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GEMTUZUMAB OZOGAMICIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Gemtuzumab ozogamicin is drug-antibody conjugate for the treatment of acute myeloid leukemia (AML).

Specific Substances

    1) Gemtuzumab
    2) CDP-771
    3) CMA-676
    4) WAY-CMA-676
    5) CAS 220578-59-6

Available Forms Sources

    A) FORMS
    1) MARKET WITHDRAWAL: Gemtuzumab ozogamicin was voluntarily withdrawn from the United States (US) market June 21, 2010, and the new drug application (NDA) will be voluntarily withdrawn effective October 15, 2010. Physician submission of an investigational new drug (IND) application to the FDA is required for future use in new patients(Pfizer Oncology, 2010).
    2) Gemtuzumab ozogamicin is manufactured as a single-use vial containing 5 mg for intravenous administration (Prod Info MYLOTARG(R) IV injection, 2006).
    B) USES
    1) Gemtuzumab ozogamicin is indicated for the treatment of CD33 positive acute myeloid leukemia in patients who are at least 60 years old, have experienced their first relapse, and who are not considered candidates for other cytotoxic chemotherapy (Prod Info MYLOTARG(R) IV injection, 2006).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Myelosuppression is the major dose limiting toxicity with gemtuzumab ozogamicin; thrombocytopenia and neutropenia develop in nearly all patients, significant anemia develops in about half. Hypersensitivity reaction, which usually occurs during the infusion or within 24 hours of administration, can include anaphylaxis, infusion reactions (a complex of symptoms including fever and chills and less frequently hypotension and dyspnea) and infrequently pulmonary events. Hepatotoxicity has been associated with therapy. Other adverse events include nausea (68%), vomiting (58%), headache (37%) and chills (66%). Less frequently reported events include hypotension (20%), hypertension (16%), hyperglycemia (10%), and hypoxia (5%).
    B) WITH POISONING/EXPOSURE
    1) No cases of overdose have been reported at the time of this review.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Hepatic veno-occlusive disease (VOD), with fatalities, has infrequently occurred following gemtuzumab ozogamicin therapy. Patients with a history of hepatotoxicity, or who have undergone stem cell transplantation prior or following gemtuzumab therapy appear to be at increased risk for developing VOD.
    2) Hepatic fibrosis and Budd-Chiari syndrome have also been rarely reported following gemtuzumab ozogamicin therapy.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Severe myelosuppression is the dose-limiting toxicity with gemtuzumab ozogamicin therapy.
    0.2.20) REPRODUCTIVE
    A) Gemtuzumab ozogamicin is classified as FDA pregnancy category D. External, visceral, and skeletal malformations, and increased rates of embryo-fetal mortality occurred in rats following maternal administration during organogenesis.

Laboratory Monitoring

    A) Monitor serial CBC with differential and platelet count following acute exposure.
    B) Monitor vital signs. Monitor daily weight; sudden weight gain suggests hepatic veno-occlusive disease.
    C) Monitor fluid and electrolyte status in patients with severe vomiting.
    D) Monitor hepatic enzymes and bilirubin levels.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) In case of gemtuzumab ozogamicin overdose, treatment is symptomatic and supportive. There is no antidote available.
    B) Severe myelosuppression may occur following an overdose. Monitor peripheral blood counts, platelet count.
    C) Transfusions of packed red blood cells and platelets may be useful if bleeding occurs.
    D) For severe neutropenia, consider filgrastim 5 mcg/kg/day subcutaneously or IV, or sargramostim 250 mcg/m(2)/day intravenous infusion over 4 hours.
    E) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    F) ALLERGIC REACTION: MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    G) INTRATHECAL OVERDOSE: No clinical reports of gemtuzumab ozogamicin are available, information is derived from experience with other agents. Keep the patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). For large overdoses, consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes of 80 to 150 mL/hr for 18 to 24 hours). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.

