In mid-November, the FDA approved the JAK inhibitor ruxolitinib for the
treatment of myelofibrosis.
Ruxolitinib (Jakafi, Incyte) is the first FDA-approved drug for symptom
alleviation in myelofibrosis, and some clinicians suggest it could be the first
in a series of breakthroughs that help alleviate the symptoms of the
progressive and frequently debilitating bone marrow disease.
The approval of ruxolitinib is such a significant medical
advancement for patients suffering from myelofibrosis, said Srdan
Verstovsek, MD, PhD, associate professor in the leukemia department at The
University of Texas MD Anderson Cancer Center. It is fair to say that
ruxolitinib has the potential to transform the way we treat myelofibrosis, and
it is a starting point for developing combination therapies that would bring to
patients additional benefits and, hopefully, eventually result in the
elimination of the disease.
Myelofibrosis, considered a type of chronic leukemia, is marked by an
enlarged spleen, anemia, decreased blood counts and weight loss.
The condition disrupts the bodys production of blood cells,
leading to the formation of scar tissue in the bone marrow and forcing blood
cells to produce in the spleen and liver.
This can result in a severely enlarged spleen and liver, as well as
anemia. Patients also may experience constitutional symptoms, weight loss,
night sweats, fever and fatigue.
Ruxolitinib is an oral drug taken twice daily that inhibits the JAK1 and
JAK2 enzymes that are involved in regulating blood and immunological
functioning. Its approval was based on the results of two clinical trials, the
COMFORT-I and COMFORT-II trials, which showed a greater reduction in spleen
size with ruxolitinib compared with placebo or best available therapy.
Levine, MD, associate member at Memorial Sloan-Kettering Cancer Center, said
ruxolitinib likely will be combined in clinical trials with other agents in
patients with myelofibrosis.
Photo by Juliana Thomas; courtesy of
Memorial Sloan-Kettering Cancer Center
In addition, the drug showed significant improvements in
myelofibrosis-related symptoms that dramatically affect patients quality
of life and performance status.
Furthermore, new longer-term follow-up data from COMFORT-I
scheduled to be presented at the 53rd ASH Annual Meeting and Exposition
indicate treatment with ruxolitinib also may prolong the survival of patients
HemOnc Today spoke with several experts in the field about
ruxolitinibs approval, its clinical significance for the treatment of
myelofibrosis and its potential benefits for patients.
Myelofibrosis is a difficult illness. Although fatal for some,
there is a burden of suffering that is more universal with the illness,
said Ruben A. Mesa, MD, director of the Acute and Chronic Leukemias
Program in the Division of Hematology-Oncology at Mayo Clinic in Arizona.
It also includes a massive enlargement of the spleen, sometimes to 20
times its normal size, where it can look like a full-term pregnancy.
Patients have difficulty walking, and the enlarged spleen stretches out
the stomach, resulting in constipation, diarrhea or other gastrointestinal
problems. Additionally, patients have many symptoms independent of the enlarged
spleen, including cachexia, fatigue, night sweats, pruritus and bone pain.
All of these symptoms combined lead to a general deterioration of the
body and quality of life and ultimately can result in a slow death.
Patients with myelofibrosis suffer greatly, particularly because
of their spleen size, their systemic symptoms and general well-being,
said Ross Levine, MD, associate member at Memorial Sloan-Kettering
Cancer Center. We have been trying lots of different agents to treat the
disease, but they have only modest effects.
The only known curative treatment for myelofibrosis is bone marrow
However, given that most patients diagnosed with myelofibrosis are aged
older than 60 years, bone marrow transplant only is a good option in about 5%
to 10% of patients diagnosed with the condition, Mesa said.
Other treatment options are targeted at reducing the primary symptoms of
myelofibrosis: enlarged spleen and anemia. Drugs such as thalidomide (Thalomid,
Celgene), lenalidomide (Revlimid, Celgene) or hydroxyurea may help to reduce
the size of the spleen, but their use and efficacy is debated among experts.
