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
Authors: Hasenkamp Justin , Hess Georg , Hertenstein Bernd , Witzens-Harig Mathias , Uharek Lutz , Gramatzki Martin , Pfreundschuh Michael , Wulf Gerald , Truemper Lorenz H. , Schmitz Norbert , Glass Bertram 
Published: October 2019

Abstract
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.

Disclosures
Off Label Use: 90Yttrium ibritumomab tiuxetan (Zevalin(R)), radioimmunotherapy of CD20+ lymphoma.