Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia.

Abstract

A survival benefit for imatinib mesylate versus interferon-alpha therapy could not be demonstrated in the randomized study in newly diagnosed Philadelphia chromosome (Ph)-positive chronic-phase chronic myelogenous leukemia (CML) due to the high rate of crossover (90%) from interferon-alpha to imatinib mesylate within a year of study entry. We compared survival in 279 patients with newly diagnosed CML treated with imatinib mesylate at our institution (2000-2004) to 650 patients treated with interferon-alpha (1982-1997). The complete cytogenetic response rates were 87% with imatinib mesylate and 28% with interferon-alpha (P < .001). The estimated 3-year survival rates were 96% with imatinib mesylate and 81% with interferon-alpha (P < .01). Survival rates with imatinib mesylate were significantly better than with interferon-alpha within each of the CML prognostic risks groups. By multivariate analysis, imatinib mesylate therapy was identified as an independent favorable prognostic factor, after accounting for the impact of pretreatment factors (hazard ratio, 0.44; P < .01). By landmark analysis at 12 months, survival within each cytogenetic response category was similar with imatinib mesylate or interferon-alpha, suggesting that the survival benefit of imatinib mesylate (versus interferon-alpha in newly diagnosed CML) is through improving cytogenetic response.

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CLINICALTRIALSAND OBSERVATIONS
Survivalbenefitwithimatinibmesylateversusinterferon-?–basedregimensin
newlydiagnosedchronic-phasechronicmyelogenousleukemia
Hagop M. Kantarjian, Moshe Talpaz, Susan O’Brien, Daniel Jones, Francis Giles, Guillermo Garcia-Manero, Stefan Faderl, Farhad Ravandi,
Mary Beth Rios, Jianqin Shan, and Jorge Cortes
A survival benefit for imatinib mesylate
versus interferon-? therapy could not
be demonstrated in the randomized
study in newly diagnosed Philadelphia
chromosome (Ph)–positive chronic-
phase chronic myelogenous leukemia
(CML) due to the high rate of crossover
(90%) from interferon-? to imatinib mesy-
late within a year of study entry. We
compared survival in 279 patients with
newly diagnosed CML treated with ima-
tinib mesylate at our institution (2000-
2004) to 650 patients treated with inter-
feron-?
cytogeneticresponserateswere87%with
imatinib mesylate and 28% with inter-
feron-? (P < .001). The estimated 3-year
survival rates were 96% with imatinib
mesylate and 81% with interferon-?
(P < .01). Survival rates with imatinib me-
sylate were significantly better than with
interferon-? within each of the CML prog-
nostic risks groups. By multivariate anal-
ysis, imatinib mesylate therapy was iden-
tified asan independent
prognostic factor, after accounting for the
(1982-1997). Thecomplete
favorable
impact of pretreatment factors (hazard
ratio, 0.44; P < .01). By landmark analysis
at12months,survivalwithineachcytoge-
netic response category was similar with
imatinib mesylate or interferon-?, sug-
gesting that the survival benefit of ima-
tinib mesylate (versus interferon-? in
newlydiagnosedCML)isthroughimprov-
ing cytogenetic response. (Blood. 2006;
108:1835-1840)
© 2006 by TheAmerican Society of Hematology
Introduction
Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor,
has revolutionized the treatment of Philadelphia chromosome
(Ph)–positive chronic myelogenous leukemia (CML), and has
become the standard of care for this disease.1,2Imatinib
mesylate induces complete hematologic response in 80% to
90% of patients with newly diagnosed chronic-phase CML, a
complete cytogenetic response in 70% to 80% of patients, and a
