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Home , Ibritumomab tiuxetan, Tositumomab

Radioimmunotherapy of

Hedieh K Eslamy, MD Seattle Children’s Hospital Overview

• • for lymphoma • regimens • 90Y- • 131 I-

Lymphomas

• Malignancies of the lymphoid tissue • Broadly classified into • Hodgkin’s lymphoma • Non- Hodgkin’s lymphomas • B-cell lymphomas: ≈ 85% • follicular and diffuse large B-cell lymphomas constitute ≤50 % of NHL • T-cell lymphomas • Clinical patterns of • Indolent (low-grade) lymphomas: ≈ 50% • Aggressive lymphomas • Ann Arbor staging is used for clinical staging

Yale J Biol Med. 2011 Dec;84(4):391-407 Lymphoma: Therapies (pediatrics)

• • Radiotherapy • only indicated for acute life-threatening complications refractory to initial chemotherapy or acute hemiplegia • Hematopoietic stem cell transplantation • Biological therapies • targeted with monoclonal • Surgery • limited role. Performed on patients in whom there is good reason to believe that total resection can be achieved without a mutilating procedure • Combinations of above Philip Lanzkowsky (ed). Manual of Pediatric Hematology and , Fifth Edition. Chapter 20, Non-Hodgkin Lymphoma, 2011 Elsevier Inc.

Lymphoma: Therapies (adults)

• Chemotherapy • Radiotherapy • Hematopoietic stem cell transplantation • Biological therapies • with monoclonal antibodies • lineage-restricted • B-cells: CD-20 epitope • others: biological response modifiers, nonspecific immunotherapy, vaccination • Radioimmunotherapy • Combinations of above

GP Canellos, TA Lister, BD Young. The Lymphomas, Second Edition. Ch 15. Biological Therapy of Non-Hodgkin’s Lymphomas. 2006, Elsevier Inc. CD20 Epitope

• CD20: 35-kd transmembrane glycoprotein • A pan B-cell marker expressed on • normal B-cells • nearly all B-cell lymphomas (>90%) • Initially appears in pre-B call stage and disappears in plasma cells • Specific function of CD20 is unknown

J Nucl Med. 2005 Jan;46 Suppl 1:128S-40S Radioimmunotherapy

• A unique therapeutic modality that uses an carrier to target high-energy, short–path-length to tumor sites with little effect on other solid organs • Components: radioisotope combined with an anti-CD20- directed antibody • 90Y-ibritumomab tiuxetan: 90Y + chelator (tiuxetan) + ibritumomab • : chimeric (murine and human) • first MAb to be approved by the U.S. FDA for the treatment of cancer (1997) • 131I-tositumomab: 131I + tositumomab • tositumomab: murine monoclonal antibody

Leuk Lymphoma. 2011 Jul;52(7):1188-99

Anti-CD20 Radioimmunoconjugates

90Y–ibritumomab tiuxetan 131 I-tositumomab • FDA approved for: • FDA approved for: • relapsed low-grade and • relapsed low-grade and follicular NHL transformed NHL • consolidation after initial • Regimen: chemotherapy • 2 two doses of unlabeled • Regimen: MAb, days 0 and 7-14 • 2 doses of unlabeled MAb, • a dose of labeled Mab days 1 and 8 calculated to deliver a 75- • a dose of labeled Mab on cGy total body dose day 8

Leuk Lymphoma. 2011 Jul;52(7):1188-99. Yale J Biol Med. 2011 Dec;84(4):391-407

RIT Administration Protocols

90Y- ibritumomab tiuxetan 131 I-tositumomab • Step A: Patient Selection • Step A: Patient Selection and Eligibility and Eligibility • Step B: Bio-distribution/ • Step B: Thyroid protection Diagnostic scan • Step C: Diagnostic and • Step C: Dose Calculation Dosimetry Scan • Step D: Therapeutic Dose • Step D: Dose Calculation Administration • Step E: Therapeutic Dose Administration

Yale J Biol Med. 2011 Dec;84(4):391-407 Patient Selection

90Y- ibritumomab tiuxetan 131 I-tositumomab • Relapsed or refractory, • CD20-positive relapsed or low-grade or follicular B- refractory, low grade, cell non-Hodgkin's follicular, or transformed lymphoma (NHL). non-Hodgkin’s lymphoma • Previously untreated who have progressed follicular NHL who achieve during or after rituximab a partial or complete therapy, including patients response to first-line with rituximab-refractory chemotherapy. non-Hodgkin’s lymphoma

http://www.zevalin.com http://www.bexxar.com Patient Selection & Eligibility (adults)

• absolute neutrophil count ≥1500 × 106/L • count ≥100,000 × 106/L • full dose of RIT: ≥150,000 × 106/L • reduced RIT dose: 100,000 × 106/L and 149,000 × 106/L • imaging: CT or PET/CT • pretreatment bone marrow aspiration and biopsy with chromosome analysis • marrow ≥15% of normal cellularity • percentage of marrow cellularity occupied by lymphoma cells <25% • in previously treated patients rule out myelodysplastic syndromes • fluorescence in situ hybridization (FISH) or • conventional cytogenetics for chromosomal markers