Range Of Toxicity

    A) There is no overdose information available for gemtuzumab ozogamicin at the time of this review.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Myelosuppression is the major dose limiting toxicity with gemtuzumab ozogamicin; thrombocytopenia and neutropenia develop in nearly all patients, significant anemia develops in about half. Hypersensitivity reaction, which usually occurs during the infusion or within 24 hours of administration, can include anaphylaxis, infusion reactions (a complex of symptoms including fever and chills and less frequently hypotension and dyspnea) and infrequently pulmonary events. Hepatotoxicity has been associated with therapy. Other adverse events include nausea (68%), vomiting (58%), headache (37%) and chills (66%). Less frequently reported events include hypotension (20%), hypertension (16%), hyperglycemia (10%), and hypoxia (5%).
    B) WITH POISONING/EXPOSURE
    1) No cases of overdose have been reported at the time of this review.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) LOW BLOOD PRESSURE
    1) WITH THERAPEUTIC USE
    a) Hypotension was reported in 20% of patients (n=277) with AML in first relapse who received gemtuzumab ozogamicin therapy, with 4% of patients experiencing grade 3 or 4 hypotension (Prod Info MYLOTARG(R) IV injection, 2006).
    B) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) During three single-arm open label clinical studies, involving 277 patients with AML in first relapse who were being treated with gemtuzumab ozogamicin, hypertension occurred in 43 patients (16%), with 2% of patients experiencing grade 3 or 4 hypertension (Prod Info MYLOTARG(R) IV injection, 2006).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Acute infusion-related dyspnea and hypoxia were reported in 26% and 5% of patients (n=277), respectively (Prod Info MYLOTARG(R) IV injection, 2006).
    B) PULMONARY HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 51-year-old man developed a cough, dyspnea, and hypoxia 3 days after receiving his second dose of gemtuzumab ozogamicin for treatment of AML. Chest radiographs showed diffuse bilateral alveolar infiltrates and a bronchoscopy demonstrated the presence of alveolar hemorrhage, which worsened with bronchoalveolar lavage. His symptoms rapidly improved following treatment with high-dose corticosteroid therapy and he was discharged home without oxygen 12 days later (Lin et al, 2005).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue has been reported by some AML patients following infusion (Sievers et al, 1999a).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) During three single-arm open label clinical studies, involving 277 patients with AML in first relapse who were being treated with gemtuzumab ozogamicin, headache occurred in 102 patients (37%), with less than 1% of patients experiencing Grade 3 or Grade 4 headaches (Prod Info MYLOTARG(R) IV injection, 2006).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures were observed in one patient following a 9 mg/m(2) infusion (Sievers et al, 1998); the contribution of gemtuzumab ozogamicin to this complication is unclear.
    D) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 70-year-old man with AML presented with fever and chills 11 days after beginning the second dose of gemtuzumab ozogamicin. Antibiotics were given and the fever disappeared 4 days later. Following the disappearance of fever, the patient experienced a loss of balance, gait disturbance, numbness and loss of sensation from a T7 level distally, which then progressed proximally to his face, with an accompanying loss of bladder and bowel control. Following initiation of daily plasmapheresis (a total of 8 sessions), the patient gradually recovered (Romani et al, 2006).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Acute infusion-related nausea and vomiting have been observed in 68% and 58% of patients (n=277), respectively (Prod Info MYLOTARG(R) IV injection, 2006). Grade 3 or grade 4 nausea was reported in 13% of patients (Sievers et al, 1998).
    B) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal hemorrhage has been reported during the postmarketing use of gemtuzumab ozogamicin (Prod Info MYLOTARG(R) IV injection, 2006).
    C) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) During three single-arm open label clinical studies, involving 277 patients with AML in first relapse who were being treated with gemtuzumab ozogamicin, stomatitis or oral mucositis occurred in 69 patients (25%), with 3% of patients experiencing grade 3 or 4 stomatitis/mucositis after receiving the first dose (Prod Info MYLOTARG(R) IV injection, 2006).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hepatic veno-occlusive disease (VOD), with fatalities, has infrequently occurred following gemtuzumab ozogamicin therapy. Patients with a history of hepatotoxicity, or who have undergone stem cell transplantation prior or following gemtuzumab therapy appear to be at increased risk for developing VOD.
    2) Hepatic fibrosis and Budd-Chiari syndrome have also been rarely reported following gemtuzumab ozogamicin therapy.
    3.9.2) CLINICAL EFFECTS
    A) TOXIC LIVER DISEASE
    1) WITH THERAPEUTIC USE
    a) Abnormalities of liver function reported in clinical studies (n=274) were often transient and reversible. One patient died 22 days after treatment with gemtuzumab ozogamicin due to liver failure in the setting of tumor lysis syndrome and multisystem organ failure. After 156 days of treatment, a second patient died after an episode of persistent jaundice and hepatosplenomegaly. Ascites, likely related to liver damage, was documented in 8 patients (Prod Info MYLOTARG(R) IV injection, 2006).
    B) HYPERBILIRUBINEMIA
    1) WITH THERAPEUTIC USE
    a) In clinical studies, 29% (80/274) patients experienced Grade 3 or Grade 4 hyperbilirubinemia. In general, hyperbilirubinemia was transient and reversible (Prod Info MYLOTARG(R) IV injection, 2006).
