10 August 2022
JAK Inhibition with Ruxolitinib versus Best Available Therapyfor Myelofibrosis / C. Harrison; J.J.
Kiladjian;H.K. Al-Ali; H.Gisslinger; R. Waltzman; V. Stalbovskaya; M. McQuitty; D. S. Hunter; R. Levy; L.
Knoops; F. Cervantes; A.M. Vannucchi; T. Barbui; G. Barosi. - In: NEW ENGLAND JOURNAL OF MEDICINE. -
ISSN 0028-4793. - STAMPA. - 366(9)(2012), pp. 787-798. [10.1056/NEJMoa1110556]
Original Citation:
JAK Inhibition with Ruxolitinib versus Best Available Therapyfor
Myelofibrosis
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DOI:
n engl j med 366;9 nejm.org march 1, 2012
787
The new england
journal
of medicine
established in 1812
march 1, 2012
vol. 366 no. 9
JAK Inhibition with Ruxolitinib versus Best Available Therapy
for Myelofibrosis
Claire Harrison, D.M., Jean-Jacques Kiladjian, M.D., Ph.D., Haifa Kathrin Al-Ali, M.D., Heinz Gisslinger, M.D.,
Roger Waltzman, M.D., M.B.A., Viktoriya Stalbovskaya, Ph.D., Mari McQuitty, R.N., M.P.H., Deborah S. Hunter, Ph.D.,
Richard Levy, M.D., Laurent Knoops, M.D., Ph.D., Francisco Cervantes, M.D., Ph.D., Alessandro M. Vannucchi, M.D.,
Tiziano Barbui, M.D., and Giovanni Barosi, M.D.
Abstr act
From Guy’s and St. Thomas’ National
Health Service (NHS) Foundation Trust,
Guy’s Hospital, London (C.H.); Hôpital
Saint-Louis et Université Paris Diderot,
Paris (J.-J.K.); University of Leipzig,
Leipzig, Germany (H.K.A.-A.); Medical
University of Vienna, Vienna (H.G.); No-
vartis Pharmaceuticals, East Hanover, NJ
(R.W.); Novartis Pharma, Basel, Switzer-
land (V.S., M.M.); Incyte, Wilmington, DE
(D.S.H., R.L.); Cliniques universitaires
Saint-Luc, Université catholique de Lou-
vain and Ludwig Institute for Cancer Re-
search, Brussels (L.K.); Hospital Clínic,
Institut d’Investigacions Biomèdiques
August Pi i Sunyer, Barcelona (F.C.); and
University of Florence, Florence (A.M.V.),
A.O. Ospedali Riuniti di Bergamo, Ber-
gamo (T.B.), and IRCCS Policlinico San
Matteo Foundation, Pavia (G.B.) — all
in Italy. Address reprint requests to Dr.
Harrison at the Department of Haematol-
ogy, Guy’s and St. Thomas’ NHS Founda-
tion Trust, Guy’s Hospital, Great Maze
Pond, London SE1 9RT, United Kingdom,
or at claire.harrison@gstt.nhs.uk.
N Engl J Med 2012;366:787-98.
Copyright © 2012 Massachusetts Medical Society.
Background
Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety
of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as com-
pared with the best available therapy, in patients with myelofibrosis.
Methods
We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis,
post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofi-
brosis to receive oral ruxolitinib or the best available therapy. The primary end point
and key secondary end point of the study were the percentage of patients with at least
a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed
with the use of magnetic resonance imaging or computed tomography.
Results
A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in
spleen volume at week 48, as compared with 0% in the group receiving the best avail-
able therapy (P<0.001); the corresponding percentages at week 24 were 32% and 0%
(P<0.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with
ruxolitinib but had increased by 4% with the best available therapy. The median dura-
tion of response with ruxolitinib was not reached, with 80% of patients still having a
response at a median follow-up of 12 months. Patients in the ruxolitinib group had
an improvement in overall quality-of-life measures and a reduction in symptoms as-
sociated with myelofibrosis. The most common hematologic abnormalities of grade
3 or higher in either group were thrombocytopenia and anemia, which were managed
with a dose reduction, interruption of treatment, or transfusion. One patient in each
group discontinued treatment owing to thrombocytopenia, and none discontinued ow-
ing to anemia. Nonhematologic adverse events were rare and mostly grade 1 or 2. Two
cases of acute myeloid leukemia were reported with the best available therapy.
