Inotuzumab ozogamicin, a CD22-directed antibody-drug conjugate consisting of a recombinant humanized immunoglobulin G4 (IgG4) kappa monoclonal antibody (inotuzumab) covalently linked to a cytotoxic calicheamicin derivative ( N -acetyl-γ-calicheamicin), is an antineoplastic agent.1, 3, 10, 11
B-cell Precursor Acute Lymphoblastic Leukemia
Inotuzumab ozogamicin is used for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (pre-B-ALL).1, 3, 6, 7 The drug has been designated an orphan drug by FDA for use in treatment of pre-B-ALL.2
The current indication for inotuzumab ozogamicin is based principally on the results of a randomized, open-label, international, multicenter phase 3 study (INO-VATE ALL) in 326 adults with relapsed or refractory pre-B-ALL that progressed following treatment with 1 or 2 induction chemotherapy regimens.1, 3 Patients enrolled in the study were required to have at least 5% blast cells in their bone marrow.1, 3 Patients were enrolled regardless of Philadelphia chromosome (Ph) status; however, patients with Ph-positive (Ph+) disease must have failed prior therapy with at least one tyrosine kinase inhibitor and standard chemotherapy.1 Patients were randomized (stratified by duration of first remission, number of salvage therapies, and age) in a 1:1 ratio to receive inotuzumab ozogamicin or investigator's choice of chemotherapy.1, 3 Patients randomized to inotuzumab ozogamicin received 0.8 mg/m2 by IV infusion on day 1 followed by 0.5 mg/m2 on days 8 and 15 of cycle 1 (21-day duration) and each subsequent 28-day cycle.3 Once complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) was achieved, the dosage of inotuzumab ozogamicin was reduced to 0.5 mg/m2 on days 1, 8, and 15 of each 28-day cycle.3 Inotuzumab ozogamicin was continued for up to 6 cycles.3 Patients randomized to the control group received combination therapy with fludarabine, cytarabine, and a granulocyte colony-stimulating factor (G-CSF); cytarabine in combination with mitoxantrone; or high-dose cytarabine.3
The primary measures of efficacy in the INO-VATE ALL study were CR and CRi (as evaluated by a blinded independent central review committee), duration of remission, and proportion of patients who achieved complete remission who had results below the threshold for negative minimal residual disease (MRD-negative).1, 3 CR was defined as the presence of less than 5% blasts in bone marrow without evidence of disease (absence of circulating blasts and resolution of extramedullary disease) and with full recovery of peripheral blood cell counts (platelet count of at least 100,000/mm3 and absolute neutrophil count [ANC] of at least 1000/mm3), CRi was defined as the presence of less than 5% blasts in bone marrow without evidence of disease and with incomplete recovery of peripheral blood cell counts (platelet count less than 100,000/mm3 and ANC less than 1000/mm3), and MRD-negativity was defined as the presence of less than 0.01% blasts using flow cytometry.1, 3
The median age of enrolled patients was 47 years (range: 18-79 years); 85% had Ph-negative (Ph-) disease, 66% had received one prior treatment regimen for their disease, 33% had received 2 prior treatment regimens for their disease, 17% had undergone hematopoietic stem cell transplantation (HSCT) prior to study entry, and 63% were in first remission for less than 12 months.1 The primary efficacy population consisted of the initial 218 patients randomized in the study; all of these patients had CD22-positive pre-B-ALL with the majority (at least 90%) expressing CD22 on at least 70% of blast cells.1
In the primary efficacy population of the INO-VATE ALL study, CR/CRi was reported in 80.7 or 29.4% of patients receiving inotuzumab ozogamicin or investigator's choice of chemotherapy, respectively;1, 3 CR/CRi was achieved within the first 2 treatment cycles in 97% of patients receiving inotuzumab ozogamicin and 94% of patients receiving investigator's choice of chemotherapy.1 The majority of patients receiving inotuzumab ozogamicin (73%) or investigator's choice of chemotherapy (91%) achieved a response within the first treatment cycle.1, 3 At the time of analysis, the median duration of response for patients achieving CR/CRi was 5.4 or 3.5 months in patients receiving inotuzumab ozogamicin or investigator's choice of chemotherapy, respectively; the median duration of response was more prolonged in inotuzumab ozogamicin-treated patients achieving CR (8 versus 4.9 months) and CRi (4.6 versus 2.9 months) compared with investigator's choice of chemotherapy-treated patients.1 Complete remission with partial hematologic recovery (CRh; defined as the presence of less than 5% blasts in bone marrow with partial recovery of peripheral blood cell counts [platelet count exceeding 50,000/mm3 and ANC exceeding 500/mm3]) was achieved in 29% of inotuzumab ozogamicin-treated patients and 6% of investigator's choice of chemotherapy-treated patients.1 MRD-negativity was reported in 89.7 or 69.4% of inotuzumab ozogamicin-treated patients who achieved CR or CRi, respectively, and in 31.6 or 23.1% of chemotherapy-treated patients who achieved CR or CRi, respectively.1 Effects of inotuzumab ozogamicin on CR, duration of response, and proportion of MRD-negative CR were comparable between the primary efficacy population and overall study population.1 Approximately one-half (48%) or 22% of inotuzumab ozogamicin-treated or chemotherapy-treated patients, respectively, in the overall study population underwent HSCT.1 Overall survival did not reach the prespecified level of statistical significance.1, 3 Results of a subgroup analysis based on relevant patient and disease characteristics suggested that the effect of inotuzumab ozogamicin on CR and CRi generally was consistent across all subgroups; however, clinical benefit for the drug compared with chemotherapy was not apparent in the subgroups of patients with baseline Ph+ disease and those bearing the t(4;11) chromosomal abnormality.3
