Blocking programmed death 1 (PD-1) signaling in relapsed Hodgkin lymphoma results in high response rates,1,2-3  and Chen et al, in this issue of Blood, report the outcome of patients treated with pembrolizumab with 2 years of follow-up.4  They confirm that responses in patients treated with this PD-1–blocking antibody are durable and find that patients continue to tolerate PD-1 blockade well with extended treatment.

The use of monoclonal antibodies targeting PD-1 in patients with Hodgkin lymphoma has resulted in high response rates, even in patients who have had multiple lines of therapy, including the use of stem cell transplantation and the antibody-drug conjugate brentuximab vedotin.1,2-3  Although the high response rates initially reported with pembrolizumab were very encouraging, longer follow-up was required to determine whether the responses would be durable in all groups of patients treated. In this study with 2 years of follow-up, responses persisted in all groups of patients, including those with primary refractory disease unable to proceed to an autologous transplant. Even in this very resistant population, the duration of response was 11 months. Equally encouraging was the fact that patients were able to remain on therapy for prolonged periods of time. Only 6.7% of patients discontinued treatment due to adverse events, confirming that pembrolizumab is well tolerated even when used for a more protracted period of time. A further encouraging finding was the fact that a subset of patients, who achieved a complete remission and then discontinued treatment but subsequently progressed, could be re-treated with pembrolizumab, and all patients responded again to PD-1–directed therapy. All of these results confirmed what had been reported in previous studies showing that PD-1 blockade is highly effective and durably beneficial for patients with relapsed classical Hodgkin lymphoma.

A notable finding in the study was the fact that patients having a complete response (CR) to pembrolizumab treatment had a particularly prolonged response, and the median duration of response has not yet been reached in patients who had a CR. Approximately one-quarter of patients had a CR with pembrolizumab therapy, and 61% of these patients have remained in remission for >2 years. Also, patients who had a CR to pembrolizumab had a 24-month progression-free survival (PFS) of 60% compared with patients with a partial response (PR), who had a 24-month PFS of 29%. These results are very similar to those seen with nivolumab, another PD-1–blocking antibody. In a similar report of longer-term follow-up of a phase 2 trial of nivolumab, the median duration of response of CR patients was 20.3 months compared with 12.8 months for patients in a PR.3  These data would suggest that relapsed Hodgkin lymphoma patients who have a negative PET scan while being treated with pembrolizumab, thereby confirming a complete metabolic response to this treatment, have an excellent outcome. Therefore, there is reason for optimism that possibly a plateau in the curve may be seen in CR patients, with some of them being cured with this therapy.

When analyzing the responses to pembrolizumab and other PD-1–blocking antibodies, it is interesting to note that although ∼25% to 30% of patients do very well and achieved a CR, a similar percentage of patients do not have an objective response to PD-1 blockade.3  It would therefore be extremely useful to be able to identify the patients who are unlikely to respond to PD-1 blockade and to be able to select other treatment in this group of patients, thereby avoiding toxicity from ineffective therapy. Similarly, it would be equally useful to be able to identify patients who are likely to have a CR and who may even potentially be cured, and consider stopping treatment in this subgroup after a CR has been achieved. Work done to develop a biomarker to separate these groups of patients has been challenging. Initial studies focused on the expression of programmed death-ligand 1 (PD-L1), the ligand for PD-1, but although expression of PD-L1 or genetic alterations of the gene was predictive in chemotherapy-treated patients,5  it was not as useful in patients treated with immune checkpoint therapy. Instead, molecules associated with antigen presentation seem to be potential biomarkers of improved outcomes with PD-1 blockade in Hodgkin lymphoma patients, and expression of major histocompatibility complex (MHC) class II molecules appears to be a biomarker of response.6  Patients with Hodgkin lymphoma who lack expression of MHC class II molecules (∼30% of patients) seem to be those at risk for a poor response to PD-1–directed therapy, whereas patients who have normal expression of MHC class II molecules (∼40% of patients) are those more likely to have a CR. In clinical trials using PD-1 blockade in patients with relapsed or refractory Hodgkin lymphoma, normal MHC class II expression was seen in almost all responding patients, and MHC class II expression correlated with PFS.6  Furthermore, mass cytometry analysis of intratumoral immune cells in biopsy specimens from patients with Hodgkin lymphoma showed that CD4+ T-regulatory cells as well as CD4+ T-effector cells may be the dominant populations necessary to target the tumor, and these cells require MHC class II expression to be effective.7  Further studies however will be needed to confirm whether MHC class II expression is a reliable biomarker for use in identifying patients who are likely to respond to PD-1 blockade or whether other biomarkers will need to be developed.

Often in the past, phase 2 clinical trial results that initially appear promising do not always remain so with longer follow-up, because responses are sometimes short lived. This, however, is not the case with the use of pembrolizumab in patients with relapsed and refractory classical Hodgkin lymphoma. Longer-term follow-up of patients treated with pembrolizumab confirms the efficacy and durability of responses to this agent. Toxicity remained acceptable, and there was no substantial increase in toxicity over time. This confirms the use of pembrolizumab as an effective therapy in patients with relapsed classical Hodgkin lymphoma, and future studies will see this agent included in earlier lines of therapy.

Conflict-of-interest disclosure: The author received research funding (to his institution for clinical trials) from Bristol Myers Squibb, Merck, Seattle Genetics, Regeneron, Trillium, Pfizer, and Affimed.

REFERENCES

REFERENCES
1.
Ansell
SM
,
Lesokhin
AM
,
Borrello
I
, et al. 
.
PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma
.
N Engl J Med
.
2015
;
372
(
4
):
311
-
319
.
2.
Chen
R
,
Zinzani
PL
,
Fanale
MA
, et al. ;
KEYNOTE-087
.
Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma
.
J Clin Oncol
.
2017
;
35
(
19
):
2125
-
2132
.
3.
Armand
P
,
Engert
A
,
Younes
A
, et al. 
.
Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 Trial
.
J Clin Oncol
.
2018
;
36
(
14
):
1428
-
1439
.
4.
Chen
R
,
Zinzani
PL
,
Lee
HJ
, et al. 
.
Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087
.
Blood
.
2019
;
134
(
14
):
1144
-
1153
.
5.
Roemer
MG
,
Advani
RH
,
Ligon
AH
, et al. 
.
PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome
.
J Clin Oncol
.
2016
;
34
(
23
):
2690
-
2697
.
6.
Roemer
MGM
,
Redd
RA
,
Cader
FZ
, et al. 
.
Major histocompatibility complex class II and programmed death ligand 1 expression predict outcome after programmed death 1 blockade in classic Hodgkin lymphoma
.
J Clin Oncol
.
2018
;
36
(
10
):
942
-
950
.
7.
Cader
FZ
,
Schackmann
RCJ
,
Hu
X
, et al. 
.
Mass cytometry of Hodgkin lymphoma reveals a CD4+ regulatory T-cell-rich and exhausted T-effector microenvironment
.
Blood
.
2018
;
132
(
8
):
825
-
836
.