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EXPERT OPINION
Targeting PD-L1 and PD-L2 signalling across the spectrum
of classical Hodgkin’s lymphoma
By Stephen Ansell, MD, PhD
Dr Ansell, Consultant, Division of Hematology, Department of Internal Medicine, Mayo Clinic, Minnesota, discusses genetic
alterations of PD-L1 and PD-L2 and evidence supporting the targeting of PD-L1 and PD-L2 signalling in relapsed and newly
diagnosed classical Hodgkin’s lymphoma.
C
lassical Hodgkin’s lymphoma
is a unique B-cell lymphopro-
liferative disorder in which
the majority of intratumoural cells
are normal immune cells and only a
minority of cells are malignant. The
immune infiltrate in this disease,
however, appears entirely ineffec-
tive, and the immune response is
unable to suppress the malignant
Reed-Sternberg cells.
Recent clinical trials have used
immune checkpoint therapy in
Hodgkin’s lymphoma to induce a
more effective antitumour response.
Trials using anti-PD-1 antibodies,
such as nivolumab and pembroli-
zumab, have shown very high re-
sponse rates and these responses
appear durable.
1,2
Correlative studies from these
initial clinical trials have shown in-
creased expression of PD-1 ligands
by immunohistochemistry, and ge-
netic analysis of the PD-L1 and PD-
L2 locus on chromosome 9p24.1
showed copy number alteration with
either copy gain or amplification in
all of the patients evaluated.
These results suggested that
genetic alterations at this locus
accounted for overexpression of
particularly PD-L1, and inhibi-
tion of PD-L1/PD-1 signalling
was responsible for the dramatic
clinical responses seen in Hodgkin’s
lymphoma.
An unknown issue, however, was
whether overexpression of PD-L1
and PD-L2 due to these genetic
alterations is only seen in relapsed
and refractory patients or whether
similar findings are present in pa-
tients at the time of diagnosis.
The initial anti-PD-1 trials includ-
ed patients who had failed multiple
therapies. A possible hypothesis was
that multiple prior therapies would
enrich for a population with a high
incidence of genetic alterations at
chromosome 9p24.1. The efficacy
of immune checkpoint therapy may
therefore be restricted to relapsed
and refractory patients.
The publication by Roemer et al
in the
Journal of Clinical Oncology
provides very valuable information
and shows that this hypothesis is
incorrect.
3
Instead, genetic altera-
tions of PD-L1 and PD-L2 are seen
in the vast majority of Hodgkin’s
lymphoma patients at diagnosis.
In this study, 108 biopsy speci-
mens from newly diagnosed classical
Hodgkin’s lymphoma patients who
were treated on a standard regimen
were analysed. The frequency and
magnitude of 9p24.1 alterations,
including polysomy, copy gain, and
amplification, were determined, and
immunohistochemistry to assess
expression of PD-L1 and PD-L2
was also done. The findings of this
study showed that only 1 patient
had normal 9p24.1 copy number
and 5 patients had polysomy of 9p.
In marked contrast, the vast majority
of patients had either 9p24.1 copy
gain (56%) or 9p24.1 amplification
(36%).
Further studies showed that the
malignant Reed-Sternberg cell com-
monly had increased expression of
pSTAT3, which co-localised with
PD-L1 and PD-L2 expression. The
study then assessed the progression-
free survival of the patients and
showed that it was significantly
shorter for patients with the 9p24.1
amplification.
These findings are important.
This study confirms the importance
of this genetic event in classical
Hodgkin’s lymphoma and shows
that the findings are relevant across
the spectrum of classical Hodgkin’s
lymphoma, including in newly diag-
nosed patients and those who have
repeatedly relapsed. It also stresses
the relevance of targeting PD-L1
and PD-L2 signalling in both the re-
lapsed and newly diagnosed setting.