    C) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In clinical studies, 18% and 9% of patients (n=274) experienced Grade 3 or Grade 4 abnormalities in AST and ALT concentrations, respectively. In general, the abnormalities were transient and reversible (Prod Info MYLOTARG(R) IV injection, 2006).
    D) VENO-OCCLUSIVE DISEASE OF THE LIVER
    1) WITH THERAPEUTIC USE
    a) SUMMARY - Veno-occlusive disease (VOD), also known as hepatic sinusoidal obstructive syndrome (SOS), is an infrequent adverse event associated with gemtuzumab ozogamicin therapy (Nabhan et al, 2004; Rajvanshi et al, 2002; Bastie et al, 2002). Patients with a history of hepatotoxicity or who have undergone stem cell transplantation (SCT) either prior to or following gemtuzumab therapy appear to be at an increased risk for developing VOD/SOS (Prod Info MYLOTARG(R) IV injection, 2006; Wadleigh et al, 2003; Leopold et al, 2002; McDonald, 2002; Tack et al, 2001).
    1) It has been suggested that a minimum of 3.5 months is needed between the last dose of gemtuzumab and SCT (Wadleigh et al, 2003).
    b) INCIDENCE - The incidence of veno-occlusive disease (VOD) is 10.2% based on an interim analysis of 225 patients reported in an industry sponsored, prospective postmarketing registry study. The incidence of VOD was 14.9% among patients with stem cell transplant (SCT) before or after gemtuzumab ozogamicin treatment (n=67) and 8.2% for patients without SCT (n=146). In 8.3% (19 of 225) patients, SCT status was not reported (Prod Info MYLOTARG(R) IV injection, 2006). Based on information from the Research on Adverse Drug Events and Reports (RADAR) project, among adult patients with acute myeloid leukemia (AML) treated with gemtuzumab ozogamicin in clinical trials, the incidence of sinusoidal obstructive syndrome (SOS) or VOD was 3% at doses less than or equal to 6 mg/m(2). This 3% incidence applied if the drug was administered as monotherapy or in combination with non-hepatotoxic agents. When administered with thioguanine the incidence increased to 28%. When gemtuzumab ozogamicin was administered as monotherapy at a dose of 9 mg/m(2) the incidence of VOD was 15%. In observational studies, the incidence of VOD was 15% to 40% if the patient received SCT within 3 months of gemtuzumab ozogamicin therapy (McKoy et al, 2007).
    c) INCIDENCE - The incidence of hepatic venoocclusive disease (VOD) was 12% (14 of 119 patients) in patients with acute myeloid leukemia or advanced myelodysplastic syndromes who had not received stem cell transplantation and were treated with gemtuzumab ozogamicin-containing regimens. Five of 14 patients who had received no prior cytotoxic therapy developed VOD, including 2 patients who received single-agent gemtuzumab ozogamicin therapy. Twelve patients died, with VOD deemed a major factor in 5 deaths, a probable factor in 3 deaths, and a possible factor in 4 deaths. A diagnosis of VOD was made according to Seattle and Baltimore standard criteria of hyperbilirubinemia (bilirubin greater than 2 mg/dL) accompanied by one or more of the following symptoms: painful hepatomegaly, ascites, or sudden weight gain (greater than 5% of pretreatment weight). The authors noted that abrupt onset of very significant weight gain, often associated with ascites, abdominal distension, and right upper-quadrant pain, distinguished the patients with VOD from very large cohorts of patients treated by the authors with non-gemtuzumab ozogamicin-containing regimens. Baseline serum bilirubin was normal in all patients who subsequently developed VOD and baseline serum glutamate pyruvate transaminase (SGPT) was normal in 11 patients and slightly elevated in 3 patients. Serum bilirubin levels increased to a median of 9.1 mg/dL at a median of 25 days after the first administration of gemtuzumab ozogamicin. SGPT levels increased to a median of 28 mg/dL at a median of 14 days after the first administration of gemtuzumab ozogamicin. Since no preventative intervention or effective therapy for VOD has been established, the authors recommend that risk factors for VOD should be assessed when considering gemtuzumab ozogamicin therapy and that serum bilirubin levels, weight gain, and pattern of renal sodium retention should be monitored in patients receiving gemtuzumab ozogamicin (Giles et al, 2001).
    d) CASE REPORTS - Fatal hepatic veno-occlusive disease developed in 2 patients with relapsed CD33+ acute myelocytic leukemia (AML) who received gemtuzumab ozogamicin (9 milligrams/square meter) on a compassionate use basis. Two weeks after his first dose of gemtuzumab ozogamicin, a 50-year-old man who had relapsed after an autologous stem cell transplant and an allogeneic bone marrow transplant, developed marked hyperbilirubinemia (27 milligrams/deciliter (mg/dL)), painful hepatomegaly, fluid retention, and massive ascites with signs of paralytic ileus. A second dose of gemtuzumab ozogamicin was not administered. Treatment with analgesics, diuretics, fluid restriction, and distigmine was unsuccessful and the patient died 6 weeks after receiving gemtuzumab ozogamicin. A 45-year-old woman experienced hyperbilirubinemia, painful hepatomegaly, and ascites 8 days after her first treatment with gemtuzumab ozogamicin. She was treated with defibrotide (10 mg/kg) in increasing dose levels in addition to repeated puncture to relieve ascites, diuretics, analgesics, and fluid restriction. The patient died of multi-organ failure after 39 days; postmortem analysis was consistent with the diagnosis of hepatic veno-occlusive disease with liver histology showing luminal narrowing, phlebosclerosis, necrosis of zone 3 hepatocytes, and obliteration of posthepatic venules. The authors suggest caution in the compassionate use of gemtuzumab ozogamicin in patients with risk factors for the development of hepatic veno- occlusive disease (Neumeister et al, 2001).
