Three-year efficacy, overall survival, and safety of ruxolitinib therapy

Published Ahead of Print on January 23, 2015, as doi:10.3324/haematol.2014.115840.
Copyright 2015 Ferrata Storti Foundation.
Three-year efficacy, overall survival, and safety of ruxolitinib
therapy in patients with myelofibrosis from the COMFORT-I study
by Srdan Verstovsek, Ruben A. Mesa, Jason Gotlib, Richard S. Levy, Vikas Gupta,
John F. DiPersio, John V. Catalano, Michael W.N. Deininger, Carole B. Miller, Richard T. Silver,
Moshe Talpaz, Elliott F. Winton, Jimmie H. Harvey, Murat O. Arcasoy, Elizabeth O. Hexner,
Roger M. Lyons, Azra Raza, Kris Vaddi, William Sun, Wei Peng, Victor Sandor,
and Hagop Kantarjian
Haematologica 2015 [Epub ahead of print]
Citation: Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger MW,
Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH, Arcasoy MO, Hexner EO, Lyons RM,
Raza A, Vaddi K, Sun W, Peng W, Sandor V, and Kantarjian H.Three-year efficacy, overall survival,
and safety of ruxolitinib therapy in patients with myelofibrosis from the COMFORT-I study.
Haematologica. 2015; 100:xxx
doi:10.3324/haematol.2014.115840
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Three-year efficacy, overall survival, and safety of ruxolitinib therapy in patients with
myelofibrosis from the COMFORT-I study
Srdan Verstovsek,1 Ruben A. Mesa,2 Jason Gotlib,3 Richard S. Levy,4 Vikas Gupta,5 John F.
DiPersio,6 John V. Catalano,7 Michael W.N. Deininger,8* Carole B. Miller,9 Richard T. Silver,10
Moshe Talpaz,11 Elliott F. Winton,12 Jimmie H. Harvey,13 Murat O. Arcasoy,14 Elizabeth O.
Hexner,15 Roger M. Lyons,16 Azra Raza,17 Kris Vaddi,4 William Sun,4 Wei Peng,4 Victor Sandor,4
and Hagop Kantarjian,1 for the COMFORT-I investigators
1
The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2
Mayo Clinic, Scottsdale, AZ, USA
3
Stanford Cancer Institute, Stanford, CA, USA
4
Incyte Corporation, Wilmington, DE, USA
5
Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
6
Washington University School of Medicine, St. Louis, MO, USA
7
Frankston Hospital and Department of Clinical Haematology, Monash University, Frankston,
Australia
8*
Oregon Health and Science University, Portland, OR, USA
9
Saint Agnes Cancer Institute, Baltimore, MD, USA
10
Weill Cornell Medical Center, New York, NY, USA
11
University of Michigan, Ann Arbor, MI, USA
12
Emory University School of Medicine, Atlanta, GA, USA
13
Birmingham Hematology and Oncology, Birmingham, AL, USA
14
Duke University Health System, Durham, NC, USA
15
Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA, USA
16
Cancer Care Centers of South Texas/US Oncology, San Antonio, TX, USA
17
Columbia Presbyterian Medical Center, New York, NY, USA
*Currently at Division of Hematology and Hematologic Malignancies and Huntsman Cancer
Institute, University of Utah, Salt Lake City, UT, USA
A complete list of the COMFORT-I investigators appears in the Appendix.
Running head: COMFORT-I study: 3-yr update on efficacy and safety
Correspondence: Srdan Verstovsek, MD, PhD; e-mail: sverstov@mdanderson.org
Current text word count: ~3300
Abstract word count: 200
Figure/table count: 6 figures/1 table; 1 supplemental figure/4 supplemental tables
Supplemental files: 1 file
Trial registration: clinicaltrials.gov identifier: NCT00952289
Funding
COMFORT-I was supported by Incyte Corporation.
Acknowledgments
This research is supported in part by the MD Anderson Cancer Center Support Grant
CA016672. The authors would like to thank the COMFORT-I investigators for their participation
in this trial. The authors would also like to acknowledge the medical writing assistance of Alfredo
Toschi, PhD, of Evidence Scientific Solutions, which was funded by Incyte Corporation.
Key words: ruxolitinib, myelofibrosis, overall survival, splenomegaly
ABSTRACT
In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided
significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was
associated with an overall survival benefit relative to placebo in patients with intermediate-2 or
high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of
ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients
originally randomized to ruxolitinib remained on treatment whereas all patients originally
assigned to placebo had discontinued or crossed over to ruxolitinib. At week 144, mean spleen
volume reduction was 34% with ruxolitinib. Previously observed improvements in quality-of-life
measures were sustained with longer-term ruxolitinib therapy. Overall survival continued to
favor ruxolitinib despite the majority of placebo patients crossing over to ruxolitinib (hazard ratio
0.69 [95% confidence interval: 0.46-1.03]; P=0.067). Exploratory analyses suggest that
crossover may have contributed to an underestimation of the true survival difference between
the treatment groups. Ruxolitinib continued to be generally well tolerated; there was no pattern
of worsening of grade ≥3 anemia or thrombocytopenia with longer-term ruxolitinib exposure.
These longer-term data continue to support the efficacy and safety of ruxolitinib in patients with
myelofibrosis. The study is registered at clinicaltrials.gov: NCT00952289.
Introduction
Myelofibrosis (MF) is a Philadelphia chromosome–negative myeloproliferative neoplasm
(MPN) that may occur as primary myelofibrosis (PMF) or develop from progression of
polycythemia vera or essential thrombocythemia (post-PV or post-ET MF, respectively).1 The
clinical hallmarks of MF are splenomegaly, cytopenias, and debilitating symptoms associated
with a hypercatabolic state and systemic inflammation.2,3 Allogeneic stem cell transplantation is
the only potentially curative therapy for MF. However, this therapy is recommended only for a
limited number of patients because of the high risk of treatment-related morbidity and mortality
as well as the poor medical condition of patients.4
Dysregulation of the Janus kinase (JAK)–signal transducer and activator of transcription
(STAT) pathway is central to the pathogenesis of MF.5-8 Approximately 65% of patients with
PMF carry the JAK2V617F gain-of-function mutation9 and 5-10% carry mutations in the
thrombopoietin receptor gene (MPL).10,11 Additional mutations leading to dysregulation of the
JAK-STAT signaling pathway have been characterized in patients with PMF and other MPNs,
suggesting a high degree of complexity and heterogeneity in disease pathogenesis.12,13
Recently, mutations in the CALR gene encoding calreticulin were detected in approximately
67%14 to 82%15 of patients with ET and in 80%15 to 88%14 of patients with PMF who did not
have JAK2 or MPL mutations. The high frequency of CALR mutations in these patients, along
with evidence linking aberrant calreticulin activity to JAK-STAT activation, supports a role for
calreticulin in the pathogenesis of MPNs.14 Despite the range of mutations, the central role of
the JAK-STAT pathway in MPNs has provided the rationale for the development of targeted
therapies that inhibit JAK-STAT signaling.16,17
The oral JAK1 and JAK2 inhibitor ruxolitinib has been evaluated in two phase III clinical
trials in patients with intermediate-2 or high-risk PMF (per International Prognostic Scoring
System)18 or post-PV MF or post-ET MF (per 2008 World Health Organization criteria): the
randomized, double-blind Controlled MyeloFibrosis Study with ORal JAK Inhibitor Treatment
(COMFORT)-I19 study (www.clinicaltrials.gov: NCT00952289) and the randomized, open-label
COMFORT-II20 study (www.clinicaltrials.gov: NCT00934544), which compared the effects of
ruxolitinib with placebo or best available therapy (BAT), respectively. Both studies showed that
ruxolitinib treatment significantly reduced splenomegaly and provided marked improvements in
MF-related symptoms and quality-of-life (QOL) measures compared with controls, regardless of
JAK2V617F mutational status.19,20 The clinical benefit and safety of ruxolitinib treatment in
COMFORT-I and COMFORT-II have been maintained with subsequent longer-term follow-up.2123
As anticipated, the effect of JAK2 inhibition on hematopoiesis resulted in dose-dependent
anemia and thrombocytopenia. The majority of these cytopenias occurred in the first 8-12
weeks of treatment, and they were generally manageable with dose reductions and/or red blood
cell transfusions. Subsequently, mean platelet counts stabilized and mean hemoglobin levels
gradually returned to a new steady state just below baseline levels.21-24 Additionally, longer-term
follow-up of the COMFORT studies has shown that ruxolitinib treatment was associated with an
overall survival advantage, despite the crossover design of these studies.19,21-23 The objective of
the current analysis is to provide an update on the efficacy, overall survival, and safety of
ruxolitinib in patients enrolled in COMFORT-I at a median follow-up of approximately 3 years
(149 weeks).
