monitored for signs and symptoms of hepatic VOD (e.g., elevated aminotransferase and/or total bilirubin concentrations, hepatomegaly [generally with pain], rapid weight gain, ascites).1, 7, 20 Liver function tests (i.e., ALT, AST, total bilirubin, alkaline phosphatase) should be assessed prior to each dose of gemtuzumab ozogamicin, and more frequently, as clinically indicated, during the post-HSCT period in patients proceeding to HSCT following therapy with gemtuzumab ozogamicin.1 If liver function test abnormalities occur, the manufacturer recommends more frequent monitoring of liver function tests and clinical manifestations of hepatotoxicity.1 Temporary interruption of therapy or drug discontinuance may be required if hepatotoxicity occurs.1 (See Hepatotoxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) If hepatic VOD occurs, gemtuzumab ozogamicin therapy should be discontinued and patients should be treated according to standard practices.1
Other Warnings and Precautions
Life-threatening or fatal infusion-related reactions (e.g., pyrexia, chills, hypotension, tachycardia, hypoxia, respiratory failure) have been reported in patients receiving gemtuzumab ozogamicin therapy, generally during or within 24 hours following the infusion.1
Premedication consisting of acetaminophen, an antihistamine (e.g., diphenhydramine), and a corticosteroid should be administered prior to each dose of gemtuzumab ozogamicin.1 Patients should be monitored during and for at least 1 hour following completion of each infusion.1 The manufacturer also recommends that vital signs be monitored frequently during infusions of the drug.1 If manifestations of an infusion-related reaction occur, especially dyspnea, bronchospasm, or hypotension, the gemtuzumab ozogamicin infusion should be immediately interrupted and the patient should be monitored until resolution of the reaction.1 All patients should receive appropriate treatment and supportive care; in addition, a reduction in infusion rate or permanent discontinuance of therapy may be required depending on the severity of the reaction.1 If severe or life-threatening infusion-related reactions (i.e., anaphylaxis, severe respiratory symptoms, clinically important hypotension) occur, gemtuzumab ozogamicin therapy should be permanently discontinued.1 (See Infusion-related Effects under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Serious or fatal hemorrhage associated with prolonged thrombocytopenia has been reported in patients receiving gemtuzumab ozogamicin therapy.1 In the ALFA-0701 trial, hemorrhage was reported in 90% of patients receiving gemtuzumab ozogamicin in combination with daunorubicin and cytarabine, and grade 3 or 4 hemorrhage was reported in 21% of patients.1 Fatal hemorrhagic events (i.e., cerebral, intracranial, and subdural hematoma) occurred in 3% of patients receiving gemtuzumab ozogamicin in combination with daunorubicin and cytarabine.1 In the ALFA-0701 trial, the risk of prolonged thrombocytopenia (platelet counts less than 50,000/mm3 lasting longer than 42 days in the absence of active disease) increased following each treatment phase.1 Prolonged thrombocytopenia occurred in 19, 24, and 35% of patients following induction therapy, first consolidation cycle, and second consolidation cycle, respectively, with gemtuzumab ozogamicin in combination with daunorubicin and cytarabine compared with 7, 7, and 24%, respectively, of those receiving combination therapy with daunorubicin and cytarabine alone.1 Hemorrhage occurred at a lower incidence during consolidation therapy (5-6%) compared with induction therapy (18%).1 In the AML-19 study, hemorrhage was reported in 25% of patients receiving gemtuzumab ozogamicin monotherapy, and grade 3 or greater hemorrhage was reported in 13% of patients.1 Fatal hemorrhagic events occurred in 1% of patients receiving gemtuzumab monotherapy in this study.1 In the MyloFrance-1 trial, grade 3 or 4 hemorrhage was reported in 7 or 0%, respectively, of patients receiving gemtuzumab ozogamicin monotherapy.1
Complete blood cell (CBC) counts should be assessed prior to each dose of gemtuzumab ozogamicin, and more frequently following treatment until resolution of cytopenias.1 Patients receiving gemtuzumab ozogamicin should be monitored for manifestations of bleeding during therapy.1 If hemorrhage or prolonged thrombocytopenia occurs, treatment delay or drug discontinuance may be required and supportive care should be instituted according to standard practice.1 (See Hematologic Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Prolongation of the QT interval has been reported in patients receiving other antibody-drug conjugates containing calicheamicin.1, 29
ECG and serum electrolytes should be monitored prior to initiating gemtuzumab ozogamicin therapy and as clinically indicated in patients with a history of or predisposition to QT interval prolongation, including those with electrolyte abnormalities and those receiving concomitant drugs known to prolong the QT interval.1
Decreased Efficacy in Patients with Unfavorable Cytogenetics
Results of a subgroup analysis in the ALFA-0701 trial suggested a lack of benefit for gemtuzumab ozogamicin in combination with daunorubicin and cytarabine compared with standard therapy alone in the subgroup of patients with unfavorable cytogenetics (hazard ratio: 1.11).1, 15
The manufacturer states that clinicians should consider the potential benefits and risks of continuing gemtuzumab ozogamicin in combination with daunorubicin and cytarabine in patients with newly diagnosed de novo AML following availability of cytogenetic test results.1 (See Combination Therapy under Acute Myeloid Leukemia: Newly Diagnosed Acute Myeloid Leukemia, in Uses.)