Because of the risk of infusion-related reactions, the manufacturer recommends a premedication regimen (i.e., corticosteroid, antipyretic, and antihistamine) prior to each inotuzumab ozogamicin infusion.1 Patients should be observed for symptoms of infusion-related reactions during and for at least 1 hour after the end of each infusion.1 (See Infusion-related Reactions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
In patients with circulating lymphoblasts, cytoreduction with a combination of hydroxyurea, a corticosteroid, and/or vincristine until peripheral blast counts decrease to 10,000/mm3 or less is recommended prior to administration of the first dose of inotuzumab ozogamicin.1
Inotuzumab ozogamicin is available only through a specialty pharmacy and specialty distributors.14 Clinicians may contact Pfizer Oncology Together at 877-744-5675 or consult the Pfizer Oncology Together website for specific availability information ([Web]).14
Reconstitution and Administration
The usual precautions for handling and preparing solutions of cytotoxic drugs should be observed with inotuzumab ozogamicin.1
Inotuzumab ozogamicin is administered by IV infusion at a rate of 50 mL/hour for 1 hour at room temperature.1 The manufacturer recommends administering final diluted solutions of the drug through polyvinyl chloride (PVC; diethylhexylphthalate [DEHP] or non-DEHP PVC), polyolefin (polypropylene and/or polyethylene), or polybutadiene administration sets with or without a filter.1 When a filter is used, a polyethersulfone (PES)-, polyvinylidene fluoride (PVDF)-, or hydrophilic polysulfone (HPS)-based filter is recommended; nylon or mixed cellulose ester (MCE) filters should not be used.1
Unreconstituted inotuzumab ozogamicin powder for injection should be stored at 2-8°C.1 Unopened vials should be retained in the original package for protection from light; freezing of the vials should be avoided.1
Prior to administration, commercially available inotuzumab ozogamicin powder for injection must be reconstituted and diluted.1 The powder for injection is reconstituted by adding 4 mL of sterile water for injection to each vial labeled as containing 0.9 mg of the drug to provide a solution containing 0.25 mg/mL.1 The vial should be gently swirled and inspected visually for particulate matter and discoloration prior to dilution and administration.1 The resulting solution should not be shaken.1 The reconstituted inotuzumab ozogamicin solution should be clear to opalescent, colorless to slightly yellow, and essentially free of visible particulates.1 The reconstituted solution may be diluted immediately, stored at 20-25°C for dilution within 4 hours, or stored at 2-8°C for dilution within 3 hours, and should be protected from light.1 The reconstituted solution should not be frozen.1
For preparation of the final diluted inotuzumab ozogamicin solution for infusion, the required amount of reconstituted inotuzumab ozogamicin solution should be withdrawn from the vial using a syringe and injected into a PVC (DEHP or non-DEHP), polyolefin (polypropylene and/or polyethylene), or ethylene vinyl acetate (EVA) infusion bag containing 0.9% sodium chloride injection to achieve a total volume of 50 mL.1 Any unused reconstituted solution left in the vial should be discarded.1 The final diluted inotuzumab ozogamicin solution for infusion should be mixed by gentle inversion and should not be shaken.1
If immediate administration of diluted inotuzumab ozogamicin solution for infusion is not possible, diluted solutions of the drug are stable for up to 4 hours after dilution when stored at room temperature or for up to 3 hours after dilution when stored under refrigeration (2-8°C); refrigerated diluted solutions of the drug should be brought to room temperature for approximately 1 hour prior to administration.1 Diluted solutions of the drug must be administered within 8 hours (including infusion time) of reconstitution and there should be no more than 4 hours between reconstitution and dilution of the solution.1 Diluted solutions of the drug should also be protected from light.1
B-cell Precursor Acute Lymphoblastic Leukemia
For the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (pre-B-ALL) in adults, the recommended dosage of inotuzumab ozogamicin during cycle 1 is 0.8 mg/m2 on day 1, followed by 0.5 mg/m2 on days 8 and 15 during a 3-week cycle .1
During subsequent cycles in patients who have achieved complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) , the recommended dosage of inotuzumab ozogamicin is 0.5 mg/m2 on days 1, 8, and 15 during each 4-week cycle .1
During subsequent cycles in patients who have not achieved CR or CRi , the recommended dosage of inotuzumab ozogamicin is 0.8 mg/m2 on day 1, followed by 0.5 mg/m2 on days 8 and 15 during each 4-week cycle .1 However, if CR or CRi is not achieved within 3 cycles, treatment with the drug should be discontinued.1
The recommended duration of inotuzumab ozogamicin therapy is 2 cycles in adults undergoing hematopoietic stem cell transplantation (HSCT) following inotuzumab ozogamicin treatment for pre-B-ALL.1 A third cycle may be considered in patients who do not achieve CR or CRi and minimal residual disease (MRD) negativity after 2 cycles (cycles 1-2).1 For patients not proceeding to HSCT, additional cycles of treatment, up to a maximum of 6 cycles, may be administered.1 (See Hepatotoxicity, including Hepatic Veno-occlusive Disease, under Warnings/Precautions: Warnings, in Cautions.)