We do not have good drugs to treat these patients, and some of the
drugs we do have are leukemogenic in a disease where 20% of people will
progress to and die of acute leukemia, said Jerry Spivak, MD,
director of the Center for the Chronic Myeloproliferative Disorders at Johns
Ruxolitinib is the first myelofibrosis-specific treatment available, and
it is the first in a line of several JAK2 inhibitors that were developed after
the discovery of the JAK2 mutation in 2005.
The JAK2 mutation is present in about half of patients with
myelofibrosis, but it is not the cause of the disease, and it is just one of
many mutations these patients have.
Not all JAK2 inhibitors are JAK2 mutation-specific, said
Verstovsek, a lead researcher on one of the phase 3 studies of ruxolitinib.
All the inhibitors we have are only JAK inhibitors. They inhibit mutated
JAK2 and normal JAK2. Patients with or without JAK2 mutations are candidates
for JAK2 inhibitors. The benefit is the same.
This non-specificity means two things, according to Verstovsek.
Clinicians do not have to test patients for JAK2 mutations before
treating them with JAK2 inhibitors, and patients who have a mutation and are
given a JAK2 inhibitor do not need to have periodic tests for JAK2 allele
burden to see how many cells are still present with JAK2 mutations.
The results from two phase 3 trials examining ruxolitinibs safety
and efficacy were presented at the 2011 ASCO Annual Meeting.
The COMFORT I and II studies had a primary endpoint of at least 35%
reduction in spleen volume and a secondary endpoint of symptom alleviation.
This was the first time in malignant hematology that symptom
improvement was a secondary endpoint, and it was assessed using a new tool
developed in conjunction with the FDA the myelofibrosis symptoms
assessment form, said Verstovsek, who presented the results of COMFORT-I.
COMFORT-I was a randomized, double blind, placebo-controlled study. It
included 240 patients with myelofibrosis who were randomly assigned to
treatment with 15 mg or 20 mg of ruxolitinib twice daily, based on baseline
platelet count, or placebo.
Almost all patients had some reduction in spleen size, and about
42% met the 35% or greater threshold, said Mesa, who helped to develop
and validate the myelofibrosis symptoms assessment form. These improvements
occurred regardless of the presence or absence of the JAK2 mutation.
In addition, about 46% of patients on ruxolitinib had at least a 50%
decrease in total symptom score as measured by the myelofibrosis symptoms
assessment form. Measured symptom improvement occurred in areas such as
abdominal discomfort, inactivity, early satiety, night sweats, itching, and
bone or muscle pain.
Serious adverse events occurred in 6.1% of patients assigned to
ruxolitinib and 5.6% of patients on placebo. Overall, 11% of patients on
ruxolitinib and 11% of patients on placebo discontinued treatment due to
adverse effects. The most common adverse events were thrombocytopenia and
anemia, which were more common in those with higher baseline grade. However,
these adverse effects rarely led to discontinuation of the drug. Only one
patient in each treatment group discontinued due to anemia. Also, with
continued time of study, thrombocytopenia and anemia decreased and approached
that of placebo levels.
Results were similar in COMFORT-II. The study compared ruxolitinib with
best available therapy, which was left up to physician choice.
After 48 weeks, 28.5% of patients on ruxolitinib achieved the primary
endpoint compared with none of the patients assigned to best available
Although these physicians said ruxolitinib is a treatment for symptoms
rather than a cure, they do not downplay the effect this drug could have on
those who have myelofibrosis.
In their day-to-day life, patients will have more energy. They
will gain weight, Mesa said. Having treated people on the clinical
trial, I saw several patients who were able to go back to work who were
previously medically disabled due to symptoms of their illness. People,
overall, will have much greater enjoyment of life and greater quality of
Despite the excitement about ruxolitinib, there are issues to which
clinicians should pay attention as they begin to use this drug.
First, researchers do not fully understand why certain patients are
benefiting more from treatment with ruxolitinib than others.
