Abstract

Objective: CD20 has been recently recognized as a potential immunotherapeutic target in Hodgkin’s lymphoma (HL), being expressed in all malignant cells in lymphocyte-predominant HL (LPHL), a subset of classical HL (cHL), and in normal surrounding B-cells. Recent data also suggest that the cancer stem cell in cHL is phenotypically distinct from Reed-Sternberg cells and expresses B-cell antigens including CD20 (

Jones RJ et al,
Blood
2006
;
108
:
abstract 470
). Given the single agent activity of the unlabeled antiCD20 monoclonal antibody, rituximab, in HL, we are conducting a phase I/II study of tositumomab and Iodine I 131 (131I-) tositumomab (BEXXAR ®, GlaxoSmithKline) for HL in the relapsed/refractory setting, regardless of tumor CD20 expression. We report on feasibility and initial safety.

Methods: Separate dose-escalation studies were performed for patients with and without prior stem cell transplantation, starting at 55 and 75 cGy total body radiation doses (TBD), respectively. Dosimetry imaging studies were performed after administration of 450 mg tositumomab and 5 mCi 131I-tositumomab. Patients then received a single patient-specific therapeutic dosage of 450 mg tositumomab and 131I-tositumomab. The TBD was escalated or de-escalated based on a continual reassessment method (CRM).

Results: Seven patients with relapsed/refractory disease (6 cHL, 1 LPHL; mean age 36 ± 9) have been enrolled. Four patients with cHL were negative for CD20 on malignant Reed-Sternberg cells and two had mixed expression. Three patients who had failed transplant received a 55 cGy TBD of 131I-tositumomab and three ineligible for transplant received 75 cGy. No dose-limiting toxicities were observed and based on the CRM, the TBD was escalated to 79 cGy for the post-transplant group and to 87 cGy for the no transplant group. To date, one in the next post-transplant cohort received 79 cGy and experienced grade 1 thrombocytopenia and grade 3 lymphopenia with count recovery. No adverse reactions occurred during infusion of unlabeled or radiolabeled tositumomab, and the agent was generally well-tolerated in all dosing cohorts. The expected hematologic adverse events were common and are summarized in the Table. No patients experienced grade 3 or 4 non-hematologic toxicity. One patient had grade 1 or 2 fever, chills, joint and muscle pain suggesting possible human anti-mouse antibody formation and immune complex mediated inflammation. One patient with LPHL had a complete response, two with cHL had stable disease (1 mixed CD20 expression, 1 CD20 negative) and 4 with cHL had progressive disease (1 mixed CD20 expression, 3 CD20 negative) at 12 weeks post-131I-tositumomab.

Conclusions: Tositumomab and 131I-tositumomab can be safely administered to patients with relapsed/refractory HL. Major toxicities are hematologic, similar to its effect in patients with non-Hodgkin’s lymphoma. The CRM was used successfully for determining TBD for subsequent cohorts, and the transplant recipients have tolerated higher doses than those previously reported in non-Hodgkin’s lymphoma. These encouraging preliminary data support further dose escalation and suggests some therapeutic effect of tositumomab and 131I-tositumomab against HL.

Hematologic Adverse Events 
 All (n=7) Grade Range of Duration of Grade 3/4 Toxicity (days) 
  1/2  
Thrombocytopenia 7–34 
Neutropenia 
Lymphopenia 1–35 
Anemia 
Hematologic Adverse Events 
 All (n=7) Grade Range of Duration of Grade 3/4 Toxicity (days) 
  1/2  
Thrombocytopenia 7–34 
Neutropenia 
Lymphopenia 1–35 
Anemia 

Disclosures: Jacene:GlaxoSmithKline: Research Funding. Ambinder:BMT CTN: Research Funding. Wahl:GlaxoSmithKline: Consultancy, Investigator, Patents & Royalties, Research Funding, Speakers Bureau. Off Label Use: Iodine-131-tositumomab is a radiolabeled antiCD20 monoclonal antibody used for the treatment of B-cell lymphomas. .

Acknowledgments: Research support for this study is provided by GlaxoSmithKline

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