NcXHF

STEPHEN ANSELL
associated with patient prognosis. 6,10 These features of an active
tumor microenvironment and immune response represent a
potential target for novel therapies.
Furthermore, the malignant Reed-Sternberg cells represent
a therapeutic target in that they express CD30, a member
of the tumor necrosis factor receptor family. 11,12 CD30 is not
typically expressed on most human tissue under normal
physiologic conditions. CD30 can, however, be expressed on
thymocytes during thymus development, on pancreatic exocrine
cells, and on cells in the uterus and endometrium
during pregnancy. Activated T cells can also transiently upregulate
CD30. The limited expression of CD30 and the substantial
expression of CD30 on Reed-Sternberg cells make
CD30 a useful target for treatment in HL.
NOVEL AGENTS IN HODGKIN LYMPHOMA
Based on the unique composition of the tumor, new agents
have been developed that either specifıcally target Reed-
Sternberg cells, target the inflammatory infıltrate, or reverse
the suppressed immune microenvironment. Many of these
agents have demonstrated substantial clinical activity in patients
with HL who have failed multiple previous lines of
treatment.
Brentuximab Vedotin
Brentuximab vedotin, although not strictly a new agent,
demonstrates the benefıt of specifıcally targeting the Reed-
Sternberg cell. Initial clinical trials utilizing this CD30-
directed antibody-drug conjugate included large numbers of
patients with HL. In an initial phase I trial, patients received
brentuximab every 3 weeks. The trial confırmed that 17 patients
with HL had objective responses (ORs) (11 patients
had complete responses). 13 Of the 12 patients with HL who
received treatment at the maximum tolerated dose, an OR
rate of 50% was seen. These results were confırmed in a pivotal
phase II trial using brentuximab vedotin in patients with
relapsed and refractory HL, all of whom had previously been
treated with an autologous stem cell transplant. 14 In a cohort
of 102 patients, all of whom received brentuximab vedotin at
KEY POINTS
Hodgkin lymhoma has a unique histologic picture that
provides opportunities for therapeutic targeting.
Brentuximab vedotin is an approved agent in relapsed Hodgkin
lymphoma and is now used as part of front-line therapy.
New agents targeting the phosphatidylinositide 3-kinase
pathway, the JAK-STAT pathway, and the tumor
microenvironment show promising activity.
Initial studies using anti–programmed death-1 antibodies,
such as nivolumab and pembrolizumab, have reported very
high response rates in relapsed and refractory patients
with Hodgkin lymphoma.
The future will require combination approaches.
a dose of 1.8 mg/kg every 3 weeks, the overall response rate
(ORR) was 75%, with a complete response rate (CRR) of 34%.
The median progression-free survival (PFS) for all patients in
the study was 5.6 months; however, the median duration of
response for patients obtaining a complete remission was
20.5 months. Long-term follow-up of this trial confırmed the
durability of the responses. 15 Of the 34 patients who obtained
complete remission, 16 (47%) remained progression free at a
median of 53.3 months.
Based on these promising results, brentuximab vedotin
subsequently has been incorporated into combination therapy.
A clinical trial utilizing brentuximab vedotin in combination
with ABVD (doxorubicin, bleomycin, vinblastine,
dacarbazine) or AVD (bleomycin omitted) chemotherapy
found that the maximum tolerated dose of brentuximab vedotin
in combination with the chemotherapy was defıned as
1.2 mg/kg. 16 Importantly, however, the study found that
when brentuximab vedotin was given with the bleomycincontaining
regimen, it resulted in signifıcant pulmonary toxicity.
A subsequent cohort of patients treated with AVD
chemotherapy tolerated the treatment far better with no additional
pulmonary toxicity; the combination was highly effective,
with CRs seen in 96% of the patients. Based on these
promising results, a front-line randomized control trial of
AVD chemotherapy plus brentuximab vedotin compared to
standard ABVD chemotherapy is currently ongoing.
Everolimus
The phosphatidylinositide 3-kinase/mammalian target of
rapamycin (PI3K/mTOR) signaling pathway has been shown
to be activated in patients with HL. Everolimus is an oral antineoplastic
agent that targets this pathway, specifıcally the
mTOR complex 1 (mTORC1). Everolimus not only may target
the signaling pathways within the Reed-Sternberg cells
but may also suppress signaling within the immune infıltrate
and production of cytokines present in the tumor microenvironment.
A clinical trial of everolimus administered at a
dose of 10 mg orally every day, was performed among 19 patients
with relapsed and refractory HL. 17 The majority of patients
had received multiple previous lines of therapy and
84% of the patients had undergone a previous autologous
stem cell transplant. In this small cohort of patients the ORR
was 47%, with one patient experiencing a complete remission
and eight patients achieving partial remissions. The median
time to disease progression was 7.2 months. Overall, the
treatment was well tolerated and four of the responding patients
remain progression free at 12 months. This study confırmed
that everolimus has single-agent activity in patients
with relapsed and refractory HL and confırmed that targeting
the mTOR pathway in HL is clinically warranted.
Panobinostat and Mocetinostat
Agents that target acetylases may regulate several oncogenic
pathways including cell cycle progression, cell survival, angiogenesis,
and antitumor immunity. Panobinostat and mocetinostat
target histone deacetylase, and these agents may be
effective in patients with HL by modulating serum cytokine
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