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Radio-immunotherapy for B-cell lymphoma

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Radio-immunotherapy for B-cell lymphoma Powered By Docstoc
					Radio-immunotherapy
for B-cell lymphoma


  Tom Pickles



                      1
Radio-immunotherapy
Adds a radioactive molecule to a monoclonal
antibody (MoAb)

90Yttrium–

Labeled
Ibritumomab
Tiuxetan




                                              2
Mononclonal Antibodies




                         Courtesy of Peter McLaughlin, 2002   3
Mononclonal Antibodies v RIT




                          Courtesy of Peter McLaughlin, 2002   4
  Radioimmunotherapy of NHL
                                             90Y   Zevalin
                      Ibritumomab

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




                                    6
     Zevalin™ Phase I/II studies
            Response by Tumor Histology

            Low       Intermediate Mantle Cell                              Total
Response   (n=34)        (n=14)      (n=3)                                 (n=51)
CR          27%           29%          0                                    25%
PR         56%               14%                         0                   41%
CR+PR      82%               43%                         0                   67%



               *Witzig T, White C, Wiseman G, et al. J Clin Oncol 1999;17(12):3793-803   7
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.                                                          ibritumomab tiuxetan
                                                      111In-labeled

                                                    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
                                                                                                               8
              Versus Rituximab Immunotherapy Journal of Clinical Oncology, Vol 20, No 10 (May 15), 2002: pp 2453-
              2463
 Estimated       90Y   Radiation Dose to Organs
                              N        Median    Range
         Organ            (patients)    (cGy)     (cGy)
Spleen                       49          667    23 - 2448
Liver                        56         341     123 - 779
Lungs                        56         255     72 - 442
Urinary Bladder Wall         56         73      33 - 253
Red Marrow                   56         53      13 - 120
Bone Surfaces                56         47       12 - 96
Kidneys                      56         38       7 - 61
All Other Organs             56         38       7 - 61

                                                            9
 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                                                                10
Zevalin™ Phase III: Design
- relapsed or refractory low-grade lymphoma
                       Randomization
                                N=143


Zevalin                N=73       Rituximab              N=70
Day 0:
       Rituximab (250  mg/m2)
                                  375 mg/m2 weekly x 4
       111In Zevalin (5 mCi)

 Day 7:
       Rituximab (250 mg/m2)
       90Y Zevalin (0.4mCi/kg)




                                                                11
 Zevalin™ Phase III: Results
                             Zevalin                                    Rituximab
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
                                                                                                                12
                Versus Rituximab Immunotherapy Journal of Clinical Oncology, Vol 20, No 10 (May 15), 2002: pp 2453-
                2463
  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

                                                                                                 13
                            Journal of Clinical Oncology, Vol 20, No 10 (May 15), 2002: pp 2453-2463
Zevalin™ : Blood counts


                                         g3                        g4              Durn
                                  ANC 25%                          32%             18d
                                  Plates 55%                       5%              16d
                                  Hb     1%                        1%              8d




                                                                                       14
                  Journal of Clinical Oncology, Vol 20, No 10 (May 15), 2002: pp 2453-2463
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+)


                                                             15
           RIT at the BCCA

1. Randomized trial
   Zevalin v no added therapy after
    CR/PR


2. Off-trial
   in relapsed low-grade lymphomas

                                       16
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)




                                              17
Patient population
Stage 3-4 Follicular NHL
• CR or PR after 1st line chemo
• 6-12 weeks after chemo
• Zevalin or no added therapy




                                  18
Endpoints
1. Progression-free survival
2. Change of response status
  – (PR turning into CR)

3. Overall survival
4. Safety and tolerability
5. Quality of Life



                               19
 Process – team effort!
                Nursing         Medical
   Radiation
   Oncology                     Oncology



Radiation       Patient
Safety                            Nuclear
                                  Medicine
     Pharmacy
                Radiopharmacy

                                             20
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)


                                                   21
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



                                                22

				
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