    e) CASE REPORT - A 69-year-old man who underwent liver transplantation due to hemochromatosis developed acute myeloid leukemia (AML) and was subsequently treated with gemtuzumab ozogamicin, 9 mg/m(2). Five days later, the patient developed abdominal pain. Laboratory analysis, obtained 7 days post-administration of gemtuzumab, revealed elevated liver enzyme concentrations. On day 15 (12 days after receiving gemtuzumab) the patient went into cardiac arrest and was intubated. Despite supportive care, the patient subsequently died on day 16. Although radiologic and pathologic studies were not conducted in order to determine causality, it is believed that the patient most likely died from hepatic VOD due to the timing of gemtuzumab therapy and the rapid development of hepatotoxicity without any other known cause (O'Boyle et al, 2003).
    E) HEPATIC FIBROSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS - Two pediatric patients (an 8-year-old girl and a 5-year-old boy) received high doses of gemtuzumab ozogamicin therapy (total doses 36 and 24 mg/m(2), respectively) approximately 6 weeks prior to stem cell transplantation. Both patients developed mild to moderate VOD with symptoms of ascites, weight gain, jaundice, and hepatomegaly. In the first patient, the ascites and weight gain resolved, but she continued to have persistent jaundice with hepatomegaly. A liver biopsy revealed mild to moderate portal fibrosis and mild centrivenular fibrosis without the presence of VOD. In the second patient, the hepatomegaly resolved but laboratory data indicated elevated liver transaminase concentrations. A liver biopsy revealed centrilobular and centrivenular congestion and peri-portal fibrosis (Perry et al, 2005). Although a specific definitive cause for the portal fibrosis could not be established, it is suggested that prolonged gemtuzumab therapy, resulting in high total doses, may have contributed.
    F) BUDD-CHIARI SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 68-year-old woman with AML developed right upper quadrant pain and hepatomegaly 41 days after receiving gemtuzumab ozogamicin therapy. Portal and hepatic venous doppler ultrasonography revealed an enlarged, congested liver, and an absence of blood flow through the right and left hepatic veins, all of which was consistent with a diagnosis of Budd-Chiari syndrome. Due to lower GI tract bleeding and grade 4 thrombocytopenia, the patient was not anticoagulated. Abdominal tomography, obtained 62 days after gemtuzumab ozogamicin therapy, demonstrated persistent hepatic venous obstruction with increasing ascites (Kurt et al, 2005).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Renal failure secondary to tumor lysis syndrome has been reported in association with the postmarketing use of gemtuzumab ozogamicin (Prod Info MYLOTARG(R) IV injection, 2006).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Severe myelosuppression is the dose-limiting toxicity with gemtuzumab ozogamicin therapy.
    3.13.2) CLINICAL EFFECTS
    A) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia (often grade IV) occurs in most acute myeloid leukemia (AML) patients (98% of patients during one clinical trial) following gemtuzumab ozogamicin infusion. Nadirs in neutrophil counts are typically seen within 7 to 14 days; recovery is generally seen in 2 to 3 weeks, although it may be prolonged in some patients (Prod Info MYLOTARG(R) IV injection, 2006; Leopold et al, 2002; Anon, 1999; Sievers et al, 1999a; Sievers et al, 1998).
    b) In one study, a return of absolute neutrophil count to greater than 500/mm(3) did not occur in one patient, who died of sepsis 50 days following the second infusion (Sievers et al, 1999a).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia (often grade IV) occurs in most acute myeloid leukemia (AML) patients (99% of patients during one clinical trial) following gemtuzumab ozogamicin infusion. Nadirs in platelet counts are typically seen within 7 to 14 days; recovery is generally seen in 2 to 3 weeks (Prod Info MYLOTARG(R) IV injection, 2006; Leopold et al, 2002; Anon, 1999; Sievers et al, 1999a; Sievers et al, 1998).
    b) Life-threatening or fatal hemorrhage associated with thrombocytopenia has been reported in some patients (Anon, 1999).
    C) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Grade 3 or Grade 4 anemia was reported in 52% of patients (n=276) who were given gemtuzumab ozogamicin during a clinical trial (Prod Info MYLOTARG(R) IV injection, 2006).
    D) BLEEDING
    1) WITH THERAPEUTIC USE
    a) Grade 3 or Grade 4 bleeding occurred in 13% of patients (n=277) receiving gemtuzumab ozogamicin therapy. The most common bleeding events in all patients included epistaxis (3%), cerebral hemorrhage (2%), intracranial hemorrhage (1%), melena (1%), petechiae (1%), hematuria (1%), and disseminated intravascular coagulation (1%) (Prod Info MYLOTARG(R) IV injection, 2006).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) During three single-arm open label clinical studies, involving 277 patients with AML in first relapse who were being treated with gemtuzumab ozogamicin, rash and pruritus were reported in 18% and 6% of patients, respectively (Prod Info MYLOTARG(R) IV injection, 2006).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Acute infusion-related hyperglycemia was reported in 10% of patients (n=277) (Prod Info MYLOTARG(R) IV injection, 2006).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Fatal hypersensitivity reactions, including anaphylaxis, have been reported with gemtuzumab ozogamicin administration (Prod Info MYLOTARG(R) IV injection, 2006; Leopold et al, 2002). One patient developed a fatal hypersensitivity reaction following administration of gemtuzumab ozogamicin on the same day that he received a platelet transfusion. The patient had previously received gemtuzumab and platelets on separate days without incident, suggesting to the authors that the gemtuzumab-platelet combination may have contributed to the patient's severe hypersensitivity reaction (Hanbali et al, 2007).

