Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia.

Abstract

The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For 5 years, we followed patients with CML who received imatinib as initial therapy.
We randomly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine and then evaluated them for overall and event-free survival; progression to accelerated-phase CML or blast crisis; hematologic, cytogenetic, and molecular responses; and adverse events.
The median follow-up was 60 months. Kaplan-Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69% by 12 months and 87% by 60 months. An estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial therapy was 89% at 60 months. Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response (P<0.001). Grade 3 or 4 adverse events diminished over time, and there was no clinically significant change in the profile of adverse events.
After 5 years of follow-up, continuous treatment of chronic-phase CML with imatinib as initial therapy was found to induce durable responses in a high proportion of patients. (ClinicalTrials.gov number, NCT00006343 [ClinicalTrials.gov].)

Full text

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original article
The new england journal of medicine
n engl j med 355;23 www.nejm.org december 7, 2006
2408
Five-Year Follow-up of Patients Receiving
Imatinib for Chronic Myeloid Leukemia
Brian J. Druker, M.D., François Guilhot, M.D., Stephen G. O’Brien, M.D., Ph.D.,
Insa Gathmann, M.Sc., Hagop Kantarjian, M.D., Norbert Gattermann, M.D.,
Michael W.N. Deininger, M.D., Ph.D., Richard T. Silver, M.D.,
John M. Goldman, D.M., Richard M. Stone, M.D., Francisco Cervantes, M.D.,
Andreas Hochhaus, M.D., Bayard L. Powell, M.D., Janice L. Gabrilove, M.D.,
Philippe Rousselot, M.D., Josy Reiffers, M.D., Jan J. Cornelissen, M.D., Ph.D.,
Timothy Hughes, M.D., Hermine Agis, M.D., Thomas Fischer, M.D.,
Gregor Verhoef, M.D., John Shepherd, M.D., Giuseppe Saglio, M.D.,
Alois Gratwohl, M.D., Johan L. Nielsen, M.D., Jerald P. Radich, M.D.,
Bengt Simonsson, M.D., Kerry Taylor, M.D., Michele Baccarani, M.D.,
Charlene So, Pharm.D., Laurie Letvak, M.D.,
and Richard A. Larson, M.D., for the IRIS Investigators*
Address reprint requests to Dr. Druker at
the Oregon Health and Science University
Cancer Institute, L592, 3181 SW Sam Jack-
son Park Rd., Portland, OR 97239, or at
drukerb@ohsu.edu.
* Authors’ affiliations and investigators in
the International Randomized Study of
Interferon and STI571 (IRIS) are listed in
the Appendix.
N Engl J Med 2006;355:2408-17.
Copyright © 2006 Massachusetts Medical Society.
ABSTRACT
Background
The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyro-
sine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to
interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For
5 years, we followed patients with CML who received imatinib as initial therapy.
Methods
We randomly assigned 553 patients to receive imatinib and 553 to receive interferon
alfa plus cytarabine and then evaluated them for overall and event-free survival; pro-
gression to accelerated-phase CML or blast crisis; hematologic, cytogenetic, and mo-
lecular responses; and adverse events.
Results
The median follow-up was 60 months. Kaplan–Meier estimates of cumulative best
rates of complete cytogenetic response among patients receiving imatinib were 69%
by 12 months and 87% by 60 months. An estimated 7% of patients progressed to
accelerated-phase CML or blast crisis, and the estimated overall survival of patients
who received imatinib as initial therapy was 89% at 60 months. Patients who had a
complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen
by at least 3 log had a significantly lower risk of disease progression than did pa-
tients without a complete cytogenetic response (P<0.001). Grade 3 or 4 adverse events
diminished over time, and there was no clinically significant change in the profile
of adverse events.
Conclusions
After 5 years of follow-up, continuous treatment of chronic-phase CML with imatinib
as initial therapy was found to induce durable responses in a high proportion of pa-
tients. (ClinicalTrials.gov number, NCT00006343.)
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Imatinib as Primary Therapy for Chronic Myeloid Leukemia
n engl j med 355;23 www.nejm.org december 7, 2006
2409
C
etic cells that carries the Philadelphia chromo-
some (Ph).1 The Ph chromosome results from a
reciprocal translocation between the long arms
of chromosomes 9 and 22, t(9;22)(q34;q11).2 The
molecular consequence of this translocation is a
novel fusion gene, BCR-ABL, which encodes a con-
stitutively active protein, tyrosine kinase.3-5 Ima-
tinib (Gleevec, Novartis; formerly called STI571) is
a relatively specific inhibitor of the BCR-ABL tyro-
sine kinase and has efficacy in CML.6-11
Before the availability of imatinib, interferon
alfa plus cytarabine was considered standard ther-
apy for patients with CML who were not plan-
ning to undergo allogeneic hematopoietic stem-
cell transplantation.12,13 A randomized trial that
compared imatinib with interferon alfa plus cyta-
rabine in the chronic phase of CML demonstrated
the significant superiority of imatinib in all stan-
dard indicators of the disease within a median
follow-up of 19 months.14 The trial was designed
as a crossover study, and given the superior results
with imatinib, a large proportion of patients in
the interferon group switched to imatinib. In ad-
dition, at the time of Food and Drug Administra-
tion approval of imatinib, many patients who were
assigned to receive interferon alfa plus cytarabine
left the study. Consequently, the trial has evolved
into a long-term study of the result of treating
newly diagnosed patients in the chronic phase of
CML with imatinib. We now report 60 months of
follow-up data and focus on patients who received
imatinib as a primary treatment.
hronic myeloid leukemia (cml) is a
myeloproliferative disorder characterized
by the expansion of a clone of hematopoi-
Methods
Study Design
The design of the study has been described pre-
viously.14 The International Randomized Study
of Interferon and STI571 (IRIS) was a multicenter,
international, open-label, phase III randomized
study. Eligible patients had to be between 18 and
70 years of age, must have been diagnosed with
Ph-positive CML in chronic phase within 6 months
before study entry, and must not have received
treatment for CML, except for hydroxyurea or ana-
grelide.
