A new possible conditionning regimen before Autologous Stem Cell Transplantation for refractory high-grade lymphoma Z-BeEAM (Ibritumomab tiuxetan, Bendamustine, Etoposide, Cytarabine, Melphalan) TARDY M., GASTAUD L., OJEDA-URIBE M., BOSCAGLI A., CARUSO S., SKAF R., GUTNECHT J., THYSS A., PEYRADE F.

Indications of Autologous Stem Cell Transplantation (ASCT) Relapsing follicular lymphoma Relapsing diffuse large B cell lymphoma Mantle cell lymphoma => High Dose chemotherapy followed by ASCT BEAM is most commonly used regimen before ASCT : Carmustine (300 mg/m² at day 1) Etoposide (200 mg/m² every 12H for 4 days) Cytarabine (200 mg/m² every 12H for 4 days) Melphalan (140 mg/m² at day 5) For chemosensitive lymphoma Mills W. et al., BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin’s lymphoma, JCO, 1995; 13:588-595

Replacement of carmustine BeEAM regimen : Bendamustine (180 mg/m² at day 1) Etoposide (200 mg/m² every 12H for 4 days) Cytarabine (200 mg/m² every 12H for 4 days) Melphalan (140 mg/m² at day 5) => Safe and effective Visani G. et al., Bendamustine, etoposide, cytarabine, melphalan, and autologous stem cell rescue produce a 72% 3-year PFS in resistant lymphoma, Blood, 2014;124:3029-3031

Use of BEAM as conditionning regimen Shortage of carmustine BeEAM (Mills, 1995) Shortage of carmustine BeEAM (Visani , 2014) 1995 2004 2012 2013 2014 Zevalin® (Ibritumomab Tiuxetan): Approval in Europe

Ibritumomab tiuxetan (Zevalin ®) Action mode Monoclonal anti-cd20 antibody Chelator Radioisotope Indications Low-grade or follicular Lymphoma relapsing during or after treatment Newly diagnosed follicular Lymphoma in response after initial anticancer therapy

Use of BEAM as conditionning regimen Shortage of carmustine BeEAM (Mills, 1995) Shortage of carmustine BeEAM (Visani , 2014) 1995 2004 2012 2013 2014 Zevalin® (Ibritumomab Tiuxetan): Approval in Europe Z-BEAM (Shimoni , 2012) P = 0,05 Z-BEAM group : 22 patients BEAM group : 21 patients Shimoni A. et al., A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as conditioning regimen before ASCT , Cancer, 2014;118:4706-4714

Use of BEAM as conditionning regimen Shortage of carmustine BeEAM (Mills, 1995) Shortage of carmustine BeEAM (Visani , 2014) 1995 2004 2012 2013 2014 Addition of Ibritumomab tiuxetan to high dose chemotherapy before ASCT is safe and effective Zevalin® (Ibritumomab Tiuxetan): Approval in Europe Z-BEAM (Shimoni , 2012) P = 0,05 Z-BEAM group : 22 patients BEAM group : 21 patients

Ibritumomab tiuxetan + BeEAM before ASCT? Safe Feasible Effective ? ? ?

Patients and disease characteristics Number of patients Median age: years (median range) 60 (51-66) Anatomopathology: Follicular lymphoma Mantle lymphoma Diffus large B cell lymphoma 1 2 3 Gender: Male Female 5 Performans Status (PS): >0 6 Number of previous chemotherapies: Disease status at transplantation: Complete response Partial response PET-CT before transplantation: Negative Positive Median time between diagnosis or relapse and ASCT (months) 8.5 (7-12) Retrospective study 2 centers in France Tardy et al., Z-BeEAM before ASCT is safe and efficient for refractory large B cell lymphoma, Experimental Hematology and Oncology, 2015:4-18.

Conditionning regimen before ASCT Rituximab (250 mg/m²) + Zevalin ® (1200UI) Rituximab (250 mg/m²) BeEAM regimen Day -21 Day -14 Day -7 to Day - 2 Day 0 Stem cells reinjection (IV)

Engrafment characteristics Tardy et al., Z-BeEAM before ASCT is safe and efficient for refractory large B cell lymphoma, Experimental Hematology and Oncology, 2015:4-18.

Non hematologic toxicities Renal toxicity 0 Tardy et al., Z-BeEAM before ASCT is safe and efficient for refractory large B cell lymphoma, Experimental Hematology and Oncology, 2015:4-18.

Efficiency After a median follow-up time of 5 months (1st March 2015) => All patients alive, in complete response (clinical, biologic and radiologic on PET-CT) and with a good hematologic recovery After a median follow up of 20,6 months (1st June 2016) => 1 lost to follow up => 5 alive : 3 complete response 2 patients relapsed after a median PFS of 16 months Tardy et al., Z-BeEAM before ASCT is safe and efficient for refractory large B cell lymphoma, Experimental Hematology and Oncology, 2015:4-18.

Conclusion ‟ Phase I” study to evaluate Z-BeEAM as a conditionning regimen before ASCT NO unexpected toxicities NO increase in the risk of Grade III/IV mucositis NO long term toxicities Efficient

Z-BeEAM is safe and effective before ASCT

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