Leuk Lymphoma. 2011 Jul;52(7):1188-99 RIT Administration Protocols

90Y- ibritumomab tiuxetan 131 I-tositumomab • Step A: Patient • Step A: Patient Selection and Eligibility Selection and Eligibility a bio• -distributionStep B: Bio scan-distribution/ was obtained as an outpatient• Step for B: Thyroid exclusion of abnormal antibody tracer distribution (0.6 toDiagnostic 1.3 percent of scan patients) that would preclude protectiontreatment • Step C: Dose • Step C: Diagnostic and Calculation Dosimetry Scan • Step D: Therapeutic • Step D: Dose Dose Administration Calculation • Step E: Therapeutic Dose Administration

Yale J Biol Med. 2011 Dec;84(4):391-407 RIT Administration: FDA removed Bioscan requirement in November 2011

90Y- ibritumomab tiuxetan (simplified protocol) • Step A: Patient Selection and Eligibility • Step B: Unlabeled Rituximab Infusion • Step C: Dose Calculation • Step D: Therapeutic Dose Administration

Cold MAB infusion, Cold MAB followed within 4 hrs infusion by radiolabelled MAb

0 1 2 3 4 5 6 7 8 9 10 days

Yale J Biol Med. 2011 Dec;84(4):391-407. http://www.zevalin.com

Antigen Sinking Effect & Preloading

• sinking effect: administered labeled MAb predominantly targets and accumulates within the normal reticuloendothelial system (liver & spleen) and circulating lymphocytes • Preloading: infusion of unlabeled Mab is performed for both biodistribution and treatment studies, in an effort to minimize the antigen sinking effect

Yale J Biol Med. 2011 Dec;84(4):391-407 RIT Administration Protocols

90Y- ibritumomab tiuxetan 131 I-tositumomab Step C: Dose Calculation Step D: Dose Calculation •platelet counts > 150,000: •tolerated maximum whole 0.4 mCi/kg (14.8 MBq/kg) body radiation dose is •platelet counts between 75cGy (65cGy, if •100 and 150,000: 0.3 are 100,000-150,000) mCi/kg (11.1 MBq/kg)

•platelets <100,000: therapy contraindicated •maximum administered activity is 32 mCi

Yale J Biol Med. 2011 Dec;84(4):391-407 SAM Question

A bio-distribution scan for the 90Y ibritumomab tiuxetan radioimmunotherapy regimen is shown. Which choice is FALSE? A. This regimen was FDA approved for the treatment of relapsed low-grade and follicular NHL in 2002 B. Rituximab is a murine monoclonal antibody (MAb) C. 111Indium is the radiotracer used for imaging D. Prior to the injection of the radiolabelled MAb, preloading is performed with unlabeled MAb to minimize the antigen sinking effect E. 90Yttrium is a beta emitter

Yttrium-90 –ibritumomab tiuxetan therapy administration protocol

Yale J Biol Med. 2011 Dec;84(4):391-407 -90 –ibritumomab tiuxetan therapy administration protocol

Premedications are used to help reduce the side effects of monoclonal antibody (Mab)

Yale J Biol Med. 2011 Dec;84(4):391-407 Yttrium-90 –ibritumomab tiuxetan therapy administration protocol

The removal of the biodistribution scan requirement approved by the FDA in November 2011 simplified ZEVALIN administration

Yale J Biol Med. 2011 Dec;84(4):391-407 Iodine-131–tositumomab therapy administration protocol

Yale J Biol Med. 2011 Dec;84(4):391-407 Evaluation for Antitumor Response

• Recommended at week 12 • Subsequent reevaluation as per standard of care • The first reevaluation often does not reflect the maximal response. Improvement in response without further therapy can occur commonly • In the setting of normal blood counts, repeat bone marrow evaluation is needed only to confirm CR when it was involved prior to treatment

Leuk Lymphoma. 2011 Jul;52(7):1188-99 Contraindications to RIT (both agents)

• Pregnancy or ongoing breast feeding • Known allergy or hypersensitivity to the murine antibodies, or components of the therapy • Absolute Neutrophil Count <1500 cells/cu mm • Platelet count <100,000 • Bone marrow involvement of more than 25 percent involvement • Effective beam of >25 percent of active marrow • Prior autologous stem cell transplant • Elevated HAMA titers with altered biodistribution

Yale J Biol Med. 2011 Dec;84(4):391-407 Contraindications to RIT (I131-tositumomab)

• Iodine allergy • Urinary incontinence (relative contraindication) • Non-compliant patients • Reduced renal function with creatinine > 1.5

Yale J Biol Med. 2011 Dec;84(4):391-407 Adverse event for RIT

• Myelosuppression most common • Predictable, generally transient, and reversible • Hematologic nadirs begin to appear at week 4, bottoming out at 6–8 weeks, with subsequent recovery • Recommended supportive care: weekly complete blood counts, assessed beginning at week 4 until the nadir is complete and blood cell counts are rising. Aspirin or coumadin is stopped once platelets are below 75,000/mm3 or at the sign of any bleeding tendency. Granulocyte growth factors may be administered if clinically indicated

Leuk Lymphoma. 2011 Jul;52(7):1188-99 Summary

• Lymphomas • Therapies for lymphoma • Radioimmunotherapy regimens • 90Y- ibritumomab tiuxetan • 131 I-tositumomab