Conclusions
Continuous ruxolitinib therapy, as compared with the best available therapy, was
associated with marked and durable reductions in splenomegaly and disease-related
symptoms, improvements in role functioning and quality of life, and modest toxic ef-
fects. An influence on overall survival has not yet been shown. (Funded by Novartis
Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.)
The
new engla nd journal
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medicine
n engl j med 366;9 nejm.org march 1, 2012
788
M
yelofibrosis, which can present
as a primary disease or can evolve from
polycythemia vera or essential thrombo-
cythemia,
1
is characterized by marrow fibrosis,
progressive anemia, and extramedullary hemato-
poiesis, manifested primarily as splenomegaly.
Severe constitutional symptoms (e.g., night sweats
and weight loss), pruritus, fatigue, and sequelae of
splenomegaly are common.
2
The median survival
from the time of diagnosis is 4 years for patients
with intermediate-2–risk disease and 2 years for
patients with high-risk disease.
3
Apart from al-
logeneic stem-cell transplantation, treatment is
palliative and does not address the characteristic
abnormality identified in myelofibrosis, a dysreg-
ulation of Janus kinase (JAK)–mediated cytokine
and growth-factor signal transduction.
4
In 2005, the JAK2 V617F mutation was identi-
fied as the most common molecular abnormality
in myeloproliferative neoplasms.
5-8
Other muta-
tions that activate the JAK pathway have been
identified, including mutations in JAK2 exon 12,
myeloproliferative leukemia virus oncogene (MPL),
and LNK.
9-11
Thus, dysregulation of the JAK signal-
ing pathway is frequently noted in patients who
have myelofibrosis, with or without the V617F mu-
tation.
12
Ruxolitinib (also known as INC424 or
INCB18424) is an orally bioavailable, potent, and
selective inhibitor of JAK1 and JAK2 that is ap-
proved for the treatment of intermediate- and high-
risk myelofibrosis.
13,14
Ruxolitinib selectively in-
hibits the proliferation of JAK2 V617F-driven Ba/F3
cells, and these effects are correlated with de-
creased levels of phosphorylated JAK2 and of
signal transducer and activator of transcription
5 (STAT5).
13
In a phase 1–2 study of patients with
myelofibrosis, ruxolitinib was associated with
weight gain, prompt and marked reductions in
spleen size, and reductions in debilitating symp-
toms.
15
We describe here results from the Con-
trolled Myelofibrosis Study with Oral JAK Inhibi-
tor Treatment II (COMFORT-II), a randomized,
phase 3 trial comparing ruxolitinib with the best
available therapy in patients with primary myelo-
fibrosis, post–polycythemia vera myelofibrosis, or
post–essential thrombocythemia myelofibrosis.
Methods
Eligibility Criteria
Patients 18 years of age or older who had primary
myelofibrosis, post–polycythemia vera myelofibro-
sis, or post–essential thrombocythemia myelofi-
brosis
16
and a palpable spleen 5 cm or more below
the costal margin were eligible for the study, irre-
spective of their JAK2 V617F mutation status. Eligi-
ble patients had two prognostic factors (interme-
diate-2 risk) or three or more prognostic factors
(high risk) according to the International Prognos-
tic Scoring System (in which the prognostic factors
are age >65 years, hemoglobin level of <10 g per
deciliter, leukocyte count of >25×10
9
per liter,
≥1% circulating myeloblasts, and presence of
constitutional symptoms),
3
a peripheral-blood
blast count of less than 10%, a platelet count of
100×10
9
or more per liter, an Eastern Cooperative
Oncology Group (ECOG) performance status
17
of
3 or less (on a scale from 0 to 5, with 0 indicating
that the patient is fully active, higher scores indi-
cating increasing disability, and 5 indicating death;
see
Table 1
in the Supplementary Appendix, avail-
able with the full text of this article at NEJM.org),
and no prior treatment with a JAK inhibitor. In ad-
dition, eligible patients were not considered to be
suitable candidates for
allogeneic stem-cell trans-
plantation
at the time of enrollment.
