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Ruxolitinib Shows Promise in
Polycythemia Vera
Ruxolitinib, a JAK1/2 inhibitor
approved by the U.S. Food and Drug
Administration for the treatment
of myelofibrosis, also has activity
in another myeloproliferative
neoplasm, polycythemia vera,
according to two reports from the
phase III RESPONSE trial presented
at the American Society of Clinical
Oncology (ASCO) and the
European Hematology Association
(EHA) annual meetings.
The drug demonstrated
improved hematocrit control
and reduction in spleen size in
patients with polycythemia vera
who were resistant or intolerant
to hydroxyurea, as reported by
Srdan Verstovsek, MD, PhD, of
the MD Anderson Cancer Center
in Houston, Texas, at the 2014
ASCO Meeting in Chicago, and
Alessandro M. Vannucchi, MD, of
the University of Florence in Italy, at
the 2014 EHA Congress in Milan.
In the RESPONSE trial, 222
patients with hydroxyurea-resistant
or -intolerant polycythemia vera
were randomized to either twicedaily 10 mg ruxolitinib (n=110,
median age 62, 60% male) or best
available treatment (BAT; n=112,
median age 60, 71% male). BAT
was identified as monotherapy,
“The [adverse
event] rate
in the ruxolitinib arm was
lower than
what would
be expected
in a high-risk
population.”
—Srdan Verstovsek, MD, PhD
ASHClinicalNews.org
consisting of one of the following:
hydroxyurea, interferon/pegylated
interferon, anagrelide, pipobroman,
immunomodulatory drugs,
or observation. Therapy could
be changed in case of lack of
response or BAT-related toxicity
requiring drug discontinuation, the
researchers noted.
At week 32 of the trial, 77 percent
of patients in the ruxolitinib arm
met at least one component of the
primary endpoint:
• 60 percent had achieved
hematocrit control without
phlebotomy
• 38 percent saw a ≥35 percent
reduction in spleen size
In the BAT group, on the other
hand, only 21 percent and one
percent of patients achieved these
endpoints, respectively.
Complete hematologic remission
(defined as maintaining hematocrit
control without phlebotomy, a
platelet count >400 x 109/L, and a
white blood cell count >10 x 109/L)
was seen by 23.6 percent (p=0.0034)
of ruxolitinib patients — compared
with 8.9 percent of BAT patients.
Out to week 48, 88.5 percent of
ruxolitinib patients had maintained
this remission, and 91 percent had
maintained hematologic response.
“Ruxolitinib is a JAK1 and JAK2
inhibitor that functions as an
inhibitor of the tyrosine kinase site
of the activated JAK1/2, meaning
it does not hamper function
of the protein while at rest and
is not specific for the mutated
JAK2V617F protein. Rather, it
functions against both mutated and
wild-type protein,” Dr. Vannucchi
explained to ASH Clinical News.
Polycythemia vera is a
myeloproliferative neoplasm
characterized by erythrocytosis.
Its symptoms include pruritus,
along with severe burning pain
in the hands or feet accompanied
by skin discoloration. It can cause
cardiovascular complications
resulting from thrombosis or
hemorrhage, and treatment
options are limited. Hydroxyurea
is the current first choice for
cytoreduction; however, many
patients become resistant or
intolerant to this therapy, according
to the researchers.
“Because JAK signaling is
essential for erythropoiesis and
platelet production, anemia and
thrombocytopenia are the most
common toxicities of the drug,”
Dr. Vannucchi noted, but overall
ruxolitinib was well-tolerated,
with 1.8 percent and 5.5 percent of
patients experiencing grade 3 or
4 anemia and thrombocytopenia,
respectively. “Thrombocytopenia
is also the dose-limiting toxicity of
ruxolitinib,” Dr. Vannucchi added.
Dr. Verstovsek observed that,
“in the RESPONSE trial, most
of the observed cytopenias were
resolved with dose adjustments,
and most of these adjustments
were only required in the first eight
weeks. Most patients maintained
their dose for the remainder of
the study, with a median dose
of approximately 25 mg per day,
which was consistent with the
twice-daily 10 mg starting dose.”
The exposure-adjusted rates
of serious adverse events per 100
patient-years were comparable in
both arms (15.3 ruxolitinib and 13.7
BAT), Dr. Verstovsek and colleagues
pointed out, but fewer patients in
the ruxolitinib arm experienced a
thromboembolic event. “The rate in
the ruxolitinib arm was also lower
than what would be expected in
a high-risk [polycythemia vera]
population,” he added.
References
• Verstovsek S, Kiladjian J-J, Griesshammer M, et al. Results
of a prospective, randomized, open-label phase 3 study
of ruxolitinib (RUX) in polycythemia vera (PV) patients
resistant to or intolerant of hydroxyurea (HU): the
RESPONSE trial. Abstract presented at: 2014 ASCO Annual
Meeting; June 3, 2014; Chicago, IL.
• Vannucchi M. Ruxolitinib proves superior to best available
therapy in a prospective, randomized, \