Patients were recruited from June 2000 through
January 2001 and were randomly assigned to re-
ceive imatinib at a dose of 400 mg orally per day
or subcutaneous interferon alfa at a daily tar-
get dose of 5 million U per square meter of body-
surface area, plus 10-day cycles of cytarabine at
a daily dose of 20 mg per square meter every
month. Patients receiving imatinib who did not
have a complete hematologic response within
3 months or whose bone marrow contained more
than 65% Ph-positive cells at 12 months could
have a stepwise increase in the dose of imatinib
to 400 mg orally twice daily as long as there were
no dose-limiting adverse events. Patients were al-
lowed to cross over to the other treatment group
if they did not achieve either a complete hema-
tologic response after 6 months of therapy or a
major cytogenetic response after 12 months or if
they had a relapse or an increase in white-cell
count or could not tolerate treatment. All cross-
over requests were made anonymously and con-
sidered weekly by the study management com-
mittee (see the Appendix).
End Points
The primary end point was event-free survival,
which was referred to in previous presentations
and articles as the time to progression, or progres-
sion-free survival. Events were defined by the first
occurrence of any of the following: death from any
cause during treatment, progression to the acceler-
ated phase or blast crisis of CML, or loss of a com-
plete hematologic or major cytogenetic response.
Secondary end points were the rate of complete he-
matologic response (defined as a leukocyte count
<10×109 per liter, a platelet count of <450×109 per
liter, <5% myelocytes plus metamyelocytes, no
blasts or promyelocytes, no extramedullary involve-
ment, and no signs of the accelerated phase or
blast crisis of CML); a cytogenetic response in mar-
row cells, categorized as complete (no Ph-positive
metaphases), partial (1 to 35% Ph-positive meta-
phases), or major (complete plus partial responses)
on the basis of G-banding in at least 20 cells in
metaphase per sample; progression to the acceler-
ated phase or blast crisis; overall survival; safety;
and tolerability. Signs of a molecular response were
sought every 3 months after a complete cytoge-
netic response was obtained with the use of real-
time quantitative polymerase chain reaction to
measure the ratio of BCR-ABL transcripts to BCR
transcripts. Results were expressed as “log reduc-
tions” below a standardized baseline derived from
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2410
a median ratio of BCR-ABL to BCR obtained from
30 untreated patients with chronic-phase CML.15
Ethics and Study Management
The study was conducted in accordance with the
Declaration of Helsinki. The study protocol was
reviewed by the ethics committee or institutional
review board at each participating center. All pa-
tients gave written informed consent, according
to institutional regulations. The academic inves-
tigators and representatives of the sponsor, No-
vartis, designed the study. Data-management and
statistical-support staff at a contract research or-
ganization collected the data, which were ana-
lyzed and interpreted by a biostatistician from No-
vartis in close collaboration with the investigators.
The study management committee and all aca-
demic investigators had access to the raw data. The
study management committee, composed of four
academic investigators, served as the writing com-
mittee. Along with the Novartis biostatistician,
they vouch for the accuracy and completeness of
the data.
Statistical Analysis
The study is ongoing, but January 31, 2006, was
the cutoff date for this analysis. This date marked
5 to 5.5 years after patients started to receive ima-
tinib treatment. We followed all 553 patients who
were assigned to receive imatinib for an analysis
of safety and efficacy until they stopped taking
imatinib, and we have continued to follow all pa-
tients until death, loss to follow-up, or withdraw-
al of consent. Survival data were also collected on
patients who underwent bone marrow transplan-
tation after imatinib treatment. We performed
analyses of survival and event-free survival, using
the Kaplan–Meier method according to the inten-
tion-to-treat principle and using all data available,
regardless of whether crossover occurred. Differ-
ences between subgroups of patients receiving
imatinib were calculated by the log-rank test. Cu-
mulative rates of complete hematologic and cyto-
genetic responses were estimated according to the
Kaplan–Meier method, in which data from patients
receiving imatinib who did not have an adequate
response, who had switched to interferon alfa plus
cytarabine, or who had discontinued treatment for
reasons other than progression of CML were cen-
sored at the last follow-up visit. For the estimation
of cumulative response rates, we censored data
from patients with progressive CML at maximum
follow-up. We used the life-table method to deter-
mine yearly event probabilities. The safety of ima-
tinib was analyzed for 551 patients who received
at least one dose of the study drug during the trial.
For the 553 patients assigned to receive interfer-
on alfa plus cytarabine, disposition and overall sur-
vival were summarized.
Table 1. Enrollment, Outcomes, and Reasons for Crossover
and Discon tinuation.*
Variable
Imatinib
(N = 553)
Interferon Alfa
plus Cytarabine
(N = 553)
no. of patients (%)
Assignment of patients
Continued first-line treatment382 (69)16 (3)
Discontinued first-line treatment157 (28) 178 (32)
Crossed over to other treatment 14 (3)359 (65)
Discontinued second-line treatment 14 (3)108 (20)
Reason for crossover
Other than progression
Intolerance of treatment† 4 (<1) 144 (26)
No complete hematologic
response at 6 mo
0 41 (7)
No major cytogenetic response
at 12 mo
1 (<1)49 (9)
Other 0 48 (9)
Progression only
Increase in white-cell count† 2 (<1)25 (5)
Loss of complete hematologic
response
5 (<1) 29 (5)
Loss of major cytogenetic
response
2 (<1)23 (4)
Reason for discontinuation‡
Adverse event23 (4)35 (6)
Death10 (2) 2 (<1)
Unsatisfactory therapeutic effect 59 (11)29 (5)
Stem-cell transplantation16 (3) 7 (1)
Protocol violation 15 (3) 17 (3)
Loss to follow-up5 (<1)6 (1)
Withdrawal of consent25 (5) 76 (14)
Other4 (<1)6 (1)
* The first patient entered the study on June 16, 2000, and enrollment ended
January 30, 2001.
