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Comparison Between Patients With Philadelphia-Positive
Chronic Phase Chronic Myeloid Leukemia Who Obtained a
Complete Cytogenetic Response Within 1 Year of Imatinib
Therapy and Those Who Achieved Such a Response After
12 Months of Treatment
Ilaria Iacobucci, Gianantonio Rosti, Marilina Amabile, Angela Poerio, Simona Soverini, Daniela Cilloni,
Nicoletta Testoni, Elisabetta Abruzzese, Enrico Montefusco, Emanuela Ottaviani, Francesco Iuliano,
Domenico Russo, Marco Gobbi, Giuliana Alimena, Bruno Martino, Carolina Terragna, Fabrizio Pane,
Giuseppe Saglio, Michele Baccarani, and Giovanni Martinelli
ABSTRACT
Purpose
Imatinib mesylate is a potent inhibitor of BCR-ABL, the constitutively active tyrosine kinase protein
critical for the pathogenesis of chronic myeloid leukemia.
Patients and Methods
We reviewed 284 patients with late chronic-phase Philadelphia chromosome (Ph) –positive chronic
myeloid leukemia treated with imatinib 400 mg daily after interferon-
␣
failure. In a retrospective
study, we evaluated the pattern and rapidity of the response to imatinib, comparing the
cytogenetic and molecular responses, progression-free and overall survival rates in patients who
obtained a complete cytogenetic response within 1 year of treatment (early responders), and in
patients where a complete cytogenetic response was detected after 12 months (late responders).
Results
After 3 or 4 years of treatment, the molecular response of the late cytogenetic responders was
similar to that of the early cytogenetic responders. At 36 months of treatment the amount of
residual disease measured by standardized quantitative reverse-transcriptase polymerase
chain reaction was 0.00047 in late responders versus 0.00022 in early responders, and at 48
months it was 0.00019 versus 0.00026 (median values, Pvalue ⫽nonsignificant). The
estimated 4-year progression-free survival rate was 88% for early responders and 100% for
late responders, while the estimated 4-year overall survival rates were 92% and 100% for
early and late responders, respectively.
Conclusion
The sensitivity and the response (cytogenic and molecular) to imatinib may require 1 year or
more. Long-term follow-up results continue to improve in terms of rates and durability of the
complete cytogenetic response, major or complete molecular response, and progession-free
and overall survival.
J Clin Oncol 24:454-459. © 2006 by American Society of Clinical Oncology
INTRODUCTION
Chronic myeloid leukemia (CML) is a clonal disor-
der arising from neoplastic transformation of hema-
topoietic stem cells, most of which are characterized
by the presence of a Philadelphia chromosome (Ph)
and by constitutive activation of Bcr-Abl tyrosine
kinase.
1
Recent therapies in CML have attempted to
suppress the Ph-positive (Ph⫹) cells or the Ph-
related Bcr-Abl kinase activity in order to alter the
natural course of the disease. Allogenic stem-cell
transplantation (SCT) produced long-term event-
free survival rates of 30% to 80% and 1-year mortal-
ity rates of 5% to 50%.
2
Interferon-alfa (IFN-
␣
)
yielded cytogenetic response rates of 30% to 70%,
which were complete in 5% to 30%.
3,4
Median
survival duration with IFN-
␣
was 5 to 7 years.
Achievement of a complete cytogenetic response
was associated with 10-year survival rates of 70%
to 85%.
5
The introduction of imatinib mesylate (for-
merly STI571; Glivec in Europe, Gleevec in the
From the Institute of Hematology and
Medical Oncology “Sera`gnoli”, Univer-
sity of Bologna, Bologna; Division of
Hematology and Internal Medicine,
Department of Clinical and Biological
Science, University of Turin, Turin; Divi-
sion of Hematology, University “Tor
Vergata”, and Division of Hematology,
University “La Sapienza”, Rome; Divi-
sion of Hematology, Hospital “Pugliese
Ciaccio”, Catanzaro; Division of Hema-
tology, University of Brescia; Division of
Hematology and Internal Medicine,
University of Genova; Division of Hema-
tology, Hospital “Bianchi Malacrino
Morelli”, Reggio Calabria; CEINGE
Biotecnologie Avanzate and Depart-
ment of Biochemistry and Medical
Biotechnology, University of Naples
Federico II, Naples, Italy.
