*2.1.1 Nivolumab and pembrolizumab*

Nivolumab and pembrolizumab are among the first fully human anti-PD-1 IgG4 monoclonal antibodies approved by the US FDA (May 2016 for nivolumab and March 2017 for pembrolizumab) for the treatment of relapsed or progressed cHL after autologous hematopoietic stem cell transplantation (auto-HSCT) and brentuximab vedotin (therefore referred as relapsed/refractory, r/r) [30, 31]. Since then, numerous clinical trials and real-world experiences have demonstrated the efficacy and safety profiles of nivolumab and pembrolizumab against HL, which is mainly (but not limited to) r/r cHL. Nivolumab and pembrolizumab are the most common ICIs used for r/r cHL patients, and many groups use both drugs in the same clinical trials (refers to them both as PD-1 ICIs). The clinical data of pembrolizumab are summarized in **Table 1** together with nivolumab.

As shown in **Table 1**, the objective response rate (ORR) for PD-1 ICIs is generally high (usually over 70%). However, the CR is rarely achieved, with a CR rate of around 30%–40%. Notably, some preconditions or previous treatments the patients experienced significantly enhance the outcomes of anti-PD-1 therapy. For example, 5 of 5 r/r cHL patients who have been given hypomethylating agents 5-azacitidine all achieved CR after ICI treatment [37]. This may suggest some potential combination therapies and numerous groups are assessing the efficacy of different treatment combinations.

#### *2.1.1.1 Combination of PD-1 inhibitors and HSCT*

The poor CR rate of anti-PD-1 antibodies suggests that monotherapy of PD-1 blockade alone may be not sufficient to cure r/r HL. Therefore, combined therapy of PD-1 blockade with other additional canonical treatments is necessary. It has been demonstrated that administration of PD-1 inhibitors before/after allogenic (allo-) or autologous (auto-) HSCT significantly enhances response rate and prolongs patient survival. Manson et al. [54] reported that none of the 13 r/r HL patients who underwent consolidation treatment of allo-HSCT together with nivolumab suffered from disease relapse. On contrary, 62.2% of those (*n* = 37) who did not undergo subsequent allo-HSCT relapsed. In another similar study, Merryman et al. [55] studied the 209 cHL patients who underwent subsequent allo-HSCT after PD-1 inhibition. With a median follow-up of 24 months, they reported that the 2-year progression-free survival (PFS) and overall survival (OS) were 69% and 82%, respectively. Merryman et al. also suggested that a shorter interval between PD-1 inhibition and allo-HSCT can significantly boost the graft-versus-lymphoma (GVL) effect of allo-HSCT. The real-life experience of 74 patients who underwent allo-HSCT after nivolumab treatment in Spain provided a similar conclusion (i.e., improved PFS and OS) as well [56].

Similarly, consolidation after auto-HSCT by PD-1 blockade also improves the treatment outcomes [57]. In this clinical trial (NCT02362997), the expected PFS after auto-HSCT increased from 60 to 82% upon pembrolizumab administration. Casadei et al. [58] also reported that auto-HSCT after PD-1 blockade further improved patient survival, with an estimated 5-year PFS of 73.4% and 4.8-year OS of 92.3%.

Although the combination of PD-1 inhibition and allo-HSCT seems to be a promising strategy against HL, increased graft-versus-host disease (GVHD) upon anti-PD-1 administration is a major concern of this treatment option [55, 56, 59]. Such GVHD can be severe and may cause multi-organ failure and even death [55, 56, 59–64]. Therefore, multiple studies indicated that post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis is required for improved PFS and therefore strongly suggested [55, 59].


#### *Immune Checkpoint Inhibitors in Hodgkin Lymphoma and Non-Hodgkin Lymphoma DOI: http://dx.doi.org/10.5772/intechopen.107435*