There definitely remains, for reasons that are not fully
understood, some heterogeneity in the response to ruxolitinib, Levine
said. There are some patients who benefit a lot and others who benefit
Second, if patients have to stop treatment with ruxolitinib
either due to adverse effects or concurrent illness symptoms of
myelofibrosis will return within 7 days.
Clinicians have to be aware that whatever symptoms were there
before the patient went on ruxolitinib are going to come back, and they have to
be prepared to deal with those sequelae, Levine said.
Finally, research still is being conducted to examine whether
ruxolitinib had any effect on anemia, another severe adverse effect of
We observed a total of 40% response rate in those individuals who
were transfusion-dependent for anemia, but we also observed a similar response
rate in those individuals who were on placebo, Mesa said. We are
analyzing the data in a variety of ways to try to get a better idea of anemia
Several abstracts were presented at the
53rd American Society of Hematology Annual Meeting and
Exposition that will provide details on a survival advantage seen with
ruxolitinib in the COMFORT-I trial and provide more details on the long-term
follow-up of patients taking ruxolitinib.
Abstract No. 278 includes a longer-term follow-up analysis that
evaluated the efficacy of ruxolitinib in COMFORT-I across patient subgroups and
examined whether a survival advantage is associated with treatment with the
In the analysis, the researchers examined the two primary endpoints of
COMFORT-I reduction in spleen volume and improvement in
myelofibrosis-related symptoms across a variety of subgroups, including
myelofibrosis disease subtype, age, International Prognosis Scoring System risk
group, presence or absence of JAK mutation, baseline hemoglobin, baseline
spleen size and baseline total symptom score.
Results indicated that ruxolitinib had a consistent benefit vs. placebo
for both spleen volume reduction and symptom alleviation across all of the
In the survival analysis, researchers found that 13 patients taking
ruxolitinib had died compared with 24 on placebo (HR=0.499; 95% CI,
It is likely that [ruxolitinib] may have an effect on slowing down
the disease or helping patients live longer by helping to alleviate the
significant debilitation and morbidity associated with their illness,
Mesa said. It is a significant moment indeed. Ruxolitinib does not cure
the illness, but it represents the most significant incremental benefit over
anything we have had in the past.
Verstovsek said he was satisfied to learn from longer follow-up of the
randomized, phase 3 COMFORT-1 study that ruxolitinib therapy not only improved
myelofibrosis-related symptoms, reduced patients enlarged spleen and
liver, improved patients weight and ability to walk, but that better
control of disease signs and symptoms resulted in the prolongation of life of
patients with advanced myelofibrosis.
Verstovsek and colleagues also were scheduled to present two additional
abstract that help to illustrate ruxolitinibs potential.
Abstract No. 793 includes data that compares patients treated with
ruxolitinib with 310 patients with myelofibrosis with patient characteristics
that would have allowed them to be enrolled in the phase 1/2 trial of
When comparing OS between ruxolitinib-treated patients and the
historical controls, treatment with the JAK inhibitor resulted in a significant
survival difference (P=.022). After a median follow-up of 32 months,
30.8% of patients in the ruxolitinib group had died vs. 60.9% of historical
control patients after 22 months of follow-up. Among high-risk patients, the
survival difference was even greater (P=.006). At follow-up, 33.3% of
ruxolitinib patients had died vs. 67.9% of historical controls.
Abstract No. 3851 includes an analysis of the longest treated patients
on ruxolitinib, those at The University of Texas MD Anderson Cancer Center who
were enrolled in the phase 1/2 trial.
Verstovsek and colleagues provided details on the 2-year survival of
these patients. The updated data involved 107 patients 63 at high risk,
34 at intermediate-2 risk, and 10 at intermediate-1 risk.
After 32 months of follow-up, 54% of patients were still receiving
treatment with ruxolitinib and 69% of patients were still alive.
However, among patients who remained on the drug, 2-year survival was
92% among those at intermediate-2 risk and 88% among those at high risk. Among
patients who discontinued therapy, 2-year survival was 32% among those at
intermediate-2 risk and 21% among those at high risk.