Study Design
Patients were stratified according to prognostic
score
3
at enrollment and were randomly assigned,
in a 2:1 ratio, to receive ruxolitinib or the best avail-
able therapy, which included any commercially
available agents (as monotherapy or in combina-
tion) or no therapy at all and which could be
changed during the treatment phase. The starting
dose of ruxolitinib tablets was 15 mg twice daily
if the baseline platelet count was 200×10
9
per liter
or less and 20 mg orally twice daily if the baseline
platelet count was greater than 200×10
9
per liter.
A protocol-specified dosing regimen required re-
ductions of the dose for reasons of safety (if neu-
tropenia or thrombocytopenia developed) and
permitted escalation of the dose to increase ef-
ficacy, although the dose could not exceed 25 mg
twice daily.
15
Patients received ruxolitinib or the
best available therapy until the criteria for disease
progression were met. At any time, patients who
met protocol-specified criteria (underwent sple-
nectomy or had an increase in spleen volume of
>25% from the nadir during the study period,
which could include the baseline volume) discon-
tinued the randomized treatment phase of the
study and could enter an extension phase. In the
extension phase, patients who had been randomly
assigned to the best available therapy could re-
Ruxolitinib vs. Best Available Therapy for Myelofibrosis
n engl j med 366;9 nejm.org march 1, 2012
789
ceive ruxolitinib if they met protocol-specified
safety criteria, and patients who had been random-
ly assigned to ruxolitinib could continue to receive
ruxolitinib if they were still deriving a clinical ben-
efit. Patients who had leukemic transformation
or underwent splenic irradiation were withdrawn
from the study.
End Points
The primary end point was a reduction of 35%
or more in spleen volume from baseline at week
48. This end point was selected on the basis of the
international response criterion of a reduction of
50% or more in spleen length as assessed by pal-
pation
18
and prior data showing a correlation of
that measurement with a 33% reduction in spleen
volume as measured by magnetic resonance im-
aging (MRI).
15
Spleen volume was assessed by MRI
or by computed tomography (CT) (in the case of
patients who were not suitable candidates for MRI)
every 12 weeks; the images were read by a reader at
a central location who was unaware of the group
assignments. Spleen and liver volumes were as-
sessed by outlining the circumference of the organ
and determining the volume using a least-squares
analysis. Spleen length was assessed by manual pal-
pation at every study visit. Throughout this report,
measurements of spleen volume were performed
by MRI or CT, whereas measurements of spleen
length were performed by palpation.
The key secondary end point was a reduction of
35% or more in spleen volume from baseline at
week 24. Additional secondary end points included
the length of time that a reduction in spleen vol-
ume of at least 35% was maintained, the time to a
reduction in spleen volume of 35% or more from
baseline, progression-free survival, leukemia-free
survival, overall survival, and change in marrow
histomorphologic features. Information regarding
other secondary and exploratory end points and
the definition of disease progression are provided
in the Supplementary Appendix.
Symptoms and Quality of Life
Symptoms and quality of life were assessed with
the use of the European Organization for Research
and Treatment of Cancer (EORTC) quality-of-life
questionnaire core model (QLQ-C30) and the Func-
tional Assessment of Cancer Therapy–Lymphoma
(FACT-Lym) scale. The EORTC QLQ-C30 includes
five scales related to functioning, nine scales re-
lated to symptoms, and a global health status
and quality-of-life scale. The FACT-Lym consists
of a general core questionnaire (FACT-G), a dis-
ease-specific questionnaire (Lymphoma Subscale
[LymS]), and a trial outcome index (FACT-TOI),
which is a summary index of physical, functional,
and symptom outcomes.