major molecular response (eg, 3-log reduction of BCR-ABL:
BCR levels compared with a standardized pretreatment level by
quantitative polymerase chain reaction [QPCR], or QPCR
? 0.05%-0.1%) in 40% of patients. The International Random-
ized trial of Interferon versus STI571 (IRIS) did not show a
survival advantage for imatinib mesylate, because 90% of
patients on interferon-? crossed over to imatinib mesylate after
a median of 9 months from start of study, thus benefiting from
imatinib mesylate therapy early into their disease.2
Additional randomized studies of imatinib mesylate versus
previous standard strategies are unlikely to be performed. A
survival advantage for imatinib mesylate therapy can then be
demonstrated only through careful comparative studies with
precisely defined historical control populations treated with
interferon-?–based regimens. This is the purpose of this study
which confirms, with long-term follow-up, the survival advan-
tage of imatinib mesylate therapy versus interferon-? in newly
diagnosed CML.3
Patients, materials, and methods
Adults with newly diagnosed Ph-positive early chronic-phase CML (ie,
within 6 months from diagnosis) treated at our institution from July 2000
until December 2004 with imatinib mesylate were analyzed. These patients
were treated on frontline therapies with 400 mg daily imatinib mesylate
orally (n ? 73), 600 mg orally daily (n ? 12), or 800 mg orally daily (400
mg orally twice daily, n ? 194). Their survival by imatinib mesylate dose
was identical, justifying their inclusion as 1 treatment group for compara-
tive survival analysis. The minimum follow-up time of these patients was
longer than 12 months. Their outcome was compared with 650 patients
treated on interferon-? regimens from 1982 to1997. Interferon-? regimens
included interferon-? alone or with hydroxyurea (n ? 270), interferon-?
plus low-dose cytarabine (n ? 285), and interferon-? plus homoharringto-
nine (n ? 95).4-6Survivals in different studies containing interferon-? were
similar, justifying their inclusion as 1 treatment category for the purpose of
comparative analysis with imatinib mesylate. The median follow-up times
with imatinib mesylate regimens was 42 months (range, 12-66 months),
and the median follow-up times with interferon-? regimens was 143
months (range, 4-270 months).All patients signed informed consents for
the respective protocols according to institutional guidelines. Eligibility
criteria were similar on all studies, and the details of the therapies were
previously reported.3-6
Response criteria were as published.4A complete cytogenetic response
referred to disappearance of Ph-positive cells (0% Ph-positive) by routine
cytogenetic analysis.Apartial cytogenetic response referred to reduction of
Ph-positive cells to 1% to 34%. A major cytogenetic response referred to
reduction of Ph-positive cells to less than 35%.Amajor molecular response
From the Departments of Leukemia, Experimental Therapeutics, and
Hematopathology, The University of Texas M. D. Anderson Cancer Center,
Houston, TX.
Submitted February 17, 2006; accepted May 2, 2006. Prepublished online as
Blood First Edition Paper, May 18, 2006; DOI 10.1182/blood-2006-02-004325.
Supported by Novartis Pharmaceutical Corp (H.K., M.T., F.G., and J.C.),
Bristol-Myers Squibb (H.K., M.T., S.O., and J.C.), and the Betty Foster
Leukemia Research Fund (H.K.).
Reprints: Hagop Kantarjian, Department of Leukemia, Unit 428, The
University of Texas M. D. Anderson Cancer Center, PO Box 301402, Houston,
TX 77230-1402; e-mail: hkantarj@mdanderson.org.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
© 2006 by TheAmerican Society of Hematology
1835BLOOD, 15 SEPTEMBER 2006?VOLUME 108, NUMBER 6

