Use of checkpoint inhibitors in patients with lymphoid malignancies receiving allogeneic cell transplantation: a review - Nature

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Use of checkpoint inhibitors in patients with lymphoid malignancies receiving allogeneic cell transplantation: a review - Nature
Bone Marrow Transplantation (2021) 56:1784–1793

                                        REVIEW ARTICLE

                                    Use of checkpoint inhibitors in patients with lymphoid malignancies
                                    receiving allogeneic cell transplantation: a review
                                    Sabela Bobillo1 Juan Camilo Nieto2 Pere Barba
                                                        ●                        ●

                                    Received: 20 November 2020 / Revised: 18 February 2021 / Accepted: 3 March 2021 / Published online: 19 March 2021
                                    © The Author(s), under exclusive licence to Springer Nature Limited 2021

                                    Monoclonal antibodies against checkpoint receptors or its ligands have demonstrated high response rates and durable
                                    remissions in patients with relapsed Hodgkin lymphoma (HL) and other lymphoid malignancies. However, most patients
                                    will eventually progress on therapy and may benefit from further treatments including allogenic hematopoietic cell
                                    transplantation (allo-HCT). Furthermore, the use of checkpoint inhibitors (CPI) has emerged as a treatment option for
                                    patients relapsing after allo-HCT. The immune effects of the checkpoint blockade leading to a T-cell activation have raised
                                    some concerns on the safety of these therapies used either before or after allo-HCT, due to the potential risk of graft-versus-

                                    host disease (GVHD). Furthermore, CPI might also induce other immune toxicities, that can affect almost any organ, as a
                                    result of the dysregulation on the immune system balance. This review aims to focus on the evidence behind the use of CPI
                                    in patients with lymphoma who undergo allo-HCT. We summarize the clinical data generated to date about the use of CPI in
                                    HL and other lymphoid malignancies, the mechanisms of checkpoint inhibition in the context of allo-HCT as well as the
                                    clinical and biological observations of different GVHD prophylaxis in this setting. Furthermore, we discuss the evidence
                                    from retrospective series and early clinical trials on the feasibility and safety of the use of CPI in patients who relapsed after

                                    Introduction                                                            checkpoint inhibition (CPI) enhances effector T-cell respon-
                                                                                                            ses, some concerns have been raised on the safety of these
                                    Monoclonal antibodies against checkpoint receptors or its               agents used either before or after allo-HCT due to a potential
                                    ligands have shown to induce responses in patients with                 increased risk of graft-versus-host disease (GVHD) and other
                                    Hodgkin lymphoma (HL) and other lymphoproliferative                     immune-related adverse events (IRAE) [5–9]. Several ques-
                                    neoplasms [1, 2]. The blockade of the programmed cell death             tions remain still unsolved regarding mechanistic implications,
                                    protein 1 (PD-1)/PD-L1 axis, cytotoxic T-lymphocyte-                    increased risk of GVHD, and best prophylactic and therapeutic
                                    associated antigen 4 (CTLA-4) and other receptors induces a             approaches in patients with prior CPI therapy; as well as safety
                                    T-cell activation in the patient leading to tumor cell lysis.           and efficacy of CPI in those patients relapsing after allo-HCT.
                                    Despite the promising overall responses obtained with these                In this review, we discuss the mechanism of action of
                                    agents in patients with relapsed or refractory (R/R) lympho-            CPI and their effects on the immune response. We also
                                    proliferative neoplasms, most of them will eventually relapse           briefly summarize the evidence behind the use of these
                                    and may undergo further therapies including allogeneic                  agents as rescue therapy for patients with R/R lymphoid
                                    hematopoietic cell transplantation (allo-HCT) [3, 4]. Since             malignancies and focus in more depth on their use before
                                                                                                            and after allo-HCT with special interest on feasibility and
                                                                                                            safety of the procedure.

