● Treatment Options For Indolent NHL

EARLY STAGE	ADVANCED STAGE
XRT XRT+CHEMOTHERAPY	● Watchful Waiting ● External Beam Radiation ● Chemotherapy ● Monoclonal Antibody Therapy-Rituximab ● Stem Cell Transplant ● Radioimmunotherapy 90Y Ibritumomab tiuxetan 131I Tositumomab ● Investigational
Key Point: While external beam radiation may cure stage I or II disease, the majority of patients with indolent NHL are diagnosed with stage III or IV disease and may require alternative treatment options. The optimal management of patients with indolent lymphoma remains a challenge, and there are many treatment options to consider. Some patients with localized, indolent NHL (stage I or II) can be cured with external beam radiation. Unfortunately, only 10% to 20% of patients with indolent NHL are diagnosed with early-stage disease.1 The remaining patients, with stage III or IV disease, may receive treatments that range from a conservative “watch and wait” approach to a more aggressive approach, such as dose-intensive chemotherapy with stem cell transplantation.1,2 Monoclonal antibodies, namely rituximab, can be used for the treatment of relapsed indolent lymphoma. A new type of therapy is radioimmunotherapy (RIT), which combines the targeting ability of a monoclonal antibody with the strength of radiotherapy. The first drug of this class was approved by the FDA in February 2002, 90Y ibritumomab tiuxetan (Zevalin®). Other types of RIT are currently being investigated for treating patients with NHL. Vose JM. Classification and clinical course of low-grade non-Hodgkin’s lymphomas with overview of therapy. Ann Oncol. 1996;7:S13–S19. Horning SJ. Natural history of and therapy for the indolent non-Hodgkin’s lymphomas. Semin Oncol. 1993;20:75–88.

● Monoclonal Antibodies/Clinical Requirements

Rituximab: First Monoclonal Antibody Approved for NHL
• Indication: Relapsed or refractory low-grade or follicular, CD20+, B-cell non-Hodgkin’s lymphoma

Rituxan (rituximab) prescribing information. South San Francisco, California: Genentech Inc; 1997. Rituximab was the first monoclonal antibody approved for immunotherapy in NHL. Rituximab targets the CD20 antigen that is found on 90% of B-cell lymphomas. Specifically, rituximab is indicated for the treatment of patients with relapsed or refractory low-grade or
follicular, CD20-positive, B-cell NHL.₁
Typically, rituximab is given at a dose of 375 mg/m₂ every week for 4 weeks.₁
In a pivotal trial in 166 patients, the overall response rate (ORR) with this regimen was 48%, with a 6% complete response rate.₁
Given the unique mechanism of action and manageable toxicity profile of rituximab, ongoing research includes its integration into standard chemotherapy regimens, use in high-grade lymphomas, and use in the front-line treatment of lymphoma._2-4
McLaughlin P, Hagemeister FB, Grillo-Lopez J. Rituximab in indolent lymphoma: the single-agent pivotal trial. Semin Oncol. 1999;26(suppl 14):79–87.
Coiffier B, Lepage E, Herbrecht R, et al. Mabthera (rituximab) plus CHOP is superior to CHOP alone in elderly patients with diffuse large B-cell lymphoma (DLCL): interim results of a randomized GELA trial.
Blood. 2000;96:223a. Abstract 950.
Czuczman MS, Fallon A, Scarpace A, et al. Phase II study of rituximab in combination with fludarabine in patients (pts) with low-grade or follicular B-cell lymphoma. Blood. 2000;96:729a. Abstract 3154.

