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1226 Part VII Hematologic Malignancies

CR PR

Lenalidomide
Everolimus

Idelalisib

Mocetinostat

Panobinostat
Pembrolizumab

Nivolumab

Brentuximab vedotin

0 20 40 60 80 100
Fig. 75.6 RESPONSE RATES OF CURRENT NOVEL AGENTS UNDER INVESTIGATION FOR
THE TREATMENT OF PATIENTS WITH RELAPSED OR REFRACTORY HODGKIN LYMPHOMA.
CR, Complete response; PR, partial response.

29a
and apoptosis via epigenetic effects on gene expression, and by setting, following compelling preclinical data. In 2013 Oki et al
interfering with T-cell chemotaxis in the tumor microenvironment published results from a phase I study evaluating the safety and
and, in turn, indirectly generating a favorable antitumor immune efficacy of panobinostat plus everolimus in patients with relapsed or
response. As such, HDAC inhibitors have attracted much interest as refractory HL and non-HL. Of the 14 patients with HL the ORR
potential agents for the treatment of patients with relapsed/refractory was 43% with a CR of 15%; however, in this study, thrombocytope-
HL and, based on promising preclinical data, several, including pano- nia was highlighted as a significant dose-limiting toxicity, suggesting
binostat, mocetinostat, vorinostat, and entinostat are currently under that although this combination is effective, future studies are needed
clinical investigation. to explore how the tolerability of this approach may be improved.
In the largest phase II prospective international study of 129
heavily pretreated patients with HL who failed prior ASCT, the
activity and safety of panobinostat (LBH 589) was explored. ORR Immunomodulators
was 27% (n = 35), of which 23% (n = 30) were partial responses and
4% (n = 5) were complete responses. Tumor reduction was observed A phase II multicenter study evaluating the efficacy of lenalidomide
in 74% of patients, and the median duration of response (DOR) was has provided preliminary evidence supporting the activity of this
6.9 months. Median PFS was 6.1 months, with an estimated 1-year known, small molecule, immunomodulatory agent in patients with
OS of 78%. Common grade 1 and 2 toxicities included diarrhea, relapsed and refractory HL. In this study of 36 evaluable patients
nausea, vomiting, and fatigue, and common grade 3 and 4 toxicities with a median of four prior therapies, the ORR was 19% and treat-
30
included thrombocytopenia, anemia, and neutropenia, which were ment was well tolerated. The combination of lenalidomide with
27
all manageable. In a similar population of 51 patients with relapsed conventional chemotherapy or with other novel agents might also be
or refractory HL, mocetinostat (MGCD0103), an oral isotype- considered a viable treatment approach in the future.
selective HDAC inhibitor has also demonstrated single-agent activity In summary, drug development continues to be an attractive and
(ORR 27%) with acceptable toxicity. 28 exciting area of clinical research in HL and future directions are likely
to focus on how best to incorporate these agents into current treat-
ment approaches. The effect of combining already established novel
PI3K/mTOR Pathway Inhibitors agents, such as BV, with first- and second-line chemotherapy is
already being evaluated and the investigation of other biologics, either
The PI3K/AKT/mTOR intracellular signaling pathway plays an as mono or dual therapy, is also expected to continue. As a result,
integral role in cell cycle regulation of metabolism, survival, and new treatment strategies are anticipated with the overall aim being to
immunity and its aberrant activation, leading to increased prolifera- improve the survival of patients with HL even further, in the most
tion and reduced apoptosis, has been implicated in a number of tolerable way possible.
malignancies, including HL. Components of this pathway have there-
fore become attractive targets for anticancer therapeutic intervention.
Idelalisib (GS-1101 or CAL1011), an oral selective PI3K-delta SPECIAL CONSIDERATIONS
inhibitor, has been shown, via the inhibition of AKT phosphoryla-
tion, to attenuate pathway signaling and induce apoptosis in cellular Hodgkin Lymphoma in the Elderly
models of relapsed HL. Furthermore, in the clinical setting, promis-
ing efficacy and manageable toxicity have been demonstrated by The number of patients living with cancer over the age of 60 years
targeting the downstream mTOR kinase: in a phase II study evero- is increasing. The outcome of elderly patients with HL may differ
limus, an oral mTOR inhibitor, was associated with an ORR of 42% significantly because of the heterogeneity of this population with
in 57 patients with heavily pretreated HL, with a median PFS of 9 regards to life expectancy, premorbid performance status, and comor-
months. 29 bidity. Establishing optimal treatment is therefore challenging, par-
More recently, the synergistic effect of combining an mTOR ticularly because older patients do not tend to be well represented in
inhibitor with an HDAC inhibitor has been explored in the clinical large clinical trials caused by tight exclusion criteria that often render