                                    * Pere Barba
                                                                                                            Blocking the immune checkpoints
                                         Department of Hematology, University Hospital Vall d’Hebron
                                         and Universitat Autònoma de Barcelona, Barcelona, Spain            Immune-checkpoint blockade is an inhibitory mechanism that
                                         Laboratory of Experimental Hematology, Vall d’Hebron Institute     normally regulates T-cell immune responses maintaining self-
                                         of Oncology (VHIO), Barcelona, Spain                               tolerance [10]. There is a wide range of immune-checkpoint
Use of checkpoint inhibitors in patients with lymphoid malignancies receiving allogeneic cell. . .                                    1785

receptors expressed on immune cells, mainly T cells, but also                 phase II trials led to the approval by the FDA and European
on activated B cells, natural killer cells, and monocytes [11].               Medicines Agency of pembrolizumab and nivolumab for R/
Taking advantage of these inhibitory pathways, malignant                      R HL [31, 32]. The KEYNOTE-087 phase II study eval-
tumor cells express ligands of these receptors to evade anti-                 uated the safety and efficacy of pembrolizumab in 210
tumoral responses from cytotoxic T cells including PD-L1 and                  patients with R/R HL enrolled in three cohorts based on
-L2 (PD-1 ligands), CD80 and CD86 (CLTA-4 ligands), and                       previous therapy with ASCT and/or BV [32]. The overall
Major Histocompatibility Complex class II and Fibrinogen-like                 response rate (ORR) and complete response rate (CR) were
Protein 1 (LAG-3 ligands) [1, 12–15].                                         69% and 22%, respectively, with a median duration of
    The PD-1-PD-L1/PD-L2 signaling pathway is probably                        response (DOR) of 16 months [31]. The efficacy of nivo-
the most deeply studied checkpoint receptor pathway and                       lumab was investigated in the Checkmate 205 phase II
has been identified as a candidate target for antibody ther-                   study that enrolled 243 patients with R/R HL who had
apy [16–18]. The PD-1-PD-L1/L2 interaction blocks sig-                        received a prior ASCT in three different cohorts according
naling in T cells by recruiting SHP-2, a phosphatase which                    to previous use of BV and ASCT [3, 4]. Results were
dephosphorylates the antigen receptor expressed by these                      similar to KEYNOTE-087, with an ORR of 69%, CR of
cells, resulting in the suppression of T-cell proliferation and               16%, and a median DOR of 16 months, confirming the
response [19, 20]. In recent years, several antibodies tar-                   activity of the PD-1 blockade in R/R HL. In these trials,
geting PD-1 have been developed for clinical use in solid                     nivolumab and pembrolizumab showed a favorable safety
tumors and hematological malignancies. Nivolumab is a                         profile, being the most common grade 3–4 adverse events
fully humanized immunoglobulin G4 (IgG4) antibody that                        lipase increases (5%) and neutropenia (2–3%) [3, 31]. The
targets epitopes on the PD-1 receptor with high affinity and                   majority of IRAE were low grade (grade ≤2), and the
specificity, blocking the interaction of PD-1 with PD-L1                       thyroid was the most commonly affected organ (hypothyr-
and PD-L2 [21]. Pembrolizumab is another humanized                            oidism 12–15%, hyperthyroidism 4%). Other less frequent
IgG4 antibody against PD-1 that also blocks PD-1 binding                      immune-mediated toxicities included hepatitis, pneumoni-
with PD-L1 and PD-L2 [22]. Both anti-PD-1 antibodies are                      tis, and rash. The majority of IRAE resolved, and only led
similar and only differ from the variable regions that bind                   to treatment discontinuation in 6–7% of patients [3, 31].
the epitope of the antigen [23, 24]. These structural features                Regarding the causes of these IRAEs in patients with
suggest that they competitively inhibit PD-L1 binding by                      lymphoma and receiving CPI, it is uncertain whether they
direct occupancy and steric blockade of the PD-L1 binding                     occur only as a result of the loss of T-cell balance between
site, suggesting potential synergism between them [25].                       self-tolerance and activation [33] or because these agents
Atezolizumab is another humanized IgG1 monoclonal                             have an effect on circulating B-cell clones harboring lym-
antibody that selectively binds to PD-L1 and disrupts its                     phoma driver mutations leading to generation of auto-
interaction with PD-1 but not with PD-L2 [26].                                antibodies, as it has been recently described [34].
    CTLA-4 was the first immune-checkpoint receptor to be                          More recently, combinations of CPI with conventional
clinically targeted. The most accepted hypothesis about its                   chemotherapy or novel agents have been explored in R/R
mechanism of action is that after T cells recognize their cog-                HL. The ECOG-ACRIN Research Group conducted a phase
nate antigen through the TCR, the inhibitory receptor CTLA-4                  I trial combining ipilimumab, nivolumab, and BV in R/R
is upregulated. Then, CTLA-4 competes with CD28 for CD80                      HL [35]. The response rate of the combination of nivolu-
and CD86 ligands, inhibiting co-stimulatory signals originated                mab + BV (arms E-D-F) and ipilimumab + BV (arms A-B-
by CD28 [27] inhibiting T helper activity and enhancing                       C) was 89% and 76% including 61% and 57% of CRs,
immunosuppression mediated by regulatory T cells (Tregs)                      respectively, with an acceptable safety profile. The triple
[28, 29]. Ipilimumab is a recombinant human IgG1 mono-                        combination of nivolumab, ipilimumab, and BV (cohorts G-
clonal antibody directed against CTLA-4. It was approved by                   H-I) demonstrated good efficacy as well (ORR 89%, CR
the Food and Drug Administration (FDA) in 2011 for the                        73%), although toxicity was higher than observed with the
treatment of metastatic melanoma [30] and it has also shown                   doublets [35]. Furthermore, nivolumab plus BV as first
to be effective in patients with hematological malignancies                   salvage therapy also demonstrated favorable responses in a
relapsing after allo-HCT [2].                                                 phase I/II study with manageable toxicity [36, 37].
                                                                                  In the frontline setting, nivolumab plus AVD led to an
                                                                              ORR of 84% and CR of 67% in 51 patients with untreated
CPI in lymphoma                                                               advanced-stage HL enrolled in the cohort D of the Check-
                                                                              Mate 205 trial, with no unexpected toxicities [38]. Nivo-
CPI has demonstrated clinical efficacy in lymphoid malig-                      lumab plus AVD also showed promising preliminary results
nancies, especially in HL and primary mediastinal B-cell                      in early-stage unfavorable HL, although longer follow-up is
lymphoma (PMBCL) [3, 4, 31]. The results of the pivotal                       required [39]. Furthermore, frontline nivolumab plus BV
1786                                                                                                                                                                S. Bobillo et al.