CD20: Normal B Cells and 90% of B cell NHL but NOT on Stem Cells or Plasma Cells
<----Bone Marrow---->			<----Blood, Lymph---->
Pluripotent Stem Cell	Lymphoid Stem Cell	Pre-B Cell	B Cell	Activated B Cell	Plasma Cell

Radioimmunotherapy with Y-90 Zevalin

• Ibritumomab

Murine monoclonal antibody parent of Rituximab

• Tiuxetan

Conjugated to antibody, forming strong urea-type bond
Stable retention of Y-90

⁹⁰ Y Zevalin Produces a Crossfire Effect

Naked Antibody	90Y Zevalin

Zevalin® and Rituximab®

The ORR based on the International Workshop NHL response criteria was 80% in the ibritumomab tiuxetan
arm and 56% in the rituximab arm (P = .002).₁
The complete response rate (including unconfirmed complete responders) was 34% in the ibritumomab
tiuxetan arm and 20% in the rituximab arm (P = .04).₁
Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of yttrium-90-labeled
ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2002:20:2453–2463.

Zevalin: ORR and Durable Remissions
	Overall Responders		CR/CRu		Ongoing CR/CRu Responders
Study N	%	Median DR (mo)	%	Median DR (mo)	%	Median DR (mo)	Range (mo)
Phase 1/2 (51)	73	11.7	29	23	19	62.1	60+ to 66+
Phase 2 (30)	83	11.5	47	23	41.2	41.2	40+ to 42+
Phase 3 (73)	80	13.9	34	23	42.2	42.2	33+ to 48+
Witzig et al. Proc Am Soc Clin Oncol. In press. *data in CR pts only Response rates and median duration of response are shown for three clinical trials in 154 patients who had a median of 2 prior therapies. These trials included a Phase 1-2 dose-finding trial in indolent and aggressive NHL Phase 2 trial of reduced dose 90Y ibritumomab tiuxetan in patients with low-grade, follicular or transformed NHL with baseline thrombocytopenia Phase 3 randomized trial that compared patients treated with 90Y ibritumomab tiuxetan with those treated with rituximab. Overall response rates were high Ranging from 73% to 83% Median duration of response in overall responders ranged from 11.5 to 13.9 months. Median duration of responses in patients with complete responses (CR/Cru) approaches 2 years Ongoing responses in complete responders are exceeding 5 years. Witzig TE, Emmanouilides C, Molina A, et al. Yttrium-90 ibritumomab tiuxetan radioimmunotherapy (RIT) induces durable complete responses (CR/CRu) in patients with relapsed or refractory B-cell non- Hodgkin’s lymphoma (NHL). Proc Am Soc Clin Oncol. In press.

Zevalin: Treatment Schema

Zevalin: Single Point Distribution System

● Scheduling/Availability Concerns

Zevalin Dose Calibrator Calibration

Zevalin PI states:
Unit dose(s) should be assayed immediately before use
Dose calibrator(s) should be operated via manufacturer’s specifications
Some method of verification or instrument calibration may be necessary

Dose Calibrator Contacts : Manufacturers
• Biodex 800-224-6339, Ext. 2143
• Cardinal Health 888-466-8257
• Capintec, Inc. 800-631-3826

Use with standards or accuracy questions: NIST 301-975-5539

● Getting started
• Y-90 Zevalin therapy dose is based on patient’s actual baseline weight and platelet levels

• 0.3 mCi/kg Y-90 Zevalin - platelets 100,000 - 149,000
• 0.4 mCi/kg Y-90 Zevalin - platelets > 150,000

NOTE: Y-90 Zevalin dose must not exceed 32 mCi

Radiopharmaceutical Characteristics
90Yttrium Chloride • DAYS OF USE: Y-90 IS AVAILABLE FOR CALIBRATION / USE ANY DAY OF THE WEEK • Same day delivery • HALF-LIFE: 64.1 hours • ENERGY: 2.281 MeV • DECAY: Beta minus

Zevalin Radioimmunotherapy: Typical Schedule

Zevalin Unit-Dose Storage & Shelf-life

Refrigerate Zevalin unit-dose (2 - 8 °C) if not ready for immediate injection
• Shelf-life 8 hours for Y-90 Zevalin after preparation