Donor Lymphocyte Infusions Induce High Response Rates and Durable Salvage in Relapsed Hodgkin Lymphoma Post T Cell Depleted Allogeneic Transplantation.

Abstract 200

The feasibility of performing allogeneic HSCT in patients with Hodgkin Lymphoma using reduced intensity conditioning (RIC) is well established. By reducing non-relapse mortality, these approaches have seemingly improved post-transplant survival outcomes compared to conventional myeloablative strategies. An EBMT registry analysis comparing outcomes with fully ablative protocols confirmed an overall survival advantage for RIC in adult patients (Sureda et al, JCO, 2008). Relapse rates, however, were higher following RIC, and relapse now represents the major cause for treatment failure following allogeneic transplant in HL. Identifying strategies that reduce relapse rates or more effectively salvage relapsing patients is therefore an imperative. There is no consensus regarding these issues, and little published evidence to guide practice. We have performed 72 RIC allografts for HL (38 matched sibling, 34 unrelated donor) incorporating T cell depletion with alemtuzumab at our institution. This high risk cohort included 33 primary refractory or salvage-refractory patients, and 53 had failed a prior autograft. Patients were monitored for lineage-specific chimerism using a PCR-based STR assay, and disease status assessed by CT-PET, potentially allowing earlier intervention for relapse. Patients received a dose-escalating donor lymphocyte protocol from 6 months post transplant for mixed chimerism or residual disease/progression. Relapse was defined by recurrence or progression of FDG-avid lesions in sites of prior disease, with or without new sites. In cases where FDG-avid lesions occurred only in new sites relapse was confirmed by biopsy if accessible (n=3), otherwise an interval scan was performed at 6–8 weeks to confirm progression in the absence of other potential pathology. Cyclosporine was withdrawn prior to consideration of DLI, which was not given to patients with active GvHD. Non-relapse mortality was 13% at 1 year and 15% at 3 years post transplant. Cumulative incidence of relapse was 46% at 3 years. Forty patients have received a total of 78 DLIs (median 2 doses, range 1–5). Median CD3+ T cell dose was 3×10e7/kg (range 1×10e6–3×10e8/kg). Treatment was given for mixed chimerism alone in 19 patients, with up to 90% recipient chimerism. This group included 9 who were primary refractory or salvage refractory prior to transplant. DLI resulted in conversion to full donor status in 12/15 evaluable patients, 2 continue to show falling recipient chimerism, and 1 failed to convert. Three are currently too early to assess and 1 died prior to evaluation. Nine remain free from GvHD, suggesting that conversion can occur in its absence. Only 1 patient in this cohort subsequently relapsed (cumulative incidence 7% at 3 years from initial DLI), and this occurred in the setting of persistent mixed chimerism. The patient received further DLI following cytoreductive chemotherapy. Disease relapse was treated in 22 patients with DLI either alone (n=15) or following debulking chemo-radiotherapy (n=7). Five relapsed/progressive patients did not receive DLI, either because of early progression within 3 months of transplant, concurrent GvHD, or lack of donor availability. Median starting doses of DLI were 1×10e6 and 1×10e7 CD3+ T cells/kg in unrelated and related donors respectively, and median maximal doses 3×10e6 and 3×10e7/kg respectively. Complete responses were seen in 10 (50%) and partial responses in 5; overall response 75% of 20 evaluable patients. The majority of responders (9/10 CR, 4/5 PR) developed GvHD (5 acute grade III–IV, 4 extensive chronic). CR is maintained in 6 patients at a median of 4.8 years (range 1.3–7.5 years) from last DLI (5/6 received DLI alone at relapse, and 4 have no current GvHD), 3 died in CR of complications of GvHD, and only 1 progressed (at 2.3 years). 2/5 with PR progressed, and follow-up in the others is short (<12 months). With a median follow-up of 2.5 years from relapse the projected 3 year OS and PFS from time of relapse are 62% and 52% in this cohort of 22 patients. The OS and current PFS for the entire cohort (n=72) are both 45% at 6 years. In conclusion, the data demonstrate favorable long term survival in this heavily pre-treated cohort, a strikingly low relapse incidence in those receiving DLI for mixed chimerism, and the ability of DLI guided by CT-PET restaging to induce high response rates and durable salvage in the setting of relapse post T cell depleted transplantation in HL.