Methods
Patients and study design
Detailed inclusion and exclusion criteria have been previously described.19 Briefly,
patients with intermediate-2 or high-risk PMF or post-PV MF or post-ET MF and splenomegaly
were randomized 1:1 to receive ruxolitinib or placebo orally twice a day (BID). The starting dose
of ruxolitinib was based on baseline platelet count: 15 mg BID or 20 mg BID for baseline platelet
counts of 100-200 × 109/L or >200 × 109/L, respectively. Doses could be modified per protocol.19
Crossover from the placebo arm to ruxolitinib was allowed prior to the primary analysis
based on defined criteria for worsening splenomegaly. Upon completion of the primary analysis,
the study was unblinded and all remaining patients receiving placebo were allowed to crossover
to ruxolitinib.19 Each participating site’s institutional review board approved the protocol. The
study sponsor analyzed and interpreted the data in collaboration with the investigators. All
authors had access to the aggregate data and any additional analyses upon request. The study
was conducted in accordance with the International Conference on Harmonization guidelines for
Good Clinical Practice. All patients provided written informed consent.19
Assessments
Timing and methods of assessment of spleen volume, symptom burden, QOL measures, and
adverse events, described previously,19 are detailed in the Supplemental Appendix.
Statistical analysis
This prospectively defined analysis was to occur when all patients either reached the 144-week
assessment or discontinued from study. Changes from baseline in spleen volume and palpable
spleen length were based on observed cases and summarized descriptively. Durability of
spleen volume reduction was evaluated using the Kaplan-Meier method in patients who
achieved a ≥35% reduction from baseline. Loss of a ≥35% spleen volume reduction was defined
as the first <35% spleen volume reduction from baseline that was also a ≥25% increase from
nadir. Overall survival was assessed using the Kaplan-Meier method for the intent-to-treat
population with patients assessed per their original randomized treatment. Survival time was
measured from study start to last known status of the patient and was not censored at time of
discontinuation from randomized treatment. The Cox proportional hazards model and log-rank
test were used to calculate the hazard ratio with 95% confidence interval (CI) and P-value,
respectively. The incidence of new-onset or worsening grade ≥3 anemia and thrombocytopenia,
and of new-onset or worsening all-grade and grade ≥3 nonhematologic adverse events, were
calculated using the life table method. Additional details on safety assessments are discussed in
the Supplemental Appendix.
To better understand the effect of crossover to ruxolitinib on survival measurement, two
exploratory analyses were performed. The first used the rank-preserving structural failure time
(RPSFT) method, a statistical method used in oncology trials to adjust for possible crossover
effect.25-27 The second analysis was a parametric statistical modeling of overall survival using
the generalized Gamma distribution,28,29 which fitted a 3-parameter regression model to the
observed survival data to calculate the corresponding hazard of death for patients originally
randomized to ruxolitinib or placebo. Full details and description of the exploratory analyses are
described in the Supplemental Appendix.
Results
Patient disposition
At a median follow-up of 149 weeks (range 19-175 weeks), 77 of the 155 patients
(49.7%) originally randomized to ruxolitinib were still receiving ruxolitinib therapy. A total of 111
of the 154 patients originally randomized to placebo crossed over to ruxolitinib therapy. Of these
111 patients, 57 (51.4%) patients were still receiving ruxolitinib therapy (Figure 1). In patients
originally randomized to ruxolitinib, discontinuation rates estimated using the Kaplan-Meier
method were 21% at year 1, 35% at year 2, and 51% at year 3. Reasons for discontinuation
included disease progression (23.1%), adverse events (19.2%), death (19.2%), and withdrawal
of consent (15.4%) (Figure 1).
The median exposure to ruxolitinib was 145 weeks for patients originally randomized to
ruxolitinib; for these patients, the mean dose of ruxolitinib remained stable after initial dose
adjustments in the first 8-12 weeks of therapy (Figure 2). For patients originally randomized to
placebo, the median exposure to placebo was 37 weeks. For patients who crossed over to
ruxolitinib from placebo, the median time to crossover was 41 weeks. The median exposure to
ruxolitinib for patients who crossed over was 105 weeks, which, at the time of this analysis, was
nearly three times longer than their exposure to placebo.
Efficacy
Reductions in spleen size were durable with longer-term treatment with ruxolitinib. The
mean percentage change from baseline in spleen volume was −31.6% at week 24 (median
−33.0%) and −34.1% at week 144 (median −38.4%) (Figure 3A). The mean percentage change
from baseline in palpable spleen length was −43.4% at week 24 (median −41.2%) and −49.4%
at week 144 (median −50.0%) (Figure 3A). Assessment of palpable spleen response using the
International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) and
European LeukemiaNet (ELN) consensus criteria,30 showed that a palpable spleen response
was achieved in 31.6% of ruxolitinib-treated patients compared with 2.0% of patients in the
placebo arm at week 24. At week 144, palpable spleen response was achieved in 24.5% of
patients originally randomized to ruxolitinib. Fifty-nine percent of patients (91/155) originally
randomized to ruxolitinib achieved a ≥35% reduction in spleen volume at any time during the
study follow-up. The majority of patients achieved a ≥35% reduction from baseline in spleen
volume by week 12, the time of the first spleen volume assessment; in these patients, the
probability of maintaining a ≥35% spleen volume reduction for at least 132 weeks corresponded
to 144 weeks on therapy. In this analysis, the probability of maintaining a ≥35% spleen volume
reduction for at least 132 weeks was 0.53. Over the course of follow-up, over 80% of patients
who achieved a ≥35% reduction in spleen volume maintained a reduction of at least 10%
(Figure 3B), a reduction that has been shown to be associated with meaningful improvements in
QOL and MF-related symptoms.21 Although the modified MF Symptom Assessment Form
version 2.0 was only assessed through week 24, improvements in QOL measures as assessed
by the European Organization for Research and Treatment of Cancer Quality of Life
Questionnaire-Core 30 (EORTC QLQ-C30) were maintained with longer-term therapy, including
improvements in global health status/QOL, fatigue, role functioning, and physical functioning
scales (Figure 4).
Overall survival
At the time of this analysis, there were 42 deaths among patients randomized to
ruxolitinib and 54 deaths among those randomized to placebo. A list of causes of death is
provided in Supplemental Data Table 1. With median follow-ups of 149.1 and 149.3 weeks for
the ruxolitinib and placebo arms, respectively, the hazard ratio for overall survival continued to
favor patients originally randomized to ruxolitinib compared with those originally randomized to
placebo (hazard ratio 0.69 [95% CI: 0.46-1.03]; P=0.067) (Figure 5A). Although the hazard ratio
continued to favor ruxolitinib, the P-value no longer reached nominal significance at the P=0.05
level. Therefore, exploratory analyses were conducted to assess the potential impact of
crossover and substantially longer exposure to ruxolitinib than placebo among patients originally
randomized to placebo. The RPSFT method estimated a hazard ratio of 0.36 (95% CI: 0.2041.035) (Figure 5B). Exploratory modeling of survival using a generalized Gamma distribution
showed that the hazard of death in patients originally randomized to placebo was initially higher
than in those randomized to ruxolitinib. This hazard subsequently decreased over time,
corresponding with an increased proportion of patients who crossed over to ruxolitinib
(Supplemental Data Figure 1).