demonstrated favorable results in the older population (>60                                these early results, a number of clinical trials are currently
years) with an acceptable safety profile [40]. Multiple stu-                                assessing the role of PD-1 inhibitors after ASCT
dies are currently investigating the effectiveness of combi-                               (NCT02681302, NCT02362997).
nations of approved or novel CPI with chemotherapy or
other agents in the frontline and R/R settings.
   Pembrolizumab was also approved by the FDA for the                                      Allo-HCT after the use of CPI
treatment of R/R PMBCL based on the good results of the
KEYNOTE-13 and KEYNOTE-170 trials, with an ORR of                                          Despite the promising response rates obtained by CPI
48% and 44% and a median DOR not reached after a                                           therapy in several lymphoid malignancies, the majority of
median follow-up of 29 and 12 months, respectively [41].                                   these patients will eventually relapse [3, 49]. This has led to
   Conversely to what observed in HL and PMBCL, the                                        the indication of allo-HCT in some patients treated with CPI
activity of CPI in other non-Hodgkin lymphoma (NHL)                                        therapy who had previously relapsed after (or were not
subtypes is considerably lower. In the CheckMate 039                                       candidates to) ASCT. However, the indication of allo-HCT
phase I study, nivolumab obtained an ORR of 30–40% in                                      as well as the optimal GHVD prophylaxis in these patients
follicular lymphoma, diffuse large B-cell lymphoma                                         remains controversial [31, 50, 51].
(DLBCL), and peripheral T-cell lymphoma [42]. However,                                        The immune effects of CPI mainly leading to a T-cell
these results were not validated in the subsequent phase II                                activation as well as their long half-life [52] have raised
studies [43]. Nivolumab also obtained disappointing results                                some concerns on performing allo-HCT in patients pre-
in DLBCL patients who were ineligible to or relapsed after                                 viously treated with these agents [7]. These concerns are
ASCT, with an ORR of 3% and 10%, respectively [44].                                        based on the hypothesis that persistence of nivolumab in the
Combinations of CPI and other agents have been tested in                                   plasma of the patients would induce T-cell activation and a
NHL as well with modest clinical activity so far [45–47].                                  potent cytotoxic response of donor-derived immune cells,
Results from ongoing trials assessing different combina-                                   which could increase the risk of acute and chronic GVHD
tions in the frontline or R/R settings are awaited.                                        [8]. Some translational studies have tried to further explain
   Finally, CPI has also been explored after high-dose                                     the effects of previous CPI therapy on T-cell reconstitution
chemotherapy and ASCT in patients DLBCL and PMBCL.                                         after allo-HCT (Fig. 1). A subgroup analysis of allo-HCT
In an international phase 2 study, three doses of pidilizumab                              patients previously treated with PD-1 blockade and inclu-
(anti-PD-1 monoclonal antibody) given 1–3 months after                                     ded in a multicenter study showed significantly decreased
ASCT resulted in a 16-month PFS of 72% [48]. Based on                                      PD-1+ T cells and decreased Tregs to conventional CD4