† The crossover of patients with this condition to the other treatment group
needed previous approval by the study management committee.
‡ A total of 157 patients who received imatinib and 178 patients who received
interferon alfa plus cytarabine discontinued therapy.
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Imatinib as Primary Therapy for Chronic Myeloid Leukemia
n engl j med 355;23 www.nejm.org december 7, 2006
2411
Results
Patients
Five years after the last of 1106 patients had started
treatment, and with a median of 60 months of
follow-up, 382 of 553 patients (69%) in the ima-
tinib group and 16 of 553 patients (3%) in the
group given interferon alfa plus cytarabine con-
tinued with their initially assigned treatment (Ta-
ble 1). Of the patients given interferon plus cyta-
rabine, 359 (65%) had crossed over to imatinib,
whereas 14 patients (3%) in the imatinib group
had switched to the alternative treatment. The most
common reason for crossover among patients
given interferon plus cytarabine was intolerance
of treatment (26%). Of these patients, 90 (16%)
switched because they did not achieve a complete
hematologic or major cytogenetic response by the
designated target dates, as did 77 patients (14%)
with disease progression. An additional 178 pa-
tients (32%) given interferon alfa plus cytarabine
discontinued therapy. The reasons most common-
ly reported were withdrawal of consent (14%) and
adverse events (6%). In the imatinib group, 23 pa-
tients (4%) discontinued therapy owing to an ad-
verse event, and 25 patients (5%) withdrew con-
sent (Table 1).
Since few patients were still receiving inter-
feron alfa plus cytarabine at 60 months, the re-
mainder of this report focuses on the long-term
follow-up of patients who received imatinib as
the initial therapy for CML. They had been treated
with imatinib for a mean (±SD) of 50±19 months
(median, 60 months). Among the 382 patients
who continued receiving imatinib, the mean daily
dose during this reporting period was 382±50 mg.
In 82% of these patients, the last reported daily
dose was 400 mg; 6% were receiving 600 mg, 4%
were receiving 800 mg, and 8% were receiving
less than 400 mg.
Table 2. Proportion of Patients Receiving First-Line Imatinib Therapy with Grade 3 or Grade 4 Adverse Events.
Hematologic or Hepatic ConditionGrade 3 or Grade 4 Adverse Events
Total Events
(N = 551)
Years 1 and 2
(N = 551)
Years 3 and 4
(N = 456)
After Year 4
(N = 409)
percent
Neutropenia 17 143*1*
Thrombocytopenia98 1*<1*
Anemia43 1† <1‡
Elevated liver enzymes55 <1* 0*
Other drug-related adverse event 17144* 2*
* P<0.001 for the comparison of events in years 3 and 4 and after 4 years with those in years 1 and 2.
† The difference between events in years 3 and 4 and those in years 1 and 2 did not reach statistical significance.
‡ P<0.01 for the comparison of events after 4 years with those in years 1 and 2.
Rates of Response (%)
80
90
70
60
40
30
10
50
20
0
06 1218 243036 42 4854 6066
Months
100
Complete hematologic response
Major cytogenetic response
Complete cytogenetic response
Figure 1. Kaplan–Meier Estimates of the Cumulative Best Response
to Initial Imatinib Therapy.
At 12 months after the initiation of imatinib, the estimated rates of having
a response were as follows: complete hematologic response, 96%; major
cytogenetic response, 85%; and complete cytogenetic response, 69%. At
60 months, the respective rates were 98%, 92%, and 87%. Data for pa-
tients who discontinued imatinib for reasons other than progression and
who did not have an adequate response were censored at the last follow-up
visit. Data for patients who did not have an adequate response and who
stopped imatinib because of progression were censored at maximum fol-
low-up.
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2412
Adverse Events
After a median follow-up of 60 months, the ad-
verse events reported were similar to those report-
ed previously.14 The most commonly reported ad-
verse events were edema (including peripheral and
periorbital edema) (60%), muscle cramps (49%),
diarrhea (45%), nausea (50%), musculoskeletal
pain (47%), rash and other skin problems (40%),
abdominal pain (37%), fatigue (39%), joint pain
(31%), and headache (37%). Grade 3 or 4 adverse
events consisted of neutropenia (17%), throm-
bocytopenia (9%), anemia (4%), elevated liver en-
zymes (5%), and other drug-related adverse events
(17%). Congestive heart failure was reported as
being drug-related in one patient (<1%). Newly oc-
curring or worsening grade 3 or 4 hematologic or
biochemical adverse events were infrequent after
both 2 and 4 years of therapy (Table 2).
Efficacy
Figure 1 shows the estimated cumulative rates
of complete hematologic remission: 96% at 12
months and 98% at 60 months. The best observed
rate of complete hematologic response was 97%.
At 12 months, the estimated rate of major cyto-
genic response was 85% and that of complete cy-
togenetic response was 69%. At 60 months, the
estimated rates were 92% and 87%, respectively.
With a median follow-up of 60 months, the best
observed rate of major cytogenetic response was
89%, and the best rate of complete cytogenetic
response was 82%. Of the 382 patients who still
received imatinib at 60 months, 368 (96%) had a
complete cytogenetic response.
There were significant differences in the rates
of cytogenetic response, according to a scoring
system devised by Sokal and colleagues,16 which
divides patients with CML into low-risk, interme-
diate-risk, and high-risk groups. In patients who
were deemed to be at low risk on the Sokal scor-
ing system, the rate of complete cytogenetic re-
sponse was 89%; the rate among patients at in-
termediate risk was 82%; and for those at high
risk, the rate was 69% (P<0.001).
Among 124 patients who had a complete cy-
togenetic response and whose blood samples tak-
en at 1 and 4 years were available, BCR-ABL tran-
scripts in the blood samples were measured. After
1 year, levels of BCR-ABL transcripts had fallen by
at least 3 log in 66 of 124 patients (53%); after
4 years, levels had fallen in 99 of 124 patients
(80%) (P<0.001). The proportion of patients with
a reduction of at least 4 log in transcript levels
increased from 22 to 41% between 1 and 4 years
(P<0.001). The median log reduction of BCR-ABL
transcripts was 3.08 at 1 year and 3.78 at 4 years
(P<0.001).