Dosage Modification for Toxicity
In patients who have required dosage reduction for toxicity, the dosage of inotuzumab ozogamicin must not be re-escalated in subsequent cycles.1
Dose delays may be required if absolute neutrophil count (ANC) and platelet counts have not recovered to recommended values prior to initiation of a new treatment cycle; interruption of inotuzumab ozogamicin therapy within treatment cycles (i.e., days 8 and/or 15) for hematologic toxicity is not necessary.1
If ANC decreases to less than 1000/mm3 in patients who had a baseline ANC of at least 1000/mm3, initiation of the next cycle should be delayed until ANC reaches or exceeds 1000/mm3.1 If prolonged neutropenia (i.e., lasting more than 28 days) occurs and is suspected to be related to inotuzumab ozogamicin, therapy with the drug should be discontinued.1
If platelet count decreases to less than 50,000/mm3 in patients who had a baseline platelet count of at least 50,000/mm3, initiation of the next cycle should be delayed until platelet count reaches or exceeds 50,000/mm3.1 If prolonged thrombocytopenia (i.e., lasting more than 28 days) occurs and is suspected to be related to inotuzumab ozogamicin, therapy with the drug should be discontinued.1
If neutropenia or thrombocytopenia occurs in patients who had a baseline ANC of less than 1000/mm3 and/or a platelet count of less than 50,000/mm3, initiation of the next cycle should be delayed until one of the following occurs: ANC and platelet count return to at least baseline values for the prior cycle, ANC reaches or exceeds 1000/mm3 and platelet count reaches or exceeds 50,000/mm3, or most recent assessment of bone marrow reveals stable or improved disease and the neutropenia and thrombocytopenia are considered to be caused by the underlying disease and not toxicity to inotuzumab ozogamicin.1
If hepatic veno-occlusive disease or other severe hepatotoxicity occurs, inotuzumab ozogamicin therapy should be permanently discontinued.1 (See Hepatotoxicity, including Hepatic Veno-occlusive Disease, under Warnings/Precautions: Warnings, in Cautions.)
In patients who exhibit increases in serum aminotransferase (ALT and/or AST) concentrations exceeding 2.5 times the upper limit of normal (ULN) or total bilirubin concentrations exceeding 1.5 times the ULN (except in patients with Gilbert's syndrome or hemolysis), therapy with inotuzumab ozogamicin should be temporarily interrupted until ALT and AST elevations decline to no more than 2.5 times the ULN and total bilirubin concentrations decline to no more than 1.5 times the ULN.1 Dosage reduction, dose omission, and/or permanent discontinuance of inotuzumab ozogamicin also may be necessary depending on the duration of the dosing interruption.1
If therapy is withheld for less than 7 days (within a treatment cycle), the next dose may be administered upon resolution of toxicity; however, the schedule of administration should be adjusted to maintain a minimum of 6 days between doses.1, 5 If therapy is withheld for 7 days or more but less than 14 days, the next dose within the treatment cycle should be omitted.1 If therapy is withheld for 14 days or more and adequate recovery has been achieved, the total dosage of inotuzumab ozogamicin should be reduced by 25% in the subsequent cycle.1 If further dosage reduction is necessary, the frequency of inotuzumab ozogamicin administration may be reduced from 3 to 2 doses per cycle in subsequent cycles.1 If dosage modification (dosage reduction then reduced frequency) of inotuzumab ozogamicin is not tolerated or elevated ALT, AST, and/or total bilirubin concentrations persist for more than 28 days despite interruption of therapy, the drug should be permanently discontinued.1
If infusion-related reactions occur, the inotuzumab ozogamicin infusion should be interrupted or permanently discontinued and appropriate treatment and supportive care should be provided.1 Depending on the severity of the reaction (except for severe or life-threatening reactions), discontinuance of the infusion or administration of corticosteroids and antihistamines should be considered.1
If severe or life-threatening infusion-related reactions occur, inotuzumab ozogamicin should be permanently discontinued.1 (See Dosage and Administration: General and see also Infusion-related Reactions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
If other nonhematologic toxicity of grade 2 or greater severity occurs during inotuzumab ozogamicin therapy, therapy with the drug should be temporarily interrupted.1 Once the nonhematologic toxicity has returned to baseline or improved to grade 1, therapy with the drug may be resumed.1 Dosage reduction, dose omission, and/or permanent discontinuance of inotuzumab ozogamicin also may be necessary depending on the duration of the dosing interruption.1
If therapy is withheld for less than 7 days (within a treatment cycle), the next dose may be administered upon resolution of toxicity; however, the schedule of administration should be adjusted to maintain a minimum of 6 days between doses.1, 5 If therapy is withheld for 7 days or more but less than 14 days, the next dose within the treatment cycle should be omitted.1 If therapy is withheld for 14 days or more and adequate recovery has been achieved, the total dosage of inotuzumab ozogamicin should be reduced by 25% in the subsequent cycle.1 If further dosage reduction is necessary, the frequency of inotuzumab ozogamicin administration may be reduced from 3 to 2 doses per cycle in subsequent cycles.1 If dosage modification (dosage reduction then reduced frequency) of inotuzumab ozogamicin is not tolerated or the nonhematologic toxicity persists for more than 28 days despite interruption of therapy, the drug should be permanently discontinued.1