                                                                  T cell activation after allo-HCT
                           PD-1       Anti-PD-1

             Donor                                                                                                                                Skin damage
                              IFN-g                                                                                       Intestinal damage
             T cell                                                                                                              GUT
                                                                                                                                                                    Liver damage



                       1                                                                            IFNg
               Allogeneic T cells
                                             PD-1                                                                                                 IFNg
                                                                               4a                                                                                    4b
                                                                                           Graft versus leukemia effect
                                                                                                                                                      Risk of GvHD
                                                                         Risk of relapse
                                                                                                                                        Graft versus host disease

       Donor-derived                         Circulating                               3
          T cells                            anti-PD-1
                                                                                T cell activation

Fig. 1 Hypothetical mechanisms of donor T-cell activation by                               might increase the graft-versus-tumor effects improving the outcome
residual anti-PD-1 antibodies, on the weeks following allogeneic                           after transplantation and diminishing the risk of relapse (4a). In con-
hematopoietic cell transplantation. Allogeneic donor-derived T cells                       trast, activated donor T cells can recognize the recipient antigens in the
expressing PD-1 (1) enter into the blood flow after transplantation and                     gut and other organs inducing a profound T-cell activation increasing
bind to residual circulating anti-PD-1 monoclonal antibodies (2). This                     its cytolytic capacity and the expansion of IFN-γ-producing T cells.
PD-1 blockade can activate donor T cells (3) inducing adhesion                             These events lead to tissue damage (mainly gut, liver, and skin) and
molecules, migratory patterns and an antitumoral activation that can                       graft-versus-host disease (4b).
reactivate immune response against tumoral cells. This activation
Use of checkpoint inhibitors in patients with lymphoid malignancies receiving allogeneic cell. . .                                                                                                                                                                                                                                                                                                                                                                               1787

                                                                                                                                                                                                                                                                                                                                                                                                                         and CD8 T cells ratios compared with a historical cohort of

                                                                                                                  El Cheikh et al. [61]

                                                                                                                                                                    N.R. non-reported, CPI checkpoint inhibition, HL Hodgkin’s lymphoma, NHL non-Hodgkin lymphoma, MDS myelodysplastic syndromes, AML acute myeloid leukemia, PT-CY post-transplant
                                                                                       Merryman et al. [8]

                                                                                       Martinez et al. [54]

                                                                                                                                          Manson et al. [57]
                                                                                       Schoch et al. [9]

                                                                                                                  Nieto et al. [53]
                                                                                                                                                                                                                                                                                                                                                                                                                         PD-1 blockade naïve patients [8]. Our group studied six

                                                                                                                                          Bekoz et al. [5]
                                                                                       Paul et al. [51]

                                                                                                                                          Ito et al. [60]
                                                                                                                                                                                                                                                                                                                                                                                                                         patients with prior nivolumab therapy who underwent allo-

                                                                                                                                                                                                                                                                                                                                                                                                                         HCT and compared them with 12 nivolumab naïve patients.
                                                                                                                                                                                                                                                                                                                                                                                                                         We observed that nivolumab was detectable in plasma for
                                                                                                                                                                                                                                                                                                                                                                                                                         up to 56 days after allo-HCT and it was able to bind to and

                                                                                                                  3/6 (10 months)
                                                                                                                                                                                                                                                                                                                                                                                                                         block the PD-1 receptor at day 21 after transplantation,

                                                                                                                                          8.4% (1 year)
                                                                                       11% (1 year)

                                                                                       13% (1 year)

                                                                                                                                                                                                                                                                                                                                                                                                                         inducing an increased activation status in donor-derived
                                                                                                                                                                                                                                                                                                                                                                                                                         T cells [53].