Page 2

was defined as BCR-ABL/ABL transcript levels less than 0.05%. A
complete molecular response was defined as undetectable BCR-ABL
transcripts (QPCR levels below ? 10?5).7,8
Differences among variables were evaluated by the chi-square test and
Mann-Whitney U test for categoric and continuous variables, respectively.
Survival probabilities were estimated by the Kaplan-Meier method and
compared by the log-rank test. Risk groups were defined by the Sokal and
Hasford models.9,10Survival was calculated from the date of start of
therapy. Transformation-free survival was calculated from the date of start
of therapy until progression to accelerated-blastic phase.11Progression-free
survival was calculated from the date of start of therapy, until cytogenetic or
hematologic resistance or relapse, or progression to accelerated-blastic
phase.12Multivariate analyses to evaluate the independent prognostic
variablesusedtheCoxproportionalhazardsregressionmodelforsurvival.13
Results
Two hundred seventy-nine patients treated with imatinib mesylate
were compared with 650 patients who received interferon-?. The
significant pretreatment characteristics of the imatinib mesylate
and interferon-? groups are detailed inTable 1. Patients on imatinib
mesylate therapy were older and had a higher incidence of marrow
basophilia. Patients on interferon-? therapy had higher incidences
of leukocytosis, and thrombocytosis, and a longer duration of
CML disease (Table 1). One hundred forty-four patients on
interferon-? therapy (22%) changed to imatinib mesylate therapy
after a median CML duration of 84 months (range, 26-267
months) in chronic phase.
Response with imatinib mesylate versus interferon-?
The complete cytogenetic response rate was 87% with imatinib
mesylate and 28% with interferon-? (Table 2). The incidence of
complete cytogenetic response with imatinib mesylate or inter-
feron-? within each risk group is shown in Table 3. With imatinib
mesylate, 163 (61%) of 267 patients who had follow-up molecular
tests performed achieved a major molecular response, and 85
(32%) patients had at least 1 negative QPCR test. There was no
difference in survival in patients treated with imatinib mesylate by
imatinib mesylate daily dose (P ? .72).
Survival with imatinib mesylate versus interferon-?
Survival of patients with imatinib mesylate versus interferon-? is
shown in Figure 1. Survival, censoring the 141 patients who
changed from interferon-? to imatinib mesylate in chronic phase at
the time of therapy change, was still significantly better with
imatinib mesylate (estimated 5-year survival, 88% vs 63%;
P ? .001). Seven patients on imatinib mesylate (5 from related
donors, 2 from unrelated donors) and 97 patients on interferon-?
(63 from related donors, 30 from unrelated donors, 4 from donors
unspecified) underwent allogeneic stem cell transplantation (SCT)
in chronic phase. Five of the 7 patients who received transplants
after imatinib mesylate remain alive without evidence of disease
(NED) after a median follow-up of 17 months (range, 2-34
months). Thirty-five of the 97 patients who received transplants
after interferon-? remain NED after a median follow-up of 126
months (range, 31-225 months). Survival with imatinib mesylate
versus interferon-? censoring patients at the time they underwent
allogeneic SCT in chronic phase demonstrates the persistent
survival benefit with imatinib mesylate (estimated 5-year survival
90% versus 67%; P ? .001). The estimated 2-year survival of
patients after allogeneic stem cell transplantation (SCT) was 80%
after imatinib mesylate and 55% after interferon-? (P ? .52).
Survival of patients within each Sokal risk group is shown in
Figure 2A-C. Within each risk group, imatinib mesylate was
associated with a significantly better survival than interferon-?.
Since some characteristics of patients treated with imatinib
mesylate versus interferon-? were different, we conducted univari-
ate then multivariate analyses of pretreatment factors associated
with survival in the total study group of 929 patients treated with
Table 1. Patient and disease characteristics
Parameter
Study group
PImatinib mesylate IFN-?
Age
60 y or older, no. (%)
Median, y (range)
Splenomegaly
Hemoglobin
Less than 120 g/L, no. (%)
Median, g/L (range)
WBC count
More than 40 ? 109/L, no. (%)
Median, ? 109/L (range)
Platelets
More than 450 ? 109/L, no. (%)
Median, ? 109/L (range)
Peripheral basophils
7% or more, no. (%)
Median % (range)
Peripheral blasts
1%-3%, no. (%)
4% or more, no. (%)
Median, % (range)
Marrow basophils
4% or more, no. (%)
Median, % (range)
Marrow blasts
5% or more, no. (%)
Median, % (range)
Cytogenetic clonal evolution, no. (%)
Chronic phase lasting 4 mo or more,
no. (%)
Sokal risk
Low, no. (%)
Intermediate, no. (%)
High, no. (%)
NA, no. (%)
Hasford risk
Low, no. (%)
Intermediate, no. (%)
High, no. (%)
NA, no. (%)
68 (24)
48 (15-84)
83 (30)
83 (13)
43 (15-76)
230 (35)
? .01
? .01
.10
113 (41)
124 (62-167)
243 (37)
125 (50-171)
.37
.09
113 (41)
27.3 (1.6-283)
342 (53)
44.4 (2.1-556)
? .01
? .01
88 (32)
358 (58-1476)
258 (40)
393 (76-2795)
.02
.05
56 (20)
3 (0-19)
110 (7)
2 (0-19)
.26
? .01
88 (32)
11 (4)
0 (0-12)
169 (26)
39 (6)
0 (0-13)
.13
.59
86 (31)
2 (0-15)
124 (19)
1 (0-15)
? .01
? .01
23 (8)
2 (0-14)
14 (5)
40 (6)
1 (0-14)
42 (6)
.26
? .01
.48
16 (6)180 (28)
? .01
174 (62)
79 (28)
26 (9)
0 (0)
430 (66)
150 (23)
67 (10)
3 (0.5)
.25
158 (57)
110 (39)
11 (4)
0 (0)
407 (63)
178 (27)
21 (3)
44 (7)
.01*
NAindicates not applicable.
*P value for the known Hasford categories.
Table 2. Cytogenetic response to therapy
Response
No. (%)
PImatinib mesylateIFN-?
Complete hematologic response
Cytogenetic response
Complete
Partial
Minor
271 (97)
266 (95)
243 (87)
17 (6)
6 (2)
538 (83)
407 (63)
182 (28)
92 (14)
133 (20)
? .001
? .001
For imatinib mesylate, N ? 279; for IFN-?, N ? 650.
1836KANTARJIAN et alBLOOD, 15 SEPTEMBER 2006?VOLUME 108, NUMBER 6