Long-term Outcomes
At 60 months, the estimated rate of event-free sur-
vival was 83% (95% confidence interval [CI], 79
to 87), and an estimated 93% of patients (95% CI,
90 to 96) had not progressed to the accelerated
phase or blast crisis (Fig. 2). Of the 553 patients
receiving imatinib, 35 (6%) progressed to the ac-
celerated phase or blast crisis, 14 (3%) had a he-
matologic relapse, 28 (5%) had a loss of major cy-
togenetic response, and 9 (2%) died from a cause
unrelated to CML. The estimated annual rate of
treatment failure after the start of imatinib ther-
apy was 3.3% in the first year, 7.5% in the second
year, 4.8% in the third year, 1.5% in the fourth
year, and 0.9% in the fifth year. The correspond-
ing annual rates of progression to the accelerated
phase or blast crisis were 1.5%, 2.8%, 1.6%, 0.9%,
and 0.6%, respectively. In the 454 patients who had
Patients without Event (%)
80
90
70
60
40
30
10
50
20
0
0 12 243648 6072
Months
100
Progression
All events
No. of Events
Progression
All events
No. at Risk
Progression
All events
8
18
513
505
22
55
461
447
29
76
431
414
33
82
409
395
35
85
280
274
Figure 2. Kaplan–Meier Estimates of the Rates of Event-free Survival
and Progression to the Accelerated Phase or Blast Crisis of CML for Pa-
tients Receiving Imatinib.
At 60 months, the estimated rate of event-free survival was 83%. At that
time, 93% of the patients had not progressed to the accelerated phase or
blast crisis. The following were considered events: death from any cause
during treatment, progression to the accelerated phase or blast crisis, loss
of a complete hematologic response, loss of a major cytogenetic response,
or an increasing white-cell count. The number of patients with events and
the number of patients available for analysis are shown.
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Imatinib as Primary Therapy for Chronic Myeloid Leukemia
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2413
a complete cytogenetic response, the annual rates
of treatment failure were 5.5% in the first year,
2.3% in the second year, 1.1% in the third year,
and 0.4% in the fourth year after a response was
achieved. The corresponding annual rates of pro-
gression to the accelerated phase or blast crisis
were 2.1%, 0.8%, 0.3%, and 0%, respectively, in
these patients.
Effect of Response on Outcome
Cytogenetic and molecular responses had signifi-
cant associations with event-free survival and de-
terrence against progression to the accelerated
phase or blast crisis (Fig. 3). A landmark analysis
of the 350 patients who had had a complete cyto-
genetic response at 12 months after the initiation
of imatinib treatment revealed that at 60 months,
97% of the patients (95% CI, 94 to 99) had not
progressed to the accelerated phase or blast crisis.
For the 86 patients with a partial cytogenetic re-
sponse, the estimate was 93% (95% CI, 87 to 99);
for the 73 patients who did not have a major cy-
togenetic response within 12 months, the esti-
mate was 81% (95% CI, 70 to 92) (overall, P<0.001;
P<0.001 for the comparison between patients with
a complete response and those without a com-
plete response, and P = 0.20 for the comparison
between patients with a complete response and
those with a partial response) (Fig. 3A).
At 60 months, the estimated risk of disease
progression was significantly higher for the high-
risk group of patients, according to the Sokal
scoring system (P = 0.002); the estimated rates for
patients in the high-risk, intermediate-risk, and
low-risk groups were 17%, 8%, and 3%, respec-
tively. However, the Sokal score was not associ-
ated with disease progression in patients who had
a complete cytogenetic response (95%, 95%, and
99% in the high-risk, intermediate-risk, and low-
risk groups, respectively) (P = 0.20 overall; P = 0.92
for the comparison between the intermediate-risk
group and the high-risk group, and P = 0.16 for the
comparison between the low-risk group and the
high-risk group).
The molecular responses at 12 and 18 months
were also associated with long-term outcomes. At
60 months, the patients who had a complete cyto-
genetic response and a reduction of at least 3 log
in levels of BCR-ABL transcripts in bone marrow
cells after 18 months of treatment had an esti-
mated rate of survival without progression of CML
of 100%. In the group with a reduction of less
Patients without Progression (%)
80
90
70
60
40
30
10
50
20
0
0 12 2436 4860 72
Months
100
Patients without Progression (%)
80
90
70
60
40
30
10
50
20
0
0 1224364860 72
Months
100
Complete cytogenetic response
with ≥3 log reduction
Complete cytogenetic response
with <3 log reduction
No complete cytogenetic response
A
B
Complete cytogenetic response
Partial cytogenetic response
No major cytogenetic response
Response at 12 Mo
Response at 18 Mo
Figure 3. Rate of Progression to the Accelerated Phase or Blast Crisis
on the Basis of Cytogenetic Response after 12 Months or Molecular
Response after 18 Months of Imatinib Therapy.
Panel A shows that at 60 months, of the 350 patients with a complete cyto-
genetic response after 12 months of imatinib therapy, an estimated 97%
had not progressed to the accelerated phase or blast crisis. The corre-
sponding rates for 86 patients with a partial cytogenetic response and for
73 patients who did not have a major cytogenetic response were 93% and
81%, respectively (P<0.001; P = 0.20 for the comparison between patients
with a complete cytogenetic response and those with a partial response).
At 12 months, 44 patients had discontinued imatinib and thus were not
included in this analysis. Panel B shows that at 60 months, of the 139 pa-
tients with a complete cytogenetic response and a reduction in levels of
BCR-ABL transcripts of at least 3 log, 100% were free from progression to
the accelerated phase or blast crisis. The corresponding rate for 54 patients
with a complete cytogenetic response and a reduction in levels of BCR-ABL
transcripts of less than 3 log was 98%; the rate for 88 patients without a
complete cytogenetic response was 87% (P<0.001; P = 0.11 for the compari-
son between patients with a major molecular response and those without
a major molecular response). At 18 months, 86 patients had discontinued
imatinib and 186 patients had achieved a complete cytogenetic response
but did not have a PCR result available.
