Autologous hematopoietic stem cell transplantation (ASCT) is curative for a proportion of patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL). However, there is a small group of patients ...with high-risk of relapse after ASCT that might benefit from other approaches. We conducted a retrospective analysis on 126 patients treated with tandem ASCT-reduced intensity conditioning (RIC)-allogeneic-SCT and reported to the EBMT registry to analyze the efficacy and safety of this approach. Patients were included if they had received an ASCT followed by a planned RIC-SCT in <6 months without relapse between the procedures. The median time between diagnosis and ASCT was 16 months (2-174). The median number of lines prior to ASCT was two (33% of the patients received >3 lines). Forty-one percent were transplanted with active disease. The median follow-up was 44 months (6-130). Three-year-progression-free survival (PFS), overall survival (OS), incidence of relapse (IR), and non-relapse mortality (NRM) after the tandem were 53% (45-64), 73% (65-81), 34% (24-42), and 13% (8-21), respectively. This is the largest series analyzing the efficacy and safety of a tandem approach in R/R HL. The low NRM and IR with promising PFS and OS suggest that this might be an effective procedure for a high-risk population.
Adiponectin has been implicated in the pathogenesis of coronary heart disease. We review the literature describing the effect of lipid-lowering agents on adiponectin bioavailability. Statins exert ...variable effects that can be influenced by patient-dependent characteristics (i.e. diabetes or insulin resistance). Fibrates and especially niacin can raise adiponectin levels. The impact of plant sterols, ezetimibe and ω-3 fish oils on adiponectin in humans remains to be defined. There was no literature on whether resins can alter adiponectin levels. As far as mechanisms are concerned, statins enhance peroxisome proliferator-activator receptor (PPAR)-γ activation and have antioxidant or anti-inflammatory potential. Niacin, ω-3 fatty acids, plant sterols and bezafibrate primarily act by increasing PPAR-γ activity and possibly by reducing oxidative stress or inflammation. Both fibrates and ω-3 fish oils act as synthetic ligands for PPAR-α. Hypolipidaemic drugs can affect adiponectin bioavailability, although the impact depends on the individual drug administered and patient characteristics. However, with the exception of niacin, the results observed are not conclusive.
Introduction
The development of mixed donor recipient (MDR) chimerism is a frequent occurrence following allogeneic transplantation (alloSCT) for lymphoid malignancies. There is evidence that ...achievement of full donor (FD) lympho-haematopoietic chimerism (LHC) is associated with a lower chance of disease recurrence and consequently donor lymphocyte infusions (DLI) are commonly employed in this setting. There is however a paucity of data describing both the efficacy of DLI in achieving FD LHC and their toxicity in terms of inducing graft versus host disease (GVHD). We therefore undertook a large survey within the EBMT to determine the efficacy and toxicity of DLI when used for MDR LHC.
Methods and Patients
All centres within the EBMT database that had administered DLI for MDR LHC in patients undergoing an alloSCT for lymphoid malignancies were invited to submit additional data for this study. Data was provided for 135 patients from 36 centres. The median age at diagnosis was 44.6 years (15-64) and the median age at SCT was 47 years (range 19-68). Patients were diagnosed with DLBCL (n=17), follicular NHL (n=45), Hodgkin lymphoma (n=21), mantle cell lymphoma (n=32), T cell lymphoma (n=14) and other lymphoid malignancies (n=6). Prior autologous transplantation had been performed in 45 patients. 122 patients underwent reduced intensity conditioning prior to transplantation from a matched sibling donor (n=90), unrelated donor (n=42) or mismatched family donor (n=3). T cell depletion (TCD) of the graft was performed in 33 cases.
Results
MDR LHC was demonstrated by analysis of whole blood (WB) in 34 patients and in T cell and myeloid lineages in 101 patients. The median time from alloSCT to the demonstration of MDR LHC was 4.9 months (range 4.6-63) and the median time to the 1st DLI was 7.8 months (range 1-63). Patients received a median of 2 DLI (range 1-20) at a median starting dose of 1x106 CD3/kg recipient (range 0.1-380 x 106/kg). Of the 135 patients receiving DLI 121 were assessable for response with 94 (78%) achieving full donor LHC, 24 (20%) remaining MDR, 2 patients became fully recipient and one patient had a mixed response (FD in T cells but MDR in myeloid lineage). For the patients that received DLI for T cell MDR chimerism (N=71, with 64 assessable for response) 55 (86%) became FD, 8 (12.5%) remained MDR and 1 became fully recipient. For patients that received DLI for myeloid MDR chimerism (with or without MDR chimerism in the T lineage) (N=30, with 29 assessable for response) 17 (59%) converted to full donor in the myeloid lineage, 10 (34%) remained MDR, 1 had a mixed response and 1 became full recipient. If patients required 3 or more DLIs the chance of conversion to FD fell significantly to 55% compared to 89% for those that only received 1 DLI (p<0.001). There was a trend to a higher rate of conversion to FD in patients that had received a T replete graft (81%) compared to those that had received a T depleted graft (52%)(p=0.063). The dose of the first DLI and donor type had no impact on conversion to DLI.
Acute GVHD developed in 45 of 134 (34%) evaluable patients after the 1st DLI (grade I in 12, grade II in 12, grade III in 6, grade IV in 8 and grade unknown in 7). Chronic GVHD developed in 36 of 130 (28%) evaluable patients which was extensive in 13 (10%). Acute GVHD (grades II-IV) was seen more commonly after the 1st DLI than after 2 or more DLIs (68% post 1st DLI vs 14% after 2 or more DLIs at 100 days p=0.002) and in patients undergoing unrelated donor transplantation (62% vs 23% at 100 days, p=0.02). Chronic GVHD was more common after DLIs given to patients that had received a TCD graft (39% vs 17% p=0.007). The median follow-up after the 1st DLI was 70 months (range 11-149). Relapse following DLI occurred in 36 (27%) patients which was more common in patients receiving DLI for myeloid MDR chimerism compared to T cell MDR (40% vs 22.5%). Disease relapse occurred in 36 (27%) patients after receiving the first DLI, 11 of whom had achieved full donor FD LHC prior to relapse. In a time-dependent Cox model conversion to FD LHC was not protective against relapse.