Page 3

either imatinib mesylate or interferon-?. The univariate analysis
selected the following poor prognostic factors (P ? .05): older age,
splenomegaly, leukocytosis, higher blast percentage, higher baso-
phil percentage, CML risk group, and longer duration of CML
(Table 4). The multivariate analysis selected the following to be
independent poor prognostic factors: older age (P ? .01), higher
peripheral blast percentage (P ? .01), increased marrow basophils
(P ? .01), and longer CML disease duration (P ? .01). Therapy
(imatinib mesylate versus interferon-?), entered into the model
after accounting for the effect of the independent pretreatment
factors, remained a significant independent factor favoring imatinib
mesylate therapy (hazard ratio, 0.44; P ? .01).
Outcome with imatinib mesylate by response at 12 months
into therapy
Response to imatinib mesylate therapy after 1 year of exposure
may help define prognosis and the need for treatment modification.
Figure 3A shows the outcome of patients by cytogenetic response
at 12 months. Patients who did not achieve a major cytogenetic
response by that time had a worse survival than others (esti-
mated 3-year survival, 99% versus 84%; P ? .001). The esti-
mated 3-year survival rates were 98% for complete cytogenetic
response (n ? 210) and 100% for partial cytogenetic response
(n ? 21). The estimated 5-year survival rates were 94% in both
cytogenetic subgroups. Survival of patients in complete cytoge-
netic response at 12 months was not different by whether they
achieved a major molecular response or not (Figure 3B).
Figure 1. Survival with imatinib mesylate versus interferon-? overall.
Table 3. Cytogenetic response within different risk groups
Risk and therapyNo.
No. cytogenetic responses
(%)
CompleteMajor
Sokal risk
Low
Imatinib mesylate
IFN-?
Intermediate
Imatinib mesylate
IFN-?
High
Imatinib mesylate
IFN-?
Hasford risk
Low
Imatinib mesylate
IFN-?
Intermediate
Imatinib mesylate
IFN-?
High
Imatinib mesylate
IFN-?
174
430
151 (87)
141 (33)
165 (95)
213 (50)
79
150
74 (94)
29 (19)
75 (95)
46 (31)
26
67
18 (69)
12 (18)
20 (77)
14 (21)
158
407
139 (88)
122 (30)
149 (94)
189 (46)
110
178
96 (87)
49 (28)
103 (94)
72 (40)
11
21
8 (73)
5 (24)
8 (73)
5 (24)
Figure 2. Survival with imatinib mesylate versus interferon-? within Sokal risk
groups. (A) Low risk. (B) Intermediate risk. (C) High risk.
SURVIVALIMATINIB vs INTERFERON-? IN CML 1837BLOOD, 15 SEPTEMBER 2006?VOLUME 108, NUMBER 6