Future studies are awaited to as-
sess whether the use of anti-PD1
therapy as part of initial treatment
is beneficial. The data presented by
Roemer et al suggest that PD-L1/
PD-1 blockade is likely to be suc-
cessful in newly diagnosed patients
as well.
References
1. Ansell SM, Lesokhin AM, Borrello I, et al.
N Engl J Med
2015;372:311-319.
2. Armand P, Shipp MA, Ribrag V, et al.
Paper presented at: American Society
of Hematology 57th Annual Meeting
& Exposition; December 5-8, 2015;
Orlando, FL. Abstract 584.
3. Roemer MG, Advani RH, Ligon AH,
et al.
J Clin Oncol
doi: 10.1200/
JCO.2016.66.4482 [published online
April 11, 2016].
JOURNAL SCAN
Improved outcomes with carfilzomib compared with bortezomib in relapsed
multiple myeloma regardless of prior treatment
Leukemia
Take-home message
•
Subgroup analysis from the randomised phase 3 ENDEAVOR study comparing carfilzomib and dexamethasone (Kd)
with bortezomib and dexamethasone (Vd) in relapsed multiple myeloma examined patients classified according to
type and number of previous therapies. For patients with one previous line of therapy, median progression-free
survival (PFS) was 22.2 months with Kd and 10.1 months with Vd compared with 14.9 months with Kd and 8.4 months
with Vd in patients with two or more prior lines. The median PFS (Kd vs Vd) for patients with prior bortezomib
exposure was 15.6 months vs 8.1 months and for patients with prior lenalidomide exposure the median PFS was 12.9
months vs 7.3 months. Overall response rates (Kd vs Vd) for one prior line, two or more prior lines, prior bortezomib,
and prior lenalidomide were 81.9% vs 65.5%, 72.0% vs 59.7%, 71.2% vs 60.3%, and 70.1% vs 59.3%, respectively.
•
Compared with bortezomib, treatment with carfilzomib improves outcomes in patients with relapsed multiple
myeloma regardless of prior exposure to bortezomib or lenalidomide or the number of prior treatment lines.
Abstract
The randomised phase 3 ENDEAVOR study (N=929) com-
pared carfilzomib and dexamethasone (Kd) with bortezomib
and dexamethasone (Vd) in relapsed multiple myeloma
(RMM). We performed a subgroup analysis from ENDEAVOR
in patients categorized by number of prior lines of therapy
or by prior treatment. Median progression-free survival (PFS)
for patients with one prior line was 22.2 months for Kd vs
10.1 months for Vd, and median PFS for patients with ≥2
prior lines was 14.9 months for Kd vs 8.4 months for Vd. For
patients with prior bortezomib exposure, the median PFS
was 15.6 months for Kd vs 8.1 months for Vd, and for patients
with prior lenalidomide exposure the median PFS was 12.9
months for Kd vs 7.3 months for Vd. Overall response rates
(Kd vs Vd) were 81.9 vs 65.5% (one prior line), 72.0 vs 59.7%
(≥2 prior lines), 71.2 vs 60.3% (prior bortezomib) and 70.1 vs
59.3% (prior lenalidomide). The safety profile in the prior lines
subgroups was qualitatively similar to that in the broader
ENDEAVOR population. In RMM, outcomes are improved
when receiving treatment with carfilzomib compared with
bortezomib, regardless of the number of prior therapy lines
or prior exposure to bortezomib or lenalidomide.
Impact of prior treatment on patients with relapsed multiple
myeloma treated with carfilzomib and dexamethasone vs
bortezomib and dexamethasone in the phase 3 ENDEAVOR
study
Leukemia
2016 Aug 05;[Epub ahead of print], Moreau P,
Joshua D, Chng W-J, et al.
This study confirms the importance of this genetic event in
classical Hodgkin’s lymphoma and shows that the findings
are relevant across the spectrum of classical Hodgkin’s
lymphoma, including in newly diagnosed patients and
those who have repeatedly relapsed.
HAEMATOLOGY
VOL. 1 • No. 3 • 2016
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