Best Practice & Research Clinical Haematology 22 (2009) 343–353

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Haematology
journal homepage: www.elsevier.com/locate/beha

Prognostic factors in chronic myeloid leukaemia

Juan Carlos Hernández-Boluda, MD, Doctor a, Francisco Cervantes, MD,
Doctor b, *
a
Haematology and Medical Oncology Department, Hospital Clı́nico Universitario, Valencia, Spain
b
Haematology Department, Hospital Clı́nic, IDIBAPS, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain

Keywords:
Prognostic factors in patients with chronic myeloid leukaemia
chronic myeloid leukaemia (CML) treated with conventional treatment include age, spleen
prognosis size, platelet count, blood percentage of blasts, basophils and
imatinib eosinophils, and cytogenetic abnormalities besides the Phila-
tyrosine kinase inhibitors delphia chromosome. The value of traditional clinical and labora-
tory features to identify patients at increased risk of imatinib
failure has not been established yet. Biological markers such as
gene expression profile, v-crk sarcoma virus CT10 oncogene
homologue (avian)-like (Crkl) phosphorylation or expression of
imatinib transporter proteins have been shown to be useful to
predict the response to imatinib. In practice, the response obtained
at different time points from the initiation of imatinib is employed
to predict the patient’s outcome, with this especially applying to
cytogenetic response. The prognostic relevance of early molecular
response to imatinib has also been pointed out. Prognostic factors
for response to second-generation tyrosine kinase inhibitors (TKI)
after imatinib failure are currently being investigated.
Ó 2009 Elsevier Ltd. All rights reserved.

The natural history of chronic myeloid leukaemia (CML) is characterised by a biphasic evolutive
course. Patients are usually diagnosed in the chronic phase (CP) of the disease but they eventually
progress to a terminal, acute leukaemia-like phase, the so-called blast crisis (BC) of CML, sometimes
preceded by an accelerated phase (AP). Since the BC remains mostly incurable, survival is essentially
determined by time to transformation. Whereas conventional treatment had a modest effect in
postponing transformation, the introduction of imatinib has changed the scenario dramatically.

* Corresponding author. Tel.: þ34 932275428; Fax: þ34 932275484.

E-mail address: fcervan@clinic.ub.es (F. Cervantes).

1521-6926/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.beha.2009.04.005
344 J.C. Hernández-Boluda, F. Cervantes / Best Practice & Research Clinical Haematology 22 (2009) 343–353

The present article summarises the current status of CML prognosis, with special emphasis on the
prognostic factors in patients under imatinib treatment.

Survival

Early studies before the advent of cytogenetic techniques showed that the average survival of
untreated CML patients was approximately 3 years [1]. Busulphan and hydroxyurea prolonged survival
to a median of 4 to 5 years [2] due to a better control of the disease complications during the chronic
phase, but had a modest effect on postponing progression. Recombinant interferon-a (IFN-a) was the
first drug to significantly delay BC appearance [3–5]. The life expectancy of IFN-treated patients was
prolonged by 1 to 2 years, mainly due to patients achieving a major cytogenetic response (MCR, Ph-
positive bone marrow metaphases <36%) [6]. The estimated 10-year survival rate of 317 patients who
achieved complete cytogenetic response (CCR) to IFN was 72% [7]. Unfortunately, only a small
proportion of patients achieve an MCR to IFN. Concomitant low-dose cytarabine resulted in higher and
faster responses, providing a survival advantage in one [8] but not in the other study [9]. Overall, with
conventional treatment, over 80% of patients eventually die from the disease [10].
Allogeneic stem-cell transplantation remains the only therapy with the potential for curing CML.
However, this option is limited to patients who can tolerate the procedure and have a suitable donor.
Mortality is significant and survival probability varies depending on the factors included in the
European Group for Blood and Marrow Transplantation (EBMT) scoring system [11]. About 50% to 60%
of patients in first CP receiving a transplant from a matched related donor are alive and leukaemia-free
after 10 years [12]. The projected survival curves appear to plateau after 3 to 7 years, but relapses have
been observed up to 21 years after transplantation [13]. Better results have recently been reported
[13,14].
The introduction of imatinib dramatically changed CML outcome. Early trials reported an impres-
sive 50% to 60% CCR rate among CP-CML patients failing to IFN [15,16]. Such responses proved to be
durable, as shown in a recent update of the largest series, in which estimated progression-free survival
at 6 years was 88% for patients achieving CCR [15]. In 2003, imatinib was approved as a first-line
treatment of chronic phase-chronic myeloid leukaemia (CP-CML) on the basis of the early results of the
International Randomised Study of Interferon (IRIS) study, a randomised trial showing better efficacy
and tolerability of imatinib over IFN plus low-dose cytarabine [17]. In a more recent update, overall
survival of patients receiving imatinib upfront was 86% at 7 years [18], and only 7% had progressed to
the advanced phases, with a clear decline in the progression rates after the third year. Such a downward
trend differs from what was seen with conventional therapy, in which only 5–10% of patients devel-
oped BC during the first 2 years and the annual progression rate increased to 20–25% afterwards [10]. In
view of these results, future trials should be evaluated in terms of response rates and time to
progression as surrogate markers for overall survival.