Reproductive

    3.20.1) SUMMARY
    A) Gemtuzumab ozogamicin is classified as FDA pregnancy category D. External, visceral, and skeletal malformations, and increased rates of embryo-fetal mortality occurred in rats following maternal administration during organogenesis.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS - Gemtuzumab ozogamicin doses of 0.060 mg/kg/day (approximately 0.04 times the recommended human single dose), administered to pregnant rats during organogenesis, resulted in fetal external, visceral, and skeletal malformations, including digital malformations of one or both hind feet, absence of the aortic arch, wavy ribs, anomalies of the long bones of the forelimbs, misshapen scapula, absence of vertebral centrum, and fused sternebrae (Prod Info MYLOTARG(R) IV injection, 2006).
    2) Fetal skeletal ossification and decreases in fetal weight occurred following maternal administration of gemtuzumab ozogamicin to pregnant rats at doses starting at 0.025 mg/kg/day (Prod Info MYLOTARG(R) IV injection, 2006).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Gemtuzumab ozogamicin is classified by the manufacturer as FDA pregnancy category D (Prod Info MYLOTARG(R) IV injection, 2006).
    B) ANIMAL STUDIES
    1) RATS - An increased number of fetal resorptions and a decreased number of live fetuses per litter were reported following gemtuzumab ozogamicin administration to pregnant rats at doses of 0.060 mg/kg/ day. Decreased maternal weight gain and decreased food consumption in the pregnant rats were also reported at this dose level (Prod Info MYLOTARG(R) IV injection, 2006).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether gemtuzumab ozogamicin is excreted in human breast milk (Prod Info MYLOTARG(R) IV injection, 2006).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Decreased fertility rates, epididymal sperm counts, and sperm motility, an increased incidence of sperm abnormalities, and microscopic evidence of decreased spermatogonia and spermatocyte count occurred following gemtuzumab ozogamicin administration to male rats at doses of 0.02 to 0.16 mg/kg/day (approximately 0.01 to 0.11 times the human dose) for 28 days. These findings continued to persist following a 9-week recovery period (Prod Info MYLOTARG(R) IV injection, 2006).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) There have been no long-term carcinogenic studies conducted in animals (Prod Info MYLOTARG(R) IV injection, 2006).