The manufacturer states that no adjustment to the initial dosage of inotuzumab ozogamicin is necessary in patients with baseline serum ALT/AST concentrations 2.5 times the ULN or less and total bilirubin concentrations 1.5 times the ULN or less.1 There are limited data in patients with serum ALT/AST concentrations exceeding 2.5 times the ULN and/or total bilirubin concentrations exceeding 1.5 times the ULN; the manufacturer does not provide any specific dosage recommendations for such patients.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1 Inotuzumab ozogamicin has not been studied in patients with end-stage renal disease, including those receiving dialysis.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer states that adjustment of the initial dosage of inotuzumab ozogamicin is not necessary in geriatric patients.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer states that there are no known contraindications to the use of inotuzumab ozogamicin.1
Hepatotoxicity, including Hepatic Veno-occlusive Disease
Hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic veno-occlusive disease (VOD; also known as sinusoidal obstruction syndrome) and liver function test abnormalities, have been reported in patients receiving inotuzumab ozogamicin therapy.1, 4 In the INO-VATE ALL study, hepatic VOD occurred during or following inotuzumab ozogamicin therapy in 5 of 164 patients (3%) without intervening hematopoietic stem cell transplantation (HSCT) and in 18 of 79 patients (23%) who underwent HSCT following therapy with the drug.1, 4 A higher incidence of hepatic VOD was reported in inotuzumab ozogamicin-treated patients enrolled in Europe and Asia than in North America.4 Most cases were grade 3 or worse,4 and some cases resulted in death.1 The median time to onset of hepatic VOD in patients who underwent HSCT was 15 days (range: 3-57 days).1 Among patients who did not undergo HSCT, hepatic VOD was reported up to 56 days following the last dose of inotuzumab ozogamicin or during follow-up.1 In the INO-VATE ALL study, grade 3 or 4 elevations in serum ALT, AST, or total bilirubin concentrations occurred in 4, 4, or 5%, respectively, of patients receiving inotuzumab ozogamicin.1
The risk of hepatic VOD is greater in patients who undergo HSCT following therapy with inotuzumab ozogamicin, those who receive a conditioning regimen containing 2 alkylating agents (e.g., busulfan in combination with other alkylating agents), and those whose most recent total bilirubin concentration is at or above the upper limit of normal (ULN) prior to HSCT.1, 4 Other risk factors for developing hepatic VOD include ongoing or prior hepatic disease, history of HSCT, older age, heavily pretreated disease (i.e., later salvage line of therapy), and increased number of treatment cycles with inotuzumab ozogamicin.1, 4, 9 Patients who have experienced prior VOD or who have serious ongoing hepatic disease (e.g., cirrhosis, nodular regenerative hyperplasia, active hepatitis) also are at an increased risk of worsening hepatic disease, including developing VOD, following therapy with inotuzumab ozogamicin.1
Because of the increased risk of hepatic VOD in patients undergoing HSCT, the manufacturer and some experts recommend reducing the inotuzumab ozogamicin treatment duration to 2 cycles in such patients; a third treatment cycle may be considered if complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) and minimal residual disease (MRD) negativity are not achieved after 2 cycles.1, 9
Patients receiving inotuzumab ozogamicin should be closely monitored for signs and symptoms of hepatic VOD (e.g., elevated total bilirubin concentrations, hepatomegaly [which may be painful], rapid weight gain, ascites, edema, jaundice).1, 9 Liver function tests (i.e., ALT, AST, total bilirubin, alkaline phosphatase) should be assessed prior to and following each dose of inotuzumab ozogamicin; however, because of the increased risk of hepatic VOD in patients who undergo HSCT, liver function tests should be closely monitored for the first month following HSCT and then less frequently thereafter, according to standard clinical practice.1 Some experts recommend preventing development of hepatic VOD in patients receiving inotuzumab ozogamicin with concurrent administration of drugs such as ursodiol.9 Dosage reduction, treatment delay, or drug discontinuance may be required if liver function test abnormalities occur during therapy with the drug.1 (See Hepatotoxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
If hepatic VOD occurs, inotuzumab ozogamicin therapy should be permanently discontinued.1 Supportive care, including maintaining an adequate fluid balance, is recommended by some experts in patients who develop hepatic VOD; continued administration of ursodiol also is recommended.9 Defibrotide sodium may be used in the treatment of patients with hepatic VOD with renal or pulmonary compromise.9 (For more information on hepatic VOD, including risk factors, clinical manifestations, and management, see Defibrotide Sodium 20:12.92.)