Prognostic factors

Pre-imatinib era

Initial prognostic factors

The disease phase is the strongest prognostic factor in CML, with patients diagnosed in the
advanced phases (w10% of the total) carrying a significantly worse outlook. With regard to the CP,
several initial variables are associated with CML prognosis and some have been incorporated into
prognostic scoring systems [19–23]. The most widely used classification is the Sokal score (Table 1),
derived from 813 patients, most of which had received busulphan [21]. Based on four clinical and
haematological characteristics (namely age, spleen size, platelet count and peripheral blood blasts),
patients could be segregated into three groups with different 4-year survival probabilities: up to 62%
for patients in the low-risk group, 43% for the intermediate-risk group, and 33% for the high-risk group.
In patients younger than 45 years, gender and haematocrit were additional prognostic variables [22].
The independent adverse prognostic weight of additional cytogenetic abnormalities at CML presen-
tation was subsequently shown [23].
 J.C. Hernández-Boluda, F. Cervantes / Best Practice & Research Clinical Haematology 22 (2009) 343–353 345

Table 1
Main prognostic risk scores in chronic phase CML.

Sokal scorea Hasford scoreb

Variables
Age 0.0116  (age  43.4) 0.6666 [when age >50]
Spleen, cm below costal margin þ0.0345  (spleen size  7.51) þ0.042  spleen size
Platelet count,  109/L þ0.188  ([platelets/700]2  0.563) þ1.0956 [when platelets >1.500]
Blood blasts, % þ0.0887  (blasts  2.1) þ0.0584  blasts
Blood basophils, % þ0.2039 [when basophils >3%]
Blood eosinophils, % þ0.0413  eosinophils

Relative risk <0.8 <780

Low risk 0.8–1.2 781–1.480
Intermediate risk >1.2 >1.480
a
Sokal risk is expressed as exponential of the total. A calculator is available on line at: http://www.roc.se/sokal.asp.
b
Hasford risk is expressed as the total  1.000. A calculator is available on line at: http://www.pharmacoepi.de/cgi-bin/
cmlscore.cgi.

Although the Sokal score was also useful in predicting the response rate and survival of IFN-treated
patients, it was unable to discriminate well between the low- and intermediate-risk groups. Therefore,
a new prognostic classification, the Hasford score (Table 1), was derived from over 900 CML patients
treated with IFN [24]. In addition to the four variables included in the Sokal score, two other features,
the blood percentages of eosinophils and basophils, were found to be prognostically relevant. In the
new scoring system, predicted 5-year survival probabilities for the low-, intermediate- and high-risk
groups were 76%, 55% and 25%, respectively.
Deletions at or encompassing the ABL/BCR junction, present in 10–15% of patients with classic Phþ
CML and in as many as 30–40% of patients with variant Ph translocations, were linked to survival in the
pre-imatinib era [25–28]. These deletions most likely arise during the translocation process, providing
some molecular heterogeneity from the beginning [26]. Several studies showed a more unfavourable
outcome for patients with such deletions when treated with hydroxyurea or IFN. The prognostic
impact of chromosome 9 deletions proved to be stronger than that of the risk classifications [27]. The
possible relevance of the location of the deletion was also pointed out, with breakpoint–spanning
deletions carrying the more adverse prognosis as compared to deletions on the BCR or the ABL side
only [28].