Submitted June 21, 2005; accepted
October 24, 2005.
Supported by COFIN 2003 (Molecular
therapy of Ph-positive leukemias), by
FIRB 2001, by the University of Bolo-
gna (grants 60%), by the Italian Associ-
ation for Cancer Research (A.I.R.C.), by
Fondazione del Monte di Bologna e
Ravenna, by European LeukemiaNet
founds, and by Associazione Italiana
contro le Leucemie grants.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Address reprint requests to Giovanni
Martinelli, MD, Molecular Biology Unit,
Institute of Hematology and Medical
Oncology “Sera`gnoli”, University of
Bologna, Via Massarenti, 9-40138
Bologna, Italy; e-mail: gmartino@
kaiser.alma.unibo.it.
© 2006 by American Society of Clinical
Oncology
0732-183X/06/2403-454/$20.00
DOI: 10.1200/JCO.2005.03.2011
JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT
VOLUME 24 䡠NUMBER 3 䡠JANUARY 20 2006
454
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Copyright © 2006 American Society of Clinical Oncology. All rights reserved.
United States; Novartis Pharmaceuticals, Basel, Switzerland) has
proven highly effective in the treatment of CML and is now approved
for the first-line pharmacotherapy of newly diagnosed CML. Imatinib
was rationally and specifically designed to bind to the adenosine
triphosphate (ATP)– docking site of tyrosine kinase proteins, in-
cluding ABL itself (p160), and the hybrid BCR/ABL proteins
(p190, p210, p230, and so on), which cause Ph⫹leukemias.
6
With
this drug, complete hematologic remission can be achieved in almost
all Ph⫹patients with CML in the chronic phase, in approximately
50% of those in the accelerated phase and in a smaller proportion of
those in the blastic phase or in those with Ph⫹acute leukemia.
7-13
More importantly, a major cytogenetic response can be achieved in
more than 50% of the patients who begin the treatment in the late
chronic phase
9-12
and in more than 80% of those who are treated in
the early phase.
14
The proper follow-up of imatinib-treated patients is
based on cytogenetic (conventional and fluorescent in situ hybridiza-
tion, as appropriate) and molecular techniques: particularly, complete
cytogenetic responders (CCgR) require assessment of the molecular
response (MR) through molecular quantification. The long-term mo-
lecular follow-up of these patients would make it possible to evaluate
the overall and major molecular response rates and the prognostic
impact of different levels of BCR-ABL transcript reduction, given the
same, complete cytogenetic result. As the presence of the BCR-ABL
gene and its products are considered a surrogate for disease activity, its
disappearance is regarded as the prerequisite for cure and the ultimate
therapeutic goal.
This article aims to compare two groups of late, chronic phase
CML patients who achieved complete cytogenetic response with ima-
tinib therapy. The difference between two groups is based on time
to achieve complete cytogenetic response and we choose 1 year as
cutoff point. We examined whether the behavior of two groups
during the 4 years of follow-up was in any way different, whether
the complete cytogenetic response is sustained or even improved at
long-term follow-up and whether the low annual mortality rates
persist in later years.
PATIENTS AND METHODS
Patients
The patients treated belonged to a study protocol (CML/002/STI571),
which was designed, sponsored, and implemented by the Italian Cooperative
Study Group on CML according to good clinical practice and the principles of
the Helsinki Declaration. Novartis Pharma supplied the drug free of charge
and partly provided the support for data and sample collection and for the
monitoring of adverse events. Patients were required to have Ph-positive
chronic phase CML after IFN-
␣
failure because of hematologic or cytogenetic
resistance or relapse, or because of IFN-
␣
toxicity. Chronic phase CML was
defined as the presence, in the peripheral blood and bone marrow, of blasts
less than 15%, basophils less than 20%, blasts together with promyelocytes less
than 30%, and platelets more than 100 ⫻10
9
/L. Failure of the hematologic
response to IFN-
␣
was defined as hematologic resistance (failure to achieve a
complete hematologic response [CHR] after at least 6 months of IFN-
␣
)or
relapse (⬎30% increase in Ph-positive metaphases on two occasions, or a
ⱖ65% increase in Ph⫹metaphases on 1 occasion). Intolerance of IFN-
␣
therapy was defined as grade 3 or 4 nonhematologic toxicity. The median age
at the time of imatinib start was 55 years (range, 29 to 74 years).
