2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

SMALL-MOLECULE INHIBITORS FOR MPN
LY2784544
In an open-label phase I trial, 19 patients received treatment
with LY2784544. 17 The MTD was 120 mg. Similar to
results with other JAK2 inhibitors, a reduction in spleen
size and systemic symptoms was observed within the first
two to three cycles of therapy. No reduction of JAK2V617F
allele burden had been noted; however, preliminary results
suggest that the compound could improve the fibrosis associated
with this disorder. Tumor lysis syndrome was observed
at the lower end of the dose range associated with
efficacy, and therefore dosing has been amended to include a
lower dose lead-in period. This study is ongoing.
HDACIs
HDACIs are compounds that inhibit activity of HDAC and
can lead to increased histone acetylation and gene expression.
Some HDACIs in clinical trials for MPNs include
givinostat (formerly known as ITF2357) and panobinostat
(formerly known as LBH589). A pilot study with givinostat
in MF was recently published. 18 Twenty-nine patients with
JAK2V617F-positive MPNs (PV, n � 12; ET, n � 1; MF, n �
16) received treatment with givinostat 50 mg twice daily.
Responses were seen in 54% of PV/ET patients (complete,
n � 1; partial, n � 6) according to European LeukemiaNet
criteria. Responses in MF were more modest: Only three of
16 patients had a major response. Adverse effects included
diarrhea, anemia, thrombocytopenia, fatigue, and QTc elongation.
Panobinostat was evaluated in a phase I trial for
patients with hematologic malignancies, including 13 patients
with MF. 19 Most patients received panobinostat
thrice weekly, and the MTD was 60 mg/dose. Grade 3 to 4
adverse effects included thrombocytopenia (33%), fatigue
(28%, DLT), neutropenia (28%), and anemia (12%). Four
patients with MF had response by IWG-MRT criteria. These
results were followed by two studies evaluating panobinostat
solely in patients with MF. Mascarenhas and colleagues
reported on a phase I study in 15 patients with MF;
thrombocytopenia was the DLT. 20 Five patients received
more than 6 months of therapy, and all achieved clinical
improvement in spleen by IWG response criteria. 21 In another
trial, 31 patients with MF received treatment with
panobinostat (initial dose was 60 mg thrice weekly) but
the toxicity precluded delivery of the medication beyond 1
month of therapy in almost all patients. 22 A combination
study of ruxolitinib and panobinostat at low dose is underway
on the basis of exciting preclinical results. 23
mTOR Inhibitor
Activated mTOR is a serine/threonine kinase which regulates
cell growth, proliferation and metabolism. Results for
30 patients from a phase I/II study of everolimus (RAD-001)
in high- or intermediate-risk primary or secondary MF were
published during 2011. 24 No DLT was observed up to 10
mg/day. At this dose, toxicities were infrequent; the most
common toxicity was grade 1 to 2 stomatitis. A splenomegaly
reduction of more than 50% from baseline occurred in 20% of
patients, whereas a more than 30% reduction occurred in
44% of patients. A total of 69% and 80% of patients experienced
complete resolution of systemic symptoms and pruritus,
respectively. Response in leukocytosis, anemia, and
thrombocytosis occurred in 15% to 25% of patients.
Immunomodulatory Inhibitory Drugs
The first published study of pomalidomide (an analog of
thalidomide, formerly CC-4047) evaluated 84 patients with
MF who were randomly assigned among four arms: pomalidomide
2 mg daily (n � 22), pomalidomide 2 mg daily plus
prednisone (n � 19), pomalidomide 0.5 mg daily plus prednisone
(n � 22) and prednisone alone (n � 21). 25 Observed
benefit was limited to improvement in anemia, according to
IWG criteria: Response rates were 23% (pomalidomide 2 mg
plus placebo), 16% (pomalidomide 2 mg plus prednisone),
36% (pomalidomide 0.5 mg plus prednisone), and 19% (prednisone
alone). The drug was very well tolerated. 25 In a phase
I/II trial, the MTD of pomalidomide was determined to be
3 mg/day, and DLT was myelosuppression. 26 In accordance
with the results of the randomized study, better response
rates were observed in patients who received low-dose pomalidomide
(63% response in anemia). 26 Begna and colleagues
recently reported the results of a use of low-dose
pomalidomide alone (0.5 mg/day) in 58 patients with MF. 27
The anemia response was 17% by IWG-MRT criteria. An
increase in platelet count in patients with thrombocytopenia
was observed in 58% of cases. No patient had an improvement
in splenomegaly. A phase III randomized study of
pomalidomide compared with placebo in patients with MF
who are transfusion dependent is underway. Patients are
randomly assigned to either pomalidomide (0.5 mg/day) or
placebo; primary end point is rate of transfusion independence
after 6 months of therapy.
Conclusion
In recent years, the outlook for patients with chronic
Ph-negative MPNs has changed with new discoveries on
molecular biology of these diseases and the subsequent
development of new compounds directed against those molecular
defects. JAK2 inhibitors and other compounds, such
as pomalidomide, are on the verge of making the transition
from clinical trials to routine clinical use. Indeed, ruxolitinib,
an oral JAK1 and JAK2 inhibitor, has recently been
approved in the United States as the first medication ever
for treatment of patients with intermediate- and high-risk
MF. 13 The most striking benefits observed with JAK2 inhibitors
are a reduction in spleen size and improvement in
constitutional symptoms. As suggested by COMFORT-I trial
results, with the better control of the symptoms and signs
of the disease, thus potentially delaying a progression of the
disease, patients with advanced MF may live longer. However,
with JAK2 inhibitors a reduction in bone marrow
fibrosis is mostly anecdotal. Similarly, with the majority of
compounds there is no significant reduction in the JAK2
allele burden. JAK2 inhibitors are not able to clonally
eradicate the disease. Therefore, JAK inhibitors are just
the first building block in our efforts to effectively treat MF,
and there is much room for improvement. We need to better
understand how these drugs work, and through which
mechanism(s) they are producing benefits for individual
patients. We need biomarkers to determine which patients
will respond to a specific agent, as well as to rationally
combine active agents for additional benefits. With coordinated
efforts and appropriate design of clinical trials, we can
hope to overcome these challenges and improve outcomes for
patients with MF, not just in controlling disease signs and
symptoms, but potentially eliminating the disease.
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