Impact of In Vivo T-Cell Depletion on Outcome Following Reduced Intensity Transplantation for Hodgkin Lymphoma: Comparison between 2 Prospective Studies.
Authors: Peggs K. S. , Sureda A. , Hunter A. , Caballero M. D. , Cavet J. , Urbano-Ispizua A. , Parker A. , Ribera J. M. , Mahendra P. , Canales M. A. , Milligan D. , Hernandez-Boluda J. C. , Morris E. C. , Alvarez I. , Goldstone A. H. , Linch D. C. , Sierra J. , Mackinnon S. 
Published: October 2019

Abstract
Despite impressive primary response rates relatively few patients with multiply relapsed or refractory Hodgkin lymphoma (HL) are ultimately cured with conventional chemotherapy. The application of allogeneic stem cell transplantation has historically been limited in this group by high transplant related mortality (TRM) rates, and evidence for a clinically relevant graft-versus-lymphoma (GvL) effect has been limited. Reduced intensity transplantation (RIT) approaches enable durable engraftment of allogeneic stem cells with a low spectrum of toxicity, but graft-versus-host disease (GvHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion (TCD), using alemtuzumab, has been shown to reduce the incidence of GvHD. However, this approach potentially adversely impacts on disease response by abrogating GvL activity. To explore the impact of TCD in HL we have compared the results in 89 recipients of a RIT enrolled in 2 prospective studies based on conditioning with the same combination of fludarabine (30mg/m2 x 5) and melphalan (140 mg/m2). The studies differed in GvHD prophylaxis. The United Kingdom regimen (MF-A, n=49) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (MF, n=40) used cyclosporin A plus methotrexate. There were no significant differences in age (median 32 versus 35 years), sex or histological subtype (nodular sclerosis in 86% versus 88%). Median follow-up in surviving patients is 826 (MF-A) versus 376 (MF) days. In those with matched sibling donors use of alemtuzumab resulted in a trend towards a lower incidence of acute GvHD (29% versus 46% at day 180, P=0.09) and significantly less chronic GvHD (10% versus 57%, P=0.0003). This was associated with a trend towards lower TRM in the MF-A group (actuarial 2 year TRM 17% versus 33% for MF, P=0.06), but no apparent excess of relapse/progression (actuarial 2 year relapse risk 49% for MF-A versus 68% for MF, P=0.16). In this sibling transplant cohort both overall and event-free survival were superior in the MF-A group (actuarial 2 year OS 72% versus 48%, P=0.04; EFS 47% versus 19%, P=0.009). Sixteen patients in the MF-A group and 10 in the MF group received donor lymphocyte infusions (DLIs) to achieve disease control. Nine (8CR, 1PR) of the former, and 6 (3CR, 3PR) of the latter achieved a response. On univariate analysis of the entire cohort chemo-sensitivity significantly influenced relapse risk (p=0.01), OS (P=0.01) and EFS (P=0.003). TCD significantly improved EFS (P=0.01) despite an excess of unrelated/mismatched donors (18 versus 3, P=0.001) and patients who had failed a prior autograft in the MF-A cohort (44 versus 29, P=0.03). Prior autograft or donor source had no significant influence on TRM, relapse, OS or EFS. More patients were chemo-sensitive prior to RIT in the MF-A group (36 versus 20, P=0.03) but TCD retained independent positive prognostic significance for EFS in multivariate analysis (P=0.02; Hazard ratio 0.69(0.51–0.93)), as did chemo-sensitivity (P=0.01). In conclusion, alemtuzumab significantly reduced GvHD without resulting in an apparent impact on disease relapse. Both groups often required DLIs to achieve tumor control and the response rates support a significant GvL activity.