90Y-Ibritumomab Tiuxetan

90Yttrium-Ibritumomab is an antineoplastic agent indicated for non-Hodgkin’s lymphoma. 90Y-Ibritumomab Tiuxetan, a monoclonal antibody, is currently unavailable in generic form due to its patented brand name, Zevalin. In February of 2002, Zevalin became the first ‘radioimmunotherapeutic’ pharmaceutical product to exist under FDA approval Zevalin is specifically indicated for previously untreated follicular non-Hodgkin’s lymphoma (NHL) as well as relapsed or refractory B-cell NHL1.

Mechanism of Action

Zevalin is given in two stages: Ibritumomab Tiuxetan is first paired with elemental ₁₁₁Indium, followed by co-administration with radioactive ₉₀Yttrium. Ibritumomab Tiuxetan, the monoclonal antibody, is therefore coupled with a radioactively cytotoxic agent capable of directly targeting cancer cells2. Once in the body, Ibritumomab Tiuxetan then binds with the CD20 receptor of B-cells, inducing apoptosis, or cell death, thereby reducing the growth of cancerous cells2. The role of 111Indium in Zevalin is to function as a tracer, determining whether the drug has been delivered to the correct tissues 2. After correct distribution is confirmed, 90Yttrium provides specificity for cancer cells, exposing them to radioactive beta emission 1,2.

Dosage and Administration

Zevalin is a seven-day chemo treatment. All treatments fall under the following FDA guidelines and scheduling3:

Relapsed or Refractory B-cell NHL

Day 1: The patient receives 250mg/m2 Rituximab intravenously. This is a common drug of chemotherapy. After four hours, the patient receives 5mCi 111In-Ibritumomab Tiuxetan over 10 minutes3.
Days 2-6: The patient receives a resting period in which medical imaging confirms or denies proper distribution, or biodistribution, of the drug3. Day 7: The patient again receives 250mg/m2 Rituximab intravenously. After fours hours, the patient receives radioactive 90Y-Ibritumomab Tiuxetan, substituting 90Yttrium for 111Indium3.
Dosing for 90Y-Ibritumomab Tiuxetan is based upon patient blood counts: Platelet levels of 100,000-149,000/m3 call for 0.3 mCi/kg over ten minutes, while counts of 150,000/m3 or more require 0.4 mCi/kg over ten minutes3. The maximum dose of Zevalin is 32 mCi. For previously untreated NHL, however, platelet counts must be a minimum of 150,000/m3 and treatment must begin within six to twelve weeks following the final dose of the patient’s previous chemotherapy3. 90Y-Ibritumomab Tiuxetan is therefore infused at 0.4mCi/kg over ten minutes3. Zevalin may also be adjusted to an eight or nine-day therapy given patient response: A physician may decide to administer 90Y-Ibritumomab Tiuxetan on days seven, eight, or nine3. Varying pre-medications are concomitantly administered and FDA required.

Medical Imaging

Radioactive imaging of Zevalin is required to be taken within 48 to 72 hours of administering its radioactive component3. A great advantage of Zevalin therapy includes the ability to use this imaging to trace the drug throughout the lymphatic system. This is essential to determining proper biodistribution. After taking body images, or scintigrams, the following equation is used to determine radioactive exposure to varying tissues6:

FSPECT = (ASTD/AO) x (CTUM/CSTD)

Where AO is the 111Indium activity and ASTD its standard deviation, and CTUM are the tumor SPECT counts and CSTD their standard deviations 6. This equation determines the fractional activity of particular components of the body and lymphatic system, such as the fraction of 111In-Ibritumomab in a tumor versus the total activity of 111In-Ibritumomab as a whole throughout the body6. For example, in one study, total body absorption of Zevalin averaged 0.83 Gy (radioactive grays) between patients, while the effective dose (ED50) averaged 1.31 Gy, and the average tumor absorption was 3.57 Gy 6. The effective dose of a drug indicates the drug dose required to achieve a minimum 50% response in all patients. Medical imaging is therefore important to confirm not only drug delivery to the correct tissues, but also whether or not radioactive exposure achieves toxic effects. Indications of improper distribution or unsafe exposure require alteration of the dose, or discontinuation of the therapy itself.

Clinical Efficacy

Two main Zevalin studies contributed to its FDA approval. In the first, 54 patients with relapsed or refractory non-Hodgkin’s follicular lymphoma underwent study to yield an overall 74% response in which 15% of patients attained a complete response to the treatment1. In the second study, a pool of 143 patients achieved comparable outcomes: In treating follicular lymphoma as well, an overall 80% response occurred in which 16% of patients attained a complete response1. Zevalin also displayed a greater efficacy than Rituximab alone, in which only a 56% response rate occurred7. In another study, event-free survival rates were on average 8.5 months longer with Zevalin therapy than with patients’ most recently prior chemotherapeutic treatment8. In mantle cell lymphoma, studies showed an average of 67% tumor shrinkage occurred9. Event-free survivals were 28 months longer, as opposed to three months in previous treatments, and an 86% overall response was achieved9. In another study yet, 61.5% of patients responded to treatment10. In conclusion, Zevalin has achieved efficacy greater than that of Rituximab, its greatest competitor in likeness. Also, it has achieved overall high response rates in multiple clinical studies, as well as lengthened event-free survival periods.