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2414
than 3 log in levels of BCR-ABL transcripts, the es-
timated rate was 98% (P = 0.11). However, in the
absence of a complete cytogenetic response, the
rate was 87% (P<0.001) (Fig. 3B). No patient who
had a complete cytogenetic response and reduc-
tion of at least 3 log in levels of BCR-ABL transcripts
at 12 months had progressed to the accelerated
phase or blast crisis at 60 months.
Overall Survival
By the cutoff date for this analysis, 57 patients
(10%) who received imatinib had died; 5 of these
patients had switched to interferon alfa plus cy-
tarabine. The estimated overall survival rate at 60
months was 89% (95% CI, 86 to 92) (Fig. 4). Allo-
geneic hematopoietic stem-cell transplantation
was carried out in 44 patients who discontinued
imatinib: 11 had progressed to the accelerated
phase or blast crisis, 15 had had a hematologic or
cytogenetic relapse, and 18 had stopped therapy
for other reasons (including safety and withdrawal
of consent). Of the 44 patients who underwent
transplantation, 14 (32%) died. At 60 months, with
data censored at the time of transplantation, the
estimated overall survival rate was 92% (95% CI,
89 to 95). After data were censored for patients
who had died from causes unrelated to CML or
transplantation, the overall estimated survival rate
was 95% (95% CI, 93 to 98) at 60 months (Fig. 4).
Discussion
The initial analysis of this study, performed at a
median follow-up of 19 months, showed a high
rate of response and an acceptable rate of side ef-
fects of imatinib as initial therapy for newly diag-
nosed chronic-phase CML.14 The present analysis,
with a median follow-up of 60 months, showed
an estimated relapse rate of 17% at 60 months, and
an estimated 7% of all patients progressed to the
accelerated phase or blast crisis. The 5-year esti-
mated overall survival rate for patients who re-
ceived imatinib as initial therapy (89%) is higher
than that reported in any previously published pro-
spective study of the treatment of CML.17
This trial allowed patients to cross over to the
alternate treatment, and most patients in the in-
terferon group either switched to imatinib or dis-
continued interferon. On the basis of an inten-
tion-to-treat analysis, there was no significant
difference in overall survival between the group
of patients who began their treatment with inter-
feron and those who began their treatment with
imatinib (data not shown). Previous randomized
studies of interferon alfa plus cytarabine, per-
formed before the availability of imatinib, showed
a 5-year overall survival of 68 to 70%.12,13 With the
use of historical comparisons, a survival advan-
tage for initial therapy with imatinib over inter-
feron alfa can be demonstrated.18
In a landmark analysis, 97% of patients with
a complete cytogenetic response within 12 months
after starting imatinib did not progress to the ac-
celerated phase or blast crisis by 60 months. No-
tably, patients who were deemed to be at high risk
on the basis of Sokal scores had a lower rate of
complete cytogenetic response (69%) than did pa-
tients who were at low risk or intermediate risk
(89% and 82%, respectively). However, the risk of
relapse in patients who had a cytogenetic response
was not associated with the Sokal score. With
interferon treatment, by contrast, the Sokal score
was important even among patients with a com-
plete cytogenetic response.19
Remarkably, no patient who had a complete
cytogenetic response and a reduction in levels of
BCR-ABL transcripts of at least 3 log at 12 or 18
months after starting imatinib had progression
Overall Survival (%)
80
90
70
60
40
30
10
50
20
0
0 1224 3648 60 72
Months
100
CML-related deaths
All deaths
No. of Deaths
Related to CML
All deaths
No. at Risk
Related to CML
All deaths
3
6
536
542
11
22
498
518
16
41
474
492
19
52
450
475
23
57
322
333
Figure 4. Overall Survival among Patients Treated with Imatinib Based
on an Intention-to-Treat Analysis.
The estimated overall survival rate at 60 months was 89%. After the cen-
soring of data for patients who died from causes unrelated to CML or trans-
plantation, the estimated overall survival was 95% at 60 months. At the
time of analysis, 57 patients had died. The number of patients with events
and the number of patients available for analysis are shown.
Copyright © 2006 Massachusetts Medical Society. All rights reserved.
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Imatinib as Primary Therapy for Chronic Myeloid Leukemia
n engl j med 355;23 www.nejm.org december 7, 2006
2415
of CML by 60 months. Only 2% of patients who
had a complete cytogenetic response and a reduc-
tion in levels of BCR-ABL transcripts of less than
3 log at 18 months had progressed to the accel-
erated phase or blast crisis at 60 months.
It is currently recommended that imatinib
therapy be continued indefinitely. Anecdotal re-
ports suggest that the discontinuation of imatinib,
even in patients with undectectable levels of BCR-
ABL transcripts, results in relapse.20-24 Although
it is not known why imatinib is not able to eradi-
cate the malignant clone, potential mechanisms
include drug efflux25 and amplification or muta-
tion of the BCR-ABL gene.26 It is also possible that
imatinib cannot completely inhibit BCR-ABL ki-
nase activity; low levels of activity would allow
cells to survive but not proliferate. As an alterna-
tive, the malignant clone could persist through
mechanisms that are independent of the BCR-ABL
kinase.27
Initial studies of two new inhibitors of the
BCR-ABL kinase that are more potent than ima-
tinib — dasatinib and nilotinib — showed high
response rates in patients who had had a relapse
during imatinib therapy.28,29 Despite their poten-
cy, these inhibitors cannot eradicate all CML cells
in vitro.30 As was the case in patients in our study,
it is assumed that in patients receiving these drugs
a durable response can be achieved even without
disease eradication if there is a reduction in lev-
els of BCR-ABL transcripts of at least 3 log.