Increased Risk of Post-transplant Non-relapse Mortality
In the INO-VATE ALL study, inotuzumab ozogamicin was associated with a higher mortality rate at day 100 post-HSCT in patients who underwent HSCT following therapy with the drug compared with the investigator's choice of chemotherapy.1 The post-HSCT non-relapse mortality rate was 31 of 79 inotuzumab ozogamicin-treated patients (39%) and 8 of 35 chemotherapy-treated patients (23%).1 The most common causes of post-HSCT non-relapse mortality in patients receiving the drug were hepatic VOD and infectious complications.1 Among inotuzumab ozogamicin-treated patients, hepatic VOD occurred in 18 patients post-HSCT and resulted in 5 fatalities.1 Multiorgan failure or infection resulting in death occurred in 6 inotuzumab ozogamicin-treated patients with ongoing hepatic VOD at the time of death.1
Patients receiving inotuzumab ozogamicin should be closely monitored for post-HSCT complications, including signs and symptoms of infection and hepatic VOD.1 (See Hepatotoxicity, including Hepatic Veno-occlusive Disease, under Warnings/Precautions: Warnings, in Cautions.)
Other Warnings and Precautions
Neutropenia and thrombocytopenia resulting in severe, life-threatening, and sometimes fatal complications have been reported in patients receiving inotuzumab ozogamicin therapy.1 In the INO-VATE ALL study, thrombocytopenia and neutropenia were reported in 51 and 49%, respectively, of patients treated with the drug.1 Platelet counts recovered to greater than 50,000/mm3 more than 45 days after the last dose of inotuzumab ozogamicin or chemotherapy in 9 or 2% of patients, respectively, who achieved CR or CRi at the end of therapy.1 Grade 4 thrombocytopenia or neutropenia occurred in 28 or 27%, respectively, of patients receiving the drug.1 Febrile neutropenia, which may be life-threatening, occurred in 26% of patients receiving inotuzumab ozogamicin.1 Infectious complications, sometimes serious, life-threatening or fatal, associated with neutropenia occurred in approximately one-half (48%) of patients receiving the drug.1 Fatal infection (i.e., pneumonia, neutropenic sepsis, sepsis, septic shock, pseudomonal sepsis) occurred in 8 of 164 patients (5%) receiving inotuzumab ozogamicin.1 Hemorrhage occurred in 33% of patients receiving the drug.1 Grade 3 or 4 hemorrhage was reported in 8 of 164 patients (5%) receiving inotuzumab ozogamicin.1 Fatal intra-abdominal hemorrhage occurred in one patient receiving the drug.1 The most common hemorrhagic event reported in the study was epistaxis.1
Complete blood cell (CBC) counts should be monitored prior to each dose of inotuzumab ozogamicin.1 Prophylactic anti-infective therapy should be administered when appropriate and surveillance testing should be employed when appropriate during and following inotuzumab ozogamicin therapy.1 Patients should be monitored for signs and symptoms of complications associated with myelosuppression (e.g., infection, bleeding or hemorrhage).1 In patients who develop neutropenia, thrombocytopenia, or other complications associated with myelosuppression, temporary interruption of therapy, dosage reduction, or drug discontinuance may be required.1 (See Hematologic Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Infusion-related reactions have been reported in patients receiving inotuzumab ozogamicin therapy, generally during the first treatment cycle shortly after completion of the infusion.1 In the INO-VATE ALL study, infusion-related reactions occurred in 4 of 164 patients (2%) receiving inotuzumab ozogamicin; all infusion-related reactions were grade 2 severity.1 Infusion-related reactions resolved either spontaneously or following medical intervention.1
The manufacturer states that premedication with a corticosteroid, antipyretic, and antihistamine should be administered prior to each dose of inotuzumab ozogamicin.1 Patients should also be closely monitored during and for at least 1 hour following infusions of the drug for the potential onset of infusion-related reactions, including symptoms such as fever, chills, rash, or breathing difficulty.1
If an infusion-related reaction occurs, the infusion should be temporarily interrupted and, depending on the severity of the reaction, discontinuance of the infusion or administration of corticosteroids and antihistamines should be considered.1 Permanent discontinuance of inotuzumab ozogamicin is necessary in patients who experience severe or life-threatening infusion-related reactions.1 (See Infusion-related Reactions under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Prolongation of the QT interval has been reported in patients receiving inotuzumab ozogamicin therapy.1 In the INO-VATE ALL study, a QTc interval (corrected for heart rate using Fridericia's formula [QTcF]) exceeding 500 msec was not reported in any inotuzumab ozogamicin-treated patients; however, 3% of inotuzumab ozogamicin-treated patients had an increase in the QTcF interval of 60 msec or more from baseline.1 Grade 2 prolongation of the QT interval occurred in 1% of patients receiving inotuzumab ozogamicin.1 In the INO-VATE ALL study, grade 3 or greater prolongation of the QT interval or torsades de pointes was not reported in any inotuzumab ozogamicin-treated patient.1 Analysis of central tendency showed a peak mean QTcF interval change from baseline of 15.3 msec during day 1 of cycle 4.1
