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DRUG RECORD

 

INOTUZUMAB OZOGAMICIN

OVERVIEW
Inotuzumab Ozogamicin

 

Introduction

Inotuzumab ozogamicin is a humanized monoclonal antibody-cytotoxin conjugate which is used in the therapy of refractory or relapsed acute lymphoblastic leukemia.  Inotuzumab ozogamicin has been linked to frequent serum enzyme elevations during therapy and with instances of clinically apparent acute liver injury, including acute sinusoidal obstruction syndrome which can be severe and even fatal.

 

Background

Inotuzumab (in" oh tooz' ue mab) ozogamicin (oh" zoe ga mye' sin) is a humanized monoclonal antibody to the human CD24 cell surface marker which is highly expressed on malignant lymphoblastic leukemia cells.  The monoclonal antibody is conjugated to a cytotoxic agent from a class of calicheamicins called ozogamicin.  When inotuzumab binds to CD24, it is internalized and the ozogamicin is released by the action of lysosomal enzymes on the linker molecule that joins it to the monoclonal antibody.  The released intracellular ozogamicin causes breaks in double stranded DNA that leads to apoptotic cell death.  This monoclonal antibody conjugate has been shown to be effective in inducing remissions in refractory acute lymphoblastic leukemia and was given accelerated approval for this indication in the United States in 2017.  Inotuzumab ozogamicin is available as 0.9 mg of lyophilized powder in single dose vials under the brand name Besponsa.  The recommended dose regimen varies by body weight, day of therapy and whether treating refractory vs relapsed acute lymphoblastic leukemia.  Common side effects include bone marrow suppression, infections, fatigue, fever, nausea, headache, abdominal pain and hemorrhage.  Less common but potentially serious side effects include severe myelosuppression, severe infections, clinically significant bleeding and hemorrhage, infusion related reactions, QTc interval prolongation and embryo-fetal toxicity.

 

Hepatotoxicity

In prelicensure clinical trials of inotuzumab ozogamicin, up to half of patients had serum ALT or AST elevations during therapy which were above 5 times the upper limit of normal (ULN) in 2% to 5%.  Hyperbilirubinemia is also common during inotuzumab therapy, generally occurring without accompanying ALT or AST elevations.  More importantly, a variable proportion of patients (ranging from 2% to 35%) developed clinically apparent sinusoidal obstruction syndrome (SOS) after inotuzumab ozogamicin therapy.  The proportion was even higher (15% to 25%) in patients who receive inotuzumab and subsequently underwent hematopoietic cell transplantation (HCT).  Symptoms of nausea, right upper quadrant pain, weight gain and abdominal distension (from ascites) arose within 5 to 20 days of the infusion and were followed in some patients by progressive rises in bilirubin, serum aminotransferase and alkaline phosphatase levels.  Clinically apparent SOS has a poor prognosis and the mortality rate is as high as 70%, most patients dying of multiorgan failure.  Risk factors for developing SOS after inotuzumab therapy include allogenic hematopoietic cell transplantation, use of other antineoplastic agents and presence of preexisting liver disease. 

Likelihood score: B (likely cause of clinically apparent liver injury, generally caused by sinusoidal obstruction syndrome).

 

Mechanism of Liver Injury

The cause of the serum enzyme elevations during inotuzumab ozogamicin therapy is not known, but they are likely due to direct toxicity of the conjugate.  The propensity of inotuzumab ozogamicin to cause sinusoidal obstruction syndrome is perhaps due to the fact that hepatic sinusoidal endothelial cells express low levels of CD24 on the cell surface, and the antibody conjugate may be taken up by these cells resulting in their damage and release of apoptotic fragments into sinusoids causing obstruction.

 

Outcome and Management

The mild-to-moderate serum aminotransferase elevations that occur during inotuzumab ozogamicin therapy are generally transient and asymptomatic and do not require dose modification or delay in therapy.  Elevations above 5 times the upper limit of normal should lead to more careful monitoring and suspension of further infusions, at least until levels return to normal or near normal levels.  Management of SOS generally rests on careful attention to fluid balance and treatment of complications.  There are no proven means of prevention or treatment of SOS due to inotuzumab ozogamicin, although pretreatment with ursodiol and acute management with defibrotide are often employed.  The adverse events profile and hepatotoxicity of inotuzumab ozogamicin are similar to those caused by gemtuzumab ozogamicin, a similar monoclonal antibody-conjugate directed to CD33 that is used to treat refractory or relapsed acute myeloid leukemia.