Evolutive prognostic factors

Time-dependant variables provide prognostic information. Thus, achievement of MCR was asso-
ciated with substantial survival prolongation in patients treated with IFN [29]. Actually, even minor
cytogenetic responses still had a favourable impact on survival [5]. Nevertheless, the survival advan-
tage was strongly dependant on the initial risk profile, since the outcome of high-risk patients was
basically unaffected by therapeutic response [29]. In patients with CCR, significant heterogeneity in the
residual disease at the molecular level was noted and the residual disease correlated with relapse
probability [30]. Although a dose–response effect of IFN was suggested, data from a prospective
randomised trial showed that low-dose IFN, when combined with hydroxyurea to keep white blood
cell counts below 5  109 L1, was as effective as higher doses [31].

Imatinib era

Imatinib as a second-line treatment

Imatinib was initially employed in CP-CML patients failing to IFN [15,16]. Long-term follow-up of
454 such patients, who received imatinib for a median of 65 months, showed a 57%–cumulative best
CCR rate [15]; 41% of patients remained in CCR at 5 years and estimated transformation-free survival
and overall survival at 6 years were 61% and 76%, respectively. Freedom from progression to the
advanced phases and survival were strongly associated with cytogenetic response at 12 months. At 6
years, the estimated transformation-free and overall survival for patients achieving MCR were 84% and
89%, respectively, the outcome being markedly worse for patients not achieving at least a minor
346 J.C. Hernández-Boluda, F. Cervantes / Best Practice & Research Clinical Haematology 22 (2009) 343–353

cytogenetic response by that time. Of note, in a study from the Italian group [32], the proportion of
patients remaining in stable CCR for two or more years was similar for early and late responders
(considering one year of therapy as cut-off time). Lower CCR rates were registered in patients with prior
haematologic resistance to IFN [15,33], in those requiring prolonged imatinib discontinuation due to
haematologic toxicity [34,35] and in those with baseline platelet counts >450  109 L1
[34–36] (Table 2). Independent risk factors for lower progression-free survival included occurrence of
myelosuppression [33], baseline platelet counts > 450  109 L1 [36], high Sokal score [34], cytogenetic
clonal evolution [37,38] and failure to achieve MCR during the first year of treatment [15,34]. It is
uncertain whether the deleterious effect of myelosuppression actually reflects more advanced disease
with reduced benign stem cell pool or, instead, it is the consequence of the decreased dose intensity
received by patients with such complication. Besides, factors such as older age or chromosome 9
deletions, traditionally with a negative prognostic impact, did not have an adverse influence in
progression-free or overall survival in the imatinib-treated patients [39–41].
To date, two studies have demonstrated that early reduction of the BCR-ABL transcript levels
predicts for subsequent MCR achievement in patients receiving imatinib after IFN failure. Higher
probability of MCR by 6 months was observed in patients with a BCR-ABL:ABL ratio <20% of the
baseline value at 2 months on imatinib [42] and in those where the value decreased to <50% after 4
weeks or to <10% after 3 months of treatment [43].
The results of imatinib therapy are considerably worse in patients with AP and BC of CML, with the
responses being generally transient and no plateau in the survival curves [44,45].

Imatinib upfront

Despite the success of imatinib, some patients fail to achieve an optimal response or eventually lose
it. In a recent update of the IRIS study, one-third of patients initially assigned to imatinib were no longer
receiving the drug at 5 years, due to insufficient efficacy, toxicity or other reasons [46]. Given the
current availability of alternative therapies, it is important to identify the factors that might discrim-
inate at the early phases of therapy those patients at increased risk of imatinib failure. However, no
comprehensive study of baseline prognostic factors in patients treated with imatinib upfront is
available as yet. Therefore, in practice, the most important prognostic information is provided by the
response obtained at different time points (Table 3).