In addition, data indicated that the degree of reduction in spleen size
was an indicator of survival.
Patients who had at least a 50% reduction in palpable spleen length
while on ruxolitinib had significantly longer survival than those with a less
than 25% reduction in spleen size (P<.0001).
Looking at data from patients in the phase 1/2 study, at this
point, many patients remain on the drug and continue to benefit from the
drug, Mesa said. It means that the drug leads to a rapid response
and then a plateau, but patients are stable with improvement in spleen [size]
and symptoms, and we have not witnessed any demonstration of a sign of any
All of the experts interviewed said ruxolitinib is the initial step in
what they hope will be a series of advances in the coming years for patients
It is the first of a family of drugs that will come on the market
because this one drug will not be the right fit for everybody with the
disease, Spivak said. It is a tremendous advance. We have a drug
that can alleviate symptoms and reduce splenomegaly without long-term marrow
Ruxolitinib, ultimately, will likely now be combined in clinical trials
with other agents in patients with myelofibrosis, Levine said.
It is my hope that this will not just lead to a new standard of
care for our patients but, more importantly, lead to the next set of trials
where we try to build on this and add to the benefit for our patients,
Levine said. by Leah Lawrence
For more information:
Disclosure: Dr. Levine has received research support from Novartis and
has served on an advisory board for Incyte. Drs. Mesa and Verstovsek report no
relevant financial disclosures. Dr. Spivak is a consultant for Incyte.
Does hydroxyurea still have a role in the treatment of primary
Primary myelofibrosis is characterized by bone marrow fibrosis,
extramedullary hematopoiesis with splenomegaly, leukoerythroblastosis in
peripheral blood and presence of the JAK2 V617F mutation in half of the
Because the median age at diagnosis of primary myelofibrosis is 64
years, many elderly patients currently are managed with supportive care only. A
2011 international consensus by the European LeukemiaNet recommended the use of
hydroxyurea as first-line therapy for patients with hyperproliferative features
of primary myelofibrosis, such as marked leukocytosis, thrombocytosis,
symptomatic splenomegaly or constitutional symptoms.
Hydroxyurea an oral and usually well-tolerated, non-alkylating,
myelosuppressive drug is widely used in practice. It is clinically
familiar, inexpensive, safe and effective, and it has had few side effects at
the dose received by most patients.
Thus, in a recent series of 40 patients with myelofibrosis, hydroxyurea
was particularly effective to control constitutional symptoms, bone pain,
pruritus, symptomatic splenomegaly, leukocytosis and thrombocytosis.
According to International Working Group for Myelofibrosis Research and
Treatment criteria, clinical improvement was observed in 40% of patients,
including a reduction in spleen size of 50% or more in 30% of patients, with
the median duration of the response being 13 months.
Worsening of pre-existing anemia often requiring
erythropoiesis-stimulating agents or danazol and pancytopenia were the
most frequent side effects. A few patients developed oral or leg ulcers.
In a phase 1/2 study, ruxolitinib (Jakafi, Incyte) an oral
JAK1/JAK2 inhibitor was effective in controlling splenomegaly and
constitutional symptoms in half of myelofibrosis patients refractory to
hydroxyurea or other previous therapies, but it was associated with cytopenias
and had limited activity in improving the anemia.
Two recent phase 3 trials comparing ruxolitinib with either placebo or
best-available therapy have shown similar outcomes. However, a recently
published study reported high rates of treatment discontinuation due to
disease progression, loss or lack of response, or toxicity and the
appearance of serious withdrawal symptoms at ruxolitinib discontinuation.
Do the results reported in these trials presage the retirement of
hydroxyurea from myelofibrosis therapy? Despite the superiority of ruxolitinib
in obtaining deeper responses in the splenomegaly and the constitutional
symptoms, it is important to note that given its palliative nature,
presumable cost, discrete effect on the anemia, short follow-up, adverse events
and severe withdrawal symptoms concerns remain about its widespread
routine use in myelofibrosis.