Page 4

Similarly, transformation-free survival was not different (esti-
mated 3-year rates, 98% with major molecular response versus
95% for others; P ? .28), nor was progression-free survival
(estimated 3-year rates, 98% versus 94%; P ? .14).
Survival with imatinib mesylate versus interferon within each
cytogenetic response category
An important question is whether imatinib mesylate offers a
survival advantage over interferon-? irrespective of cytogenetic
response. The median time to a complete cytogenetic response was
3 months with imatinib mesylate versus 13.5 months with inter-
feron-?. The median times to partial cytogenetic response were 3
and 9 months, respectively. To account for this time bias, we
conducted a landmark analysis of the association of response at 12
months with survival among patients alive at 12 months and
receiving imatinib mesylate or interferon-?. Within each cytoge-
netic group imatinib mesylate was associated with a similar
survival as interferon-? (Table 5), suggesting that in newly
diagnosed CML, imatinib mesylate improves survival through
improving cytogenetic response (ie, a better control of
CML disease).
Table 4. Association of patients and disease characteristics with survival (N ? 929)
ParameterNo.Survival at 3 y/5 y, %Median survival, mo
P
Log-rank Cox continuous variable
Age
Below 60 y
At least 60 y
Splenomegaly
No
Yes
Hemoglobin
Below 120 g/L
At least 120 g/L
WBC
No more than 40 ? 109/L
Above 40 ? 109/L
Platelets
No more than 450 ? 109/L
Above 450 ? 109/L
Peripheral basophils
Below 7%
At least 7%
Peripheral blasts
0%
1% to 3%
At least 4
Marrow basophils
Below 4%
At least 4%
Marrow blasts
Below 5%
At least 5%
Cytogenetic clonal evolution
No
Yes
Sokal risk
Low
Intermediate
High
Hasford risk
Low
Intermediate
High
Duration of chronic phase
0 to 3 mo
At least 4 mo
Study group
Imatinib mesylate
IFN-?
Dose of imatinib mesylate
400 mg/d
600 mg/d
800 mg/d
775
154
84/71
88/65
117
89
.025.02
614
313
87/72
81/66
118
101
.04—
356
573
83/68
86/71
103
112
.32.11
474
455
85/72
85/68
119
103
.04.004
583
346
85/71
85/68
118
96
.12 .18
762
166
86/72
78/60
117
76
? .01.07
621
257
50
86/72
83/69
81/46
119
103
58
? .01
? .01
715
210
87/73
80/61
118
79
? .01
? .01
862
63
86/70
78/66
112
118
.26.05
872
56
85/70
76/66
111
94
.30—
604
229
93
87/75
83/65
76/50
131
96
58
? .01—
565
288
32
85/73
87/69
81/52
123
95
60
.05—
733
196
86/73
81/61
122
96
? .01 .002
279
650
96/88
81/65
NR
101
? .01—
73
12
194
93/85
100/90
97/96
NR
NR
NR
.72—
NR indicates not reached; —, categorical value (P value not applicable).
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Page 5