Notably, the rate of disease progression in pa-
tients in our study is apparently trending down-
ward, although the trend has not reached statis-
tical significance. If it persists, such a trend would
be consistent with the findings that mutations
in the BCR-ABL gene are the major cause of relapse
in patients treated with imatinib.31 If we presume
that mutations precede imatinib therapy (as the
data suggest),32,33 the emergence of resistance to
the drug would depend on the size of the mutant
clone at the start of therapy and its doubling
time. Since most mutated and unmutated BCR-
ABL clones have similar doubling times,34 a pa-
tient with a mutant clone should be at highest risk
for relapse during the first several years of thera-
py. This prediction is in line with the apparent
downward trend in the risk of disease progres-
sion observed in our study.
Dr. Druker’s institution is the site of clinical trials sponsored
by Novartis, but neither he nor his laboratory reports receiving
funds from Novartis. Dr. Guilhot reports receiving consulting
and lecture fees from Novartis; Dr. O’Brien, consulting fees from
Novartis and Bristol-Myers Squibb and lecture fees from Novar-
tis; Ms. Gathmann, being an employee of and having equity
ownership in Novartis; Dr. Kantarjian, consulting fees from No-
vartis, Bristol-Myers Squibb, and MGI Pharma; Dr. Gattermann,
consulting and lecture fees from Novartis and Pharmion; Dr.
Deininger, consulting and lecture fees from Novartis and Bris-
tol-Myers Squibb; Dr. Silver, consulting fees from Novartis; Dr.
Goldman, lecture fees from Novartis; Dr. Stone, consulting and
lecture fees and grant support from Novartis and Bristol-Myers
Squibb; Dr. Cervantes, consulting fees from Novartis and lec-
ture fees from Novartis and Bristol-Myers Squibb; Dr. Hochhaus,
consulting and lecture fees from Novartis and Bristol-Myers
Squibb; Dr. Powell, lecture fees from Pharmion; Dr. Gabrilove,
consulting fees from Novartis; Dr. Rousselot, lecture fees from
Novartis Oncology; Dr. Cornelissen, consulting fees from Novar-
tis Oncology; Dr. Hughes, consulting and lecture fees from No-
vartis; Dr. Fischer, consulting fees from LymphoSign and Novar-
tis and lecture fees from Novartis; Dr. Saglio, consulting and
lecture fees from Novartis; Dr. Gratwohl, consulting fees from
Novartis, Pfizer, and Amgen and lecture fees from Novartis; Dr.
Radich, consulting fees from Novartis and Bristol-Myers Squibb
and lecture fees from Novartis; Dr. Simonsson, consulting fees
from Novartis and Bristol-Myers Squibb; Dr. Taylor, consulting
fees from Amgen, Novartis, Bristol-Myers Squibb, and Celgene
and lecture fees from Novartis; Dr. Baccarani, consulting fees
from Novartis, Bristol-Myers Squibb, Merck, and Pfizer and
lecture fees from Novartis, Bristol-Myers Squibb, Schering, and
Pfizer; Dr. So, being an employee of Novartis and having equity
ownership in Novartis and Pfizer; Dr. Letvak, being an employee
of and having equity ownership in Novartis; and Dr. Larson,
consulting and lecture fees from Novartis. No other potential
conflict of interest relevant to this article was reported.
We thank the coinvestigators; the members of the medical,
nursing, and research staff at the trial centers; the clinical trial
monitors and the data managers and programmers at Novartis
for their contributions; and Tillman Krahnke and Manisha
Mone for their invaluable collaboration.
Appendix
From the Oregon Health and Science University Cancer Institute, Portland (B.J.D.); Centre Hospitalier Universitaire, Poitiers, France
(F.G.); University of Newcastle, Newcastle, United Kingdom (S.G.O.); Novartis, Basel, Switzerland (I.G.); M.D. Anderson Cancer Center,
Houston (H.K.); Heinrich Heine University, Dusseldorf, Germany (N.G.); Universität Leipzig, Leipzig, Germany (M.W.N.D.); Weill–Cor-
nell Medical Center, New York (R.T.S.); National Heart, Lung, and Blood Institute, Bethesda, MD (J.M.G.); Dana–Farber Cancer Institute,
Boston (R.M.S.); Hospital Clinic I Provincial, Barcelona (F.C.); University of Heidelberg, Mannheim, Germany (A.H.); Wake Forest Uni-
versity Baptist Medical Center, Winston-Salem, NC (B.L.P.); Mount Sinai School of Medicine, New York (J.L.G.); Hôpital Saint Louis,
Paris (P.R.); Centre Hospitalier Universitaire de Bordeaux, Pessac, France (J.R.); Erasmus Medical Center, Rotterdam, the Netherlands
(J.J.C.); Royal Adelaide Hospital, Adelaide, Australia (T.H.); Universitätsklinik für Innere Medizin I, Vienna (H.A.); Johannes Gutenberg
Universität, Mainz, Germany (T.F.); University Hospital Gasthuisberg, Leuven, Belgium (G.V.); Vancouver Hospital, Vancouver, BC, Cana-
da (J.S.); Azienda Ospedaliera S. Luigi Gonzaga, Orbassano, Italy (G.S.); University Hospital Basel, Switzerland (A.G.); Aarhus
Amtssygehus, Aarhus, Denmark (J.L.N.); Fred Hutchinson Cancer Research Center, Seattle (J.P.R.); Akademiska Sjukhuset, Uppsala, Swe-
den (B.S.); Mater Hospital, Brisbane, Australia (K.T.); Policlinico S. Orsola–Malpighi, Bologna, Italy (M.B.); Novartis, Florham Park, NJ
(C.S., L.L.); and University of Chicago, Chicago (R.A.L.).
Copyright © 2006 Massachusetts Medical Society. All rights reserved.