Genotoxicity

    A) Gemtuzumab ozogamicin was clastogenic in mice in an in vivo micronucleus test (Prod Info MYLOTARG(R) IV injection, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serial CBC with differential and platelet count following acute exposure.
    B) Monitor vital signs. Monitor daily weight; sudden weight gain suggests hepatic veno-occlusive disease.
    C) Monitor fluid and electrolyte status in patients with severe vomiting.
    D) Monitor hepatic enzymes and bilirubin levels.
    4.1.2) SERUM/BLOOD
    A) Monitor serial CBC with differential and platelet count following an acute exposure. Myelosuppression is the most common adverse event observed with gemtuzumab ozogamicin.
    B) Monitor fluids and electrolytes in patients with severe vomiting.
    C) Monitor hepatic enzymes and bilirubin levels. Hepatic veno-occlusive disease (VOD) has been reported in patients following gemtuzumab ozogamicin therapy. Patients who have undergone stem cell transplantation (SCT) either prior to or following gemtuzumab therapy may be at an increased risk for developing VOD.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs including temperature and blood pressure. Monitor daily weight; sudden weight gain suggests hepatic veno-occlusive disease.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor serial CBC with differential and platelet count following acute exposure.
    B) Monitor vital signs. Monitor daily weight; sudden weight gain suggests hepatic veno-occlusive disease.
    C) Monitor fluid and electrolyte status in patients with severe vomiting.
    D) Monitor hepatic enzymes and bilirubin levels.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is not indicated because an ingestion is unlikely; gemtuzumab ozogamicin is administered intravenously.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) See the PARENTERAL EXPOSURE treatment section for further information.

Enhanced Elimination

    A) LACK OF EFFICACY
    1) HEMODIALYSIS: Gemtuzumab ozogamicin is not dialyzable (Prod Info MYLOTARG(R) IV injection, 2006).
    B) PLASMAPHERESIS
    1) CASE REPORT: A 70-year-old man with AML developed sensorimotor peripheral neuropathy that consisted of a loss of balance, gait disturbance, numbness and a loss of feeling from T7 to caudal extension, progressing to his face, with an accompanying loss of bladder and bowel control. Following initiation of daily plasmapheresis (a total of 8 sessions), the patient gradually recovered (Romani et al, 2006).

Range Of Toxicity

Summary

    A) There is no overdose information available for gemtuzumab ozogamicin at the time of this review.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dosage regimen of gemtuzumab ozogamicin is 9 milligrams/square meter, intravenously infused over a 2-hour period, given every 14 days for a total of 2 doses (Prod Info MYLOTARG(R) IV injection, 2006).
    B) Gemtuzumab ozogamicin should NOT be administered as an intravenous push or bolus (Prod Info MYLOTARG(R) IV injection, 2006).
    7.2.2) PEDIATRIC
    A) Safety and efficacy of gemtuzumab ozogamicin in pediatric patients have not been established (Prod Info MYLOTARG(R) IV injection, 2006); however a dose of 6 mg/square meter has been used in some children (Perry et al, 2005).

Maximum Tolerated Exposure

    A) There is no overdose information available for gemtuzumab ozogamicin at the time of this review (Prod Info MYLOTARG(R) IV injection, 2006).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Gemtuzumab ozogamicin is drug-antibody conjugate for the treatment of acute myeloid leukemia (AML) (Prod Info MYLOTARG(R) IV injection, 2006; Bernstein, 1999; Matthews, 1998). It consists of a recombinant humanized anti-CD33 monoclonal antibody (hP67.6) conjugated to the cytotoxic antibiotic calicheamicin via an Nac-gamma linker molecule (Appelbaum, 1999; Sievers et al, 1999; King & Adair, 1999). The goal of systemic therapy with gemtuzumab ozogamicin is to selectively target calicheamicin to the myeloid cell-surface antigen CD33, which is expressed on most myeloid leukemia blast cells, most or all of malignant precursors in at least some patients with AML, and normal myeloid precursors (Kossman et al, 1999; Sievers et al, 1999; Appelbaum, 1999).