Patients received 400 mg of imatinib alone, once daily at the same dosage
until disease progression. Criteria for dose reductions and treatment discon-
tinuation have been described in a previous study.
15
Cytogenetic and Molecular Studies
Cytogenetic studies were performed by standard banding techniques
and at least 20 metaphases were analyzed. The cytogenetic response (CgR) was
rated according to the proportion of Ph negative (Ph⫺) metaphases, as com-
plete (Ph⫺100%), partial (Ph⫺66% to 99%), minor (Ph⫺34% to 65%), and
minimal or none (Ph⫺ⱕ33%). BCR-ABL transcripts were detected by
real-time quantitative reverse transcriptase-polymerase chain reaction (Q-
PCR) analysis on bone marrow aspirate. Bone marrow samples were collected
before treatment (baseline), after 3 and 6 months and at the end of the study
treatment period (12 months). Subsequent samples were obtained every 6
months only from the patients who were in CCgR. Total leukocytes were
extracted from 3 to 5 mL of bone marrow aspirate after separation on a Ficoll
Hypaque gradient. Mononuclear cells were resuspended in 500
L of GITC
and stored at ⫺20°C. Total RNA was isolated using the RNA easy kit (Qiagen,
Spoorstraat, the Netherlands) according to the manufacture’s instructions.
RNA quality was assessed on an ethidium bromide–stained 2% agarose gel.
Minimal residual disease was detected during the follow-up by a stan-
dardized RTQ-PCR method that was established within the framework of the
EU Concerted Action.
16,17
The method independently measures, in each sam-
ple by real time PCR, the copy number of mRNA encoding for the p210
BCR/ABL protein and for a control gene to verify sample-to-sample RNA
quality variations. In this study

2 microglobulin (

2M) was selected and used
as a control gene. The reverse transcription (RT) reaction conditions were the
same for BCR-ABL and

2M mRNA amplifications. Real time quantitative
RT-PCR was performed on an ABI PRISM 7700 Sequence Detector (Perkin
Elmer, Foster City, CA). The quantification principles and procedure using the
TaqMan probe have been previously described.
15
All real time RT-PCR exper-
iments were performed in duplicate. The quantitative RQ-PCR assays for the
quantification of BCR-ABL were designed to detect b2a2 and b3a2 transcripts
in a single reaction. The copy number of BCR-ABL and

2M transcripts was
derived by the interpolation of threshold cycle (ct) values to the appropriate
standard curve, and the result, for each sample, was expressed as a ratio of
BCR-ABL mRNA copies to

2M mRNA. The threshold was systematically set
at 0.1 in order to avoid any particular problems of baseline creeping. To ensure
that RNA was not degraded, samples that gave

2M ct values higher than 25.7
were discarded. The lowest level of detectability of the method is 0.00001. This
ratio would correspond to about 0.001 using ABL or GUS as a control gene.
Statistics
Comparison of means was made with the t-test, and comparison of
frequencies with the
2
test or the Fisher’s exact test, as appropriate. Median
ranges between pairs of continuous variables were analyzed by the Wilcoxon
rank test. The correlation coefficients between pairs of continuous variables
were calculated by Pearson correlation. The significance level for all statistical
tests was .05. Overall survival and time to progression to the accelerated or
blastic phase were calculated by the product-limits method of Kaplan and
Meier.
18
All statistical calculations were performed using GraphPad Prism 4.