Discussion
Imatinib mesylate therapy is presently the standard of care in
Ph-positive CML. A survival advantage for imatinib mesylate
versus interferon-? could not be demonstrated from the random-
ized IRIS trial because of the crossover design and the commercial
availability of imatinib mesylate, resulting in 90% of patients on
interferon-? changing to imatinib mesylate within a median of 9
months from start of therapy. The present analysis confirms the
benefit of imatinib mesylate versus interferon-? for survival
through comparison with a historical study group receiving inter-
feron-?–based regimens. Imatinib mesylate was associated with a
56% reduction in mortality compared with interferon-? overall.
The survival benefit was noted even in the low-risk patients.
Our results are similar to those of Roy et al,14who compared
survival with imatinib mesylate (551 patients from IRIS) to their
past experience with interferon-? plus cytarabine (325 patients
from CML 91). Imatinib mesylate was associated with higher
complete cytogenetic response rates at 12 months (70% versus
14%) and at 36 months (87% versus 42%), with better 36-month
rates of transformation-free survival (90% versus 82%; P ? .005)
and survival (92% versus 84%; P ? .001).14In contrast to the study
of Roy et al, our study included patients on different imatinib
mesylate daily doses, and patients on different interferon-? regi-
mens. However, since survival by imatinib mesylate dose is similar
(Table 4) and survival by different interferon-regimens also similar,
the comparative analysis of the 2 treatment groups (imatinib
mesylate versus interferon-?) is reasonable.Also, although 22% of
patients on interferon-? crossed over to imatinib mesylate, this
occurred quite late (median time to crossover, 84 months) and
would not affect the comparative survival analysis in the first 3 to 5
years. Censoring these 22% of patients on interferon-? at the time
of treatment crossover also yielded identical results. Thus, despite
the differences between the study groups in the analysis of Roy et
al14and ours, the very similar results in the 2 studies further
strengthen the conclusion that imatinib mesylate therapy offers a
significant survival advantage over interferon-? therapy.
As in previous studies, the 12 month cytogenetic response to
imatinib mesylate was predictive of prognosis.2,12Patients who had
achieved less than a major cytogenetic response had a worse
prognosis (Figure 3A). However, among patients achieving a
complete cytogenetic response, the degree of molecular response at
12 months was so far not associated with significant differences in
survival, transformation-free survival, or progression-free survival
(Figure 3B). This is in contrast to the recently updated IRIS results
showing a difference in transformation-free survival by the degree
of molecular response.11This may be due to differences in the
imatinib mesylate dose schedules, definitions of major molecular
response and failure, QPCR methodologies, size of the study
groups, and nature of the analysis. In particular, the IRIS study
included a larger number of patients treated with imatinib mesylate
(n ? 551) compared with our study (n ? 279), and the IRIS study
was prospective in nature, while this analysis is a retrospective one.
An important issue is whether imatinib mesylate can improve
survival independent of cytogenetic response. This study shows
that the survival benefit in newly diagnosed CML (compared with
interferon-?) with imatinib mesylate is through improving cytoge-
netic responses. This is different from the results of imatinib
mesylate versus other therapies in late chronic-phase CML after
interferon-? failure,15which showed better survival with imatinib
mesylate within each cytogenetic response category.
Table 5. Survival within each cytogenetic response category by cytogenetic response achieved at 12 months
with imatinib mesylate and interferon-?
Cytogenetic response at 12 mo
Imatinib mesylateIFN-?
P No.
Survival
No.
Survival
At 3 y, % Median, mo.At 3 y, % Median, mo.
Complete
Partial
Minor
None
210
21
99
100
75
88
NR
NR
NR
56
70
64
132
194
97
94
90
84
NR
NR
118
95
.40
.54
.97
.94
6
11
NR indicates not reached.Analysis excluded patients who died before 12 months or who were taken off therapy prior to the 12-month analysis.
Figure 3. Survival with imatinib mesylate by response. (A) Cytogenetic response
at 12 months. (B) Molecular response at 12 months in patients in complete
cytogenetic response.
SURVIVALIMATINIB vs INTERFERON-? IN CML1839BLOOD, 15 SEPTEMBER 2006?VOLUME 108, NUMBER 6

Page 6

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