Initial prognostic factors

In the IRIS trial, the Sokal score was predictive of both response achievement and progression-free
survival [46]. In patients with low-, intermediate- and high-risk CML, cumulative best CCR rates at 60
months were 89%, 82% and 69%, respectively, and estimated risk of progression was 3%, 8% and 17%.
However, in contrast to previous experience with IFN [7], the Sokal score lost its predictive value for
disease progression in high-risk patients achieving a CCR. There is increasing evidence supporting that
imatinib could also overcome the poor prognostic influence of deletions of the derivative chromosome
9. Thus, the lower cytogenetic response rates reported in patients with chromosome 9 deletions [47]
was not confirmed [41,48,49]. Moreover, no differences in survival have been noted in patients with or
without chromosome 9 deletions. Pre-therapeutic BCR-ABL transcript levels also failed to show
prognostic significance in this setting [50].

Table 2
Main prognostic factors in chronic phase CML with imatinib as second-line treatment.

Predictors of cytogenetic response Predictors of progression-free and overall survival

- Prior response to IFN-a therapy - Baseline platelet counts
- Baseline platelet counts - Sokal risk score
- Time off-imatinib due to myelosuppression - Cytogenetic clonal evolution
- Molecular response at 2–3 months - Myelosuppression in first 3 months
- Cytogenetic response at 12 months
 J.C. Hernández-Boluda, F. Cervantes / Best Practice & Research Clinical Haematology 22 (2009) 343–353 347

Table 3
Main prognostic factors in chronic phase CML with imatinib as front-line treatment.

Predictors of cytogenetic response Predictors of progression-free and overall survival

- Sokal risk score - Sokal risk score
- Pretherapy in vitro IC50 - Haematological response at 3 months
- Pretherapy OCT-1 activity - Cytogenetic response at 6 and 12 months
- ABCB1 gene polymorphisms - Molecular response at 12 and 18 months
- Imatinib dose
- Imatinib plasma levels
- In vivo IC50
- Molecular response at 3 months

The limitations of traditional clinical and laboratory parameters to identify patients with increased
risk of imatinib failure have encouraged the search for new biomarkers useful for this purpose. Zheng
and colleagues, using gene expression profiling of CD34þ cells, identified a prediction set of 34 genes
allowing sample classification as chronic or blastic phase CML [51]. In similar studies, Radich et al. [52]
and Frank et al. [53] showed that the gene expression pattern in CP-CML imatinib-resistant patients
closely resembled the pattern in the advanced phases. Yong et al. found the combination of low CD7
expression and high proteinase 3 or elastase expression in CD34þ cells to be associated with longer
survival [54], and they also reported the predictive value of the expression of the transcriptional
repressor BMI1, with lower levels being associated with longer survival [55]. Since most of these data
were derived from patients diagnosed before the imatinib era, confirmation in an independent cohort
of patients receiving imatinib upfront is warranted. In this sense, McLean et al. identified a set of 55
genes differentially expressed in patients who achieved CCR to imatinib as compared to those who did
not [56]. In turn, Villuendas et al., based on the expression of six genes in bone marrow cells, generated
a model predicting MCR achievement at 12 months of treatment [57]. In contrast, Crossman et al. did
not find significant differences in the transcriptional signature associated with cytogenetic refracto-
riness to imatinib [58]. Overall, the available data do not allow to delineate distinct gene signatures that
could be incorporated into treatment guidelines. However, this technology has provided some
candidate prognostic genes to be tested in future prospective trials.
A different approach to predict the results of imatinib therapy has been pioneered by the Adelaide
group. They first demonstrated that the Sokal score and pre-therapy imatinib blood concentration
producing a 50% decrease in the phosphorylation level of the BCR-ABL substrate Crkl (IC50imatinib)
could predict molecular response in CP-CML patients treated with imatinib upfront [59]. A further
report provided experimental evidence supporting that the major determinant of interpatient vari-
ability in the IC50imatinib at diagnosis was the efficiency of the imatinib intracellular uptake, mediated
by the OCT-1 influx protein [60]. The interaction between imatinib dose and OCT-1 activity, as
determined in a pre-therapy functional assay, was studied in the same cohort of patients and correlated
with the molecular response at 18 months [61]. Patients with high OCT-1 activity responded equally
well to standard or high-dose imatinib, whereas patients with less active transporter responses were
better in those receiving high doses, indicating that imatinib dose intensity could overcome the
negative effect of low OCT-1 activity. Other imatinib transporter proteins might be also important in
determining the amount of imatinib that actually reaches the target inside the leukaemic cell. Indeed, it
has been demonstrated that the multi-drug resistance efflux pump P-glycoprotein (now known as
ABCB1) can actively efflux imatinib; and that its overexpression can contribute to imatinib resistance in
CML cell lines [62]. Recently, a link between common genetic variants of the ABCB1 gene and proba-
bility of response to standard-dose imatinib has been demonstrated, as 85% of homozygous patients for
the allele 1236T achieved an MMR compared with only 48% of patients with other genotypes [63].
Interestingly, an association was noted between 1236TT genotype and higher imatinib plasma
concentrations.
The role of higher initial imatinib dose in CP-CML patients is currently being evaluated [64–66].
Imatinib doses higher than 400 mg day1 appear to produce faster cytogenetic and molecular
responses, but whether such earlier responses would translate into a benefit in progression-free and
overall survival remains unknown.
348 J.C. Hernández-Boluda, F. Cervantes / Best Practice & Research Clinical Haematology 22 (2009) 343–353