RESULTS
Cytogenetic Response
A total of 284 patients with late chronic phase CML treated with
imatinib mesylate after IFN-
␣
failure were analyzed. The cytogenetic
response rates throughout the entire study period are reported in
Table 1. These results have been previously reported in part. One
hundred and fifty-one of 284 (53%) obtained a CCgR and 88 patients
(31%) achieved a cytogenetic response ranging from partial to mini-
mal (PCgR). Only 45 patients (16%) had no cytogenetic response to
imatinib therapy. Patients who achieved a CCgR were divided into
two groups according to the rapidity of the complete cytogenetic
response. To the first group belonged 114 of 151 patients (73%) who
obtained the CCgR within 12 months on imatinib (early responders)
at a median time of 5 months (range, 2 to 12 months). In this group 47
CML Early Responders and CML Late Responders
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Copyright © 2006 American Society of Clinical Oncology. All rights reserved.
patients (41%) obtained a CCgR within three months, 36 patients
(32%) obtained the same response in six months and 31 (27%) pa-
tients in the period between 6 and 12 months. The second group
consisted of 37 of 151 patients (27%) who achieved the CCgR after 12
months of therapy (late responders). The median time from start of
imatinib therapy to achievement of CCgR was 25.5 months (range, 15
to 40 months). In particular, 17 patients (46%) achieved a CCgR
within 24 months on imatinib, 18 patients (49%) between 24 and 36
months and the remaining (two patients, 5%) after 36 months of
treatment. Overall in the three groups of late responders Ph⫹met-
aphases progressively and slowly decreased over time (ranging from
100% Ph⫹to 65% and 35% Ph⫹metaphases before 12 months) and
finally become negative after 12 months at the checkpoints before
described. In this way the most of late responders had already a good
cytogenetic response within 1 year, even if not complete. Only two
patients had a different pattern of cytogenetic response. In fact, they
had 100% Ph⫹metaphases for more than 12 months, and then they
become negative at 30 and 28 months after the start of therapy. In this
case, they lost CCgR after 3 and 5 months, respectively.
Durability of Complete Cytogenetic Response
Of the 114 patients who achieved a complete cytogenetic re-
sponse within 12 months, 92 (81%) still displayed a durable complete
cytogenetic response without evidence of clonal progression at the
time of the last follow-up, while 22 (19%) showed loss of complete
cytogenetic response (defined as a 30% or more increase in Ph-
positive cells, documented on 14 occasions, an increase to 65% on two
occasions and an increase to 95% or more in six patients). Of the 37
patients who obtained a complete cytogenetic response after 12
months of imatinib therapy, 30 (81%) maintained a stable complete
cytogenetic response after 48 months. Of the seven patients who lost
the response, six had a major cytogenetic response, while a minor
cytogenetic response was documented in one patient. There was no
difference between early and late responders in terms of loss of com-
plete cytogenetic response.
Molecular Response
One hundred fifty-one patients with chronic phase CML and
failure on IFN-
␣
therapy, treated with imatinib mesylate, had RTQ-
PCR. The median molecular follow-up was 36 months (range, 9 to 54
months). The amount of BCR-ABL transcript in bone marrow cells
was measured with quantitative PCR analysis before treatment (base-
line), at 3 months and every 6 months up to 48 months. Table 2 and
Figure 1 show the MR patterns in the early and late cytogenetic re-
sponders. The amounts of BCR-ABL transcript level, expressed as the
ratios of BCR-ABL to

2M ⫻100 before treatment were 0.2811 and
0.3123, respectively, in early and late responders (median values). At
baseline and at 3 months there was no significant difference between
two groups of patients (P⬎.05), but after 12 months of imatinib the
amount of BCR-ABL transcript in early responders was decreased by
three logs, whereas in late responders the BCR-ABL transcript level
gradually decreased by two logs. At 12, 18 and 24 months the differ-
ences in BCR-ABL transcript level were significant (P⫽.0005,
P⫽.0004, P⫽.0229, respectively). At 36 months and 48 months the
amount of BCR-ABL transcript level of late responders was similar to
that of early responders (the median values were 0.00047 v0.00022
and 0.00019 v0.00026, respectively, P⫽nonsignificant). Table 3
presents the distribution of complete, stable CCgRs according to
the maximum reduction in BCR-ABL level at 12 and 24 months on
Table 1. Cytogenetic Response to Imatinib Mesylate Therapy and
Stability and Duration of CCgRs CML/002/STI571
Cytogenetic Response
Patients
No. %
Complete, stable 151/284 53
Early CCgRs 114/151 73
Late CCgRs 37/151 27
Early responders remaining in CCgR for 2
or more years
92/114 81
Late responders remaining in CCgR for 2
or more years
30/37 81
Partial to minimal 88/284 31
None 45/284 16
NOTE. 151 patients out of 284 (53%) obtained a complete cytogenetic
response: 114 patients (73%) obtained the CCgR within 12 months on
imatinib (early responders) and 37 (27%) achieved such a response after 1
year (late responders). There was no difference in term of loss of CCgR
between two groups.