Safety
As expected given the role of JAK2 in erythropoietin and thrombopoietin signaling,
anemia and thrombocytopenia were the most common adverse events observed with ruxolitinib
therapy. The incidence of new-onset or worsening grade 3 or 4 anemia and thrombocytopenia
were highest during the first 6 months of therapy and decreased with longer-term ruxolitinib
treatment (Figure 6A). Consistent with this observation, mean hemoglobin levels and platelet
counts in ruxolitinib-treated patients decreased in the first 8-12 weeks. Mean hemoglobin levels
reached a nadir in this time frame, then subsequently increased to a new steady-state level by
week 24 and remained stable through the course of longer-term follow-up. Mean platelet counts
remained stable with longer-term follow-up after the initial decrease (Figure 6B). Since the last
reported analysis at a median follow-up of 102 weeks,21 no additional patients have
discontinued from the study for anemia or thrombocytopenia.
The most common nonhematologic adverse events that occurred more frequently with
ruxolitinib compared with placebo in the primary analysis were ecchymosis (18.7%), dizziness
(14.8%), and headache (14.8%).19 When adjusted for exposure to ruxolitinib, the incidence of
these adverse events as well as other nonhematologic events decreased with longer-term
therapy (Table 1), as did rates of grade ≥3 adverse events (Supplemental Data Table 2).
Urinary tract infections (UTIs) and herpes zoster were infections that occurred in patients
receiving ruxolitinib during randomized treatment;31 however, no increase in incidence was
noted with long-term ruxolitinib therapy. A comprehensive analysis of MedDRA preferred terms
associated with these infections showed the incidence of UTI per the life table method was
10.5% (n=15) for 0-<12 months, 6.7% (n=7) for 12-<24 months, 7.7% (n=6) for 24-<36 months,
and 6.0% (n=2) for ≥36 months in patients originally randomized to ruxolitinib. Two UTIs were
grade ≥3, one occurring between months 12 and 24 and one occurring between months 24 and
36. The incidences of herpes zoster were 2.1% (n=3) for 0-<12 months, 3.5% (n=4) for 12-<24
months, 3.4% (n=3) for 24-<36 months, and 0% for ≥36 months in patients originally
randomized to ruxolitinib; all herpes zoster infections were grade 1 or grade 2. No other
opportunistic infections occurred with long-term ruxolitinib therapy. The overall pattern of
adverse events observed after treatment interruption or discontinuation continued to support the
absence of a specific withdrawal effect (Supplemental Data Tables 3-4).
Four new cases of acute myeloid leukemia (AML) have been reported since the previous
analysis (two in patients originally randomized to ruxolitinib; two in patients originally
randomized to placebo who developed AML after crossover to ruxolitinib), for a total of eight
cases since study initiation (four in patients originally randomized to ruxolitinib; four in patients
originally randomized to placebo). The rate of leukemic transformation per person-year of
ruxolitinib exposure was 0.0121/person-year and 0.0233/person-year in patients originally
randomized to ruxolitinib or placebo, respectively.
Discussion
In this planned analysis of the COMFORT-I study with a median follow-up of 149 weeks,
ruxolitinib treatment continued to be associated with durable reductions in spleen volume and
improvements in QOL measures. Longer-term follow-up revealed a slight decline in QOL
measures. However, this may be related to the well-described phenomenon of “response shift,”
which reflects the changes in patients’ perspective on key QOL domains owing to repeated
testing over the course of treatment.32 Despite this potential for response shift, the EORTC
QLQ-C30 scales indicated that QOL was still improved relative to baseline with longer-term
ruxolitinib treatment.
The hazard ratio for overall survival continued to favor ruxolitinib compared with placebo
despite the majority of patients having crossed over from placebo to ruxolitinib, although
statistical significance was not maintained. Although the rate of discontinuation from randomized
treatment was higher in the placebo group than the ruxolitinib group at the primary analysis,19
follow-up for overall survival was well balanced between the two treatment arms. The exposure
to ruxolitinib in patients who crossed over from placebo was substantially longer than their
exposure to placebo (105 weeks vs. 37 weeks for median exposure to ruxolitinib and placebo,
respectively), thus confounding the comparison of overall survival between the two treatment
groups in favor of the placebo arm. To understand the effect of crossover to active treatment in
placebo-controlled studies, several statistical methods have been developed. The exploratory
analysis of overall survival using the RPSFT showed that crossover from placebo may have led
to an underestimation of overall survival difference. This is consistent with findings from other
oncology trials using this method, where crossover to active treatment may also have led to an
underestimation of the survival difference between placebo and active treatment.26,27 Consistent
with the RPSFT analysis, the exploratory analysis using the generalized Gamma function
showed that the probability of death in the placebo group was initially higher than in the original
ruxolitinib-treated group, and that this probability decreased over time as patients originally
assigned to placebo crossed over to receive ruxolitinib treatment. This finding is expected for a
crossover trial in which the active treatment has a positive impact on survival.29 Although the
specific mechanism underlying the prolonged survival observed in patients originally
randomized to ruxolitinib in COMFORT-I is unknown, the reductions in spleen volume and
improvements in functional status and QOL measures may have had a modulatory effect on the
common causes of death not related to disease progression in patients with MF.18
Consistent with our findings, a separate report of the COMFORT-II study showed that
long-term ruxolitinib therapy was associated with an overall survival advantage relative to BAT
at 3 years of follow-up (hazard ratio 0.48 [95% CI: 0.28-0.85]; P=0.009).23 Similar to what was
observed in COMFORT-I, this analysis is likely biased against ruxolitinib owing to patients
crossing over from BAT. However, in COMFORT-II the confounding effect of crossover is less
severe than in COMFORT-I because of the longer exposure to BAT prior to crossover to
ruxolitinib (median time of follow-up at primary analysis: 52 weeks in COMFORT-II20 and 32
weeks in COMFORT-I19). Additionally, a prespecified analysis of overall survival from pooled
data from COMFORT-I and COMFORT-II supports an overall survival benefit of ruxolitinib
compared with controls (hazard ratio 0.65 [95% CI: 0.46-0.90]; P=0.01). Further exploratory
RPSFT analysis of pooled survival data from the COMFORT studies suggests an
underestimation of the survival difference between treatment groups because of the effect of
crossover (RPSFT-corrected hazard ratio 0.29 [95% CI: 0.13-0.63]; P=0.01).33
In this 3-year update of COMFORT-I, ruxolitinib treatment demonstrated durable efficacy
at doses that were stable over the course of long-term follow-up. Dose adjustments occurred
primarily in the first 8-12 weeks of the study, particularly in patients with baseline platelet counts
between 100 and 200 × 109/L who received a starting dose of 15 mg BID. By week 24, the
median titrated dose was 10 mg BID for this subgroup of patients and 20 mg BID for those with
baseline platelet count >200 × 109/L; doses stabilized with longer-term treatment.24
Overall, no unexpected safety or tolerability issues were reported with longer-term
ruxolitinib treatment. As expected, anemia and thrombocytopenia mainly occurred early in the
course of treatment, and there was no pattern of worsening of these events with longer-term
exposure to ruxolitinib in patients who remained in the study. An additional analysis of the
incidence of new-onset or worsening grade ≥3 anemia and thrombocytopenia that counted
patients who experienced both grade 3 and 4 events in each grade yielded similar results.34 As
previously noted, the initial increases in anemia and thrombocytopenia observed in the first 6
months of treatment and the subsequent decline in the incidence of these events was consistent
with the timing of ruxolitinib dose adjustments. In ruxolitinib-treated patients, the rate of red
blood cell transfusions increased in the first 8 weeks of treatment and later declined to levels
similar to the placebo arm by week 36 and remained stable thereafter. This was consistent with
the observed pattern of hemoglobin levels, which initially decreased and subsequently stabilized
at a new steady state.24 Although cases of UTIs and herpes zoster infections were observed in
patients randomized to ruxolitinib, the incidence of these infections did not increase with longer-
term therapy. As previously described, systematic review of the pattern of adverse events
observed after treatment interruption or discontinuation in this analysis fails to support a specific
withdrawal syndrome other than return to baseline disease.19,21
Longer-term ruxolitinib treatment did not affect the risk of transformation to AML. The
rates of leukemic transformation per person-year of ruxolitinib exposure in patients originally
randomized to ruxolitinib (0.0121/person-year) and in those originally randomized to placebo
after they crossed over to ruxolitinib (0.0233/person-year) showed no evidence of an increased
risk of leukemic transformation when compared with the rate derived from a historical control
population of 310 patients with MF (0.038/person-year).35
In summary, patients receiving ruxolitinib treatment for a median of 3 years in the
COMFORT-I study maintained durable reductions in spleen volume and meaningful
improvements in QOL measures. Overall survival continued to favor those patients originally
randomized to ruxolitinib compared with those originally randomized to placebo despite the
majority of those assigned to placebo crossing over to ruxolitinib treatment. This crossover may
have contributed to an underestimation of the true survival difference between the two treatment
arms. Ruxolitinib treatment continued to be generally well tolerated, and the incidence of newonset grade 3 or 4 anemia and thrombocytopenia decreased with longer-term therapy.