Fetal/Neonatal Morbidity and Mortality
There are no available data regarding the risk of gemtuzumab ozogamicin use in pregnant women; however, based on its mechanism of action and animal findings, the drug may cause fetal harm.1 Embryofetal toxicity (e.g., decreased fetal growth, embryofetal death) and teratogenicity (e.g., skeletal anomalies) have been demonstrated in rats receiving gemtuzumab ozogamicin at maternally toxic dosages that resulted in exposure levels approximately 0.4 times the human exposure at the maximum recommended dosage.1
Pregnancy should be avoided during gemtuzumab ozogamicin therapy.1 The manufacturer recommends confirmation of pregnancy status prior to initiation of gemtuzumab ozogamicin, and women of childbearing potential should be advised to use effective contraceptive methods during and for at least 6 months after the last dose.1 In addition, men with female partners of childbearing potential should use effective methods of contraception during and for at least 3 months after the last dose.1 Patients should be apprised of the potential hazard to the fetus if gemtuzumab ozogamicin is used during pregnancy.1
Results of animal studies suggest that gemtuzumab ozogamicin may impair male and female fertility.1 In one study, decreased numbers of implantation sites, corpora lutea, and viable embryos were observed in female rats receiving gemtuzumab ozogamicin at exposure levels approximately 0.4 times the human exposure at the maximum recommended dosage for 14 days prior to mating.1 In a fertility and general toxicology study, degeneration of reproductive tissues and adverse effects on sperm were observed in male animals receiving gemtuzumab ozogamicin at exposure levels approximately 1.2 times the human exposure at the maximum recommended dosage for 28 days followed by mating with untreated females either at the end of the dosing period or 9 weeks after the last dose.1 Adverse effects on male and female reproductive organs also have been observed in animals receiving other antibody-drug conjugates containing calicheamicin.1, 29
As with all therapeutic proteins, there is a potential for immunogenicity with gemtuzumab ozogamicin.1 Clinical trials did not evaluate the immunogenic potential of the drug at recommended dosages.1
Gemtuzumab ozogamicin may cause fetal harm if administered to pregnant women based on animal findings.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
It is not known whether gemtuzumab ozogamicin is distributed into human milk.1 Because of the potential for serious adverse reactions to gemtuzumab ozogamicin in nursing infants, women should be advised to discontinue nursing during therapy and for at least 1 month after discontinuance of therapy.1 The effects of the drug on nursing infants or on milk production are unknown.1
Safety and efficacy of gemtuzumab ozogamicin alone or in combination with daunorubicin and cytarabine have not been established in pediatric patients with newly diagnosed AML.1
Use of gemtuzumab ozogamicin monotherapy in pediatric patients 2 years of age or older with relapsed or refractory AML is supported by a noncomparative study that included 13 patients 2 years to less than 12 years of age and 15 patients 12-18 years of a only 1 patient was younger than 2 years of age.1 No overall differences in safety and efficacy were observed by age.1
In the ALFA-0701 trial evaluating gemtuzumab ozogamicin in combination with daunorubicin and cytarabine for newly diagnosed de novo AML, no overall differences in safety and efficacy were observed between geriatric patients 65 years of age or older and younger adults.1
In the AML-19 study evaluating gemtuzumab ozogamicin monotherapy for newly diagnosed AML, all patients were 60 years of age or older and 65% were 75 years of age or older.1 No overall differences in safety and efficacy were observed by age.1
In the MyloFrance-1 trial evaluating gemtuzumab ozogamicin monotherapy for relapsed or refractory AML, no overall differences in safety and efficacy were observed between geriatric patients 65 years of age or older and younger adults; however, pyrexia and infection of severe or greater severity occurred more frequently in geriatric patients compared with younger adults.1
The pharmacokinetics of gemtuzumab ozogamicin do not appear to be substantially altered in patients with mild hepatic impairment.1 Data are not available in patients with moderate or severe hepatic impairment (total bilirubin concentration exceeding 1.5 times the upper limit of normal [ULN]).1
Patients with moderate to severe hepatic impairment may have a higher risk of developing gemtuzumab ozogamicin-induced hepatic veno-occlusive disease.1 (See Hepatotoxicity under Warnings/Precautions: Warnings, in Cautions.)