Abbreviation: CCgRs, complete cytogenetic responders.
Table 2. BCR-ABL Transcript Level (expressed as the ratio of BCR-ABL to

2 microglobulin ⫻100) on Bone Marrow Samples in Patients Who Achieved a
Complete Cytogenetic Response Within 1 Year (early responders) and After 1 Year of Therapy (late responders)
Months
Early Responders Late Responders
P
No. of
Samples Median Mean SD
No. of
Samples Median Mean SD
Baseline 86/92 0.28110 0.35522 0.30247 29/29 0.31239 0.52625 0.55047 .1776
3 85/87 0.00641 0.10124 0.39883 27/29 0.05382 0.19136 0.45702 .3467
6 82/85 0.00106 0.01891 0.05282 24/24 0.02448 0.08325 0.11816 .0004
12 80/83 0.00084 0.00810 0.03103 21/22 0.00597 0.06889 0.12840 .0005
18 43/45 0.00032 0.00190 0.00398 9/10 0.00374 0.01961 0.03499 .0004
24 34/34 0.00020 0.00205 0.00429 16/16 0.00144 0.01086 0.01791 .0229
30 25/27 0.00030 0.00326 0.00457 10/10 0.00162 0.00294 0.00313 .1390
36 24/24 0.00022 0.00571 0.01157 12/12 0.00047 0.00043 0.00061 .5699
42 22/22 0.00023 0.00716 0.01596 12/12 0.00028 0.00277 0.04761 .4613
48 14/14 0.00026 0.00027 0.00011 11/11 0.00019 0.00005 0.00003 .8431
NOTE. Pvalues have been calculated using unpaired test which compares the means between two groups of patients.
Iacobucci et al
456 JOURNAL OF CLINICAL ONCOLOGY
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imatinib therapy and its relationship with CCgR loss. The log reduc-
tion patient evaluation method was not based on measurements rela-
tive to the baseline value of each individual, but each result was
referenced to an absolute value that was referred to as the standardized
baseline, similar to that reported by Hughes et al. The original stan-
dardized baseline value that was used to determine a log reduction in
this study was established by measuring the BCR-ABL levels of 151
patients before commencing imatinib. The median BCR-ABL/

2M ⫻
100 ratio in our laboratory was 0.29766. At 12 months, the maximum
reduction in BCR-ABL level was less than 2 logs in 21% of early
patients and in 39% of late patients, it was between 2 and 3.9 logs in
63% of early patients and in 42% of late patients, and it was equal to or
more than 4 logs in 16% and in 19%, respectively. Although these
relationships cannot be significant, due to the small number of
cases and events, at 24 months we observed that the molecular
response rates become even more similar between two groups of
patients. It is interesting to note that the reduction in BCR-ABL
level was ⱖ4 logs in 33% of early patients and in 29% of late
patients. Among these, only one patient lost CCgR during subse-
quent follow-up.
