Amar U. Kishan, MS Amar IV U. Kishan, MSIV Gillian Lieberman, Gillian MD Lieberman, MD June 2011 Click to edit Master title style Click to edit Master text styles Radioimmunotherapy of Non Second level Hodgkin Lymphoma with Third level 90 Y Ibritumomab Fourth level tiuxetan Fifth level Amar U. Kishan, Harvard Medical School Year IV 1
Outline Review of Radioactive Decay Introduction to Radioimmunotherapy 90 Y IT: Brief Literature Review Mechanics of 90 Y IT Therapy Selected Cases 2
Review of Radioactive Decay Alpha Decay: Release of an α particle, or helium nucleus. These particles are highly ionizing, and consequently lose energy very quickly, leading to a low penetration depth (these can be shielded by the skin or a piece of paper). Beta Decay: Release of a β particle, either an electron or a positron (along with an antineutrino or neutrino). β particles have higher penetration depths than α particles (shielding can require thin plastic, glass, aluminum, wood). From Wikipedia Commons. Available at: http://en.wikipedia.org/wiki/file:alpha_decay.svg and http://en.wikipedia.org/wiki/file:beta_decay.svg. 3
Review of Radioactive Decay Gamma Decay: Release of a γ particle, or photon. As it has no charge or mass, a gamma particle has a high penetration depth (shielding thus requires dense materials like lead or concrete). Composition Alpha Beta Gamma Helium Nucleus Electron or positron Hazard Internal Superficial, Internal Photon External Shielding Paper/Skin Plastic Lead From Wikipedia Commons. Available at: http://en.wikipedia.org/wiki/file:gamma_decay.svg. 4
Introduction to Radioimmunotherapy Image adapted from Karesh, Stephen. "Radioimmunotherapy of Non Hodgkin's Lymphoma with Radiolabeled Antibodies." April 2010. 5
Radioimmunotherapy Principles Utilizes the fact that most cells of a given tumor will express a certain antigen, e.g. CD20 Administering an antibody against this antigen will then activate immune mediated killing upon antibody binding Conjugated a radionuclide to the antibody will allow for localized radiation Advantages of radioimmunotherapy Can reach undetected tumor foci Crossfire effect allows irradiation of poorly perfused or non antigen expressing adjacent cell clusters Normal overlying tissues are not irradiated 6
Choosing a Radionuclide α emitters such as 211 At, 212 Bi, and 213 Bi have been investigated Path length (χ 90 ; radius over which 90% of particle energy will be dissipated) is 50 100 microns, on the order of single cell Very short t 1/2 (~1 hr for Bi isotopes) Area of active research γ emitters Large path length, so most of the radiation will escape the local environment 7
β Emitters in Radioimmunotherapy 90 Y 131 I t 1/2 (hr) 64 196 Decay Type Beta Beta, Gamma Particle Energy (MeV) 0.6 2.3 Particle Path Length (mm) 5.3 0.8 Conjugation Chelation w/ tiuxetan Direct iodination Compound Ibritumomab tiuxetan (Zevalin TM ) Tositumomab (Bexxar ) Image adapted from Karesh, Stephen. "Radioimmunotherapy of Non Hodgkin's Lymphoma with Radiolabeled Antibodies." April 2010. Table adapted from Goldsmith SJ. Semin Nucl Med 2010; 40:122 35. 8
Brief Aside: Follicular Lymphoma Follicular lymphoma is an indolent NHL, with an incidence of ~18,000 cases/year. 50 75% of patients achieve a complete remission during first line chemotherapy; unfortunately the median duration of remission is only 2 years. There is also a 5%/year risk of transformation to an aggressive B cell lymphoma. Median overall survival remains only 8 10 years. From Lichtman MA, Shafer MS, Felgar RE, et al. Lichtman s Atlas of Hematology: http://www.accessmedicine.com. 9
90 Y IT: Brief Literature Review Rituximab (Rituxan ) is a chimeric monoclonal antibody targeting CD20, which is expressed on B cells Approved in 1997 for chemotherapy refractory B cell NHL Part of the standard R CHOP regimen for diffuse large B cell lymphoma (DLBCL) in many centers Ibritumomab tiuxetan (IT) is a murine monoclonal IgG 1 κ antibody also targeting CD20 Tiuxetan is a modified diethylene triamine pentaacetic acid (DTPA) moiety used to chelate the yttrium isotope 10