The pharmacokinetics of gemtuzumab ozogamicin do not appear to be substantially altered in patients with mild or moderate renal impairment (creatinine clearance of 30-89 mL/minute).1 Data are not available in patients with severe renal impairment (creatinine clearance of 15-29 mL/minute).1
Adverse effects reported in at least 15% of adults receiving gemtuzumab ozogamicin in combination with daunorubicin and cytarabine for newly diagnosed de novo AML in the ALFA-0701 trial include hemorrhage,1 infection,1 prolonged thrombocytopenia (platelet counts less than 50,000/mm3 lasting longer than 42 days in the absence of active disease),1 anemia,1 and neutropenia.1 Grade 3 or greater laboratory abnormalities reported in at least 10% of patients receiving gemtuzumab ozogamicin who had grade 2 or lesser severity of the laboratory abnormality at baseline include hypophosphatemia,1 hypokalemia,1 hyponatremia,1 elevated concentrations of alkaline phosphatase,1 and elevated concentrations of aminotransferases (ALT, AST).1
Adverse effects reported in at least 15% of adults receiving gemtuzumab ozogamicin monotherapy for newly diagnosed AML in the AML-19 study include hepatotoxicity,1 fatigue,1 infection,1 cardiac effects,1 hemorrhage,1 febrile neutropenia,1 and metabolic abnormalities.1
Adverse effects reported in at least 15% of patients receiving gemtuzumab ozogamicin monotherapy for relapsed or refractory AML include pyrexia,1 infection,1 elevated concentrations of ALT and/or AST,1 hemorrhage,1 nausea and vomiting,1 constipation,1 mucositis,1 headache,1 and rash.1 Grade 3 adverse effects reported in more than 30% of these patients include sepsis.1
In vitro, gemtuzumab ozogamicin is unlikely to inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 at clinically relevant concentrations.1 In vitro studies also indicate that the calicheamicin derivative of the antibody-drug conjugate is unlikely to inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 inhibit uridine diphosphate-glucuronosyltransferase (UGT) 1A1, 1A4, 1A6, 1A9, and 2B7, or induce CYP isoenzymes 1A2, 2B6, and 3A4 at clinically relevant concentrations.1
The calicheamicin derivative of the antibody-drug conjugate also is unlikely to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, organic anion transport protein (OATP) 1B1, and OATP1B3.1
No formal drug interaction studies have been performed to date with gemtuzumab ozogamicin.1
Drugs that Prolong the QT Interval
ECG and electrolyte monitoring is recommended in patients receiving gemtuzumab ozogamicin concomitantly with other drugs known to prolong the QT interval.1 (See Prolongation of QT Interval under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, is an antineoplastic agent.1 The anti-CD33 antibody, a recombinant humanized IgG4 kappa immunoglobulin, is covalently linked to the cytotoxic antitumor antibiotic N -acetyl-γ-calicheamicin; the cytotoxic moiety is a derivative of calicheamicin, a natural product isolated from the microorganism Micromonospora echinospora subsp. calichensis .1, 14, 16, 17, 22, 23 The formulation of gemtuzumab ozogamicin consists of both conjugated and unconjugated antibody;1, 22 on average, approximately 2-3 moles of the calicheamicin derivative are attached to each mole of antibody.1 The antibody portion of gemtuzumab ozogamicin binds specifically to antigen CD33,1 a transmembrane glycoprotein that is expressed on the surface of leukemic blasts in more than 80% of patients with acute myeloid leukemia (AML).14, 16, 22 Following binding of the antibody portion of gemtuzumab ozogamicin to antigen CD33, the resultant complex is internalized by the myeloid cell.1, 23 The calicheamicin derivative of the antibody-drug conjugate is released via hydrolytic cleavage of the linker and binds to DNA in the minor groove causing double-strand breaks and subsequent cell cycle arrest and apoptosis.1, 22, 23
