Phase I Study of 131-I-Tositumomab Radioimmunotherapy (RIT) in Patients with Relapsed or Residual CD20 Antigen-Expressing B Cell Lymphomas Following Autologous Hematopoietic Stem Cell Transplantation

Abstract Introduction: I-131-Tositumomab is a radiolabeled murine monoclonal antibody that binds to the CD20 antigen on the surface of malignant and normal B lymphocytes, targeting radiation to B cells. I-131-Tositumomab has been studied with chemotherapy and in high-doses as part of conditioning regimens for autologous stem cell transplant (ASCT) in relapsed/refractory B cell lymphoma patients (pts). Non-myeloablative I-131-tositumomab was approved in the US and Canada for treatment of CD20 antigen-expressing relapsed or refractory low-grade follicular or transformed non-Hodgkin lymphomas (NHL). Since February 2014, tositumomab and I-131-tositumomab, the Bexxar¨ therapeutic regimen, is no longer commercially available. Methods: We conducted a single-center, phase I trial of I-131-tositumomab in pts with CD20+ B cell NHL with relapsed or progressive lymphoma after ASCT. Eligibility criteria included creatinine <1.5; total bilirubin, AST and ALT <1.5 upper limit of normal; and no bone marrow involvement by lymphoma. Eligible pts had stored autologous stem cell products (> 2 x106 CD34+ cells/kg). Pts with active infection, ANC < 1,500/uL, platelet count <100,000/uL, prior anti-B cell RIT, or previous total body radiation were excluded from the study. After thyroid blockade, pts received a dosimetric dose of I-131-tositumomab to determine biodistribution and total body residence time for calculation of the therapeutic dose. Pts with expected biodistribution then received the calculated therapeutic dose 7 - 14 days later, according to a dose escalating 3+3 design based on platelet count (Table 1). Dose limiting toxicity (DLT) was defined as any >grade 3 adverse event according to the CTCAE v.3. All pts in each cohort had to be evaluable for response and toxicity before escalation to the next dose level. After enrollment of the first cohort, DLT was re-defined as any >grade 3 non-hematologic adverse event. After treatment, pts were monitored weekly for 13 weeks for hematological and other toxicities with response assessments at weeks 7 and 13, and then evaluated at weeks 26, 39, and 52, then every 3 months during year 2, every 4 months during year 3, every 6 months during year 4, and yearly thereafter. Results: 12 pts were enrolled and received both dosimetric and therapeutic doses of I-131-tositumomab; 6 pts (50%) were men. Median age was 58.5 years (range: 49-66). 5 of 12 (41.6%) pts had diffuse large B cell lymphoma (DLCBL), 4/12 (33.3%) follicular lymphoma (FL), and 3/12 (25.0%) FL transformed to DLBCL. Median number of prior therapies was 4 (range: 3 - 8); median time from ASCT was 1.6 years (range: 0.3 - 6.8). 2 pts had progressive disease after ASCT (1 transformed FL; 1 DLBCL); 10 pts had relapsed from complete remission (CR) after ASCT. 7 pts received 25cGy I-131-tositumomab. The cohort receiving 25cGy was expanded to 6 due to grade 4 neutropenia (1 pt), and then expanded to 7 because 1 pt progressed prior to week 7 response assessment. 3 pts received 50cGy and 1 pt each received 65cGy and 75cGy. At all doses, I-131-tositumomab was well-tolerated. Treatment-related toxicities > grade 3 were exclusively hematological and not dose dependent, including thrombocytopenia (2/12: 1 grade 3, 1 grade 4), neutropenia (2/12: 1 grade 3, 1 grade 4) and anemia (2/12: 2 grade 3). Hematologic toxicities were reversible in all cases, with median time to recovery to < grade 3 toxicity 7 days. Non-hematological adverse events were mild and < grade 2. The most commonly reported non-hematological adverse event was fatigue. Overall response rate at week 7 was 41.6% (5/12) with 33.3% (4/12) pts achieving CR (2 pts with FL; 2 pts with DLBCL). Median duration of response was 13.8 months. As of May 2014, 2 pts are still in CR, including 1 pt with FL at 10.3 months and 1 pt with DLBCL at 5.5 years. Median progression free survival is 6.5 months; median time to treatment failure is 4.4 months. At the median follow-up of 21.9 months (range: 10.3 – 66.3), overall survival is 68.7%; no secondary hematologic malignancies have been observed. Conclusion: This is the first study of I-131-tositumomab RIT in pts with relapsed or progressive NHL after ASCT. In pts with CD20+ DLBCL, FL, or transformed FL following ASCT, non-myeloablative I-131-tositumomab is well-tolerated and can achieve sustained complete remissions. Table 1:Dose Escalation SchemaPlatelet count>100,000, </=150,000>150,000Dose level 120 cGy25 cGyDose level 240 cGy50 cGyDose level 355 cGy65 cGy Disclosures Schuster: GlaxoSmithKline: Research Funding.

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