                                                                                                                                                                                                                                                                                                                                                                                                                            Several studies, most of them with a limited number of
                                                                                                                                          –                                                                                                                                                                                                                                                                              patients, have focused on the safety and efficacy of allo-
                                                                    Chronic GVHD

                                                                                                                                                                                                                                                                                                                                                                                                                         HCT in patients previously treated with CPI (Table 1).
                                                                                                                                                                                                                                                                                                                                                                                                                         Merryman et al. reported 39 HL and NHL patients pre-
                                                                                                                                                                    cyclophosphamide, SIRO sirolimus, TAC tacrolimus, ATG anti-thymocytic globuline, GVHD graft-versus-host disease, NRM non-related mortality.                                                                                                          viously treated with CPI who received allo-HCT from





                                                                                                                                                                                                                                                                                                                                                                                                                         related and unrelated donors using several GVHD prophy-

                                                                                                                                                                                                                                                                                                                                                                                                                         lactic regimens. The cumulative incidence of grade 2–4
                                                                                                                                                                                                                                                                                                                                                                                                                         acute and chronic GVHD at 1 year were 44% and 41%,
                                                                                                                                                                                                                                                                                                                                                                                                                         respectively, whereas the 1-year non-related mortality
                                                                                       44% (grades 2–4)

                                                                                                                                          14/17 grades 1–4
                                                                                       6/14 grade 2. No

                                                                                       3/6 (grades 2–4)
                                                                                       8/9 (grades 2–4)

                                                                                                                                          3/15 grades 2–4

                                                                                                                                                                                                                                                                                                                                                                                                                         (NRM) was 11% [8]. Another multicenter study including
                                                                    Acute GVHD

                                                                                       grade 3–4

                                                                                                                                                                                                                                                                                                                                                                                                                         39 patients with HL previously treated with nivolumab and
                                                                                                                                                                                                                                                                                                                                                                                                                         undergoing allo-HCT from various donor types and


                                                                                                                                                                                                                                                                                                                                                                                                                         receiving different GVHD prophylactic strategies reported
                                                                                                                                                                                                                                                                                                                                                                                                                         an incidence of grade 2–4 acute and chronic GVHD of 33%
                                                                                                                  Various types (ATG in seven

                                                                                                                                                                                                                                                                                                                                                                                                                         and 35%, respectively [54]. Recently, Paul et al. reported a
                                                                                                                  PT-CY-based TAC-SIRO

                                                                                                                                                                                                                                                                                                                                                                                                                         similar cohort of HL patients receiving allo-HCT with non-
                                                                    GVHD prophylaxis

                                                                                                                                                                                                                                                                                                                                                                                                                         myeloablative conditioning and post-transplant cyclopho-
                                                                                                                  Several strategies
                                                                                                                  Several strategies
                                                                                                                  Several strategies

                                                                                                                                                                                                                                                                                                                                                                                                                         sphamide (PT-CY)-based prophylaxis. In this study the
                                                                                       Various types


                                                                                                                                                                                                                                                                                                                                                                                                                         incidences of grade 2–4 acute and 2-year chronic GVHD

                                                                                                                                                                                                                                                                                                                                                                                                                         were 33% and 3%, respectively, with very promising PFS
                                                                                                                                                                                                                                                                                                                                                                                                                         and OS (≥90% at 3 years). Long-term (1–3 years) PFS and
                                                                                                                                                                                                                                                                                                                                                                                                                         OS in these three studies ranged from 90% to 78% and 94%
                                                                                                                                                                                                                                                                                                                                                                                                                         to 74%, respectively [8, 51, 54], suggesting that even if the
                                                                                       Lymphoid malignancies

                                                                                       Lymphoid malignancies

                                                                                                                                                                                                                                                                                                                                                                                                                         incidence of grade 2–4 acute GVHD was significant, its
                                                                                                                                                                                                                                                                                                                                                                                                                         development did not translate into a major impact on sur-
                                                                                                                                                                                                                                                                                                                                                      Four patients received nivolumab in combination with ipilimumab.

                                                                                                                                                                                                                                                                                                                                                                                                                         vival for these patients. Moreover, the incidence of lym-
 Table 1 Larger studies of checkpoint inhibitors before allo-HCT.