Therefore, for the time being, it remains unclear whether ruxolitinib
should be given to all myelofibrosis patients or could be restricted to
second-line therapy for patients resistant or intolerant to hydroxyurea.
Eduardo Arellano-Rodrigo, MD, is a consultant
hematologist in the hemotherapy and hemostasis department of the Hospital
Clínic in Barcelona, Spain. References: Arellano-Rodrigo E. N
Engl J Med. 2010;363:2464. Barbui T. J Clin Oncol. 2011;29:761-770.
Harrison CN. J Clin Oncol. 2011;29(Suppl) abstract LBA6501.
Mart?nez-Trillos A. Ann Hematol. 2010;89:1233-1237. Tefferi A. Mayo
Clin Proc. 2011 (Published online ahead of print Oct. 27). Tefferi A. N
Engl J Med. 2011;365:1455-1457. Verstovsek S. J Clin Oncol.
2011;29(Suppl) abstract 6500. Verstovsek S. N Engl J Med.
2010;363:1117-1127. Disclosure: Dr. Arellano-Rodrigo reports no relevant
Myelofibrosis an uncommon hematological malignancy has a
median prognosis of 5 years, although in the lowest-risk asymptomatic patients,
this increases to 14 years.
The cardinal features are abnormalities of the blood count, ranging from
myeloproliferation to pancytopenia; splenomegaly, which often is massive;
severe impairment of quality of life; and a tendency to progressive marrow
failure and acute myeloid leukemia.
Quality-of-life concerns are a dominant feature for these patients, with
previous studies demonstrating quality-of-life scores equivalent to those of
patients with metastatic malignancy.
A wide variety of current treatments are used to address this disease,
ranging from observation and blood transfusion to blunt, nontargeted and
possibly leukemogenic agents such as hydroxyurea.
Patients typically receive many different therapies, as response is
infrequent and often not durable. Potentially curative stem cell
transplantation rarely is appropriate and is associated with 30% to 50%
mortality. None of these treatments has, until recently, been evaluated in a
randomized trial in myelofibrosis.
The discovery of JAK2 activation and the highly prevalent JAK2 V617F
mutation in myelofibrosis provided a target for therapy, and two phase 3 trials
with a JAK inhibitor ruxolitinib (Jakafi, Incyte) recently have
been reported. One was a placebo-controlled trial in patients refractory to
hydroxyurea. In the second, the drug was compared with physicians choice
of best available therapy the most common of which being hydroxyurea.
In both trials, regardless of whether patients had the JAK2 V617F
mutation, there was a highly significant advantage for ruxolitinib in
controlling splenomegaly and constitutional symptoms. The median duration of
response has not been reached, and most patients continue the drug.
The mechanism for control of symptoms is suggested to be reduction of
inflammatory cytokines via JAK1 inhibition. Thus, on drug withdrawal, these
symptoms will return, as is seen with other drugs that have anti-inflammatory
In the large phase 3 trials, no new adverse effects were documented and
there were no new events related to withdrawal.
All therapies have limitations and should be used with due caution.
However, well-established routes of drug development and safety testing
demonstrate unprecedented benefits for myelofibrosis patients treated with
In comparison, hydroxyurea causes similar rates of myelosuppression, is
less effective at control of symptoms and splenomegaly, and never has been
tested in a phase 3 trial, apart from that compared with ruxolitinib, where it
was clearly inferior.
The FDA approved ruxolitinib for the treatment of patients with
myelofibrosis on Nov. 16, and it undoubtedly will improve the lives of those
suffering with myelofibrosis.
Claire Harrison, MD, is a consultant hematologist with
Guys and St. Thomas NHS Foundation Trust in London.
References: Harrison CN. J Clin Oncol. 2011;29(Suppl) abstract
LBA6501. Mart?nez-Trillos A. Ann Hematol. 2010;89:1233-1237. Verstovsek
S. J Clin Oncol. 2011;29(Suppl) abstract 6500. Disclosure: Dr.
Harrison is an investigator with the COMFORT-II trial.