Warnings

Do not use Zevalin while pregnant or breastfeeding, as it may cause damage to the unborn fetus or infant3. Do not combine Zevalin with anticoagulants (ie. Warfarin, Aspirin, Heparin) as they will thin the blood and may cause excessive bleeding, a serious and potentially fatal adverse event11. 80% of fatal therapies occurred within the first Rituximab infusion. Zevalin should not be given to patients with greater than 25% damaged lymphatic marrow3.

Side Effects

Common side effects include thrombocytopenia and neutropenia, or low red blood cell and white blood cell counts, respectively3,12,13. Thrombocytopenia of all grades clinically occurs in 62-95% of patients while neutropenia of all grades occurs in 45-77% of patients12,13. Joint pain, infection, and fatigue are also prominent. Mild side effects include dizziness, hypoxia, anorexia, and gastrointestinal effects (ie. nausea, vomiting, diarrhea, abdominal pain)3. Severe adverse events include extreme hematological toxicity, immune system infection due to vulnerability, heart attack, uncommon dermatological effects, and overexposure of radiation3.

Expense

A single dose of Zevalin costs ranges $22,000 to $24,000 in a hospital setting, making it the most expensive single-dose drug on the market4. This treatment, however, comprises a full therapy (seven to nine days), whereas most chemotherapy regimens consist of multiple drugs on varying days. A typical chemotherapy regimen costs a patient on average between $20,000 and $30,000, making Zevalin a somewhat middle-of-the-road regimen in terms of chemotherapy financial expense4,5.

References

2. Elsevier. Clinical Pharmacology. Zevalin: Monograph. 2010 [cited Sept. 29]. Available from: http://http://clinicalpharmacology.com/Forms/drugoptions.aspx?cpnum=2573&n=Zevalin.
3. Micromedex. Ibritumomab Tiuxetan. [serial on the Internet]. 2010 Feb. 8 [cited 2010, Sept. 29];22. Available from: http://www.thomsonhc.com/hcs/librarian/ND_T/HCS/ND_PR/Main/CS/426746/DUPLICATIONSHIELDSYNC/421FFD/ND_PG/PRIH/ND_B/HCS/SBK/2/ND_P/Main/PFActionId/hcs.common.RetrieveDocumentCommon/DocId/2224/ContentSetId/31#secN1006A
4. Timmerman, L. Biogen Radiation Drug, a Single Shot, Halts Lymphoma [serial on the Internet]. 2007 Dec. 9 [cited 2010 Oct. 25];1, Available from: http://www.bloomberg.com/apps/news?pid=newsarchive&sid=ahnHMD8ehySY
6. Erwin, W, et. al. Estimation of Yttrium-90 Zevalin Tumor-Absorbed Dose in Ocular Adnexal Lymphoma Using Quantitative Indium-111 Zevalin Radionuclide Imaging. [serial on the Internet]. 2009 Sept. [cited 2010, Sept. 29];6. Available from: http://ovidsp.tx.ovid.com/.
7. Pacilio, M, et. al. A Theoretical Dose-Escalation Study Based on Biological Effective Dose in Radioimmunotherapy With 90Y-Ibritumomab Tiuxetan (Zevalin). [serial on the Internet]. 2010 Jan. 13 [cited 2010, Oct. 7];13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 20069297/.
8. Cicone, F, et. al. Follicular Lymphoma at Relapse After Rituximab Containing Regimens: Comparison of Time to Event Intervals Prior to and After 90Y-Ibritumomab-Tiuxetan. [serial on the Internet]. 2010 Aug. 6 [cited 2010 Sept. 29];8. Available from: http://www.wileyonlinelibrary.com.
9. Wang, M, et al. Phase II Study of Yttrium-90–Ibritumomab Tiuxetan in Patients With Relapsed or Refractory Mantle Cell Lymphoma. [serial on the Internet]. 2009 Nov. 1 [cited 2010 Sept. 29];6. Available from: http://www.jco.ascopubs.org.
10. Ferrucci, P, et. al. High Activity 90Y-Ibritumomab Tiuxetan (Zevalinâ) With Peripheral Blood Progenitor Cells Support in Patients With Refractory/Resistant B-cell Non-Hodgkin Lymphomas. [serial on the Internet]. 2007, Aug. 1 [cited 2010 Sept. 29];10. Available from: http://www.onlinelibrary.wiley.com.
11. West, S, et. al. Cutaneous Surgeons Cannot Predict Blood-Thinner Status by Intraoperative Visual Inspectio. [serial on the Internet]. 2001 Aug. 30 [cited Oct. 7]6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12087237/.
12. Borghaei, H, et. al. Safety and Efficacy of Radioimmunotherapy with Yttrium 90 Ibritumomab Tiuxetan (Zevalin). [serial on the Internet]. 2004 Jan. [cited 2010, Oct. 7];7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14762738/.
13. Costantini, D, et. al. 111In-Labeled Trastuzumab (Herceptin) Modified with Nuclear Localization Sequences (NLS): An Auger Electron-Emitting Radiotherapeutic Agent for HER2/neu-Amplified Breast Cancer. [serial on the Internet]. 2007 May 15 [cited 2010, Oct. 7];12. Available from: http://jnm.snmjournals.org/cgi/content/abstract/48/8/1357/.