Collectively, long-term analyses from COMFORT-I and COMFORT-II continue to support the
sustained efficacy and safety of ruxolitinib and provide evidence to support a meaningful ability
of ruxolitinib to improve overall survival in patients with MF, and possibly modify the course of
the disease.
Authorship and disclosures
SV, RAM, and HK performed the research and contributed to concept design, data
collection, and data interpretation. JG, VG, JFD, JVC, MWND, CBM, RTS, MT, EFW, JHH Jr,
MOA, EOH, RML, and AR performed research and contributed to data collection and
interpretation. RSL and VS contributed to research design and data interpretation. WS and WP
performed statistical analyses. KV contributed to research design. All authors assisted with
drafting the manuscript and/or critical revision of the content and approved the final manuscript
submitted.
SV has received research funding from Incyte Corporation, AstraZeneca, Lilly Oncology,
Roche, Geron, NS Pharma, Bristol Myers Squibb, Novartis, Celgene, Infinity Pharmaceuticals,
YM Biosciences, Gilead, Seattle Genetics, Promedior, and Cell Therapeutics Inc. RAM has
received research funding from Genentech, Gilead, Incyte, Lilly, NS Pharma, Sanofi-Aventis,
and YM Biosciences. JG has served on an advisory committee and has received research
funding and travel reimbursement from Incyte Corporation. VG has served as a
consultant/advisory board member for Incyte and Novartis, and has received research funding
from Celgene, Incyte, and Novartis through his institution. MWND has served as a
consultant/advisory board for Bristol Myers Squibb, Ariad, Incyte, and Novartis, and has
received research funding from Celgene, Bristol Myers Squibb, Gilead, and Novartis through his
institution. CBM has served as a consultant/advisory board for Incyte and Novartis, and has
received research funding from Incyte and Novartis through her institution. RTS has served on
an advisory committee for Incyte and Gilead Sciences and has received honoraria from both
companies. He has received research funding from Incyte, NS Pharma, Lilly Oncology,
Novartis, Promedior, and Inhibikase Corp through his institution. MT has served as a
consultant/advisory board member for Bristol Myers Squibb, Ariad, Novartis, and Pfizer. EFW
has served as a consultant/advisory board member for Incyte, and has received research
funding from Incyte through his institution. MOA has received research funding from Incyte
through his institution. RML has served as a consultant/advisory board for Gilead, and has
received research funding from Incyte, Celgene, Amgen, Lilly, Seattle Genetics, Gilead, Ariad,
GlaxoSmithKline, and Novartis through his institution. AR has served in a speakers bureau for
Novartis and has received research funding from Oncova Inc. HK has received research funding
from Ariad, Novartis, Bristol Myers Squibb, and Pfizer through his institution. RSL, KV, WS, WP,
and VS are employees of Incyte Corporation and have equity ownership. JFD, JVC, JHH Jr, and
EOH have no relevant financial relationship to disclose.
Appendix
COMFORT-I Investigators
The following investigators contributed to the study (listed in alphabetical order by country):
Australia: P Cannell, Royal Perth Hospital, Perth, WA; JV Catalano, Frankston Hospital and
Department of Clinical Haematology, Monash University, Frankston, Victoria; BH Chong, St.
George Hospital, Kogarah, NSW; P Coughlin, Monash University/Box Hill Hospital, Box Hill,
Victoria; STS Durrant, Royal Brisbane and Women’s Hospital, Herston, Queensland; TE Gan,
Monash Medical Centre, Clayton, Victoria; HC Lai, Townsville Hospital, Douglas, Queensland;
MF Leahy, Fremantle Hospital and Health Service, Fremantle, WA; M Leyden, Maroondah
Hospital, Ringwood East, Victoria; R Lindeman, Prince of Wales Hospital, Randwick, NSW; D
Ma, St. Vincent’s Hospital, Darlinghurst, NSW; A Perkins, Haematology and Oncology Clinics of
Australia, Milton, Queensland; AC Perkins, Princess Alexandra Hospital, Woolloongabba,
Queensland; D Ross, Flinders Medical Centre, Bedford Park, SA; W Stevenson, Royal North
Shore Hospital, St. Leonards, NSW. Canada: K Grewal, Eastern Health, St. John’s, NL; V
Gupta, Princess Margaret Hospital, University of Toronto, Toronto, ON; K Howson-Jan, London
Health Sciences Centre, London, ON; S Jackson, St. Paul’s Hospital, Vancouver, BC; C
Shustik, Royal Victoria Hospital, Montreal, QC; R van der Jagt, Ottawa Hospital-General
Campus, Ottawa, ON. United States: L Afrin, Hollings Cancer Center, Charleston, SC; LP
Akard, Indiana Blood and Marrow Transplantation, LLC, Beech Grove, IN; MO Arcasoy, Duke
University Medical Center, Durham, NC; E Atallah, Froedtert Hospital and Medical College of
Wisconsin, Milwaukee, WI; J Altman, Northwestern Memorial Hospital, Chicago, IL; J
Camoriano, Mayo Clinic Arizona, Scottsdale, AZ; TP Cescon, Berks Hematology Oncology
Associates, West Reading, PA; CR Cogle, University of Florida, Gainesville, FL; R Collins, Jr,
University of Texas Southwestern Medical Center, Dallas, TX; KH Dao, Oregon Health and
Science University, Portland, OR; HJ Deeg, Fred Hutchinson Cancer Research Center, Seattle,
WA; M Deininger, Oregon Health and Science University, Portland, OR; NJ DiBella, Rocky
Mountain Cancer Centers, Aurora, CO; JF DiPersio, Washington University School of Medicine,
St. Louis, MO; A Faitlowicz, University of California-Irvine Medical Center, Orange, CA; FA
Fakih, Florida Pulmonary Research Institute, LLC, Winter Park, FL; R Frank, Norwalk Hospital,
Norwalk, CT; NY Gabrail, Gabrail Cancer Center Research, Canton, OH; SL Goldberg,
Hackensack University Medical Center, Hackensack, NJ; J Gotlib, Stanford Cancer Institute,
Stanford, CA; HM Gross, Dayton Physicians, LLC, Dayton, OH; JH Harvey, Jr, Birmingham
Hematology and Oncology Associates, LLC, Birmingham AL; RH Herzig, University of
Louisville, Louisville, KY; E Hexner, Abramson Cancer Center at the University of Pennsylvania,
Philadelphia, PA; CE Holmes, Vermont Cancer Center, Burlington, VT; E Ibrahim, Beaver
Medical Group, Highland, CA; R Jacobson, Palm Beach Cancer Institute, West Palm Beach, FL;
C Jamieson, Moores University of California-San Diego Cancer Center, La Jolla, CA; K
Jamieson, University of Iowa Hospitals and Clinic, Iowa City, IA; CM Jones, Jones Clinic, PC,