Conclusions. In this large series of patients with lymphoid malignancies the administration of DLI is an effective strategy for achieving FD chimerism particularly when the MDR chimerism is restricted to the T cell lineage. Development of GVHD is a significant complicating factor particularly in the unrelated donor setting and when the original graft was T cell depleted.
Robinson:Roche: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Sandoz: Speakers Bureau. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding. Beelen:Medac: Consultancy, Other: Travel Support.
Introduction
Relapse of non-Hodgkin lymphoma (NHL) following allogeneic stem cell transplantation (alloSCT) is a common occurrence associated with a poor outcome with limited treatment options. Donor ...lymphocyte infusions (DLI) are commonly employed in this setting in an attempt to exploit the allogeneic graft versus lymphoma (GVL) effect to induce remissions. There is however a paucity of data describing the efficacy of DLIs in inducing remissions in NHL subtypes and the risk of subsequently developing graft versus host disease (GVHD). We report here the largest series of patients with NHL receiving DLI for relapse after alloSCT.
Methods
Patients relapsing after an alloSCT for NHL and receiving DLI were identified on the EBMT database. Centres were invited to contribute additional data. 118 patients follicular lymphoma (FL) n=28, diffuse large B cell lymphoma (DLBCL) n=28, T cell lymphoma (TCL) n=52 and mantle cell lymphoma (MCL) n=10 from 39 centres who received DLI as the only treatment for relapse were identified. Patients receiving DLI in combination with other therapy were excluded from this analysis. The median age at alloSCT was 50 (range 18-73) years. There were 81 male and 37 female patients who underwent an alloSCT with reduced intensity (RIC) (n=90) or myeloablative conditioning (MAC) (n=28) at a median of 2.4 (range 0.3-26.3) years from diagnosis. Allogeneic cells were provided from matched sibling (n=63), unrelated (n=47) or mismatched family (n=8) donors and 85 patients received either ATG/ALG or CAMPATH as part of GVHD prophylaxis. The median time from alloSCT to relapse was 3.8 months (range 18 days-67 months).
Results
Patients received a median of 1 (range 1-19) DLI at a median starting dose of 1.5 x106 CD3/kg (range 0.01-120x106 CD3/kg) at a median of 152 days (range 18-2136) post alloSCT. The median last dose of DLI was 10x106/kg (range 0.1-180x106/kg) given at a median of 353 days (range 41-2725) post alloSCT. The median time from relapse to the first DLI was 35 days (range 0-168). Acute GVHD and chronic GVHD prior to DLI was reported in 29% and 14% of patients, respectively. Of 93 evaluable patients 47 (51%) patients achieved a complete remission, 10 (11%) a partial remission, 13 (14%) stable disease and 23 (25%) had progressive disease following DLI. The median duration of response was 36 months (range 1-168). When analysed according to histology the overall response rate (ORR) (CR+PR) for FL was 84% (CR 68%), DLBCL 41% (32% CR), TCL 54% (46% CR) and MCL 86% (CR 71%). The median duration of responses for FL, DLBCL, TCL and MCL were 30 (range 2-150), 38 (4-76), 37 (range 1-168) and 50 months (13-116) respectively. With a median follow up of 77 months after the 1st DLI 36 (31%) patients remain in complete remission, 29 (25%) without any further therapy. 37 (35%) went on to receive additional antilymphoma therapy after the DLI. Of 17 patients with FL achieving a CR post DLI 12 (71%) remain in remission without further therapy at a median of 78 (9-158) months after DLI. Of 18 patients with TCL that achieved a CR with DLI, 15 (83%) remain in remission without further therapy at a median of 95 (range 42-161) months after DLI. Following the DLI 43 (36%) patients developed aGVHD (6 grade I, 13 grade II, 11 grade III, 9 grade IV, 4 grade unknown) and 33 (28%) developed cGVHD (11 limited, 20 extensive, 2 unknown). Following the first DLI the cumulative incidence of relapse was 31% (CI 22-41) at 4 years and of NRM 28% (CI 20-37). The 4-year PFS after 1st DLI was 39% (CI 30-50) and the OS, 44% (CI 35-54).
Conclusions
DLI induce significant rates of disease response in patients with NHL relapsing after alloSCT providing clear proof of principle of the allogeneic GVL effect. The rates of response are most impressive in FL and MCL. The majority of patients with TCL and FL that achieve a CR post DLI remain in remission with long term follow up. Acute and chronic GVHD is a significant complication of DLI.
Robinson:Sandoz: Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Beelen:Medac: Consultancy, Other: Travel Support. Finke:Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding. Tischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Corradini:Amgen: Honoraria, Other: Advisory Board & Lecturer; Novartis: Honoraria, Other: Advisory Board & Lecturer; Abbvie: Honoraria, Other: Advisory Board & Lecturer; Sandoz: Other: Advisory Board; Sanofi: Honoraria, Other: Advisory Board & Lecturer; Gilead: Honoraria, Other: Advisory Board & Lecturer; Takeda: Honoraria, Other: Advisory Board & Lecturer; Roche: Honoraria, Other: Advisory Board & Lecturer; Janssen: Honoraria, Other: Lecturer; Celgene: Honoraria, Other: Advisory Board & Lecturer.
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