Evolutive factors
Due to the lack of factors easily available at presentation that allow to predict the outcome to
imatinib, management decisions are currently based on the response dynamics. Obviously, not having
achieved a complete haematological response within the first few months of treatment is the worst
scenario [67]. However, since this is infrequent, in most cases the decision relies on cytogenetics. Not to
obtain some degree of cytogenetic response by three months of treatment is associated with low CCR
probability [67]. However, the most important predictor is the cytogenetic response at 6 months. Both
in the IRIS study and in the Hammersmith series, lack of cytogenetic response at 6 months correlated
with low CCR probability and significantly lower progression-free survival [46,67]. Additionally, in the
IRIS, less than a partial cytogenetic response at 12 months was associated with lower survival free from
the advanced phases and progression-free survival; at 60 months, the estimated rates of survival free
from advanced phases were 97% for patients achieving CCR at 12 months, 93% for those with partial
cytogenetic response and 81% for the remainder (Fig. 1). Progression-free survival of patients in CCR at
18 months was 100% for those in MMR versus 98% for the remainder, the difference not being
significant [68]. Overall, the data from the IRIS highlight the prognostic importance of achieving a CCR.
Based on these data, the current goal of therapy should be to achieve at least a CCR within 18 months of
treatment [69]. However, although patients in CCR at 18 months had a similar outcome in terms of
progression-free or overall survival irrespective of their molecular status, this may be due to the
efficacy of alternative therapies, since patients in CCR but not in MMR at 18 months were more likely to
lose the CCR than those in MMR [70,71].
MMR protects against progression. Indeed, in patients achieving MMR after 18 months, the esti-
mated rate of survival without progression to the advanced phases was 100% at 60 months [68]. But the
timing to achieve the MMR might also influence long-term stability of the response. Thus, the prob-
ability of an event, defined as the acquisition of BCR-ABL mutations and/or the loss of MMR, was 0%, 12%
and 19% for patients achieving a MMR by 6 months, >6 to 12 months, and >12 to 18 months,
respectively [72].
In both the IRIS and TIDEL trials, molecular response at 3 months was a good predictor of achieving
MMR by 24 months [73,74]. Branford et al. reported that in patients not achieving 1-log reduction by 3
months, the MMR rate at 24 months was 13%, compared to 69% and 100% for those achieving 1–2 log
and >2-log reduction, respectively [73]. Furthermore, failure to achieve an MMR in the group with less

Fig. 1. Survival free from evolution to the advanced phases of CML according to the cytogenetic response at 12 months in patients
treated with imatinib upfront in the IRIS study (Druker et al, with permission).
 J.C. Hernández-Boluda, F. Cervantes / Best Practice & Research Clinical Haematology 22 (2009) 343–353 349