Progression-Free Survival and Overall Survival
Of the 151 patients with complete cytogenetic responses ana-
lyzed, 122 are still alive in CCgR and on imatinib mesylate therapy
after 4 years (19 are alive in the chronic phase but not in CCR, four are
alive in the accelerated or blastic phase, and six have died). The esti-
mated 4-year progression-free survival rate was 88% for early re-
sponders and 100% for late responders (Fig 2A; P⫽nonsignificant),
whereas the estimated 4-year overall survival rate was 92% for early
responders and 100% for late responders (Fig 2B; P⫽nonsignificant).
Despite the fact that late responders achieved complete cytogenetic
remission after 1 year of imatinib therapy, they showed a progression-
free survival rate and an estimated 4-year overall survival rate similar
to those of early responders.
DISCUSSION
The introduction of imatinib has ushered in a new era in the treatment
of CML. In chronic phase CML after IFN-
␣
failure, imatinib mesylate
induced major cytogenetic response rate of 60% and complete cyto-
genetic response rate of 40% but we don’t yet know whether the
complete cytogenetic responses will be sustained or even improve with
long-term follow-up.
In this analysis, we evaluated the pattern and rapidity of the
response to imatinib, making a comparison between patients who
obtained the CCgR very quickly, after 3 or 6 months of treatment, and
patients where a CCgR could be detected only later, after 12 months of
treatment. We have called these two categories of patients “early” and
“late” complete cytogenetic responders, respectively, and we exam-
ined whether their behavior was any different at subsequent follow-
up. Data demonstrate that the response in late cytogenetic responders
was only delayed but we were unable to find any evidence that after 3
or 4 years of treatment the molecular response of late cytogenetic
responders was worse than that of early cytogenetic responders. We
observed that with therapy there was a continued increase in cumula-
tive complete cytogenetic response rates. Given the controversy about
dose increase, the consideration for transplant in appropriate patients
and the availability of new TK inhibitors, it was important to describe
the pattern of response in the late patients. For this group the median
time from start of imatinib therapy to achievement of CCgR was 25.5
months (range, 15 to 40 months). Overall in the late responders Ph⫹
metaphases progressively and slowly decreased over time (ranging
from 100% Ph⫹to 65% and 35% Ph⫹metaphases before 12 months)
and finally become negative after 12 months at the checkpoints before
described. In this way the most of late responders had already a good
Table 3. Maximum Reduction, Expressed As a Logarithm, of the BCR-ABL Transcript Level at 12 Months and at 24 Months of Imatinib Therapy and
Its Relationship With CCgR Loss
Maximum Reduction of BCR-ABL
Early Patients
Patients Who Lost
the CCgR Late Patients
Patients Who Lost
the CCgR
No. % No. % No. % No. %
At 12 months
Less than 2 logs 20 21 8 40 10 39 2 20
2-3.9 logs 61 63 7 11 11 42 1 9
4 logs or more 16 16 1 6 5 19 1 2
At 24 months
Less than 2 logs 9 16 3 33 3 14 1 33
2-3.9 logs 29 51 1 3 12 57 2 17
4 logs or more 19 33 1 5 6 29 0 0
Abbreviation: CCgR, complete cytogenetic responder.
Fig 1. Molecular response. At 12 months of imatinib, the amount of BCR-ABL
transcript in early responders was decreased by 3 logs, whereas in late responders
there was a reduction of 2 logs but after 3 or 4 years the amount of BCR-ABL
transcript level of late responders has become similar to that of early responders.
CML Early Responders and CML Late Responders
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cytogenetic response within 1 year, even if not complete. Only two of
37 patients had a different pattern of cytogenetic response. In fact, they
had 100% Ph⫹metaphases for more than 12 months and then they
become negative at 30 and 28 months after the start of therapy.
For CML patients, methods for predicting and monitoring re-
sponse to treatment have changed considerably in recent years from
the repeated examination of bone marrow metaphases for the pres-
ence of the Ph⫹positive chromosome in patients treated with IFN or
SCT, to quantitative assays based on reverse transcriptase polymerase
chain reaction. QRT-PCR using specific fluorescent hybridization
probes and standard procedures with internal controls has proved
extremely valuable for assessing and monitoring minimal residual
disease in patients who achieve Ph negativity after treatment with
IFN-
␣
or with imatinib mesylate or after allogenic SCT. In our study
after 36 and 48 months of treatment the amount of residual disease
measured by QRT-PCR was similar between early and late responders.
