Minimum Tolerable Interval of Radioimmunotherapy and Autologous Stem Cell Transplantation after High-Dose Chemotherapy for Relapsed or Refractory Aggressive B Cell Non-Hodgkin-Lymphoma Provides Excellent Disease Control

Background: Patients with aggressive B cell Non-Hodgkin-Lymphoma failing from immune-chemotherapy show disappointing results with standard salvage therapies and consolidation of high-dose chemotherapy with autologous stem cell transplantation. Especially in cases never in remission or with early relapse outcome is poor. Several groups started trials combining high-dose chemotherapy of carmustin, etoposide, cytarabine and melphalan (BEAM) with ⁹⁰Yttrium ibritumomab tiuxetan to enhance the efficacy of the preparative regimen. In this trial we tested safety, feasibility and studied efficacy of reduced intervals of ⁹⁰Yttrium ibritumomab tiuxetan to autologous stem cell transplantation after BEAM.

Methods: Patients without disease progression during salvage therapy of relapsed or refractory CD20+ aggressive B-NHL were included in this prospective, multicenter, phase I/II trial. Primary endpoint was the minimum tolerable interval of ⁹⁰Yttrium ibritumomab tiuxetan given as close as possible to ASCT defined as <2 patients with dose limiting toxicity in a 6+6 patient cohort. We reduced the time interval of standard dose ⁹⁰Yttrium ibritumomab tiuxetan (0.4 mCi/kg body weight) to ASCT after BEAM from 14 to 12 and finally 10 days to foster the disease control by more concomitant radioimmunotherapy and high-dose chemotherapy.

Results: From 2006 to 2009 42 patients were screened for inclusion. Reasons for screening failure were progressive disease during salvage therapy (n=8), death (n=2), not aggressive B-NHL (n=2), impaired organ function (n=2), and other (n=2). Median age of the 26 patients enrolled was 58 years (34-66). 12 patients were allocated to cohort 1 (interval 14 days), 6 patients to cohort 2 (interval 12 days) and 8 patients to cohort 3 (interval 10 days). Histology included 14 DLBCL, 6 FL III°, 5 transformed FL and 1 aggressive B-NHL without further subtyping. 11 from 26 patients had primary refractory disease or early relapse within 12 months after diagnosis. Secondary IPI was >1 in 14 patients. Response to salvage therapy was CR in 6/26 patients and PR in 12/26 patients. 20/26 patients achieved CR after study treatment. Two early deaths (d +7, +18) occurred due to infections. All patients receiving stem cells engrafted with median recovery of leukocytes and platelets at d+10 and +13, respectively. We observed no correlation of toxicities and the study cohorts with the different intervals. At median follow-up of the survivors of 3.5 years the overall survival is 76%, the progression free survival is 67% and time to progression 26%. Lymphoma was the main cause of death. Stratified to time intervals of ⁹⁰Yttrium ibritumomab tiuxetan and autologous stem cell transplantation revealed time to progression of 50% with ⁹⁰Yttrium ibritumomab tiuxetan at d-14, 16% at d-12 and 0% at d-10.

Conclusions: ⁹⁰Yttrium ibritumomab tiuxetan and BEAM followed by autologous stem cell transplantation was safe and feasible. The minimum tolerable interval of ⁹⁰Yttrium ibritumomab tiuxetan and autologous stem cell transplantation is 10 days. With shorter intervals of radioimmunotherapy and high-dose chemotherapy and therefore more concomitant therapy, we did not observed excessive toxicity, but enhanced disease control of refractory or relapsed aggressive B-NHL. Our results compare favorable to standard BEAM or allogeneic stem cell transplantation. A formal comparison in a phase III trial is warranted.