Germantown, TN; HM Kantarjian, University of Texas MD Anderson Cancer Center, Houston,
TX; A Kassim, Vanderbilt Clinic, Nashville, TN; CM Kessler, Georgetown University Medical
Center, Washington, DC; T Kindwall-Keller, University Hospitals Case Medical Center,
Cleveland, OH; PPN Lee, Tower Cancer Research Foundation, Beverly Hills, CA; RM Lyons,
Cancer Care Centers of South Texas/US Oncology, San Antonio, TX; R Marschke, Jr, Front
Range Cancer Specialists, Fort Collins, CO; J Mascarenhas, Mount Sinai School of Medicine,
New York, NY; E Meiri, Palm Beach Institute of Hematology and Oncology, Boynton Beach, FL;
A Menter, Kaiser Permanente, Denver, CO; RA Mesa, Mayo Clinic-Arizona, Scottsdale, AZ; C
Miller, St. Agnes HealthCare, Inc., Baltimore, MD; C O’Connell, University of Southern
California, Los Angeles, CA; I Okazaki, Straub Clinic and Hospital, Honolulu, HI; R Orlowski,
Carolina Oncology Specialists, PA, Hickory, NC; R Paquette, University of California-Los
Angeles Medical Hematology and Oncology, Los Angeles, CA; VR Phooshkooru, Mid Dakota
Clinic, PC, Bismarck, ND; B Powell, Wake Forest University Health Services, Winston-Salem,
NC; JT Prchal, Huntsman Cancer Institute, Salt Lake City, UT; R Ramchandren, Karmanos
Cancer Institute, Detroit, MI; F Rana, Shands Jacksonville Clinical Center, Jacksonville, FL; A
Raza, Columbia University Medical Center, New York, NY; C Rivera, Mayo Clinic-Jacksonville,
Jacksonville, FL; EA Sahovic, Western Pennsylvania Hospital, Pittsburgh, PA; M Scola, Carol
G. Simon Cancer Center, Morristown, NJ; M Scouros, Houston Cancer Institute, PA, Houston,
TX; M Sekeres, Cleveland Clinic, Cleveland, OH; J Shammo, Rush University Medical Center,
Chicago, IL; RS Siegel, George Washington University, Washington, DC; RT Silver, Weill
Cornell Medical Center, New York, NY; CP Spears, Sierra Hematology and Oncology,
Sacramento, CA; M Talpaz, University of Michigan Medical Center, Ann Arbor, MI; M Tsai, Park
Nicollet Institute, St. Louis Park, MN; S Verstovsek, University of Texas MD Anderson Cancer
Center, Houston, TX; T Walters, Mountain States Tumor Institute, Boise, ID; RS Weiner, Arena
Oncology Associates, PC, Lake Success, NY; EF Winton, Emory University Hospital, Atlanta,
GA; SE Young, Somerset Hematology-Oncology Associates, Somerville, NJ; F Yunus,
University of Tennessee Cancer Institute, Memphis, TN.
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Verstovsek S, Kantarjian HM, Estrov Z, et al. Long-term outcomes of 107 patients with
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to matched historical controls. Blood. 2012;120(6):1202-1209.
TABLES
Table 1. Incidence of new-onset all-grade nonhematologic adverse events regardless of
causality.
Ruxolitinib
12-<24
24-<36
0-<12 months
months
months
≥36 months
(n=155)
(n=130)
(n=103)
(n=82)
Fatigue
29.0
15.2
15.3
7.7
Diarrhea
27.8
6.7
10.8
3.9
Ecchymosis
21.2
10.4
5.7
0
Peripheral edema
21.3
8.4
12.6
0
Dyspnea
19.2
10.2
2.9
3.3
Dizziness
18.1
10.4
3.0
3.5
Pain in extremity
18.0
6.2
4.2
3.3
Headache
16.6
5.1
2.7
0
Nausea
16.6
6.8
5.1
5.9
Constipation
14.5
8.6
10.1
9.0
Abdominal pain
13.8
5.7
3.6
0
Insomnia
13.8
5.7
3.7
0
Vomiting
13.7
2.8
2.4
5.5
Pyrexia
13.5
7.3
8.5
2.9
Cough
13.1
13.3
4.0
6.0
Arthralgia
11.8
5.8
6.6
6.3
Upper respiratory tract
7.7
11.1
4.0
3.2
Incidence, %
infection
Percentage of patients for each event was based on the effective sample size of the time interval (number of patients
at risk at the beginning of the interval minus half of the censored patients during the time interval). Adverse event is
included if the incidence was >10% at any yearly interval.
FIGURE LEGENDS
Figure 1. Patient disposition. *For the placebo arm, there were three patients who were
not evaluable for safety (N=151); these patients were excluded from the calculation of the
percentage of patients who discontinued (40/151). †Patients in the placebo group could
crossover to ruxolitinib prior to the primary analysis based on defined criteria for
worsening splenomegaly. After the primary analysis was completed, the study was
unblinded and all remaining patients receiving placebo were allowed to crossover to
ruxolitinib. ‡The percentages of patients who discontinued for the reasons listed are
based on the number of patients who discontinued within the treatment group and not on
the total number of patients in the treatment group. BID: twice a day.
Figure 2. Mean daily dose of ruxolitinib over time in patients originally randomized to
ruxolitinib. BID: twice a day; SEM: standard error of the mean.
Figure 3. (A) Percentage change in spleen size over time. Mean percentage change from
baseline in spleen volume (left panel) and palpable spleen length (right panel).
(B) Durability of spleen volume reduction in patients originally randomized to ruxolitinib.
The probability of maintaining a spleen volume reduction in patients who achieved a
≥35% decrease in spleen volume over the course of the study is shown. Also shown is
the probability of maintaining a ≥10% spleen volume reduction—a spleen volume
reduction that has been shown to be associated with meaningful improvements in quality
of life and myelofibrosis-related symptoms21—in patients who achieved a ≥35% decrease
in spleen volume.
Figure 4. Mean change in quality-of-life (QOL) measures assessed using the European
Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core
30. Shown are global health status, two functional domains (role and physical
functioning), and symptom scores for fatigue, a key symptom impacting QOL, in patients
with myelofibrosis. Arrows indicate improvement.
Figure 5. (A) Overall survival in the intent-to-treat population as assessed by the KaplanMeier method. (B) Overall survival in the intent-to-treat population as assessed by the
rank-preserving structural fail time (RPSFT) method. CI: confidence interval: HR: hazard
ratio.
Figure 6. (A) Incidence of new-onset or worsening grade 3 or 4 anemia and
thrombocytopenia over time. (B) Mean hemoglobin level and platelet count and
hemoglobin level over time. *All patients receiving placebo at the primary analysis
crossed over or discontinued within 3 months of the primary analysis; therefore, data for
patients receiving placebo are shown for up to 6 months only. RUX: ruxolitinib; PBO:
placebo.