90 Y IT: Brief Literature Review Phase I/II trial in 51 pts with relapsed or refractory low grade, intermediate grade or mantle cell NHL (Witzig et al. J Clin Oncol 1999; 17: 3793:3803) ORR of 67% (CR 26%, PR 41%) Median TTP in responders of 12.9+ months 1 pt (2%) had HACA/HAMA response Phase II trial in 30 pts with relapsed or refractory low grade, follicular, or transformed NHL (Wiseman et al. Blood 2002; 99: 4336 42) ORR: 83% (CR 37%, PR 40%) Median TTP in responders was 12.6 11
90 Y IT: Brief Literature Review Phase II trial in 57 pts rituximab refractory follicular NHL (Witzig et al. J Clin Oncol 2002; 20: 3262 9) ORR of 74% (CR 15%, PR 59%) Median TTP in responders of 8.7 months Phase III randomized trial in 143 pts with relapsed or refractory low grade, follicular, or transformed NHL. 73 pts received 90 Y IT, 70 received rituximab (Witzig et al. J Clin Oncol 2002; 20: 2453 2463) ORR was 80% vs 56% for 90 Y IT and rituximab, respectively (p=0.002) (CR 30% vs 16% [p=0.04]) Median TTP in responders was 11.2 vs 10.1 months (p=0.173). Durable response of at least 6 months was 67% vs 47% (0.030) 12
90 Y IT: Brief Literature Review From Witzig TE et al. J Clin Oncol 2002; 20:2453 2463 (left) and Schering AG. European Pharmacotherapy 2005 (right). 13
90 Y IT: Brief Literature Review Phase III randomized trial in patients with stage III or IV follicular lymphoma who received a response to induction. 208 had consolidation with 90 Y IT, 206 did not. (Morschhauser et al. JCO 2008; 26: 5156 64) Pts with consolidation had PFS of 36.5 months, vs 13.3 months in control arm (p<0.0001) 77% of patients with advanced follicular lymphoma who a PR with induction therapy converted to CR/CRu with 90 Y IT 90 Y IT is now FDA approved for first line consolidation therapy of low grade or follicular NHL, and also for second line therapy for relapsed or refractory low grade or follicular NHL. 14
Mechanics of 90 Y IT Therapy 111 In IT is used initially because it is a gamma emitter; thus, one can track the biodistribution of IT with a gamma camera before carrying out the therapeutic intervention, which occurs on days 7,8, or 9 with the beta emitting 90 Y IT Why is rituximab being administered in this protocol? From Goldsmith SJ. Semin Nucl Med 2010; 40:122 35. 15
Mechanics of 90 Y IT Therapy Prior administration of a cold antibody is thought to be necessary in order to soak up sites in the spleen and on circulating normal B cells, such that later administration of the therapeutic antibody will home to tumor foci. For 90 Y IT, the analogous cold antibody is rituximab. From Wahl RL. J Nucl Med 2005; 46: 128S 140S. 16
Sample 111 In IT Scan Administered radiotracer dose was approximately 185 MBq (5 mci) of 111 In. Note relative increase in RLQ and mid abdominal lymphatic uptake from 24 72 hours, reflecting uptake by the lymphoma. From Goldsmith SJ. Semin Nucl Med 2010; 40:122 35. 17
Side Effects of 90 Y IT Therapy Grade IV Toxicity Bone Marrow Involvement (n=304 pts) 0 0 5% 5 20% >20% Neutropenia 23 36 37 53 Anemia 3 9 2 13 Thrombocytopenia 7 0 13 25 Myelotoxicity remains the major side effect of 90 Y IT therapy. Patients require a CBC every week for 6 weeks; there is an expected nadir on week 6 7, and full recovery is anticipated 12 weeks after treatment. Contraindications: Bone marrow involvement>25% <1500 PMN/μL, plateletes <100,000/ μ L Myelodysplastic or very hypocellular marrow Pregnancy Altered biodistribution of 111 In IT From Emmanouilides C. J Clin Exp Hematop. 2007; 47:43 60 18
Our First Patient: JD 67 y/o F with following oncologic history: Noticed lump on left neck; bx showed low grade follicular CD20+ NHL. CT scan showed mediastinal and retroperitoneal LAD. Tx d with rituximab, entered remission. Three years later: Noticed lump near ear; pre auricular lymph node dissection showed low grade follicular CD20+ follicular NHL, thought to be a recurrence. CT showed ~10 mm anterior mediastinal lymph node but no other evidence of disease. How about 90 Y IT? 19
Pt JD: 111 In IT Scan Note that uptake by the liver is greater than uptake by the lungs or kidneys. Fortunately for the patient, the tumor burden is low enough that focal tumor uptake cannot be appreciated on this scan. From PACS, BIDMC 20
Pt JD: Response on Coronal C+ Chest CT From PACS, BIDMC 1 month before 90 Y IT 2 months after 90 Y IT Anterior mediastinal lymphadenopathy (blue box) before (left) and after (right) 90 Y IT. 21