Inotuzumab ozogamicin should be used with caution in patients with a history of or predisposition for prolongation of the QTc interval, patients concurrently receiving other drugs known to prolong the QT interval, and in patients with electrolyte abnormalities.1 (See Drug Interactions: Drugs that Prolong the QT Interval.) The manufacturer recommends monitoring ECGs and serum electrolytes prior to initiation of inotuzumab ozogamicin therapy, following initiation of any drug known to prolong the QTc interval, and periodically during therapy as clinically indicated.1
Fetal/Neonatal Morbidity and Mortality
There are no available data on inotuzumab ozogamicin use in pregnant women; however, based on its mechanism of action and animal findings, inotuzumab ozogamicin may cause fetal harm.1 Embryofetal toxicity (e.g., increased resorption, fetal growth retardation) has been demonstrated in rats receiving inotuzumab ozogamicin at exposure levels approximately 0.4-2 times the human exposure at the maximum recommended dosage.1
Pregnancy should be avoided during inotuzumab ozogamicin therapy.1 The manufacturer states that pregnancy status should be verified prior to initiation of inotuzumab ozogamicin therapy in women of childbearing potential and that such women should be advised to use effective contraceptive methods during therapy and for at least 8 months after discontinuance of the drug.1 In addition, men with female partners of childbearing potential should use effective methods of contraception during therapy and for at least 5 months after discontinuance of the drug.1 Patients should be apprised of the potential hazard to the fetus if inotuzumab ozogamicin is used during pregnancy or if the patient becomes pregnant while receiving the drug.1
Results of animal studies suggest that inotuzumab ozogamicin may impair male and female fertility.1
In a reproductive study, increased resorptions and decreased number of viable embryos and gravid uterine weights were observed following administration of inotuzumab ozogamicin daily for 2 weeks prior to mating through day 7 of gestation (at exposure levels approximately 2 times the human exposure at the maximum recommended dosage) in female animals.1 In toxicology studies, decreased ovarian and uterine weights and ovarian and uterine atrophy were observed followed administration of inotuzumab ozogamicin to female animals for 26 weeks.1
In toxicology studies, decreased testicular weight, testicular atrophy, hypospermia, and prostatic and seminal vesicle atrophy were observed following administration of inotuzumab ozogamicin to male animals for 26 weeks; testicular degeneration and hypospermia were irreversible following discontinuance of the drug for 4 weeks.1
There is a potential for immunogenicity with inotuzumab ozogamicin therapy.1 In clinical studies, anti-inotuzumab ozogamicin antibody formation occurred in 3% of patients receiving the drug; neutralizing antibodies were not detected in any of these patients.1 Clearance of inotuzumab ozogamicin was not affected by the presence of anti-inotuzumab ozogamicin antibodies.1
Inotuzumab ozogamicin may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Pregnancy status should be verified in women of childbearing potential prior to initiation of inotuzumab ozogamicin therapy.1
It is not known whether inotuzumab ozogamicin or its metabolites are distributed into human milk or if the drug has any effect on milk production or the nursing infant.1 Because of the potential for adverse reactions to inotuzumab ozogamicin in nursing infants, women should be advised not to breast-feed while receiving the drug and for at least 2 months after discontinuance of therapy.1
Safety and efficacy of inotuzumab ozogamicin have not been established in pediatric patients.1
In the INO-VATE ALL study, 18% of patients were 65 years of age or older.1 No differences in efficacy or safety were observed between geriatric patients and younger adults in this study;1, 8 however, thrombocytopenia, febrile neutropenia, and elevated concentrations of γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP) occurred more frequently in geriatric patients compared with younger adults.8
Older age is associated with an increased risk for developing hepatic VOD in inotuzumab ozogamicin-treated patients.1, 4, 8 (See Hepatotoxicity, including Hepatic Veno-occlusive Disease, under Warnings/Precautions: Warnings, in Cautions)
Among patients 18-92 years of age, age did not appear to substantially affect the pharmacokinetics of inotuzumab ozogamicin.1 Initial dosage adjustment of the drug in geriatric patients is therefore not necessary.1
Analysis of population pharmacokinetic data indicates that clearance of inotuzumab ozogamicin is not altered in patients with preexisting mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration exceeding the ULN but not more than 1.5 times the ULN with any AST concentration).1
Although clearance of inotuzumab ozogamicin did not appear to be reduced in 4 patients with either moderate or severe hepatic impairment (total bilirubin concentration exceeding 1.5 times the ULN with any AST concentration), only limited data are available in such patients.1
Analysis of population pharmacokinetic data indicates that clearance of inotuzumab ozogamicin is not altered in patients with renal impairment (creatinine clearance 15-89 mL/minute).1 Efficacy and safety of the drug in patients with end-stage renal disease with or without hemodialysis currently are unknown.1