Randomized
(N=309)
Ruxolitinib
15 mg BID or
20 mg BID
(n=155)
Placebo BID*
(n=154)
Crossed over to
ruxolitinib
(n=111)†
Discontinued‡
78 (50.3%)
Death
Adverse event
Consent withdrawn
Disease progression
Noncompliance (meds)
Noncompliance (study)
Other
15 (19.2%)
15 (19.2%)
12 (15.4%)
18 (23.1%)
1 (1.3%)
1 (1.3%)
16 (20.5%)
54 (48.6%)
Death
Adverse event
Consent withdrawn
Disease progression
Noncompliance (meds)
Other
11 (20.4%)
8 (14.8%)
11 (20.4%)
15 (27.8%)
2 (3.7%)
7 (13.0%)
40 (26.5%)
Death
Adverse event
Consent withdrawn
Disease progression
Other
Remain on treatment
77 (49.7%)
57 (51.4%)
0
7 (17.5%)
9 (22.5%)
7 (17.5%)
13 (32.5%)
4 (10.0%)
20 mg BID starting dose
15 mg BID starting dose
Mean daily dose (mg, BID) ± SEM
25
20
15
10
5
0
0
No. of patients
20 mg BID 100
15 mg BID
55
8
16
24
98
49
32
40
48
93
35
56
64
72
80
Weeks
77
33
88
96
73
30
104
112
120
69
26
128
136
144
62
20
A
Spleen volume
Mean percentage change from baseline
0
n= 148 139 120 107 100
Placebo
84
73
132 107
35
–10
–20
–30
–40
–50
–60
B
12 24 48 72 96 120 144
Weeks
Ruxolitinib
10
Mean percentage change from baseline
Ruxolitinib
10
Palpable spleen length
0
n= 153 152 150 141 130 110 102
90
79
147 141 136 109
47
–10
–20
–30
–40
–50
–60
12 24 48
Placebo
4
8
12 24 48 72 96 120 144
Weeks
4
8
12 24 48
1.0
≥10% reduction (n=91)
Probability
0.8
≥35% reduction (n=91)
0.6
0.4
0.2
0
0
8
No. of patients at risk
≥35%
91
86
reduction
16
24
32
40
48
56
64
72
80
88
96
104
112
120
128
136
144
27
25
23
1
1
Weeks from initial ≥35% spleen volume reduction
77
75
68
62
59
54
51
49
42
40
38
37
Mean change from baseline
Global health status/QOL
20
15
10
5
0
–5
–10
–15
0
12
24
36
48
60
72 84
Weeks
96 108 120 132 144
Role functioning
Mean change from baseline
25
20
15
10
5
0
–5
–10
–15
–20
–25
Mean change from baseline
0
12
24
36
48
60
72 84
Weeks
96 108 120 132 144
Fatigue
10
5
0
–5
–10
–15
–20
–25
–30
–35
0
12
24
36
60
72
Weeks
84
96
108 120 132 144
Physical functioning
15
Mean change from baseline
48
10
5
0
–5
–10
0
12
24
36
48
60
72
Weeks
84
96
108 120 132 144
Ruxolitinib
Placebo
A
1.0
Original ruxolitinib
Probability
0.8
Original placebogruxolitinib
0.6
HR: 0.69 (95% CI: 0.46-1.03); P=0.067
0.4
No. of deaths: ruxolitinib = 42; placebo = 54
Median follow-up: 149 weeks
0.2
Percentage of at-risk placebo who crossed over or discontinued
0
0
4
13
22
35
54
73
88
97
99 100 100 100 100 100 100 100 100 100 100 100 100 100
8
16
24
32
40
48
56
64
72
80
88 96 104 112 120 128 136 144 152 160 168 176
Weeks
No. of patients at risk
Ruxolitinib
155 155 153 148 145 143 137 131 125 124 122 115 112 111 111 108 106 101
84
45
19
1
0
Placebo
68
38
28
8
0
B
154 153 149 144 134 129 119 114 107 105 100 100
95
92
88
85
82
79
1.0
Probability
0.8
Ruxolitinib
0.6
Placebog ruxolitinib
0.4
Placebo-RPSFT
0.2
HR: 0.36 (95% CI: 0.204-1.035)
0
0
8
16
24
32
40
48
56
64
72
80
88 96
Weeks
104 112 120 128 136 144 152 160 168 176
A
Ruxolitinib grade 4
Placebo* grade 3
Placebo* grade 4
Anemia
50
45
45
40
40
35
28.4
30
25
20
15
11.5
10.7
10
5
3.1
4.0
3.4
4.8
0-<6
6-<12
4.2
2.9
12-<18
B
18-<24
Months
1.6
0
24-<30
0
2.1
30-<36
0
0
≥36
15
8.7
105
100
95
90
24
36
48
60
72 84
Weeks
0.8
3.4
0
0-<6
1.6 1.6
0.9 0.9
1.1 1.0
6-<12
12-<18
18-<24
Months
96 108 120 132 144
No. of patients
RUX 155 145 143 136 124 113 110 107 104 100 94
PBO 151 132 113 83 37
88
79
3.5
1.1
2.1 1.9
24-<30
30-<36
0
0
≥36
Platelet count
370
Mean platelets, × 109/L
Mean hemoglobin, g/L
20
Placebo
110
12
25
0
Hemoglobin
115
0
30
5
Ruxolitinib
85
35
10
0
0
Thrombocytopenia
50
Percentage of patients
Percentage of patients
Ruxolitinib grade 3
320
270
220
170
120
0
12
24
36
48
60
72 84
Weeks
96
108 120 132 144
No. of patients
RUX 155 144 143 136 124 112 110 107 104 100 94
PBO 151 128 112 82 37
88
79
Verstovsek S, et al.
Online Supplement
Detailed methods
Patients and study design
Patients enrolled in COMFORT-I had intermediate-2 or high-risk primary myelofibrosis
(MF) according to the International Prognostic Scoring System1 or post–polycythemia vera MF
or post-essential thrombocythemia MF according to the 2008 World Health Organization criteria,
had splenomegaly (palpable ≥5 cm below the left costal margin), and had a platelet count
≥100 × 109/L. Detailed inclusion and exclusion criteria have been previously described.2 Eligible
patients were randomized 1:1 to ruxolitinib or placebo given orally twice a day (BID). The
starting dose of ruxolitinib was based on baseline platelet count: 15 mg BID for a baseline
platelet count between 100 and 200 × 109/L or 20 mg BID for patients with a baseline platelet
count >200 × 109/L. Doses could be decreased for safety or increased to enhance efficacy, as
specified by the study protocol.2
The primary analysis occurred when all patients had either completed the week 24
evaluation or discontinued from the study and half of those remaining in the study completed the
week 36 visit. Patients in the placebo group could crossover to ruxolitinib prior to the primary
analysis based on defined criteria for worsening splenomegaly. After the primary analysis was
completed, the study was unblinded and all remaining patients receiving placebo were allowed
to crossover to ruxolitinib.2 The protocol was designed by Incyte Corporation and approved by
the institutional review board at each participating site. The study sponsor’s clinical and
statistical teams analyzed and interpreted the data in collaboration with the investigators. All
authors had access to the aggregate study data and any additional analyses upon request. The
study was conducted in accordance with the International Conference on Harmonization
guidelines for Good Clinical Practice. All patients provided written informed consent.2
1
Verstovsek S, et al.
Assessments
The primary endpoint was the proportion of patients achieving a ≥35% reduction from
baseline in spleen volume at week 24, assessed by abdominal imaging (magnetic resonance
imaging or computed tomography).2 Spleen volume was measured at baseline, weeks 12, 24,
36, 48, 60, 72, and every 24 weeks thereafter. Palpable spleen length was assessed at baseline
and at each study visit. Symptom burden, assessed by the modified MF Symptom Assessment
Form version 2.0 electronic diary,2,3 was measured up to week 24. Quality of life was evaluated
using the European Organization for Research and Treatment of Cancer Quality of Life
Questionnaire-Core 30 at baseline and each study visit. Adverse events were evaluated using
the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.
