Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) after Treatment with Nivolumab for Relapsed/Refractory Hodgkin Lymphoma
Authors: Armand Philippe , Zinzani Pier Luigi , Collins Graham P. , Cohen Jonathon B. , Halwani Ahmad S. , Carlo-Stella Carmelo , Millenson Michael M. , Provencio Mariano , Domingo Domenech Eva , Giulino Roth Lisa , Castagna Luca , Kato Kazunobu , Popa McKiver Mihaela , Sumbul Anne , Zhu Lili , Santoro Armando 
Published: October 2019

Abstract
Introduction: Allo-HSCT is a potentially curative option for patients (pts) with classical Hodgkin lymphoma (cHL) who relapse after autologous (auto)-HSCT. Nivolumab (nivo) is approved in the US for treatment of relapsed or progressive cHL after auto-HSCT and post-transplant brentuximab vedotin. Nivo was studied in pts with relapsed cHL in ph 1 (CheckMate 039, NCT01592370) and multicohort ph 2 (CheckMate 205, NCT02181738) studies. Response rate in 95 heavily pretreated cHL pts across those studies was 65%, with an estimated median duration of response of 8.7 mo. Decision to proceed to allo-HSCT after nivo was not restricted within the studies and was at the discretion of treating clinicians; some pts were referred and elected to undergo subsequent allo-HSCT. Allo-HSCT-related immune complications, including graft vs host disease (GVHD) after prior exposure to PD-1 blockade have been reported (Nivolumab US PI; 2016). Here we report safety outcomes in HL pts from these 2 studies who received nivo and subsequent allo-HSCT.
Methods: Pts from the CheckMate 039 cHL monotherapy cohort (n=23) and all CheckMate 205 cohorts (n=243) who underwent allo-HSCT after study treatment are included in this post hoc analysis. Basic post-allo-HSCT outcomes (transplant date, GVHD, disease status) were prospectively collected in CheckMate 205. Further details from CheckMate 205 (stem cell source, preparative regimen, additional post-allo-HSCT safety data) and all post-allo-HSCT data from CheckMate 039 were collected retrospectively. Non-relapse mortality (NRM) was defined as death without disease relapse. Steroid-responsive febrile syndrome (SRFS) was defined as steroid-responsive, non-infectious fever that could be accompanied by skin, joint, or liver symptoms.
Results: This analysis includes pts from CheckMate 039 (n=5) and 205 (n=12) who underwent allo-HSCT. Median age at time of allo-HSCT was 33 y (range 18-56). Pts had received a median of 9 nivo doses (range 4-16); 16 underwent allo-HSCT without disease progression or intervening therapy between nivo and allo-HSCT; the remaining pt had disease progression on nivo and received combination chemotherapy before allo-HSCT. Median interval between last nivo dose and allo-HSCT was 29 d (range 11-94). Stem cell source was peripheral blood (n=14) or bone marrow (n=3). Donors were HLA-matched sibling (n=3), single-antigen mismatched related (n=1), haploidentical (n=5), matched unrelated (n=7), and mismatched unrelated (n=1). Reduced-intensity conditioning (RIC) was used in 15 pts and myeloablative conditioning (MAC) in 2. Acute GVHD occurred in 14 pts (82%): grade (g)2-4 in 10 pts (59%) and g3-4 in 5 (29%). Among those 14 pts, organs involved were skin (3 g1, 4 g2, 4 g4, 1 g unknown), gut (1 g2, 1 g3, 4 g4), liver (4 g4), and lung (1 g unknown). Median time to onset of g3-4 acute GVHD was 22 d (range 13-139). Two pts had hyperacute GVHD (onset ≤14 d post-transplant). One pt with hepatic veno-occlusive disease died due to multiorgan GVHD. Five pts had SRFS (onset 0-53 d post-allo-HSCT). Two pts experienced g3 encephalitis: 1 lymphocytic encephalitis case without an identified infectious cause resolved on corticosteroids, and 1 suspected viral encephalitis case resolved on antiviral therapy. There were 6 deaths among 17 pts; all 6 were NRM-related: 5 due to GVHD in pts who had received RIC allo, and 1 due to pulmonary injury in a pt who had received MAC. Median time from allo-HSCT to death was 119 d (range 39-440). There were no deaths due to disease progression. Follow-up is ongoing and additional results will be presented.
Conclusions: Results of this small cohort indicate that severe GVHD with rapid onset and unique complications such as SRFS, and NRM may occur in pts with prior exposure to PD-1 blockade. Although the data set is small and follow-up is limited, results support a hypothesis that prior anti-PD-1 exposure could potentially magnify the risk of immune-related complications after transplantation. While these data should not be interpreted as showing that allo-HSCT is contraindicated, they highlight a need for caution when considering allo-HSCT after PD-1 blockade. Studies of larger cohorts with longer follow-up and immunologic analyses should be pursued to confirm and understand these results.
Funding: BMS. Writing support F. Beebe, Caudex.

Disclosures
Armand: Infinity Pharmaceuticals: Consultancy; Sequenta Inc: Research Funding; Roche: Research Funding; Merck: Consultancy, Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Zinzani:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Collins:Takeda: Consultancy, Honoraria, Speakers Bureau. Cohen:Bristol-Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Halwani:Abbvie: Consultancy, Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding; Pharmacyclics: Consultancy, Research Funding; Immune Design: Research Funding; Seattle Genetics: Research Funding; Kyowa Hakko Kirin: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Carlo-Stella:Boehringer Ingelheim: Consultancy; Rhizen Pharmaceuticals: Research Funding. Millenson:Janssen: Other: Spouse's employment/salary. Kato:Bristol-Myers Squibb: Employment. Popa McKiver:Bristol-Myers Squibb: Employment, Equity Ownership. Sumbul:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment. Santoro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; ArQule: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.