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Radio-immunotherapy for B-cell lymphoma

Radio-immunotherapy for B-cell lymphoma. Tom Pickles. Radio-immunotherapy. Adds a radioactive molecule to a monoclonal antibody (MoAb). 90 Yttrium–Labeled Ibritumomab Tiuxetan. Mononclonal Antibodies. Courtesy of Peter McLaughlin, 2002. Mononclonal Antibodies v RIT.

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Radio-immunotherapy for B-cell lymphoma

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  1. Radio-immunotherapyfor B-cell lymphoma Tom Pickles

  2. Radio-immunotherapy Adds a radioactive molecule to a monoclonal antibody (MoAb) 90Yttrium–Labeled Ibritumomab Tiuxetan

  3. Mononclonal Antibodies Courtesy of Peter McLaughlin, 2002

  4. Mononclonal Antibodies v RIT Courtesy of Peter McLaughlin, 2002

  5. Ibritumomab Tiuxetan CD 20 B Radioimmunotherapy of NHL 90Y Zevalin • Ibritumomab (murine antibody parent of Rituximab) • Tiuxetan (MX-DTPA) conjugated to antibody forming strong urea-type bond • Stable retention of 90Y 90Y 90Y Zevalin CD20 antigen • Expressed only on B lineage cells • Does not shed, internalize or modulate • Yttrium-90 • T1/2 = 64 hours • Outpatient administration • Beta emission 90 = 5 mm

  6. Clinical results with Zevalin90Yttrium Ibritumomab Tiuxetan

  7. Zevalin™ Phase I/II studies Response by Tumor Histology *Witzig T, White C, Wiseman G, et al. J Clin Oncol 1999;17(12):3793-803

  8. Zevalin™ Biodistribution The 4-hour scan demonstrates the residual blood pool. The 63-hour and 140-hour scans demonstrate axillary, inguinal, and periaortic lymphoma, as well as uptake in the liver. 111In-labeled ibritumomab tiuxetan images from a representative patient. Thomas E. Witzig, Leo I. Gordon, Fernando Cabanillas, et al. Randomized Controlled Trial of Yttrium-90 –Labeled Ibritumomab Tiuxetan Radioimmunotherapy Versus Rituximab Immunotherapy Journal of Clinical Oncology, Vol 20, No 10 (May 15), 2002: pp 2453-2463

  9. Estimated 90Y Radiation Dose to Organs

  10. 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 Thomas E. Witzig, Leo I. Gordon, Fernando Cabanillas, Myron S. Czuczman, Christos Emmanouilides, Robin Joyce, Brad L. Pohlman, Nancy L. Bartlett, Gregory A. Wiseman, Norman Padre, Antonio J. Grillo-Lo´pez, Pratik Multani, and Christine A. White Journal of Clinical Oncology, Vol 20, No 10 (May 15), 2002: pp 2453-2463

  11. Zevalin™ Phase III: Design - relapsed or refractory low-grade lymphoma Randomization N=143 ZevalinN=73 Day 0: Rituximab (250 mg/m2) 111In Zevalin (5 mCi)Day 7: Rituximab (250 mg/m2) 90Y Zevalin (0.4mCi/kg) RituximabN=70 375 mg/m2 weekly x 4

  12. Zevalin™ Phase III: Results ZevalinRituximab Response rate CR 30% 16% PR 45% 36% Overall RR 80% 56% p=0.002 Duration of response after 6 mo 74% 52% p=0.02 after 1 yr 47% 30% p=ns Thomas E. Witzig, Leo I. Gordon, Fernando Cabanillas, et al. Randomized Controlled Trial of Yttrium-90 –Labeled Ibritumomab Tiuxetan Radioimmunotherapy Versus Rituximab Immunotherapy Journal of Clinical Oncology, Vol 20, No 10 (May 15), 2002: pp 2453-2463

  13. Zevalin™ Phase III: Toxicity Mostly transient • Infusion-related to Rituximab • Fever, chills, rigors, urticaria • Nausea, diarrhoea, arthralgia • Rarely • Dyspnoea, hypotension, bronchospasm • Significant • Bone marrow supression Journal of Clinical Oncology, Vol 20, No 10 (May 15), 2002: pp 2453-2463

  14. Zevalin™ : Blood counts g3g4Durn ANC 25% 32% 18d Plates 55% 5% 16d Hb 1% 1% 8d Journal of Clinical Oncology, Vol 20, No 10 (May 15), 2002: pp 2453-2463

  15. Zevalin in Rituximab-Refractory Disease Follicular NHL Response rates • Overall 74% • Complete 15% • response to prior Rituximab CR was 32% p=0.002 • response to prior chemo CR was 67% p=ns Response duration • In responders 9.1 months (3.5 to 26+)

  16. RIT at the BCCA Randomized trial Zevalin v no added therapy after CR/PR Off-trial in relapsed low-grade lymphomas

  17. 1. Randomized Study • Prospective, multicentred, multinational, randomized phase III clinical trial • 350 patients in approximately 85 centres (EU, Canada) • 8 in Canada (BC the first)

  18. Stage 3-4 Follicular NHL CR or PR after 1st line chemo 6-12 weeks after chemo Zevalin or no added therapy Patient population

  19. Endpoints • Progression‑free survival • Change of response status • (PR turning into CR) • Overall survival • Safety and tolerability • Quality of Life

  20. Process – team effort! Nursing MedicalOncology RadiationOncology Patient RadiationSafety Nuclear Medicine Pharmacy Radiopharmacy

  21. 2. Zevalin off-study • Not yet available in Canada • Patients travel to Seattle • Cost ~$40,000 – Out of Country Claim • ? When available in Canada (soon) • ? Cost $20,000 (+ Rituximab) • BCCA PEC application under consideration • Funding applied for 21 patients/year ($500k)

  22. Zevalin off-study Placed as ‘end-of-line’ palliative therapy • After chemo, 1st and 2nd line • After localized RT • After experimental protocols (anti CD-22) • After Rituximab ~50% response rate for ~9 months

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