Dose Finding Trial of Yttrium 90 (90Y) Ibritumomab Tiuxetan with Autologous Stem Cell Transplantation (ASCT) in Patients with Relapsed or Refractory B-Cell Non-Hodgkin’s Lymphoma (NHL).
Authors: Flinn Ian W. , Kahl Brad S. , Frey Eric , Bianco Jesus A. , Hammes Richard J. , Billing Lynn S. , Swinnen Lode J. , Sgouros George , Wahl Richard L. 
Published: October 2019

90Y ibritumomab tiuxetan (Zevalin®) is an effective agent for patients with relapsed or refractory low grade lymphoma. Unfortunately, dose escalation is limited by hematopoetic toxicity. In order to determine the non-hematopoetic maximum tolerated dose, we are conducting a dose finding study of 90Y ibritumomab tiuxetan with ASCT. Patients are eligible if they have relapsed or refractory low-grade, mantle cell, or diffuse large cell NHL. Additional eligibility criteria included rituximab sensitivity, age >18 years, platelet count >75,000/mm3, WBC >3,000/mm3, bone marrow involvement <35%, and acceptable renal and hepatic function. Patients receive weekly rituximab (375 mg/m2) for 4 consecutive weeks followed by a single dose of cyclophosphamide (2.5 g/m2). Filgrastim 10 mcg/kg is administered post cyclophosphamide until stem cell collection. Following successful collection of at least 2 X 106 CD34/kg, patients receive a dosimetric dose of indium 111 (111In) ibritumomab tiuxetan (5 mCi) on day 1, quantitative planar and SPECT/CT scans followed by cohort specific dose of 90Y ibritumomab tiuxetan on day 15. Stem cell infusion occurs when estimated marrow dose rate is < 1 cGy/hour. Thirteen patients (7M:6F) have been entered onto study and received in vivo purging and stem cell mobilization with rituximab, cyclophosphamide, and filgrastim. Patients had the following histologies: small lymphocytic lymphoma (n = 2), follicular lymphoma (n = 6), transformed or mixed follicular lymphoma (n = 3), and MCL (n = 2). The median age of patients was 55 years (range, 45–70) and patients had received a median of 2 prior regimens (range, 1–8). Two patients failed to mobilize stem cells and did not receive 90Y ibritumomab tiuxetan. Eleven patients have been treated with 90Y ibritumomab tiuxetan to the following dose cohorts: 0.4 mCi/kg = 3; 14–18 Gy to the liver = 5; 24 Gy to the liver = 3. The range of administered 90Y ibritumomab tiuxetan activities was 20.2–121.7 mCi. All patients engrafted rapidly. In the 24 Gy cohort, the 2 evaluable patients recovered neutrophils > 500/mm3 10 days post ASCT. Platelet recovery (platelets >20,000/mm3 for 3 consecutive days) required an average of 13.9 days (range, 0–20) in this cohort. Overall, one patient died from progressive disease (day 3 post-transplant), and a second patient died of complications due to pneumonia (day 27 post-transplant). Of the 6 patients qualifying for evaluation at 60 days post-transplant, 4 patients achieved a CR, 1 patient had a PR, and 1 had progressive disease. Three patients maintained a complete response, and 2 had progressive disease at the 6-month follow-up. The most common treatment-related toxicities were hematologic, as expected. This therapy was delivered completely in the outpatient setting. Two patients required admission post 90Y ibritumomab tiuxetan for febrile neutropenia and 1 patient was admitted for progressive disease. No significant hepatotoxicity has been seen to date despite the fact that the liver is the organ that receives the highest absorbed dose of radiation. In conclusion, significant dose escalation with 90Y ibritumomab tiuxetan can be achieved with autologous stem cell rescue. Dose escalation continues and the MTD has yet to be determined.