                                                                                                                                                                                                                                                                                                                                                                                                                         phoma relapse after transplantation in these studies (4–14%)

                                                                                                                                                                                                                                                                                                                                                                                                                         was in the lower range of what it is expected in this



                                                                                                                                                                                                                                                                                                                                                                                                                         population [55, 56].
                                                                                                                                                                                                                                                                                                                                                                                                                            Other studies including
1788                                                                                                           S. Bobillo et al.

development of GVHD after allo-HCT in those patients             promising PFS and OS observed in most of the studies.
who had been treated with anti-PD-1 therapy, mostly with         Clinical and biological observations suggest that the use
nivolumab. Murine model studies suggest that PT-CY               of PT-CY-based prophylaxis might be especially bene-
prophylaxis might restore regulatory and effector T-cell         ficial in this setting.
homeostasis in transplant recipients with PD-1 blockade
[59]. Ito et al. reported 24 patients receiving several GVHD
prophylactic strategies for allo-HCT after previous use of       Use of CPI therapy for relapse after allo-HCT
CPI. The overall incidence of acute GVHD was 47% but
patients receiving PT-CY-based prophylaxis showed a trend        After the promising results observed with PD-1 blockade
toward a lower incidence of acute GVHD [60]. Two other           in R/R HL, the use of CPI emerged as an option for
studies used PT-CY-based prophylaxis for allo-HCT in 37          patients who relapsed after allo-HCT. Initial reports
and 14 patients with lymphoid malignancies in this setting       showed high response rates with nivolumab and pem-
[9, 51]. Very few patients in both studies experienced           brolizumab in patients with HL relapsing after allo-HCT,
severe GVHD while the cumulative incidence of long-term          although an increased risk of GVHD and fatal IRAE was
NRM was
Use of checkpoint inhibitors in patients with lymphoid malignancies receiving allogeneic cell. . .                                       1789

Table 2 Larger studies of checkpoint inhibitors after allo-HCT.
Study design Drugs                        N    Disease            Time since           Response        GVHD      GVHD          Reference
                                                                  HCT, median                                    mortality

Retrospective Nivolumab                   20 HL                   23 months            ORR             30%       2 (10%)       Herbaux et al.
                                                                                       95%, CR 42%                             [70]
Retrospective Nivolumab                   31 HL (29)              790 days             ORR             17 (55%) 8 (26%)        Haverkos
              Pembrolizumab                  NHL (2)                                   77%, CR 50%                             et al. [71]
Retrospective Nivolumab (6)               9    HL (4)           1.2 years              NR              0%a       _             Schoch et al.
              Pembrolizumab (1)                AML (1)                                                                         [72]
              Ipilimumab (3)                   MDS (1)
                                               Solid cancer (3)
Phase I           Nivolumab               28 Myeloid (19)         21 months            32% (8/25)      11 (39%) 2 (7%)         Davids et al.
                                             Lymphoid (9)                                                                      [73]
Phase I/Ib        Ipilimumab              28 AML (12)             675 days             ORR 32%         4 (14%)   0%           Davids et al.
                                             HL (7)                                    CR 23% (AML)              1 death IRAE [2]
                                             NHL (4)
                                             Others (5)
Phase Ib          Ipilimumab              29 HL 14                366 days             ORR 10%         0%a       –             Bashey et al.
                                             MM (10)                                   CR 7% (HL)                              [74]
                                             AML (2)
                                             CLL (2)
                                             Other (5)
Phase II          Ipilimumab +            10 MCL (3)              29 months            ORR 70%         0%b       –             Khouri et al.
                  lenalidomide               CLL (3)                                   CR 40%                                  [75]
                                             FL (2)
                                             DLBCL (1)
                                             ALCL (1)
HCT hematopoietic cell transplantation, HL Hodgkin’s lymphoma, NHL non-Hodgkin lymphoma, MDS myelodysplastic syndromes, AML acute
myeloid leukemia, ORR overall response rate, CR complete response rate, GVHD graft-versus-host disease, IRAE immune-related adverse events.
    One patient developed GVHD after LDI given after CPI therapy for progressive disease.
    One patient had a flare of prior GVHD while taking lenalidomide that precluded further treatment.