Maximum delivery of calicheamicin to leukemic blast cells appears to be dependent on saturation of a high percentage of antigen CD33; in a pharmacodynamic analysis, near maximal saturation of antigen CD33 in peripheral blood was observed with gemtuzumab ozogamicin doses as low as 2 mg/m2.1, 15 Although formal pharmacokinetic analyses have not been conducted in patients receiving a gemtuzumab ozogamicin dosage of 3 mg/m2 on days 1, 4, and 7 (fractionated regimen), simulations suggest that peak plasma concentrations and systemic exposure of the drug are reduced following the initial dose and full course of a fractionated regimen compared with peak plasma concentrations following dosing with an unfractionated regimen (gemtuzumab ozogamicin 9 mg/m2 for 2 doses administered 14 days apart).1, 6, 15 Because increased peak plasma concentrations following the initial dose of gemtuzumab ozogamicin 9 mg/m2 have been correlated with an increased risk of hepatic veno-occlusive disease (VOD),1, 15 these data suggest that a lower-dose fractionated regimen may reduce the risk of hepatic VOD without compromising efficacy.15 (See Uses: Acute Myeloid Leukemia.)
In vitro studies indicate that the calicheamicin derivative of the antibody-drug conjugate is extensively metabolized, primarily by nonenzymatic reduction.1 In vitro, the calicheamicin derivative is approximately 97% bound to plasma proteins.1 The terminal half-life of unconjugated gemtuzumab is 62 and 90 hours following the first and second doses, respectively, of the antibody-drug conjugate.1
Risk of hepatotoxicity, including severe, life-threatening, or fatal hepatic veno-occlusive disease (VOD).1 Importance of informing patients that the risk of developing hepatic VOD may be increased in patients who have previously undergone or plan to undergo hematopoietic stem cell transplantation (HSCT).1 Importance of regular monitoring for signs and symptoms of hepatotoxicity (e.g., rapid weight gain, right upper-quadrant abdominal pain or tenderness, hepatomegaly, ascites) during therapy.1
Risk of thrombocytopenia and hemorrhage.1 Importance of informing clinicians if signs and symptoms of bleeding occur.1
Risk of infusion-related reactions.1 Importance of reporting signs and symptoms of such reactions, including fever, chills, rash, or breathing difficulty.1
Risk of fetal harm.1 Necessity of advising women of childbearing potential and men who are partners of such women that they should use an effective method of contraception while receiving the drug and for at least 6 and 3 months, respectively, after discontinuance of therapy.1 Importance of women informing clinicians if they are or plan to become pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1
Importance of advising women to discontinue nursing during therapy and for at least 1 month after discontinuance of the drug.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions October 15, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Wyeth. Mylotarg® (gemtuzumab ozogamicin) for injection prescribing information. Philadelphia, PA; 2018 Apr. [Web]
2. Amadori S, Suciu S, Selleslag D et al. Gemtuzumab Ozogamicin Versus Best Supportive Care in Older Patients With Newly Diagnosed Acute Myeloid Leukemia Unsuitable for Intensive Chemotherapy: Results of the Randomized Phase III EORTC-GIMEMA AML-19 Trial. J Clin Oncol . 2016; 34:972-9. [PubMed 26811524]
3. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2019 May 18. [Web]
5. Battipaglia G, Labopin M, Candoni A et al. Risk of sinusoidal obstruction syndrome in allogeneic stem cell transplantation after prior gemtuzumab ozogamicin treatment: a retrospective study from the Acute Leukemia Working Party of the EBMT. Bone Marrow Transplant . 2017; 52:592-599. [PubMed 28092357]
