NcXHF

NEW DRUGS IN HODGKIN LYMPHOMA
levels and the expression of PD1 on intratumoral T cells. In
one study, 129 patients with relapsed and refractory HL received
40 mg of panobinostat orally three times per week. 18
Treatment with panobinostat was effective as tumor reductions
were seen in 74% of the patients, and ORs were achieved
by 35 patients (27%). Thirty patients (23%) had partial responses
to treatment and fıve patients (4%) had CRs. The median
duration of response was 6.9 months, and the median
PFS was 6.1 month. The agent was reasonably well tolerated,
and serum testing for TARC showed reduction in TARC levels
for patients responding to treatment.
Mocetinostat has also been tested in patients with relapsed
and refractory classical HL. 19 In a clinical trial, 51 patients
were treated at a dose level of either 110 mg or 85 mg. The
group who received 110 mg had increased toxicity; 85 mg was
felt to be a more optimal dose level. Among the 51 patients,
two had CRs and 12 had PRs. Serum cytokines were also
tested in each of the patients, and levels of multiple cytokines
signifıcantly decreased after treatment was initiated. TARC
levels decreased by more than 40% between baseline and day
8 of treatment and correlated with clinical benefıt.
JAK Inhibitors
JAKs are a family of intracellular non-receptor tyrosine
kinases that transduce signals from cell surface receptors activated
by cytokines and growth factors. After phosphorylation,
JAKs lead to recruitment of STAT proteins. The STAT
proteins subsequently translocate to the nucleus and trigger
transcription of target genes involved in cell proliferation,
cell survival, and immune response.
Aberrant activation of the JAK-STAT pathway has been
linked to a variety of malignancies, including HL. SB1518 is a
small molecule inhibitor of JAK2 kinase with preclinical activity
in lymphoid malignancies. This JAK inhibitor has been
tested in a phase I clinical trial of a variety of lymphomas,
including refractory HL. 20 Doses of 100 to 600 mg/day were
tested, and the drug was found to be well tolerated. Among
the study’s 34 patients, the ORR was 14%, including three
partial remissions. In the group of patients with HL, however,
none of the 14 patients had a partial remission or better.
However, at least fıve of the patients with HL did benefıt from
the treatment, with a decrease in the sites of active disease.
Lenalidomide
Lenalidomide has a diverse set of possible mechanisms of action.
It is proposed to directly induce cell death in malignant
B cells and to indirectly regulate the tumor microenvironment.
Lenalidomide has immunomodulatory and antiangiogenic
properties and may specifıcally modulate many
of the changes in the microenvironment, including the
skewing of the cytokine profıle, the altered immune cell
infıltrate, and the recruitment of macrophages to the tumor
microenvironment.
In view of the potential benefıts to modulating the microenvironment
by using lenalidomide, this agent has been
tested in a clinical trial of relapsed and refractory classical
HL. 21 In a study of 38 patients with classical HL, most of
whom had previously been treated with an autologous stem
cell transplant, patients received a standard dose of 25 mg
daily for 3 out of every 4 weeks. Overall, the treatment was
well tolerated, and of 36 evaluable patients, the study confırmed
one complete remission and six partial remissions, resulting
in an ORR of 19%. When patients who clinically
benefıted were included, a third of the patients benefıted
from treatment. Serum levels of cytokines were tested and
plasma levels of CCL17 and CCL22 were associated with subsequent
response. Lenalidomide was potentially benefıcial in
patients with refractory HL.
Anti-PD-1 Antibodies
The PD-1 pathway serves as an immune checkpoint to
dampen immune responses. As outlined above, the tumor
microenvironment in classical HL overexpresses the PD-1 ligands,
resulting in a successful mechanism of tumor immune
escape. Blocking PD-1 interactions with its ligands is therefore
a promising treatment approach, particularly as genetic
alterations result in PD-L1 and PD-L2 copy gain and thus
overexpression of PD-1 ligands. As mentioned above,
Epstein-Barr virus infection is a further mechanism that upregulates
PD-1 ligand expression. Two recent clinical trials
targeting PD-1/PD-1-ligand interactions have been reported,
both with remarkable clinical results. In a clinical trial
utilizing nivolumab, 23 patients with relapsed or refractory
HL were treated every 2 weeks with 3 mg/kg of the antibody.
22 The majority of these patients had previously received
an autologous stem cell transplant, and most had
received previous brentuximab vedotin. In this group of patients,
an ORR of 87% (20 out of 23) patients was seen, with a
CRR of 17% and a PR rate of 70%. The PFS at 24 weeks was
86% and 11 of the patients continued on therapy, suggesting
that the responses were durable.
In a second clinical trial utilizing the anti-PD-1 monoclonal
antibody pembrolizumab (MK-3475), patients received
the drug at a dose of 10 mg/kg administered every 2 weeks. 23
In this group of very heavily previously treated patients, pembrolizumab
was well tolerated and similar dramatic clinical
responses were seen. The ORR was 53%, with three patients
(20%) having a complete remission and fıve additional patients
(33%) having a partial remission. Virtually all patients
appeared to have benefıtted from therapy and the responses
also appeared durable.
CONCLUSIONS AND FUTURE DIRECTIONS
The results presented above show that multiple agents have
substantial activity in relapsed and refractory HL. These
agents have all been tested as single agents, and therefore an
important future approach will be to combine these agents
with each other as well as with standard chemotherapy approaches.
These future studies will specifıcally need to exclude
the possibility of overlapping toxicities. However,
provided the treatments can be safely given together, the future
of patients with HL may be markedly improved as these
agents move into earlier lines of treatment.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
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