Outcomes After Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation with Total Lymphoid Irradiation and Anti-Thymocyte Globulin in Lymphoid Malignancies After Failed Autologous Transplantation

Patients with lymphoid malignancies who relapse after autologous hematopoietic cell transplantation (HCT) have few curative treatment options. Allogeneic HCT using full dose conditioning can cure selected patients but high non-relapse mortality (NRM) limits its broad applicability. We developed reduced intensity conditioning for allogeneic HCT with total lymphoid irradiation and rabbit anti-thymocyte globulin (TLI-ATG) that was safe, well tolerated, protected against GVHD and allowed for retained graft-versus tumor reactions. We report the outcomes of 47 consecutive patients with lymphoid malignancies who relapsed after auto-HCT and received TLI-ATG conditioning followed by the infusion of G-mobilized allografts. Included were 29 (62%) patients at high risk of relapse because the disease failed to achieve remission with salvage therapy prior to TLI-ATG, 20 (43%) patients with relapse within 18 months of their auto-HCT, and 22 (47%) patients at high risk of developing GVHD due to the lack of fully HLA-matched related donor. 26 patients had B-cell NHL (diffuse large B-NHL (n=19), mantle cell lymphoma (n=4) or other subtypes (n=3)) all of whom received prior rituximab, 6 patients had T cell NHL, and 15 had Hodgkin lymphoma. The TLI-ATG regimen was well tolerated and 46 (98%) patients received their graft infusion as an outpatient.  The hospital readmission rate in the first 100 days was 28% (n=13). Only 13 (28%) and 4 (9%) patients recorded an ANC <0.5x10⁹/L or a platelet count <10x10⁹/L respectively, during the first 30 days post HCT. Durable chimerism was achieved in 45 (96%) patients. The cumulative incidence of grade II-IV acute GVHD at day 100 was 12% and extensive chronic GVHD at 1-yr was 36%. Non-relapse mortality (NRM) at 3 years was 7%. The median follow up for all patients was 1142 days and 1525 days (range; 365-3667) for the 34 (72%) living patients. The 36-month probability of progression free and overall survival (OS) was 40% and 79% respectively.  It is noteworthy that among the 23 patients with progressive disease after TLI-ATG, 11 were returned to durable (>1 year) complete remission without subsequent relapse following a donor lymphocyte infusion or chemo-radiotherapy. 13 patients died (relapse=8 and other causes=5). Proportional hazards model showed improved relapse free survival with higher CD3⁺ donor chimerism (p=0.01). We conclude that for patients with lymphoma relapse after auto-HCT, allogeneic HCT from a sibling or unrelated donor using TLI-ATG conditioning was a well tolerated outpatient procedure, did not induce significant cytopenias and was associated with 3 year NRM of <10%. It is unlikely that TLI-ATG conditioning itself provided long-term lymphoma control in these heavily pre-treated patients, with advanced disease. Rather the 79% 3-yr OS and the fact that the majority of patients continue in durable CR suggest retained graft antitumor reactions following TLI-ATG.