Statistical analysis
The current analysis is a prospectively defined analysis of efficacy and safety, the timing
of which was prespecified to occur when all patients either reached the 144-week assessment
or discontinued from the study. Changes from baseline in spleen volume and palpable spleen
length were based on observed cases and summarized descriptively. Durability of spleen
volume reduction was evaluated using the Kaplan-Meier method in patients who achieved a
≥35% reduction from baseline in spleen volume. Loss of a ≥35% spleen volume reduction was
defined as the first <35% spleen volume reduction from baseline that was also a ≥25% increase
from nadir. Overall survival, a prespecified secondary endpoint, was assessed using the
Kaplan-Meier method for the intent-to-treat (ITT) population with patients assessed per their
original randomized treatment regardless of subsequent crossover. Survival time was measured
from study start to last known status of the patient and was not censored at time of
discontinuation from randomized treatment. The Cox proportional hazards model and log-rank
test were used to calculate the hazard ratio with 95% confidence interval and P-value,
2
Verstovsek S, et al.
respectively. The Kaplan-Meier method was used to estimate discontinuation rates at years 1,
2, and 3 based on time to discontinuation in the ruxolitinib arm. The incidence (conditional
probability of event) of new-onset or worsening grade ≥3 anemia and thrombocytopenia (based
on laboratory data) and of new-onset or worsening all-grade and grade ≥3 nonhematologic
adverse events were calculated using the life table method based on the time to first event
censored at the date of last laboratory evaluation for anemia and thrombocytopenia and the
earlier of discontinuation or date of data cutoff for nonhematologic adverse events. Because the
majority of the anemia and thrombocytopenia events occurred early in the study, the incidence
of new-onset or worsening grade 3 or 4 anemia or thrombocytopenia was assessed at 6-month
intervals in patients originally randomized to ruxolitinib; the placebo group was included only in
the first 6-month interval because all patients receiving placebo discontinued or crossed over to
ruxolitinib within 3 months of the primary analysis. The incidence of nonhematologic events was
assessed in yearly intervals for patients originally randomized to ruxolitinib. Per the life table
method, the incidence of each adverse event was based on the effective sample size of the time
interval, which was the number of patients at risk at the beginning of the interval minus half of
the censored patients during the time interval.
To better understand the effect of patients from the placebo arm crossing over to
ruxolitinib treatment on survival measurement, two exploratory analyses were performed. The
first exploratory analysis used the rank-preserving structural failure time (RPSFT) method, a
statistical method used in oncology trials to adjust for possible crossover effect.4-6 This method
adjusts for crossover in the placebo group by relating the portion of observed survival time after
crossover to active treatment to a multiplicative coefficient that represents either the beneficial
or the harmful effect of treatment on survival, and applies this coefficient to estimate survival
times as if crossover in the placebo group had not occurred. The hazard ratio was estimated
using Cox regression analysis of reconstructed survival times, and the 95% confidence interval
was estimated using the bootstrap method. As the null hypothesis of the RPFST method was
3
Verstovsek S, et al.
the original ITT analysis, the method does not alter the P-value from the original ITT analysis. Additional model description and implementation details, including re-censoring of the
reconstructed survival time, are described by Robins and Tsiatis4 and Korhonen et al.7 In the
second analysis, a parametric statistical modeling of overall survival using the generalized
Gamma distribution was conducted;8,9 this involved fitting a three-parameter regression model
to the observed survival data that resulted in a smooth curve representing an estimated survival
function curve. The survival function curve was then visually compared with the Kaplan-Meier
curve over the period used for the model to understand how well it reflected the actual data. The
fitted model was subsequently used to calculate the corresponding hazard of death for patients
originally randomized to ruxolitinib and those randomized to placebo.
References
1.
Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary
myelofibrosis based on a study of the International Working Group for Myelofibrosis
Research and Treatment. Blood. 2009;113(13):2895-2901.
2.
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of
ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.
3.
Mesa RA, Gotlib J, Gupta V, et al. Effect of ruxolitinib therapy on myelofibrosis-related
symptoms and other patient-reported outcomes in COMFORT-I: a randomized, doubleblind, placebo-controlled trial. J Clin Oncol. 2013;31(10):1285-1292.
4.
Robins JM, Tsiatis A. Correcting for non-compliance in randomized trials using rank
preserving structural failure time models. Commun Stat Theory Methods.
1991;20(8):2609-2631.
4
Verstovsek S, et al.
5.
Demetri GD, Garrett CR, Schoffski P, et al. Complete longitudinal analyses of the
randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal
stromal tumor following imatinib failure. Clin Cancer Res. 2012;18(11):3170-3179.
6.
Sternberg CN, Hawkins RE, Wagstaff J, et al. A randomised, double-blind phase III
study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma:
final overall survival results and safety update. Eur J Cancer. 2013;49(6):1287-1296.
7.
Korhonen P, Zuber E, Branson M, et al. Correcting overall survival for the impact of
crossover via a rank-preserving structural failure time (RPSFT) model in the RECORD-1
trial of everolimus in metastatic renal-cell carcinoma. J Biopharm Stat. 2012;22(6):12581271.
8.
Lawless JF. Statistical Models and Methods for Lifetime Data. Hoboken, NJ: WileyInterscience; 2002.
9.
Yavari P, Abadi A, Amanpour F, Bajdik C. Applying conventional and saturated
generalized gamma distributions in parametric survival analysis of breast cancer. Asian
Pac J Cancer Prev. 2012;13(5):1829-1831.
5
Verstovsek S, et al.
Supplemental Data Table 1. Causes of death by randomized treatment allocation.*
Cause of death, n
Ruxolitinib
(N=155)
Acute leukemia
Acute myeloid leukemia
Placebo
(N=154)
1
2
2
Acute myeloid leukemia progression
1
Anastomotic hemorrhage
1
Anemia, systemic
1
Cardiac arrest
1
Cardiac failure congestive
1
Cerebral hemorrhage
1
Completed suicide
1
Congestive heart failure resulting from pneumonia
1
Death
1
Disease progression
6
9
Disease progression and cardiac failure
1
Gastrointestinal hemorrhage
1
Graft versus host disease
1
Intestinal perforation
1
Intra-abdominal hemorrhage
1
Leukemia or underlying leukemia
1
Leukemic transformation
1
Muscular weakness
1
1
Metastatic colon cancer
1
Multi-organ failure
1
Myelodysplastic syndrome disease progression
1
Myelofibrosis
3
Myelofibrosis progression
1
3
6
Verstovsek S, et al.
Myelofibrosis with possible transformation to acute myeloid
leukemia and pneumonia
1
Myeloproliferative disease
1
Myocardial infarction
2
Non-small cell lung cancer metastatic
1
Pancreatic carcinoma
1
Pneumonia
1
Pneumonia, multi-organ failure
1
Pneumonia and septic shock
1
Renal failure
1
Respiratory failure
1
Road traffic accident
Sepsis or septic shock
1
1
3
Shock hemorrhagic
3
1
Shock, respiratory and cardiac failure; hemorrhage following
splenectomy
1
Splenic infarction
1
Splenic rupture
1
Staphylococcal infection
1
Subdural hematoma
1
Subdural hemorrhage
1
Surgical complications
1
1
Unknown
9
11
Total
42
54
*Causes of death were collected verbatim as reported during long-term follow-up, thus cause of death was not
available for all patients.
7
Verstovsek S, et al.
Supplemental Data Table 2. Incidence of new-onset grade 3 or 4 nonhematologic adverse
events regardless of causality.