Toxicologic Mechanism

    A) HEPATIC SINUSOIDAL OBSTRUCTION/VENO-OCCLUSIVE DISEASE
    1) The specific mechanism for the development of hepatic veno-occlusive disease (VOD), also known as hepatic sinusoidal obstruction syndrome (SOS), following gemtuzumab therapy is unknown. There are 3 potential mechanisms that have been hypothesized to cause cell injury in hepatic sinusoids (Saviola et al, 2003; Rajvanshi et al, 2002):
    1) Exposure to unconjugated calicheamicin in the circulation
    2) Non-specific uptake of the antibody-calicheamicin complex by Kupffer cells
    3) Receptor-mediated uptake of the antibody-calicheamicin complex through CD33 expression on one or more of the cell populations of the liver.

References

General Bibliography

    1) Addiego JE, Ridgway D, & Bleyer WA: The acute management of intrathecal methotrexate overdose: pharmacologic rationale and guidelines. J Pediatr 1981; 98(5):825-828.
    2) Anderson S & Files J: Tumor lysis syndrome secondary to Gemtuzumab Ozogamicin in a patient with acute myelogenous leukemia. J Miss.State Med Assoc 2002; 43(4):105-106.
    3) Anon: Celltech/Wyeth-Ayerst to file CMA 676 NDA in third quarter. F-D-C Reports: The Pink Sheet. May 24 1999; 61:18-19.
    4) Appelbaum FR: Antibody-targeted therapy for myeloid leukemia. Semin Hematol 1999; 36(suppl 6):2-8.
    5) Bastie JN, Suzan F, Garcia I, et al: Veno-occlusive disease after an anti-CD33 therapy (gemtuzumab ozogamicin). Br J Haematol 2002; 116(4):924-.
    6) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    7) Bernstein I: Hematologic malignancies. Curr Opin Hematol 1999; 6:199-200.
    8) Giles FJ, Kantarjian HM, Kornblau SM, et al: Mylotarg(TM) (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation. Cancer 2001; 92(2):406-413.
    9) Gosselin S & Isbister GK: Re: Treatment of accidental intrathecal methotrexate overdose. J Natl Cancer Inst 2005; 97(8):609-610.
    10) Hanbali A, Wollner I, Neme K, et al: Fatal hypersensitivity reaction to gemtuzumab ozogamicin associated with platelet transfusion. Am J Health Syst Pharm 2007; 64(13):1401-1402.
    11) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    12) King DJ & Adair JR: Recombinant antibodies for the diagnosis and therapy of human disease. Curr Opin Drug Disc Develop 1999; 2(2):110-117.
    13) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    14) Kossman SE, Scheinberg DA, Jurcic JG, et al: A phase I trial of humanized monoclonal antibody HuM195 (anti-CD33) with low-dose interleukin 2 in acute myelogenous leukemia. Clin Cancer Res 1999; 5:2748-2755.
    15) Kurt M, Shorbagi A, Altundag K, et al: Possible association between Budd-Chiari Syndrome and gemtuzumab ozogamicin treatment in a patient with refractory acute myelogenous leukemia. Am J Hematol 2005; 80(3):213-215.
    16) Lannoy D, Decaudin B, GrozieuxdeLaguerenne A, et al: Gemtuzumab ozogamicin-induced sinusoidal obstructive syndrome treated with defibrotide: a case report. J Clin Pharm Ther 2006; 31(4):389-392.
    17) Leopold LH, Berger MS, & Feingold J: Acute and long-term toxicities associated with gemtuzumab ozogamicin (Mylotarg) therapy of acute myeloid leukemia. Clin Lymphoma 2002; 2 Suppl 1:S29-S34.
    18) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    19) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    20) Lin TS, Penza SL, Avalos BR, et al: Diffuse alveolar hemorrhage following gemtuzumab ozogamicin. Bone Marrow Transplant 2005; 35(8):823-824.
    21) Matthews DC: Immunotherapy in acute myelogenous leukemia and myelodysplastic syndrome. Leukemia 1998; 12(suppl 1):S33-S36.
    22) McDonald GB: Management of hepatic sinusoidal obstruction syndrome following treatment with gemtuzumab ozogamicin (Mylotarg). Clin Lymphoma 2002; 2 Suppl 1:S35-S39.
    23) McKoy JM, Angelotta C, Bennett CL, et al: Gemtuzumab ozogamicin-associated sinusoidal obstructive syndrome (SOS): an overview from the research on adverse drug events and reports (RADAR) project. Leuk Res 2007; 31(5):599-604.
