Discussion
The presented results show that PD-L1 score was higher in the PMF group
vs the control group regardless of JAK2 mutation status, which turned
out to be statistically significant. This helps build on the data
reported by Prestipino et al that showed oncogenic JAK2 activity led to
STAT phosphorylation which in turn enhanced PD-L1 promoter activity and
PD-L1 protein expression in JAK2 mutant cells [1]. In addition,
PD-L1 expression was higher on primary cells isolated from patients with
JAK2-mutated MPNs as compared to healthy individuals and declines upon
JAK2 inhibition [1]. Moreover, Lee et al were able to demonstrate
that PD-L1 expression was significantly associated with overt
myelofibrosis and JAK2 mutational status [9]. Moreover, in the
previously mentioned study, there were 4 patients who were found to have
a particularly high PD-L1 expression that also harbored the JAK2
mutation [9].
This supports further that PD-L1 may play a more important role than
previously realized in MPNs and should perhaps be a future target in our
current small armamentarium of viable drugs. To the best of our
knowledge, there have only been 2 small phase II trials in which the
investigators tested the utility of PD-L1 inhibition (pembrolizumab and
nivolumab) in patients with PMF. Hobbs, et al conducted a phase 2,
single arm study of pembrolizumab in patients with Dynamic International
Prognostic Scoring System (DIPSS) intermediate-2 or greater, primary, or
secondary, post essential thrombocythemia or post polycythemia vera MF
who were ineligible for or previously treated with ruxolitinib [9].
This study had 10 patients, 5 with JAK2 mutation who were treated with
pembrolizumab without objective clinical responses. However, an
important takeaway from this data showed that flow cytometry, T-Cell
receptor (TCR) sequence and proteomics demonstrated changes in the
immune makeup of patients, suggesting improved T cell responses
[10]. Although this study was terminated early as no objective
clinical responses were seen, the latter changes mentioned suggest that
perhaps PD-L1 inhibition is not enough to elicit a clinical response and
combination therapy may be more effective.
Another study, in which Dalle et al investigated the efficacy and safety
of single agent nivolumab in 8 adult patients with myelofibrosis, was
also terminated early due to failure to meet predetermined efficacy
endpoint (primary endpoint was objective response rate (ORR) defined as
complete response (CR), partial response (PR) and clinical improvement
(CI) after 8 doses) [11]. The median duration of enrolled patients
on the study was 5.4 months with a median number of cycles of 3.
Unfortunately, in this study, none of the patients responded to
nivolumab therapy. These patients showed more advanced disease including
intermediate 2 and high risk DIPSS score with 5 patients failing
ruxolitinib and 7 with clonal evolution, i.e., progressive disease
[11].
It is important to note that these two described studies had very small
sample sizes, with most patients in the high risk DIPSS category,
multiple previous lines of therapy, and complex mutational status or
clonal evolution. However, they were able to characterize changes in the
patient’s immune milieu after administration of PD-L1 blockade
[10,11]. It’s noteworthy to the authors that both studies employed
PD-L1 blocked only after patients had undergone multiple lines of
therapy, in a relapsed or refractory setting, raising the question that
perhaps this is not the right setting to use this line of therapy. In
addition, it would be interesting to expand further on the hypothesis
that perhaps PD-L1 blockade is not enough and combination therapy with
ruxolitinib may be more effective in patients with PMF.