Feasibility and Efficacy of Post-Transplant Consolidation Immunotherapy with Nivolumab Supported By the Reinfusion of Unselected Autologous Lymphocytes in Patients Affected By Relapsed/Refractory Hodgkin Lymphoma
Authors: Guolo Fabio , Minetto Paola , Ballerini Filippo , Canale Filippo Antonio , Frello Michela , Coviello Elisa , Manconi Lorenzo , Kunkl Annalisa , Tedone Elisabetta , Mangerini Rosa , Contini Paola , Fenoglio Daniela , Miglino Maurizio , Bo Alessandra , De Luigi Maria Carla , Ruzzenenti Maria Rosaria , Carlier Paolo , Serio Alberto , Luchetti Silvia , Marcenaro Emanuela , Strada Paolo , Ravetti Jean Louis , Gobbi Marco , Lemoli Roberto Massimo 
Published: October 2019

Abstract
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 <0.05) as compared to HD patients receiving FEAM conditioning and ASCT without immunotherapy at the same time points after ASCT (days +30, +60, +90, +120). Moreover, after ALI administration, cytotoxic NK cells (CD56+,CD16+,CD57+) showed the most significant consistent increase (Fig. 1, p<0.05). Nivolumab administration by itself determined only a modest and transient increase in T-effector cell population. No grade 3 or 4 adverse events were recorded so far. In one patient grade 2 fever was observed after 1st ALI. All treated patient achieved negative PET scan after the procedure and are alive and disease-free after a median follow-up of 9 months.
PRELIMINARY CONCLUSIONS
Post-ASCT ALI proved to be feasible and effective allowing a faster immune recovery in heavily-pre-treated HD patients. Moreover, the early administration of check point inhibitors combined with ALI as post-ASCT consolidation therapy, may improve the low rate of CR expected with anti-PD1 blockade alone, providing a more effective option for refractory patient, which are usually considered not candidate for ASCT.
Figure 1. Figure 1.

Disclosures
Gobbi: Amgen: Consultancy; Ariad: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pfister: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy.