PS1535 AUTOLOGOUS STEM CELL TRANSPLANT FOLLOWED BY POST‐TRANSPLANT IMMUNOTHERAPY WITH NIVOLUMAB AND UNSELECTED AUTOLOGOUS LYMPHOCYTES INFUSION AS SALVAGE THERAPY FOR RELAPSED/REFRACTORY HODGKIN LYMPHOMA
Authors: Guolo F. , Minetto P. , Ballerini F. , Canale F.A. , Frello M. , Coviello E. , Manconi L. , Kunkl A. , Tedone E. , Contini P. , Mangerini R. , Fenoglio D. , Bo A. , De Luigi M.C. , Ruzzenenti M.R. , Carlier P. , Serio A. , Lucchetti S. , Strada P. , Gobbi M. , Ravetti J.L. , Marcenaro E. , Lemoli R.M. 
Published: June 2019

Background:

About 30% of Hodgkin Lymphoma (HL) patients are refractory to induction therapy or relapse. Standard salvage treatment is often followed by high‐dose chemotherapy and autologous stem cell transplantation (ASCT) if at least a partial remission is achieved. However 30–50% of relapsed‐refractory (R/R) patients fail to achieve PR. Recently the PD‐1 targeting antibody Nivolumab has shown promising activity in HL patients relapsed after ASCT but the expected CR rate is only about 20%. Administration of nivolumab as early post‐ASCT consolidation might improve results However, several reports have highlighted the relevance of patient immune‐competence. In this view, T‐cell count is severely depleted after ASCT.

Aims:

Here we report the preliminary results of a prospective trial investigating the feasibility, and the efficacy of post‐ASCT Nivolumab with the support of unselected autologous lymphocyte reinfusions (ALI).

Methods:

HL patients under the age of 60 with active, relapsed/refractory disease who have already failed at least two chemotherapy lines and Brentuximab were eligible for the trial. All enrolled patient underwent lymphocyte aphaeresis, with a minimum target of 5x107 CD3+/kg. All patients then received ASCT with FEAM conditioning. After ASCT, the first ALI wasdelivered 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 12‐colours flow cytometry. Clinical response was evaluated 21 days after completion of the fourth ALI + Nivolumab.

Results:

Five R/R HD patient have completed treatment so far and one is currently being treated. All patients failed to achieve CR with first and second line chemotherapy and then progressed during BV therapy. PET scan before ASCT showed progressing disease in all patients, with multiple‐extra nodal involvement in 4 of them. All patients achieved complete engraftment after a median of 10 days (8–12).

Overall, ALI allowed to achieve significantly higher lymphocyte counts at day 90 in all patients, if compared to HL patients receiving the same conditioning without ALI (p <0.05), especially in the T‐lymphocyte effector‐memory (CD45RA‐, CD68L‐, CD27+) compartment (p < 0.03). After ALI administration, naïve (CD45RA+, CD62L+, CD27+, CD28+) CD8+ cell (p < 0.03) and cytotoxic (CD56+,CD16+,CD57+) NK cells (Fig. 1, p < 0.05) showed the most consistent and most durable increase. Nivolumab administration determined only a modest and transient increase in T‐effector‐memory population. No grade 3 or 4 adverse events were recorded so far. All treated patients so far achieved negative PET scan after the procedure and are alive and disease free after a median follow‐up of 12 months.

Summary/Conclusion:

Post‐ASCT ALI proved to be feasible and effective in a heavily‐pre‐treated population, resulting in a quicker immune recovery and in a complete response in all treated patients. Immunotherapy as post‐ASCT consolidation therapy might improve the CR rate expected with anti‐PD1 blockade alone, providing a more effective option for refractory patients, who are usually considered not candidate for ASCT.

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