Adverse effects reported in 20% or more of patients with relapsed or refractory acute lymphoblastic leukemia receiving inotuzumab ozogamicin as a single agent in the INO-VATE ALL study include thrombocytopenia,1 neutropenia,1 infection,1 anemia,1 leukopenia,1 fatigue,1 hemorrhage,1 pyrexia,1 nausea,1 headache,1 febrile neutropenia,1 elevated concentrations of aminotransferases (ALT, AST),1 abdominal pain,1 elevated concentrations of γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP),1 and hyperbilirubinemia.1
In vitro studies indicate that N -acetyl-γ-calicheamicin dimethylhydrazide is primarily metabolized by nonenzymatic reduction.1 In vitro, N -acetyl-γ-calicheamicin dimethylhydrazide is unlikely to substantially inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 or uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes 1A1, 1A4, 1A6, 1A9, and 2B7 at clinically relevant concentrations.1 In vitro studies also indicate that N -acetyl-γ-calicheamicin dimethylhydrazide is unlikely to substantially induce CYP isoenzymes 1A2, 2B6, and 3A4 at clinically relevant concentrations.1 N -acetyl-γ-calicheamicin dimethylhydrazide is a substrate of P-glycoprotein (P-gp).1 N -acetyl-γ-calicheamicin dimethylhydrazide is unlikely to inhibit P-gp, breast cancer resistance protein (BCRP), organic anion transporter (OAT) 1 and OAT3, organic cation transporter (OCT) 2, and organic anion transport protein (OATP) 1B1 and OATP1B3.1
In vitro studies indicate that inotuzumab ozogamicin is unlikely to substantially inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 or induce CYP isoenzymes 1A2, 2B6, and 3A4 at clinically relevant concentrations.1
Drugs that Prolong the QT Interval
Concomitant use of inotuzumab ozogamicin and drugs known to prolong the QT interval or cause torsades de pointes may increase the risk of clinically important corrected QT (QTc)-interval prolongation.1 The manufacturer recommends discontinuance of such drugs or concomitant use of alternative drugs not known to prolong the QT/QTc interval while patients are receiving inotuzumab ozogamicin therapy.1 If concomitant use of other drugs known to prolong the QT/QTc interval cannot be avoided, the manufacturer recommends more frequent monitoring of ECGs and serum electrolyte concentrations (i.e., prior to initiation of inotuzumab ozogamicin therapy, after initiation of any drug known to prolong the QTc interval, and periodically during therapy as clinically indicated).1 (See Prolongation of QT Interval under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Because the risk of developing hepatic veno-occlusive disease (VOD) is significantly higher in patients with relapsed or refractory acute lymphoblastic leukemia who undergo hematopoietic stem cell transplantation (HSCT) following inotuzumab ozogamicin therapy, including those who received conditioning regimens containing 2 alkylating agents (e.g., busulfan, melphalan, thiotepa), use of such conditioning regimens should be avoided in patients who received inotuzumab ozogamicin therapy prior to HSCT.1, 4, 9 (See Hepatotoxicity, including Hepatic Veno-occlusive Disease, under Warnings/Precautions: Warnings, in Cautions.)
Because hepatic VOD and liver function test abnormalities are associated with inotuzumab ozogamicin therapy, some experts recommend avoiding concomitant therapy with other drugs known to cause hepatotoxicity (e.g., azole antifungals) in patients receiving inotuzumab ozogamicin and high-dose conditioning regimens with alkylating agents, if possible.9 (See Hepatotoxicity, including Hepatic Veno-occlusive Disease, under Warnings/Precautions: Warnings, in Cautions.)
Because hepatic VOD and liver function test abnormalities are associated with inotuzumab ozogamicin therapy, some experts recommend avoiding concomitant therapy with other drugs known to cause hepatotoxicity such as azole antifungals.9 (See Hepatotoxicity, including Hepatic Veno-occlusive Disease, under Warnings/Precautions: Warnings, in Cautions.)
Inotuzumab ozogamicin, a CD22-directed antibody-drug conjugate, is an antineoplastic agent.1, 3, 10, 11 The antibody-drug conjugate consists of 3 components: a recombinant humanized immunoglobulin G4 (IgG4) kappa monoclonal antibody (inotuzumab), which is specific for human CD22; N -acetyl-γ-calicheamicin, a cytotoxic calicheamicin derivative that causes double-stranded DNA breaks; and an acid-cleavable linker (known as dimethylhydrazide), which covalently attaches N -acetyl-γ-calicheamicin to inotuzumab.1, 3, 10, 11, 12 N -acetyl-γ-calicheamicin is a semisynthetic derivative of the microorganism Micromonospora echinospora subsp. calichensis .1, 10, 11, 12 On average, approximately 6 molecules of N -acetyl-γ-calicheamicin are attached to each inotuzumab molecule (range: 2-8).1
The anticancer activity of inotuzumab ozogamicin appears to be produced by the binding of the antibody-drug conjugate to CD22-expressing tumor cells.1 The antibody portion of inotuzumab ozogamicin recognizes and binds specifically to human CD22,1, 3 a transmembrane glycoprotein specific to B cells that is expressed on the surface of malignant cells in greater than 90% of B-cell acute lymphoblastic leukemia (ALL) cases, including B-cell precursor ALL.3, 10, 13 Following binding of the antibody-drug conjugate to CD22-expressing tumor cells, the resultant complex is internalized by the cell.1, 3 N -acetyl-γ-calicheamicin is then released via hydrolytic cleavage of the linker and binds to DNA in the minor groove causing double-strand DNA breaks and subsequent cell cycle arrest and apoptosis.1, 3, 12