6. Appelbaum FR, Bernstein ID. Gemtuzumab ozogamicin for acute myeloid leukemia. Blood . 2017; 130:2373-2376. [PubMed 29021230]
7. Fan CQ, Crawford JM. Sinusoidal obstruction syndrome (hepatic veno-occlusive disease). J Clin Exp Hepatol . 2014; 4:332-46. [PubMed 25755580]
8. Amadori S, Suciu S, Selleslag D et al. Randomized trial of two schedules of low-dose gemtuzumab ozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy. A phase II study of the EORTC and GIMEMA leukaemia groups (AML-19). Br J Haematol . 2010; 149:376-82. [PubMed 20230405]
9. Olombel G, Guerin E, Guy J et al. The level of blast CD33 expression positively impacts the effect of gemtuzumab ozogamicin in patients with acute myeloid leukemia. Blood . 2016; 127:2157-60. [PubMed 26929274]
10. Food and Drug Administration. Center for Drug Evaluation and Research (CDER): Oncologic Drugs Advisory Committee (ODAC) meeting. Silver Spring, MD; 2017 Jul 11. [Web]
11. Food and Drug Administration. Gemtuzumab ozogamicin. Silver Spring, MD; 2010 Jun 21. From FDA website. [Web]
12. Shapiro M. Dear healthcare professional letter: Pfizer prepares for voluntary withdrawal of US New Drug Application and for discontinuation of commercial availability of Mylotarg for relapsed acute myelogeneous leukemia. New York, NY: Pfizer; 2010 Jun 21. [Web]
13. Report of study: S0106 Phase III. Presented at Southwest Oncology Group spring group meeting. San Francisco, CA: 2010 Apr 17. [Web]
14. Godwin CD, Gale RP, Walter RB. Gemtuzumab ozogamicin in acute myeloid leukemia. Leukemia . 2017; 31:1855-1868. [PubMed 28607471]
15. Food and Drug Administration. FDA briefing document: Oncologic drugs advisory committee meeting. Silver Spring, MD; June 2017. From FDA web site. [Web]
16. Wyeth Pharmaceuticals. Mylotarg® (gemtuzumab ozogamicin) for injection prescribing information. Philadelphia, PA; 2001 Jul.
17. Yilmaz M, Richard S, Jabbour E. The clinical potential of inotuzumab ozogamicin in relapsed and refractory acute lymphocytic leukemia. Ther Adv Hematol . 2015; 6:253-61. [PubMed 26425338]
20. Magwood-Golston JS, Kessler S, Bennett CL. Evaluation of gemtuzumab ozogamycin associated sinusoidal obstructive syndrome: Findings from an academic pharmacovigilance program review and a pharmaceutical sponsored registry. Leuk Res . 2016; 44:61-4. [PubMed 27030962]
21. Burnett A, Cavenagh J, Russell N et al. Defining the dose of gemtuzumab ozogamicin in combination with induction chemotherapy in acute myeloid leukemia: a comparison of 3 mg/m2 with 6 mg/m2 in the NCRI AML17 Trial. Haematologica . 2016; 101:724-31. [PubMed 26921360]
22. Cowan AJ, Laszlo GS, Estey EH et al. Antibody-based therapy of acute myeloid leukemia with gemtuzumab ozogamicin. Front Biosci (Landmark Ed) . 2013; 18:1311-34. [PubMed 23747885]
23. Jen EY, Ko CW, Lee JE et al. FDA Approval: Gemtuzumab Ozogamicin for the Treatment of Adults with Newly Diagnosed CD33-Positive Acute Myeloid Leukemia. Clin Cancer Res . 2018; [PubMed 29476018]
24. Pfizer, Philadelphia, PA: Personal communication.
25. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761060Orig1s000/761060Orig2s000: Summary Review. From FDA website. [Web]
26. Castaigne S, Pautas C, Terré C et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet . 2012; 379:1508-16. [PubMed 22482940]
27. Tallman MS, McDonald GB, DeLeve LD et al. Incidence of sinusoidal obstruction syndrome following Mylotarg (gemtuzumab ozogamicin): a prospective observational study of 482 patients in routine clinical practice. Int J Hematol . 2013; 97:456-64. [PubMed 23460018]
28. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761060Orig1s000/761060Orig2s000: Clinical Review. From FDA website. [Web]
29. Wyeth Pharmaceuticals. Besponsa® (inotuzumab ozogamicin) for injection prescribing information. Philadelphia, PA; 2017 Aug. [Web]