    24) Meggs WJ & Hoffman RS: Fatality resulting from intraventricular vincristine administration. J Toxicol Clin Toxicol 1998; 36(3):243-246.
    25) Nabhan C, Rundhaugen L, Jatoi M, et al: Gemtuzumab ozogamicin (MylotargTM) is infrequently associated with sinusoidal obstructive syndrome/veno-occlusive disease. Ann Oncol 2004; 15(8):1231-1236.
    26) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    27) Neumeister P, Eibl M, Zinke-Cerwenka W, et al: Hepatic veno-occlusive disease in two patients with relapsed acute myeloid leukemia treated with anti-CD33 calicheamicin (CMA-676) immunoconjugate. Ann Hematol 2001; 80:119-120.
    28) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    29) O'Boyle KP, Murigeppa A, Jain D, et al: Probable veno-occlusive disease after treatment with gemtuzumab ozogamicin in a patient with acute myeloid leukemia and a history of liver transplantation for familial hemochromatosis. Med Oncol 2003; 20(4):379-384.
    30) O'Marcaigh AS, Johnson CM, & Smithson WA: Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and trathecal instillation of carboxypeptidase G2. Mayo Clin Proc 1996; 71:161-165.
    31) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    32) Perry R, Penk J, Kapoor N, et al: Gemtuzumab ozogamicin exposure and portal fibrosis. Pediatr Blood Cancer 2005; 45(1):82-83.
    33) Pfizer Oncology: MYLOTARG(R) withdrawal letter. Pfizer Oncology. New York, NY. 2010. Available from URL: http://media.pfizer.com/files/news/press_releases/2010/mylotarg_discontinuation_062110.pdf. As accessed 2010-06-21.
    34) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    35) Product Information: MYLOTARG(R) IV injection, gemtuzumab ozogamicin IV injection. Wyeth Pharmaceuticals,Inc, Philadelphia, PA, 2006.
    36) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    37) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    38) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    39) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    40) Rajvanshi P, Shulman HM, Sievers EL, et al: Hepatic sinusoidal obstruction after gemtuzumab ozogamicin (Mylotarg) therapy. Blood 2002; 99(7):2310-2314.
    41) Romani C, Murru R, Adamo F, et al: Sensorimotor peripheral neuropathy in an elderly AML patient in complete remission while receiving gemtuzumab ozogamicin as maintenance therapy. Ann Hematol 2006; 85(6):411-412.
    42) Saviola A, Luppi M, Potenza L, et al: Late occurrence of hepatic veno-occlusive disease following gemtuzumab ozogamicin: successful treatment with defibrotide. Br J Haematol 2003; 123(4):752-753.
    43) Sievers EL, Appelbaum FR, Spielberger RT, et al: Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood 1999; 93(11):3678-3684.
    44) Sievers EL, Appelbaum FR, Spielberger RT, et al: Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood 1999a; 93(11):3678-3684.
    45) Sievers EL, Bernstein ID, & Spielberger RT: Dose escalation phase I study of recombinant engineered human antii-CD33 antibody-calicheamicin drug conjugate (CMA-676) in patients with relapsed or refractory acute myeloid leukemia (AML) (abstract 8). Proceedings of ASCO 1997; 16:3a.
    46) Sievers EL, Larson RA, Estey LE, et al: Interim analysis of the efficacy and safety of CMA-676 in patients with AML in first relapse (abstract 2527). Blood 1998; 92(suppl):613.
    47) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    48) Tack DK, Letendre L, Kamath PS, et al: Development of hepatic veno-occlusive disease after Mylotarg infusion for relapsed acute myeloid leukemia. Bone Marrow Transplant 2001; 28(9):895-897.
    49) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    50) Versluys B, Bhattacharaya R, Steward C, et al: Prophylaxis with defibrotide prevents veno-occlusive disease in stem cell transplantation after gemtuzumab ozogamicin exposure. Blood 2004; 103(5):1968-1968.
    51) Wadleigh M, Richardson PG, Zahrieh D, et al: Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood 2003; 102(5):1578-1582.
    52) Widemann BC, Balis FM, Shalabi A, et al: Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2. J Nat Cancer Inst 2004; 96(20):1557-1559.