O’Dwyer et al reported major differences in treatment outcomes on
imatinib therapy at 3 or 6 months
19
in patients with chronic phase
chronic myelogenous leukemia treated after failure of IFN-
␣
therapy.
Similarly, the IRIS trial demonstrated significant differences in
progression-free survival as revealed by the 12-month response to
imatinib mesylate: patients not achieving a complete cytogenetic re-
sponse by then had an 80% progression-free survival rate.
14
Our data
suggest that in late chronic phase patients a benefit from an early
cytogenetic CR versus late CR is not apparent. However the findings in
this group of late chronic phase patients may not applicable to newly
diagnosed patients in whom the response rate is much higher.
Because complete or major (Q-PCR reduction to less than 0.05%
BCR-ABL/ABL or by 3 logs or more) molecular responses have been
associated with an excellent prognosis with both IFN-
␣
and imatinib
mesylate therapy, we compared early and late responders in terms of
reduction in BCR-ABL transcript level. According to published
reports we chose to compare the log reduction to a standardized
PCR value. Cortes et al.
20
calculated a log-reduction in two differ-
ent ways. First they used the median of the total population as the
baseline value. Then they used each individual patient’s pretreat-
ment BCR-ABL/ABL value as their own baseline to determine log
reduction. They demonstrated that the difference between two
ways was not statistically significant.
The advantage of defining molecular response in terms of a
reduction from a median pretreatment level is that once a laboratory
has established its median baseline level, results can be expressed on a
common scale internationally. Another advantage is that the molecu-
lar response can be calculated without needing to know the actual
baseline level for that particular patient. A possible disadvantage is that
it may be difficult to realize which minimal residual disease threshold
could be “safe” for predicting a cure and possibly for increasing or
modulating the individual drug-uptake.
We found no significant difference between early and late re-
sponders in the achievement of a 3-log reduction or more in the
BCR-ABL/

2M ratio. At 12 months the maximum reduction in BCR-
ABL level was equal to or more than 4 logs in 16% of early versus 19%
of late responders. At 24 months, good molecular responders were
33% in the first group as against 29% in the second group. We also
analyzed whether there was any difference between early and late
responders in terms of progression-free survival and overall sur-
vival and found no difference. Though late responders achieved
complete cytogenetic remission after 1 year of imatinib therapy,
they showed a progression-free survival rate and an estimated
4-year overall survival similar to those of early responders (88% v
100% and 92% v100%, respectively).
These results suggest that the sensitivity and the response to
imatinib may require 1 year or more and that it could be possible to
continue the same dose of imatinib even if a CCgR had not been
reached by 12 months. This is particularly true in patients, as the late
responders, who had already a good cytogenetic response within one
year, even if not yet complete. For the patients who had not this
pattern of response and who had no cytogenetic response within one
year of imatinib other approaches, as the dose increase, transplant or
therapy with the new TK inhibitors available could be appropriate.
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■■■
Acknowledgment
The assistance of Katia Vecchi is kindly acknowledged.
Appendix
The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF (via
Adobe® Acrobat Reader®) version.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Author Contributions
Conception and design: Giovanni Martinelli
Provision of study materials or patients: Gianantonio Rosti, Giovanni Martinelli
Collection and assembly of data: Angela Poerio, Simona Soverini, Daniela Cilloni, Elisabetta Abruzzese, Enrico Montefusco, Francesco Iuliano,
Domenico Russo, Marco Gobbi, Giuliana Alimena, Bruno Martino
Data analysis and interpretation: Nicoletta Testoni, Emanuela Ottaviani, Carolina Terragna, Fabrizio Pane, Giuseppe Saglio, Ilaria Iacobucci,
Gianantonio Rosti, Marilina Amabile
Manuscript writing: Ilaria Iacobucci
Final approval of manuscript: Michele Baccarani
CML Early Responders and CML Late Responders
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