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The new england journal of medicine
n engl j med 355;23 www.nejm.org december 7, 2006
2416
The following investigators participated in IRIS: Australia — Royal Brisbane Hospital, Herston: S. Durrant; Monash Medical Centre, Mel-
bourne: A. Schwarer; Sir Charles Gairdner Hospital, Perth: D. Joske; Australian Leukemia and Lymphoma Group, Melbourne: J. Seymour; Royal Mel-
bourne Hospital, Parkville: A. Grigg; St. Vincent’s Hospital, Darlinghurst: D. Ma; Royal North Shore Hospital, St. Leonards: C. Arthur; Westmead Hos-
pital, Westmead: K. Bradstock; Royal Prince Alfred Hospital, Sydney: D. Joshua. Belgium — A.Z. Sint-Jan, Brugge: A. Louwagie; Institut Jules Bordet,
Brussels: P. Martiat; Cliniques Universitaires, Yvoir: A. Bosly. Canada — McGill University, Montreal: C. Shustik; Princess Margaret Hospital, Toronto:
J. Lipton; Queen Elizabeth II Health Sciences Centre, Halifax, NS: D. Forrest; McMaster University Medical Centre, West Hamilton, ON: I. Walker; Uni-
versité de Montréal, Montreal: D.-C. Roy; CancerCare Manitoba, Winnipeg: M. Rubinger; Ottawa Hospital Regional Cancer Centre, Ottawa: I. Bence-
Bruckler; University of Calgary and Tom Baker Cancer Centre, Calgary, AB: D. Stewart; London Regional Cancer Centre, London, ON: M. Kovacs; Cross
Cancer Center, Edmonton, AB: A.R. Turner. Denmark — Kobenhavns Amts Sygehus i Gentofte, Hellerup: H. Birgens; Danish University of Pharmaceuti-
cal Sciences and University of Southern Denmark, Copenhagen: O. Bjerrum. France — Hôpital Claude Huriez, Lille: T. Facon; Hôtel Dieu Hospital, Nantes:
J.-L. Harousseau; Henri Mondor Hospital, Creteil: M. Tulliez; Centre Hospitalier Universitaire (CHU) Brabois, Vandoeuvre-les-Nancy: A. Guerci; Insti-
tut Paoli-Calmettes, Marseille: D. Blaise; Hopital Civil, Strasbourg: F. Maloisel; CHU la Milétrie, Poitiers: M. Michallet. Germany — University of
Regensburg, Regensburg: R. Andreesen; Krankenhaus Muenchen Schwabing, Munich: C. Nerl; Universitätsklinikum Rostock, Rostock: M. Freund;
Heinrich Heine University, Düsseldorf: N. Gattermann; Carl-Gustav Carus Universität, Dresden: G. Ehninger; Leipzig University Hospital, Leipzig: M.
Deininger; Medizinische Klinik III, Frankfurt: O. Ottmann; Clinical Center Rechts der Isar, Munich: C. Peschel; University of Heidelberg, Heidelberg: S.
Fruehauf; Philipps-Universität Marburg, Baldingerstra?e, Marburg: A. Neubauer; Humboldt Universität, Berlin: P. Le Coutre; Robert Bosch Hospital,
Stuttgart: W. Aulitzky. Italy — University Hospital, Udine: R. Fanin; San Orsola Hospital, Bologna: G. Rosti; Università La Sapienza, Rome: F.
Mandelli; Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia: M. Lazzarino; Niguarda Ca’ Granda Hospital, Milan:
E. Morra; Azienda Ospedaliera e Cliniche Universitarie San Martino, Largo R Benzi, Genoa: A. Carella; University of Pisa, Pisa: M. Petrini; Azienda Os-
pedaliera Bianchi-Malacrino-Morelli, Reggio Calabria: F. Nobile; University of Bari, Policlinico, Bari: V. Liso; Cardarelli Hospital, Naples: F. Ferrara;
University of Parma, Parma: V. Rizzoli; Ospedale Civile, Pescara: G. Fioritoni; Institute of Hematology and Medical Oncology Seragnoli, Bologna: G.
Martinelli. the Netherlands — Vrije Universiteit Academic Medical Center, Amsterdam: G. Ossenkoppele. New Zealand — University of Auckland,
Auckland: P. Browett. Norway — Medisinsk Avdeling, Rikshospitalet, Oslo: T. Gedde-Dahl; Ullevål Sykehus, Oslo: J.-M. Tangen; Hvidovre Hospital,
Betalende: I. Dahl. Spain — Hospital Clinic, Villarroel, Barcelona: J. Odriozola; University of Barcelona, Barcelona: J.C. Hernández Boluda; Hospital
Universitario de la Princesa, Madrid: J.L. Steegman; Hospital Universitario de Salamanca, Salamanca: C. Cañizo; San Carlos Clinical Hospital, Madrid:
J. Diaz; Institut Català d’Oncología, Barcelona: A. Granena; Hospital Lluis Alcanyis, Cta Xativa-Silla: M.N. Fernández. Sweden — Karolinska Hos-
pital, Stockholm: L. Stenke; Huddinge Sjukhus, Huddinge: C. Paul; Medicinkliniken Universitetssjukhuset, Örebro: M. Bjoreman; Regionsjukhuset,
Linköping: C. Malm; Sahlgrenska Hospital, Göteborg: H. Wadenvik; Endokrinsekt/Medklin Universitetssjukhuset, Lund: P.-G. Nilsson; Universitetss-
jukhuset Malmo University Hospital, Malmo: I. Turesson. Switzerland — Kantonsspital, St. Gallen: U. Hess; University of Bern, Bern: M. Solentha-
ler. United Kingdom — University of Nottingham and Nottingham City Hospital, Nottingham: N. Russell; Kings College, London: G. Mufti; St.