 

Drug Class:  Antineoplastic Agents; Monoclonal Antibodies

 

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PRODUCT INFORMATION
Inotuzumab Ozogamicin

 

REPRESENTATIVE TRADE NAMES
Inotuzumab Ozogamicin – Besponsa®

 

DRUG CLASS
Antineoplastic Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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CHEMICAL FORMULA AND STRUCTURE
Inotuzumab Ozogamicin
DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Inotuzumab Ozogamicin 635715-01-4 Monoclonal Antibody Not Available

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ANNOTATED BIBLIOGRAPHY
Inotuzumab Ozogamicin

 

References updated: 08 August 2018
Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; HCT, hematopoietic cell transplantation; SOS, sinusoidal obstruction syndrome (also known as hepatic veno-occlusive disease).

  1. DeLeve LD. Gemtuzumab ozogamicin. Liver sinusoidal endothelial cells and liver injury. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2011, pp. 142-3.  (Review of agents that damage liver sinusoidal cells including gemtuzumab ozogamicin; mentions that CD33 which is present on leukemic blast cells is also present on liver sinusoidal endothelial cells).

  2. Chabner BA, Barnes J, Neal J, Olson E, Mujagiv H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-53.  (Textbook of pharmacology and therapeutics).

  3. https://www.accessdata.fda.gov/scripts/cder/daf/  (FDA Drug Approvals website that has product labels [package inserts], letters of approval and full FDA scientific review of the new drug application for safety and efficacy which mentions that ALT elevations occur in up to 50% of inotuzumab ozogamicin treated subjects and are above 5 times ULN in 2% to 5%, but these abnormalities are generally are self-limited and without symptoms or jaundice, but that SOS occurs in 3% of treated subjects not undergoing HCT and as many as 22% of those with HCT [before or after treatment]).

  4. Rajvanshi P, Shulman HM, Sievers EL, McDonald GB. Hepatic sinusoidal obstruction after gemtuzumab ozogamicin (Mylotarg) therapy. Blood 2002; 99: 2310-4. PubMed Citation  (Among 23 patients with relapsed, refractory acute myeloid leukemia [AML] treated with gemtuzumab ozogamicin, liver injury suggestive of SOS developed in 11, 7 of whom died of hepatic failure 8-47 days after the infusion).

  5. 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: S29-34. PubMed Citation  (Review of adverse side effects of gemtuzumab ozogamicin therapy; mentions mild ALT and AST [Grade 1 and 2] elevations in 26% and elevations ≥5 times ULN in 16% and clinically apparent SOS in 2-12% of patients, risk factors for this complication being HCT, concurrent cytotoxic therapies, higher and more frequent doses and underlying liver disease).

  6. McDonald GB. Management of hepatic sinusoidal obstruction syndrome following treatment with gemtuzumab ozogamicin (Mylotarg). Clin Lymphoma 2002; 2 Suppl 1: S35-9. PubMed Citation  (Review of management of SOS).

  7. Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, York S, 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 Citation  (Among 49 patients with refractory or relapsed ALL treated with inotuzumab, 57% had an objective response and adverse events included fever [59%], ALT elevations [57%: all but 1 being less than 5 times ULN], hyperbilirubinemia [26%], hypotension [26%] and SOS in 5 of 22 [23%] who subsequently underwent HCT, 1 case being fatal).

  8. Wagner-Johnston ND, Goy A, Rodriguez MA, Ehmann WC, Hamlin PA, Radford J, Thieblemont C, et al. A phase 2 study of inotuzumab ozogamicin and rituximab, followed by autologous stem cell transplant in patients with relapsed/refractory diffuse large B-cell lymphoma. Leuk Lymphoma 2015; 56: 2863-9. PubMed Citation  (Among 63 patients with relapsed or refractory large B cell lymphoma treated with inotuzumab and rituximab, the objective response rate was 29% and adverse events were common including AST elevations in 43%; 4 of 18 patients [22%] who subsequently underwent HCT developed significant hepatotoxicity, 2 with suspected SOS).

  9. Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 2016; 375: 740-53. PubMed Citation  (Among 326 patients with refractory or relapsed ALL treated with inotuzumab ozogamicin or standard intensive chemotherapy, complete remissions were more frequent with inotuzumab [81% vs 29%] and medial overall survival was greater [7.7 vs 6.7 months], and while adverse events were frequent in both groups, SOS occurred in 11% [including 2 fatal cases following HCT] with inotuzumab vs 1% with standard therapy).

