ALBERT

Description: BACKROUND: Hodgkin Lymphoma (HL) is characterized by a high degree of response to chemotherapy and an overall favorable outcome in responding patients. Despite the efficacy of first line therapy, however, about 30% of patients affected by HL eventually relapse or are refractory (R/R) to first or second line therapy followed by autologous hemopoietic stem cell transplantation (ASCT). Recently, the clinical application of immune checkpoint inhibitors (CI), in particular the PD-1 targeting antibody Nivolumab, has dramatically improved the prognosis of patients affected by advanced phase solid tumours. In HL, Nivolumab has shown good activity in the difficult setting of patients relapsing after ASCT; however, complete response (CR) rate was less than 20%. Many studies in the solid tumours field have shown that the efficacy of CI is strictly related to the host degree of immune competence, which is greatly impaired in heavily pre-treated HL patients who received ASCT. Therefore, there is a strong rationale in enhancing the activity of the CI with the co-infusion of autologous lymphocytes (ALI), that have been collected in the early phase of therapy, and that are functionally activated. AIMS OF THE STUDY: Primary endpoint of this prospective trial was the evaluation of the efficacy of ALI in combination with pre-emptive CI administration early post ASCT in patients affected by R/R HL. Secondary pre-clinical endpoint was the study of the peripheral blood lymphocyte subpopulation, pre and post adoptive immune cell therapy and CI administration. METHODS: HL patients under the age of 60 with active R/R disease who have already failed at least two chemotherapy lines and Brentuximab (BV) were eligible for the trial. All enrolled patient underwent early lymphocyte apheresis, with a target cell dose of 5x107 CD3+/kg. All patients then received ASCT with FEAM conditioning. After ASCT, the first ALI was delivered 7 days after engraftment. ALI dosing was incremental, one logarithm at each step, starting from 1x104/kg in the first infusion to a maximum of 1x107/kg in the fourth and last infusion. Each ALI was followed after 48 hours by the administration of Nivolumab 240 mg flat dose. The second ALI dose was administered at 14 days after the first one. The third and the fourth were given every 21 days. Lymphocyte subpopulations were extensively studied on peripheral blood samples before and after each ALI and each Nivolumab administration, by 8-colours flow cytometry. Clinical response was evaluated 21 days after completion of the fourth ALI + Nivolumab. RESULTS: Six R/R HD patient have completed treatment so far and one is currently being treated. All patients failed to achieve CR with chemotherapy and then progressed during BV therapy. PET scan before ASCT showed progressing disease in all patients, with multiple-extra nodal involvement in 5 of them. All patients achieved complete hematological engraftment after a median of 10 days (8-12) from ASCT. Overall, infusion of ALI resulted in significantly higher lymphocyte counts at day 90, as compared to HL patients receiving the same conditioning without ALI (p

Description: BACKROUND Hodgkin lymphoma (HL) is a lymphoid malignancy of B-cell origin with a high long-term survival. Despite the efficacy of frontline therapy, about 30% of patient will show relapse or refractory disease (R/R). In this patient population, the treatment of choice consists of salvage chemotherapy followed by intensive conditioning regimen and autologous stem cell transplantation (ASCT). However 30-50% of patients receiving salvage chemotherapy fail to achieve at least PR and further therapy with Brentuximab-Vedotin (BV) may be administered to induce a clinical response. Nonetheless, therapeutic options for truly refractory patients are still limited. Recently, immune-check point inhibitors have shown promising results in HL patients relapsed after ASCT. Anti-PD1 Nivolumab is currently approved with this indication. Unfortunately,expected CR rate is only about 20%.Thus, we reasoned that earlier administration of Nivolumab, as post-ASCT consolidation, might improve its efficacy. However, several reports have highlighted the importance of patient immune-competence, which is severely impaired in heavily pre-treated lymphoma patients undergoing ASCT, to achieve durable response with anti-PD1 immunotherapy. AIMS OF THE STUDY Here we report the preliminary results of a prospective trial investigating the feasibility, and the efficacy, in terms of both immunological recovery andclinical response,ofthe reinfusion of autologous lymphocytes (ALI), early after ASCT, concomitant with anti-PD1 consolidation immunotherapy in very high-risk HD patients. METHODS Patients under the age of 60 with high risk HD identified by PET2 or PET6 positivity following ABVD were scheduled for a pre-emptive lymphocyte apheresis with a target of 5x107 CD3+/kg. Patients who failed to achieve at least PR with salvage chemotherapy proceeded to ASCT with FEAM conditioning followed by early Nivolumab and ALI.The first ALI was performed 7 days after engraftment; the second ALI was administered at day +14 after the first dose whereas the third and the fourth doses were given every 21 days. ALI dosing was incremental, one logarithm at each infusion, starting from 1x104CD3+ cells/kg in the first infusion to a maximum of 1x107/kg in the fourth and last infusion. Each ALI was followed within 48 hours by the administration of Nivolumab 240 mg flat dose. Toxicity was evaluated and graduated according to CTCAE-EORTC standards. Circulating lymphocyte subpopulationswere extensively studied before and after each ALI and each Nivolumab administration by 12-colours flow cytometry. Clinical response was evaluated 21 days after completion of the fourth ALI + Nivolumab. PRELIMINARY RESULTS Four R/R HD patients have completed the treatment and3are currently under treatment. All patientshad failed to achieve CR with first and second line chemotherapy. PET scan before ASCT showed progressing disease in all patients despite BV therapy, with multiple-extra nodal involvement in 3 of them. Study patients underwent ASCT with FEAM conditioning and achieved complete engraftment after a median of 10 days (8-12). ALI induced faster T-cell recovery (p