Superiority of Allogenic Stem Cell Transplantation after Anti-PD1 Therapy over Anti-PD1 Monotherapy Alone in Relapse/Refractory Hodgkin Lymphoma: Real World Evidence from the French Early Access Program
Authors: Manson Guillaume , Mear Jean-Baptiste , Herbaux Charles , Schiano de Collela Jean Marc , Casasnovas Rene-Olivier , Stamatoullas Aspasia , Deau-Fisher Bénédicte , Schmitt Anna , Garnier Georges , Molina Lysiane , Bouabdallah Krimo , Moles Marie-Pierre , Ghesquieres Herv , Tempescul Adrian , Dulery Remy , Nicolas-Virelizier Emmanuelle , Delmer Alain Jacques , Borel Cecile , Chauchet Adrien , Dercle Laurent , Brice Pauline , Houot Roch 
Published: October 2019

Abstract
Background: Nivolumab demonstrated remarkable activity in patients with relapse or refractory (R/R) Hodgkin lymphoma (HL). However, long term efficacy and the need for a consolidation with allogenic stem cell transplantation remain unclear.
Patient and method: We retrospectively analyzed 78 patients with R/R HL treated with nivolumab in the French Early Access Program and compared their outcome according to subsequent alloHSCT.
Results: After a median follow-up of 31.5 months, the best overall response rate was 64%, including 37.3% complete response (CR). The median progression-free survival (PFS) was 12.1 months and median overall survival (OS) was not reached. At 3 years, PFS and OS rates were 35% and 65%, respectively. Patients reaching a CR upon nivolumab had a significantly longer PFS than those reaching a PR (median = not reached vs 10.1 months).
In our cohort, 17 patients underwent consolidation with allogenic stem cells transplantation (alloHSCT) after nivolumab therapy (Figure 1). At the time of transplantation, 8 patients were in CR, 5 in partial response (PR) and 4 had progressed of whom 3 received a salvage therapy before alloHSCT. Interestingly, 6 out of 7 patients who were not in CR at the time of transplantation (5 PR and 1 progressive disease) converted into a CR after alloHSCT. At the time of analysis, 14 patients were alive and 13 remained disease-free after a median follow-up of 30.4 months. One-year OS and PFS from alloHSCT were 82% and 76%, respectively. Among responding patients (i.e. in CR or PR) after nivolumab monotherapy, those who underwent subsequent alloHSCT (N=13) had a better outcome than those who were not consolidated with alloHSCT (N=35) (Figure 2). In the transplanted group, none of the patients relapsed whereas in the non-transplanted group 60% of the patients relapsed (p<0.001). In the transplanted group, all patients experienced graft-versus-host disease (GVHD), acute (N=14) and/or chronic (N=7) GVHD, including 7 patients with grade III-IV GVHD. At the time of analysis, GVHD had resolved in 9 out of 13 patients. Two patients experienced non-infectious febrile syndrome which resolved with corticosteroids and one patient experienced a sinusoidal obstructive syndrome. Two patients died, one from steroid-refractory GVHD and encephalitis, one from unexplained hemoptysis after experienced steroid-refractory GVHD.
Conclusions: Although patients who achieve a CR upon anti-PD1 therapy may experience prolonged remissions, most R/R HL patients treated with anti-PD1 antibody eventually progress or relapse. Our study demonstrates unprecedented disease-free survival in patients undergoing consolidation with alloHSCT after anti-PD1 therapy. Interestingly, alloHSCT post anti-PD1 can convert incomplete responses into CR in most cases. Despite expected toxicities, alloHSCT after anti-PD1 therapy appears manageable and safe in most patients. Our results suggest that consolidation with alloHSCT may represent a good option in patients treated with anti-PD1, notably in patients who are unable to achieve a CR.

Disclosures
Herbaux: Gilead Sciences, Inc.: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Stamatoullas:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA: Consultancy. Brice:bristol myers squibb: Consultancy, Honoraria. Houot:bristol myers squibb: Consultancy, Honoraria.