  10. Kantarjian HM, Vandendries E, Advani AS. Inotuzumab ozogamicin for acute lymphoblastic leukemia. N Engl J Med 2016; 375: 2101. PubMed Citation  (Further follow up of patients in a controlled trial [Kantarjian 2016] mentions that 15 of 71 patients [21%] who underwent HCT after receipt of inotuzumab for ALL developed SOS, and that there was no correlation between time after receipt of the agent and frequency of SOS).

  11. Goy A, Forero A, Wagner-Johnston N, Christopher Ehmann W, Tsai M, Hatake K, Ananthakrishnan R, et al. A phase 2 study of inotuzumab ozogamicin in patients with indolent B-cell non-Hodgkin lymphoma refractory to rituximab alone, rituximab and chemotherapy, or radioimmunotherapy. Br J Haematol 2016; 174: 571-81. PubMed Citation  (Among 81 patients with refractory non-Hodgkin lymphoma treated with inotuzumab ozogamicin, the objective response rate was 67% and adverse events were common including thrombocytopenia [74%], neutropenia [56%], anemia [15%], ALT elevations [20%: only 1 rising above 5 times ULN] and hyperbilirubinemia [15%]).

  12. Kantarjian HM, DeAngelo DJ, Advani AS, Stelljes M, Kebriaei P, Cassaday RD, Merchant AA, 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 Citation  (Secondary analysis of liver related adverse events in a large controlled trial of inotuzumab vs placebo [Kantarjian 2016], with follow up data on all 326 patients enrolled, reported elevations in ALT in 15% vs 13%, AST in 23% vs 11%, Alk P in 13% vs 7%, bilirubin in 21% vs 17% and SOS in 13% [n=22, 5 fatal] vs <1% with SOS occurring without intervening HCT in 5 [3%] vs none).

  13. Dang NH, Ogura M, Castaigne S, Fayad LE, Jerkeman M, Radford J, Pezzutto A, et al. Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Br J Haematol 2018; 182 (4): 583-6. PubMed Citation  (Among 332 patients with non-Hodgkin lymphoma treated with rituximab combined with inotuzumab ozogamicin or with standard chemotherapy, overall survival was similar in the two groups while adverse events were more frequent with inotuzumab including elevations in ALT [17% vs 8%], Alk P [13% vs 5%], bilirubin [8% vs 2%] and SOS [2% vs none]).

  14. Lamb YN. Inotuzumab ozogamicin: first global approval. Drugs 2017; 77: 1603-10. PubMed Citation  (Review of the history of development, mechanism of action, pharmacology, clinical efficacy and safety of inotuzumab ozogamicin shortly after its approval in the US; mentions that cases of SOS were more frequent with inotuzumab than standard therapy [13% vs 1%], some cases arising years after its administration, often after HCT).

  15. Kantarjian H, Ravandi F, Short NJ, Huang X, Jain N, Sasaki K, Daver N, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol 2018; 19: 240-8. PubMed Citation  (Among 52 elderly patients [60 years or older] with newly diagnosed ALL treated with inotuzumab ozogamicin and low intensity standard chemotherapy, almost all patients had an objective response, and all had hepatic adverse events including SOS in 4 patients [8%], 2 of which were fatal, 1 occurring after HCT).

  16. Jabbour E, Ravandi F, Kebriaei P, Huang X, Short NJ, Thomas D, Sasaki K, et al. Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD for patients with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: a phase 2 clinical trial. JAMA Oncol 2018; 4: 230-4. PubMed Citation  (Among 59 patients with relapsed or refractory ALL treated with inotuzumab and lower dose standard chemotherapy, the overall objective response rate was 78%, while 95% had at least one hepatic adverse event and 9 [15%] developed SOS, all of whom had received HCT either before or after inotuzumab therapy).

  17. Inotuzumab ozogamicin (Besponsa)--an antibody-drug conjugate for ALL. Med Lett Drugs Ther 2018; 60 (1547): e90-e91. PubMed Citation  (Concise review of the mechanism of action, clinical efficacy, safety and costs of inotuzumab ozogamicin, shortly after its approval as therapy of refractory or relapsed, B-cell precursor ALL in adults, mentions that SOS occurred in 18 of 79 patients [23%] treated with inotuzumab who subsequently underwent HCT, the mortality rate of which was 28%).

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OTHER REFERENCE LINKS
Inotuzumab Ozogamicin
  1. PubMed logoRecent References on Inotuzumab Ozogamicin

  2. Clinical Trials logoTrials on Inotuzumab Ozogamicin

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