ipilimumab of 3–10 mg/kg every 3 weeks only patients in                          Finally, although some patients who relapse after allo-
the 10-mg/kg cohort responded, with an ORR of 32%.                            HCT might benefit from CPI, alternative treatments should
There were four cases of GVHD and six IRAE, including                         also be considered given the risk of severe GVHD and other
one fatal case of hepatitis and pneumonitis [2]. Notably,                     IRAE observed in this setting.
patients with history of severe GVHD or recent immu-
nosuppressive treatment were excluded from these trials.
Finally, the combination of ipilimumab and lenalidomide                       Conclusion and future directions
showed good responses in ten patients with lymphoma
relapsing after allo-HCT, including four CR and three PR,                     CPI therapy has been shown to be effective and relatively
with no cases of GVHD [75].                                                   safe in patients with lymphoid malignancies, especially
   Recently, an international working group provided a set                    those with HL and PMBCL. Considering that most of these
of consensus recommendations to help guide treatment                          patients will eventually relapse, allo-HCT is still an option
decisions in patients receiving PD-1 blockade after an allo-                  for patients responding to CPI. Studies focusing on the use
HCT [62]. After considering prior history of GVHD and                         of allo-HCT show that even if severe acute GVHD occurs in
timing of relapse after allo-HCT, it is advisable starting with               some patients with prior use of CPI, this procedure is fea-
a low dose and considering escalation if no response and no                   sible and patients account with a promising probability of
toxicity are seen. If GVHD occurs, CPI should be imme-                        long-term remissions. Noteworthy, OS and PFS after allo-
diately discontinued and initiation of corticosteroids                        HCT in these studies seem higher than the expected in this
(methylprednisolone 2 mg/kg) is highly recommended.                           population of lymphoma patients, with a low incidence of
Finally, promptly escalation to second-line immunosup-                        relapse after transplantation. Despite most of the evidence
pression should be taken if no rapid GVHD improvement is                      coming from retrospective small sample-size studies, the
observed after steroid therapy [62].                                          use of PT-CY as GVHD prophylaxis seems to provide
1790                                                                                                                               S. Bobillo et al.

promising outcomes to these patients both from the efficacy                      accelerates graft-versus-host disease lethality by an IFN-gamma-
and safety perspectives.                                                        dependent mechanism. J Immunol. 2003;171:1272–7.
                                                                           7.   Holderried TAW, Fraccaroli A, Schumacher M, Heine A, Brossart
   In the post-transplant setting, where treatment options are
                                                                                P, Stelljes M, et al. The role of checkpoint blockade after allo-
scarce, CPI has emerged as a promising therapy. So far,                         geneic stem cell transplantation in diseases other than Hodgkin’s
retrospective studies and a few prospective trials have                         Lymphoma. Bone Marrow Transplant. 2019;54:1662–7. https://
shown good responses with PD-1 blockade, although an                  
                                                                           8.   Merryman RW, Kim HT, Zinzani PL, Carlo-Stella C, Ansell SM,
increased number of IRAE and fatal GVHD has been
                                                                                Perales MA, et al. Safety and efficacy of allogeneic hematopoietic
reported, especially in patients with prior history with                        stem cell transplant after PD-1 blockade in relapsed/refractory
GVHD. Furthermore, optimal doses, as well as specific                            lymphoma. Blood. 2017;129:1380–8.
strategies to control emerging toxicities are yet to be defined                  blood-2016-09-738385.
                                                                           9.   Schoch LK, Cooke KR, Wagner-Johnston ND, Gojo I, Swinnen
in this setting.
                                                                                LJ, Imus P, et al. Immune checkpoint inhibitors as a bridge to
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hopefully provide a better understanding of the mechanisms                      Blood Adv. 2018;2:2226–9.
of CPI in the context of allo-HCT and will eventually lead                      nces.2018019208.
                                                                          10.   Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of
to a better patient selection and treatment management.
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Conflict of interest SB has received honoraria from Roche, BMS, and
                                                                                immune       suppression     in    lymphoma.       Cancer    Lett.
Janssen, not related with the present study. PB declares having
received honoraria from Amgen, BMS, Gilead, Novartis, and Pfizer
                                                                          13.   Onishi H, Fujimura A, Oyama Y, Yamasaki A, Imaizumi A,
and not related with the present article. PB has received funding from
                                                                                Kawamoto M, et al. Hedgehog signaling regulates PDL-1
Asociación Española Contra el Cancer. Ideas Semilla 2019. The other
                                                                                expression in cancer cells to induce anti-tumor activity by acti-
author declares no competing interests.
                                                                                vated lymphocytes. Cell Immunol. 2016;310:199–204. https://doi.
Publisher’s note Springer Nature remains neutral with regard to           14.   Topalian SL, Drake CG, Pardoll DM. Immune checkpoint
jurisdictional claims in published maps and institutional affiliations.          blockade: a common denominator approach to cancer therapy.
                                                                                Cancer Cell. 2015;27:450–61.
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