George’s Hospital, Medical School, London: J. Cavenagh; Royal Liverpool University Hospital, Liverpool: R.E. Clark; Cambridge Institute for Medical Re-
search, Cambridge: A.R. Green; Glasgow Royal Infirmary, Glasgow: T.L. Holyoake; Manchester Royal Infirmary, Manchester: G.S. Lucas; Leeds Gen-
eral Infirmary, Leeds: G. Smith; Queen Elizabeth Hospital, Edgbaston, Birmingham: D.W. Milligan; Derriford Hospital, Plymouth: S.J. Rule; University
Hospital of Wales, Cardiff: A.K. Burnett; United States — Walt Disney Memorial Cancer Institute, Orlando, FL: R. Moroose; Roswell Park Cancer Center,
Buffalo, NY: M. Wetzler; Gibbs Cancer Center, Spartanburg, SC: J. Bearden; Ohio State University School of Medicine, Columbus: S. Cataland; Univer-
sity of New Mexico Health Sciences Center, Albuquerque: I. Rabinowitz; University of Maryland Cancer Center, Baltimore: B. Meisenberg; Montgomery
Cancer Center, Montgomery, AL: K. Thompson; State University of New York Upstate Medical Center, Syracuse: S. Graziano; University of Alabama at
Birmingham, Birmingham: P. Emanuel; Hematology and Oncology, Inc., Dayton, OH: H. Gross; Billings Oncology Associates, Billings, MT: P. Cobb;
City of Hope National Medical Center, Duarte, CA: R. Bhatia; Cancer Center of Kansas, Wichita: S. Dakhil; Alta Bates Comprehensive Cancer Center, Berkeley,
CA: D. Irwin; Cancer Research Center of Hawaii, Honolulu: B. Issell; University of Nebraska Medical Center, Omaha: S. Pavletic; Columbus Community
Clinical Oncology Program, Columbus, OH: P. Kuebler; Michigan State University Hematology/Oncology, Lansing: E. Layhe; Brown University School of
Medicine, Providence, RI: P. Butera; Loyola University Medical Center, Shreveport, LA: J. Glass; Duke University Medical Center, Durham, NC: J. Moore;
University of Vermont, Burlington: B. Grant; University of Tennessee, Memphis: H. Niell; University of Louisville Hospital, Louisville, KY: R. Herzig;
Sarah Cannon Cancer Center, Nashville: H. Burris; University of Minnesota, Minneapolis: B. Peterson; Cleveland Clinic Foundation, Cleveland: M. Ka-
laycio; Fred Hutchinson Cancer Research Center, Seattle: D. Stirewalt; University of Utah, Salt Lake City: W. Samlowski; Memorial Sloan-Kettering
Cancer Center, New York: E. Berman; University of North Carolina School of Medicine, Charlotte: S. Limentani; Atlanta Cancer Center, Atlanta: T. Seay;
University of North Carolina School of Medicine, Chapel Hill: T. Shea; Indiana Blood and Marrow Institute, Beech Grove: L. Akard; San Juan Regional
Cancer Center, Farmington, NM: G. Smith; University of Massachusetts Memorial Medical Center, Worcester: P. Becker; Washington University School of
Medicine, St. Louis: S. Devine; Veterans Affairs Medical Center, Milwaukee: R. Hart; Louisiana State University Medical Center, New Orleans: R. Veith;
Decatur Memorial Hospital, Decatur, IL: J. Wade; Rocky Mountain Cancer Centers, Denver: M. Brunvand; Oncology-Hematology Group of South Florida,
Miami: L. Kalman; Memphis Cancer Center, Memphis, TN: D. Strickland; Henry Ford Hospital, Detroit: M. Shurafa; University of California, San Diego,
Medical Center, La Jolla: A. Bashey; Western Pennsylvania Cancer Institute, Pittsburgh: R. Shadduck; Tulane Cancer Center, New Orleans: H. Safah;
Southbay Oncology Hematology Partners, Campbell, CA: M. Rubenstein; University of Texas Southwest Medical Center, Dallas: R. Collins; Cancer Care
Associates, Tulsa, OK: A. Keller; Robert H. Lurie Comprehensive Cancer Center, Chicago: M. Tallman; Northern New Jersey Cancer Center, Hackensack: A.
Pecora; University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh: M. Agha; Texas Oncology, Dallas: H. Holmes; and New Mexico
Oncology Hematology Consultants, Albuquerque: R. Guidice. Study Management Committee: Oregon Health and Science University Cancer Institute
Research and Patient Care, Portland: B.J. Druker; University Hospital, Poitier, France: F. Guilhot; University of Chicago, Chicago: R.A. Larson; Univer-
sity of Newcastle upon Tyne, Newcastle upon Tyne, UK: S.G. O’Brien. Independent Data Monitoring Board: Rambam Medical Center, Haifa, Israel:
J. Rowe; Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit: C.A. Schiffer; International Drug Development Institute, Brussels: M.
Buyse. Protocol Working Group: Policlinico San Orsola–Malpighi, Bologna, Italy: M. Baccarani; Hospital Clinic, Barcelona: F. Cervantes; Erasmus
Medical Center, Rotterdam, the Netherlands: J. Cornelissen; Johannes Gutenberg Universität, Mainz, Germany: T. Fischer; Universität Heidelberg,
Mannheim, Germany: A. Hochhaus; Hanson Institute Centre for Cancer, Adelaide, Australia: T. Hughes; Medical University of Vienna, Vienna: K. Lech-
ner; Aarhus Amtssygehus, Aarhus, Denmark: J.L. Nielsen; CHU de Bordeaux, Pessac, France: J. Reiffers; Hôpital Saint Louis, Paris: P. Rousselot; San
Luigi Gonzaga Hospital, Turin, Italy: G. Saglio; Vancouver Hospital, Vancouver, BC, Canada: J. Shepherd; Akademiska Sjukhuset, Uppsala, Sweden:
B. Simonsson; University Hospital, Basel, Switzerland: A. Gratwohl; Imperial College, London: J.M. Goldman; University of Michigan Health
System, Ann Arbor: M. Talpaz; Mater Misericordiae Public Hospital, Brisbane, Australia: K. Taylor; and University Hospital Gasthuisberg, Leuven,
Belgium: G. Verhoef.
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