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.
 

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

 

90Y 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 transfored 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
*0.4 mCi/kg in patients with a platelet count ³150,000/mL or 0.3 mCi/kg with a platelet count 100,000–149,000/mL.
 

Zevalin: Single Point Distribution System
 

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
 

Calculate Patient Dose

•         In-111 Zevalin imaging dose is 5 mCi

•         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
111Indium Chloride 90Yttrium Chloride

•     APPROVED MANUFACTURER(S): GE/Amersham Health or Covidien/Mallinckrodt

•     DAYS OF USE: MON,TUES or WED

•    HALF-LIFE:  67.3 hours

•    ENERGY:  171 and 245 keV

•      DECAY:  Electron Capture

•     APPROVED MANUFACTURER: only MDS Nordion

•     DAYS OF USE:   TUES or WED

•       Same day delivery 

•    HALF-LIFE:  64.1 hours

•    ENERGY:  2.281 MeV

•      DECAY:  Beta minus  
 

Zevalin Radioimmunotherapy:
Typical Schedule

The drug should be ordered at least 5 days before the scheduled administration of the first dose.
This calendar shows a suggested schedule in which the drug administration and all gamma scans can be done during a week.
 

Zevalin Unit-Dose Storage & Shelf-life

•        Refrigerate Zevalin unit-dose (2 - 8 °C) if not ready for immediate injection

•    Shelf-life 12 hours for In-111 Zevalin after preparation

•   Shelf-life  8 hours for Y-90 Zevalin after preparation