Safety
The safety population consisted of all patients in
the ruxolitinib group who received at least one dose
of study drug and all patients in the best-available-
therapy group. Adverse events were monitored con-
tinuously during the study and were graded accord-
ing to the National Cancer Institute’s Common
Toxicity Criteria, version 3. Throughout the study,
patients provided blood samples at specified times,
and the samples were analyzed by the same labo-
ratory throughout the study to ensure consistency
in values.
Study Oversight
The study was sponsored by Novartis Pharmaceu-
ticals and designed by Incyte. It was approved by
the institutional review board at each participating
institution, and was conducted in accordance with
the principles of the Declaration of Helsinki. All
patients provided written informed consent. Data
were analyzed and interpreted by the sponsor’s
clinical and statistical teams in collaboration with
authors who were not affiliated with the sponsor.
An independent data and safety monitoring board
reviewed the trial data and made recommendations
regarding the continuation of the study. The first
author prepared the first draft of the manuscript,
with assistance from a medical writer who was
funded by Novartis Pharmaceuticals, and made the
final decision to submit the manuscript for publi-
cation. All the authors and representatives of the
sponsor reviewed and amended the manuscript.
All the authors vouch for the accuracy and com-
pleteness of the data and verify that the study as
reported conforms to the protocol and statistical
analysis plan (both of which are available at
NEJM.org).
Statistical Analysis
The efficacy analysis was performed according to
the intention-to-treat principle, with data from all
patients who underwent randomization. The data-
base cutoff date was January 4, 2011, the date on
which the last patient completed the week 48 study
visit. Patients who did not undergo an assessment
of spleen volume at week 48 were considered not
to have had a response. The two groups were com-
The
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n engl j med 366;9 nejm.org march 1, 2012
790
pared with the use of the exact Cochran–Mantel–
Haenszel test, stratified according to prognostic
category (intermediate-2 risk or high risk). The
family-wise alpha level was controlled at 0.05 over-
all for two prespecified comparisons (the primary
and key secondary end points). The key secondary
end point was to be tested only if the primary end
point showed significance at a two-sided alpha
level of 0.05. No formal adjustment for multiple
comparisons has been made. Survival curves for
leukemia-free survival, overall survival, and pro-
gression-free survival were estimated with the use
of the Kaplan–Meier method. Hazard ratios and
the corresponding 95% confidence intervals were
estimated with the use of the Cox proportional-
hazards model, stratified according to baseline
prognostic category; the between-group treatment
difference was tested with the use of a stratified
two-sided log-rank test.
Results
Characteristics of the Patients
During the period from July 1, 2009, through Jan-
uary 22, 2010, a total of 219 patients underwent
randomization, of whom 146 were assigned to re-
ceive ruxolitinib and 73 were assigned to receive
the best available therapy. The baseline charac-
Table 1. Baseline Characteristics of the Study Patients.*
Characteristic
Ruxolitinib
(N = 146)
Best Available Therapy
(N = 73)
Age (yr)
Median 67 66
Range 35–83 35–85
Sex (%)
Male 57 58
Female 43 42
Risk category (%)†
Intermediate-2 40 40
High 60 59
Not determined 0 1
ECOG performance status (%)‡
0 40 36
1 53 51
2 7 12
3 1 1
Myelofibrosis subtype (%)
Primary 53 53
Post–polycythemia vera 33 27
Post–essential thrombocythemia 14 19
Previous myelofibrosis therapy (%) 76 73
Hydroxyurea 75 68
Radiotherapy 0 5
Palpable spleen length below costal margin (cm)
Median 14 15
Range 5–30 5–37
Spleen volume (cm
3
)§
Median 2408 2318
Range 451–7766 728–7701