Ruxolitinib
12-<24
24-<36
0-<12 months
months
months
≥36 months
(n=155)
(n=130)
(n=103)
(n=82)
Fatigue
6.2
0.9
3.3
0
Pneumonia
5.6
3.6
3.5
0
Abdominal pain
4.2
0
3.2
0
Arthralgia
2.1
0
0
0
Diarrhea
2.1
0
0
0
Dyspnea
2.1
0.9
2.2
2.5
Pain in extremity
2.1
0
1.1
0
Hyperuricemia
1.4
0.9
0
2.5
Fall
1.4
0.9
0
0
GI hemorrhage
1.4
0.9
0
0
Septic shock
1.4
0
0
0
Muscular weakness
1.4
0
1.1
0
Hypoxia
1.4
0
2.2
0
Sepsis
0.7
1.7
2.2
0
Epistaxis
0.7
1.7
0
0
Renal failure acute
0.7
0.9
2.2
2.4
Abdominal pain upper
0.7
0
2.2
0
Myocardial infarction
0
0.9
0
4.8
Incidence, %
Percentage of patients for each event was based on the effective sample size of the time interval (number of patients
at risk at the beginning of the interval minus half of the censored patients during the time interval). Adverse event is
included if the incidence was ≥2 patients at any yearly interval. GI: gastrointestinal.
8
Verstovsek S, et al.
Supplemental Data Table 3. Summary of treatment-emergent (grade 3 or higher) and
SAEs reported during study drug interruption.
Ruxolitinib (N=59)
Adverse event
Grade ≥3
Any SAE
Number (%) of patients with any adverse event
27 (45.8)
21 (35.6)
Anemia
9 (15.3)
3 (5.1)
Thrombocytopenia
5 (8.5)
0
Hemoglobin decreased
2 (3.4)
1 (1.7)
Pneumonia
2 (3.4)
2 (3.4)
Sepsis
2 (3.4)
1 (1.7)
Disseminated intravascular coagulation
1 (1.7)
0
Neutropenia
1 (1.7)
0
Platelet count decreased
1 (1.7)
1 (1.7)
Cardiac failure congestive
1 (1.7)
1 (1.7)
Abdominal pain
1 (1.7)
1 (1.7)
Gastrointestinal hemorrhage
1 (1.7)
1 (1.7)
Nausea
1 (1.7)
0
Obturator hernia
1 (1.7)
1 (1.7)
Esophageal varices hemorrhage
1 (1.7)
1 (1.7)
Rectal hemorrhage
1 (1.7)
1 (1.7)
Retroperitoneal hematoma
1 (1.7)
0
Vomiting
1 (1.7)
1 (1.7)
Asthenia
1 (1.7)
0
Fatigue
1 (1.7)
0
Systemic inflammatory response syndrome
1 (1.7)
0
Diverticulitis
1 (1.7)
0
Lung infection
1 (1.7)
1 (1.7)
Perirectal abscess
1 (1.7)
1 (1.7)
Pseudomonas sepsis
1 (1.7)
1 (1.7)
9
Verstovsek S, et al.
Urinary tract infection
1 (1.7)
1 (1.7)
Fall
1 (1.7)
0
Post-procedural hemorrhage
1 (1.7)
1 (1.7)
Tibia fracture
1 (1.7)
1 (1.7)
Troponin increased
1 (1.7)
0
Bone pain
1 (1.7)
0
Acute myeloid leukemia
1 (1.7)
1 (1.7)
Delirium
1 (1.7)
0
Renal failure acute
1 (1.7)
0
Dyspnea
1 (1.7)
1 (1.7)
Pneumonia aspiration
1 (1.7)
0
Pneumonitis
1 (1.7)
1 (1.7)
Pulmonary hypertension
1 (1.7)
0
Febrile neutropenia
0
1 (1.7)
Diastolic dysfunction
0
1 (1.7)
Pyrexia
0
1 (1.7)
Urosepsis
0
1 (1.7)
All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary
analysis; therefore, no additional data beyond what were previously reported (Verstovsek S, Mesa RA, Gotlib J, et al.
Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of
COMFORT-I. Haematologica. 2013;98(12):1865-1871) are available for these patients. SAEs: serious adverse
events.
10
Verstovsek S, et al.
Supplemental Data Table 4. Summary of treatment-emergent (grade 3 or higher) and
SAEs reported after study drug discontinuation.
Ruxolitinib (N=78)
Adverse event
Grade ≥3
Any SAE
Number (%) of patients with any adverse event
31 (39.7)
32 (41.0)
Thrombocytopenia
6 (7.7)
2 (2.6)
Pneumonia
3 (3.8)
4 (5.1)
Renal failure acute
3 (3.8)
1 (1.3)
Sepsis
3 (3.8)
3 (3.8)
Abdominal pain
2 (2.6)
2 (2.6)
Acute myeloid leukemia
2 (2.6)
3 (3.8)
Disease progression
2 (2.6)
2 (2.6)
Dyspnea
2 (2.6)
1 (1.3)
Hypokalemia
2 (2.6)
0
Hypotension
2 (2.6)
1 (1.3)
Myocardial infarction
2 (2.6)
2 (2.6)
Splenic infarction
2 (2.6)
2 (2.6)
Acute respiratory failure
1 (1.3)
1 (1.3)
Anemia
1 (1.3)
1 (1.3)
Anuria
1 (1.3)
0
Asthenia
1 (1.3)
1 (1.3)
Atrial fibrillation
1 (1.3)
0
Cardiac arrest
1 (1.3)
0
Cardiac failure congestive
1 (1.3)
1 (1.3)
Cholecystitis infective
1 (1.3)
1 (1.3)
Clostridial infection
1 (1.3)
1 (1.3)
Confusional state
1 (1.3)
0
Death
1 (1.3)
1 (1.3)
Disseminated intravascular coagulation
1 (1.3)
0
11
Verstovsek S, et al.
Edema
1 (1.3)
0
Epistaxis
1 (1.3)
0
Fatigue
1 (1.3)
1 (1.3)
Febrile neutropenia
1 (1.3)
0
Hemoglobin decreased
1 (1.3)
0
Hepatosplenomegaly
1 (1.3)
1 (1.3)
Hyperbilirubinemia
1 (1.3)
0
Hyperglycemia
1 (1.3)
0
Hypoxia
1 (1.3)
0
Lactic acidosis
1 (1.3)
0
Leukocytosis
1 (1.3)
0
Malnutrition
1 (1.3)
0
Muscular weakness
1 (1.3)
1 (1.3)
Pancreatic carcinoma
1 (1.3)
1 (1.3)
Platelet count increased
1 (1.3)
0
Portal vein thrombosis
1 (1.3)
0
Pulmonary edema
1 (1.3)
0
Pulmonary tuberculosis
1 (1.3)
1 (1.3)
Pyrexia
1 (1.3)
3 (3.8)
Renal failure
1 (1.3)
1 (1.3)
Renal tubular necrosis
1 (1.3)
0
Respiratory failure
1 (1.3)
1 (1.3)
Septic shock
1 (1.3)
1 (1.3)
Splenic hemorrhage
1 (1.3)
1 (1.3)
Subdural hematoma
1 (1.3)
1 (1.3)
Subdural hemorrhage
1 (1.3)
1 (1.3)
Supraventricular tachycardia
1 (1.3)
0
Transaminases increased
1 (1.3)
0
Transient ischemic attack
1 (1.3)
1 (1.3)
12
Verstovsek S, et al.
Abdominal pain upper
0
1 (1.3)
Cellulitis
0
1 (1.3)
Dehydration
0
1 (1.3)
Diarrhea
0
1 (1.3)
Fall
0
1 (1.3)
Pneumonia aspiration
0
1 (1.3)
Postoperative wound infection
0
1 (1.3)
All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary
analysis; therefore, no additional data beyond what were previously reported (Verstovsek S, Mesa RA, Gotlib J, et al.
Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of
COMFORT-I. Haematologica. 2013;98(12):1865-1871) are available for these patients. SAEs: serious adverse
events.
13
Verstovsek S, et al.
Supplemental Data Figure 1. Generalized Gamma distribution–based model of overall survival and hazard of death.
14