Our Next Patient: JD, Jr. 58 y/o F with following oncologic history: Began experiencing n/v, abdominal pain. Colonoscopy showed diffuse nodules in the terminal ileum; bx showed low grade CD20+ follicular NHL. She completed six cycles of R CHOP. PET CT after four cycles showed near complete response, but persistent focal thickening in the terminal ileum was found on MRE. ANOTHER CANDIDATE FOR 90 Y IT 22
Pt JD, Jr,: 111 In IT Scan 111 In IT pre scan. Again, focal tumor uptake cannot be appreciated on this scan. From PACS, BIDMC 23
Pt JD, Jr.: Lack of Response on Coronal MRI From PACS, BIDMC 1 month before 90 Y IT 2 months after 90 Y IT Terminal ileal wall thickening (blue box) before (left) and after (right) 90 Y IT. Note: These are FIESTA (Fast Imaging Employing Steady state Acquisition) MRI images. 24
JD, Jr.: Post 90 Y IT Course Given persistence of ileal thickening, an ileocecectomy was performed. Fortunately, no evidence of lymphoma was found. Over a year later, JD, Jr. is doing well and has no evidence of recurrent disease. Did she even have residual disease prior to 90 Y IT administration? This question cannot be answered. As exemplified by both cases, the 111 In scan will not allow direct visualization of lymphoma in the setting of non bulky disease perhaps the setting in which 90 Y IT therapy is the most helpful. The 111 In scan has limited spatial and contrast resolution and cannot supplant a PET CT. 25
Our Last Patient: JD, III 46 y/o M with following oncologic history: Presented with syncope x1 in setting of cough, SOB, night sweats, and ~10 lb weight loss over 8 weeks. Found to have pericardial effusion with tamponade physiology. Tap revealed malignant effusion secondary to primary mediastinal B cell lymphoma (CD20+ NHL). Refractory to 4 months of EPOCH. Given severity of disease, was treated with ICE R and BEAM with goal of asct. 90 Y IT was added to this in further hopes of eradicating the disease. 26
Pt JD, III: Evidence of Bulky Disease From PACS, BIDMC Marked subcarinal lymph node enlargement on presentation (blue box) is easily seen on this axial C+ CT image. 27
Selected Case: Pt JD, III Left esophageal and anterior epicardial (left) and left anterior diaphragmatic (right) lymphadenopathy is easily appreciated on these axial C+ CT images. From PACS, BIDMC 28
Pt JD, III: 111 In IT Scan Possible focal tumor uptake over right shoulder, but, again, difficult to draw conclusions. From PACS, BIDMC 29
Pt JD, III: Post 90 Y IT Course Following 90 Y IT infusion, interval PET imaging did show improvement in lymphadenopathy, and pt underwent an asct. However, serial CT scanning three months later was not promising 30
Pt JD, III: Relapse on Axial C+ CT Marked resolution of subcarinal lymphadenopathy (left, blue box) but numerous hypoattenuating foci (right, blue boxes) suggestive of widespread disease. Pt expired within 1 month. 31 From PACS, BIDMC
Our Three Patients: An Update Pt JD: 67 y/o F with relapsed follicular lymphoma had an excellent response to 90 Y IT therapy. She remains in remission four months later. Pt JD, Jr: 58 y/o F with ileal follicular lymphoma ultimately underwent an ileocectomy as mentioned. She is disease free two years later. Pt JD, III: 46 y/o M with primary mediastinal B cell lymphoma, ultimately underwent an asct. He expired within 1 month of detection of hepatic and splenic involvement. 32
Summary 90 Y ibritumomab tiuextan (Zevalin TM ) is an effective agent that is FDA approved for first line consolidation therapy of low grade or follicular NHL, and also as a second line agent for relapsed or refractory low grade or follicular NHL. It binds to the CD20 receptor found on B cells. The 90 Y is a beta emitter; therapeutic effect is derived from the fact that the path length of released beta particles is ~5.3 mm, leading to death of numerous adjacent tumor cells regardless of their CD20 status. As a pure beta emitter, 90 Y IT poses limited if any external threat. Only minor precautions regarding body fluid handling need to be observed. The major adverse effect is myelotoxicity. 33
Acknowledgements J. Anthony Parker, MD, PhD Yiming Gao, MD Mrs. Emily Hanson 34
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