Salvage High-Dose Melphalane and Autologous Peripheral Blood Stem Cell Transplantation for Diffuse Large b-Cell Lymphoma Refractory to 2nd or 3rd Line Treatment
Authors: Kaddu-Mulindwa Dominic , Held Gerhard , Pfreundschuh Michael , Bittenbring Joerg Thomas 
Published: November 2019

Abstract
Background: Refractory or early relapsed (<1 year) diffuse large B-cell lymphoma has a dismal prognosis especially for those not responding to salvage chemotherapy (Van den Neste; Bone Marrow Transplant. 2016 Jan;51(1):51-7). Allogeneic stem cell transplantation is potentially curative (Glass et al; Lancet Oncology 2014 Jun;15(7):757-66). Even though this is less likely in those not responding or having frank progression pre-transplantation.
Methods: At our institution we identified all patients with aggressive B-cell lymphoma (diffuse-large B-cell lymphoma and blastoid mantle cell lymphoma) who were refractory or progressive to salvage chemotherapy with R-DHAP and who had peripheral blood stem cells (> 2x10^6 CD34+/kg body weight) collected after the 1st or 2nd cycle. These patients were eligible and planned to receive salvage high-dose melphalane and autologous stem cell transplantation as remission induction before allogeneic stem cell transplantation. Allogeneic transplantation was performed from sibling donors or matched unrelated or mismatched unrelated donors: The conditioning regimen with fludarabine, busulfane, cyclophosphamide and anti-thymocyte globuline as published (Glass et al; Lancet Oncology 2014 Jun;15(7):757-66) was used in all but 2 patients. Statistical analysis was performed with Prism©; GraphPad Software; (LaJolla CA)
Results: From2006 to 2015 we identified 28 patients (21 male , 7 female, age 18-67 years, median age 47 years), 25 had diffuse large B-cell lymphoma and 3 had blastoid mantle cell lymphoma. 22 had relapsed within 1 year after primary diagnosis and 6 within a median of 25.3 months. After high-dose melphalane and autologous stem cell transplantation 13 patients had a partial and 6 a complete remission. 1 patient died due to neutropenic infection, 2 patients died due to progressive disease leading to a transplant related mortality of 3.5 %. Median progression-free survival after autologous transplantation was 4.6 months.
24 proceeded to allogeneic stem cell transplantation. 8 patients had a matched related sibling, 9 had a matched unrelated donor and 7 had a mismatched unrelated donor. Transplant related mortality was 42 % in this heavily pretreated population. 2-year overall survival of all patients intended for treatment is 21 %. One of these patients with relapsed mediastinal lymphoma after allogeneic transplantation was cured by salvage radiotherapy and is in long-term remission (> 2 years).
Conclusions: Salvage high-dose melphalane and autologous peripheral blood stem cell transplantation for diffuse large B-cell lymphoma as a bridge to allogeneic transplantation is potentially curative for a minor fraction of these patients. However, the remission rate of 79 % (46% PR, 21% CR) and progression-free survival of 4.6 months after high-dose melphalane and autologous stem cell transplantation provides a window of opportunity to use new drugs and cellular therapies in these poor prognosis patients.

Disclosures
No relevant conflicts of interest to declare.