The pharmacokinetics of inotuzumab ozogamicin following IV administration are characterized by a 2-compartment model with linear and time-dependent clearance components.1 Following repeated doses of inotuzumab ozogamicin in patients with ALL, mean peak plasma concentrations of the antibody-drug conjugate increased with subsequent cycles.13 Plasma concentrations of unconjugated N -acetyl-γ-calicheamicin are below the lower limit of quantification.1, 13 Following repeated doses of inotuzumab ozogamicin, steady-state concentrations are reached by the fourth cycle of therapy; estimated systemic accumulation of the antibody-drug conjugate is 5.3-fold.1 In vitro studies indicate that N -acetyl-γ-calicheamicin is metabolized by nonenzymatic reduction.1 In vitro, N -acetyl-γ-calicheamicin dimethylhydrazide is approximately 97% bound to plasma proteins.1 The terminal elimination half-life of the antibody-drug conjugate is 12.3 days.1
Population pharmacokinetic analyses indicate that age (range of 18-92 years), gender, and race (Asian versus non-Asian) do not have clinically important effects on the pharmacokinetics of the antibody-drug conjugate.1 Dosage of inotuzumab ozogamicin is based on body surface area (BSA) because disposition of the antibody-drug conjugate is significantly affected by BSA.1
Risk of hepatotoxicity, including hepatic veno-occlusive disease (VOD) and elevated serum aminotransferase (ALT and/or AST) concentrations, during inotuzumab ozogamicin therapy.1 Importance of informing patients of the signs and symptoms of hepatic VOD (e.g., elevated serum bilirubin concentrations, rapid weight gain, abdominal swelling [which may be painful]) and advising them to seek immediate medical advice if such symptoms occur.1, 9 Importance of informing patients to carefully consider the potential benefits and risks of inotuzumab ozogamicin treatment if they have a history of hepatic VOD or serious ongoing hepatic disease.1
Risk of treatment-related mortality following hematopoietic stem cell transplantation (HSCT); most common causes are infectious complications or hepatic VOD.1 Importance of informing clinicians if signs and symptoms of infection occur.1
Risk of myelosuppression.1 Importance of reporting signs and symptoms of myelosuppression (e.g., infection, bleeding/hemorrhage). 1
Risk of infusion-related reactions.1 Importance of advising patients to inform their clinician if symptoms of such reactions, including fever, chills, rash, or breathing difficulty, occur during infusion of inotuzumab ozogamicin.1
Risk of QT-interval prolongation.1 Importance of informing clinicians if syncope or feelings of dizziness or faintness occur.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 effective contraception while receiving the drug and for at least 8 and 5 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 avoid nursing during therapy and for at least 2 months 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 (e.g., hepatic impairment, cardiovascular disease).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.
Distribution of inotuzumab ozogamicin is restricted.14 (See Restricted Distribution under Dosage and Administration: General.)
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 Pharmaceuticals Inc. Besponsa® (inotuzumab ozogamicin) for injection prescribing information. Philadelphia, PA; 2017 Aug. [Web]
2. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2018 Apr 24. [Web]
3. Kantarjian HM, DeAngelo DJ, Stelljes M et al. Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. N Engl J Med . 2016; 375:740-53. [PubMed 27292104]
4. Kantarjian HM, DeAngelo DJ, Advani AS et al. Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. Lancet Haematol . 2017; 4:e387-e398. [PubMed 28687420]
5. Pfizer. New York, NY: Personal communication.
6. Kantarjian H, Thomas D, Jorgensen J et al. Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer . 2013; 119:2728-36. [PubMed 23633004]
7. Kantarjian H, Thomas D, Jorgensen J et al. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol . 2012; 13:403-11. [PubMed 22357140]
8. Jabbour EJ, DeAngelo DJ, Stelljes M et al. Efficacy and safety analysis by age cohort of inotuzumab ozogamicin in patients with relapsed or refractory acute lymphoblastic leukemia enrolled in INO-VATE. Cancer . 2018; 124:1722-1732. [PubMed 29381191]
9. Kebriaei P, Cutler C, de Lima M et al. Management of important adverse events associated with inotuzumab ozogamicin: expert panel review. Bone Marrow Transplant . 2018; 53:449-456. [PubMed 29330398]
10. George B, Kantarjian H, Jabbour E et al. Role of inotuzumab ozogamicin in the treatment of relapsed/refractory acute lymphoblastic leukemia. Immunotherapy . 2016; 8:135-43. [PubMed 26780449]
11. 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]
12. Shor B, Gerber HP, Sapra P. Preclinical and clinical development of inotuzumab-ozogamicin in hematological malignancies. Mol Immunol . 2015; 67:107-16. [PubMed 25304309]
13. DeAngelo DJ, Stock W, Stein AS et al. Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study. Blood Adv . 2017; 1:1167-1180. [PubMed 29296758]
14. Pfizer Inc. Besponsa® (inotuzumab ozogamicin) access and reimbursement. 2018. From the Pfizer Oncology together website. Accessed 2018 Jul 11. [Web]