than 1-log reduction at 3 months was largely due to resistance, occurring in 83% of patients compared
with only 5% and 0% of those in the 1–2 log and >2 log groups, respectively. The prognostic significance
of the amount of residual disease was evaluated in 85 CP-CML patients who had achieved CCR after
a median time of 9 months of imatinib therapy [75]. When CCR was first recognised, great heteroge-
neity was observed in the depth of the molecular response, with the range of BCR-ABL transcript levels
being greater than 3 to 5 logs. Of note, patients failing to achieve at least a 2-log reduction in the BCR-
ABL transcript levels (58% of all CCR patients) had significantly shorter time to progression. It is
unknown whether the more durable remissions observed in early molecular responders reflect a more
biologically favourable disease or, instead, are the consequence of a more rapid leukaemia debulky that
reduces the number of cells at the risk of transformation. If the latter turns to be true, it can be expected
that the earlier molecular responses achieved with the use of high-dose imatinib or more potent TKIs
will lead to more durable responses.
In order to identify the determinants of the molecular response to imatinib, Cortés et al. analysed
163 CP-CML patients achieving a CCR with first-line imatinib at 400 or 800 mg daily, showing that
high-dose imatinib was the only variable associated with higher probability of achieving MMR at any
time [76]. In a similar study of 103 newly diagnosed CP-CML patients on imatinib 600 mg day1, the
spleen size and baseline values of basophils and platelets were the variables independently associated
with MMR achievement by 12 months [65]. Despite this, the association between the Sokal or Hasford
scores and MMR was not significant at multivariate analysis, probably due to the substantial proportion
of cases with missing data.
There is considerable interpatient variability in imatinib plasma levels, which could, at least
theoretically, influence treatment results. In the IRIS study, patients with the lowest plasma levels on
day 29 of therapy had lower probability of cytogenetic and molecular response and a trend for inferior
event-free survival [77]. Moreover, in a study from the Bordeaux group, imatinib plasma levels above
1002 ng mL1 at one year or more of treatment provided the best sensitivity and specificity to
distinguish patients with different probability of MMR [78]. These preliminary data have to be
confirmed in prospective studies that take into account other factors, such as intrapatient variability or
the impact of dose adjustments [79].
An attractive approach to predict the response to imatinib is the in vivo measurement of the Crkl
phosphorylation while on treatment. This biological end point reflects the dose received and an
otherwise unmeasured array of patient-specific pharmacokinetic and pharmacodynamic factors. The
predictive value of this assay has recently been illustrated by the results of the TIDEL trial, in which all
patients achieving more than 50% reduction in p-Crkl within the first month of therapy achieved MMR
by 24 months versus only 56% of patients failing to reach such threshold [80].

Second-generation tyrosine kinase inhibitors (TKIs)

Information on the long-term outcome of CP-CML patients who receive a second-generation TKI
after imatinib failure is limited [81,82]. The MD Anderson group analysed the determinants of
response in 113 such patients treated with nilotinib or dasatinib [83]. Projected 2-year overall
survival was 87%, with a significant difference between patients achieving an MCR at 12 months or
not. At landmark analysis, the probability of progression over the next year was 3% for patients in
MCR at that time and 17% for those in minor cytogenetic response or complete haematological
response only. Therefore, achieving a MCR at 12 months could be considered an important prog-
nostic milestone in patients on second-line TKIs. Of note, at multivariate analysis, cytogenetic
response at 3 months was the only independent predictor of MCR by 12 months; in patients not
achieving at least a minor cytogenetic response at 3 months, the probability of attaining MCR at 12
months was only 7%, indicating that such patients should be considered for alternative therapies.
More recently, in a study of 80 CP-CML patients receiving a second-generation TKI after imatinib
failure, baseline factors predictive of lower CCR probability were intermediate- or high-risk Sokal
score, need of granulocyte-colony stimulating factor (G-CSF) during previous imatinib therapy,
institution of the second TKI more than 18 months after imatinib failure and lack of cytogenetic
response to imatinib [84]. The 3-year cumulative incidence of CCR for patients with 0 or 1 of the
above factors was 96% versus only 19% for those with 3 or 4 factors. The 3-month BCR-ABL
350 J.C. Hernández-Boluda, F. Cervantes / Best Practice & Research Clinical Haematology 22 (2009) 343–353

transcript levels proved to be a powerful early indicator of the outcome, with 3-year survival
probability being 100% for patients with a BCR-ABL/control gene ratio <15% versus 77% for those
with a ratio >15%.

Practice points

- In CML patients under imatinib treatment, the high-risk Sokal score is associated with lower
complete cytogenetic response (CCR) and progression-free survival. However, unlike in IFN
therapy, the predictive value of the Sokal score disappears if high-risk patients achieve a CCR.
- Cytogenetic response obtained at certain time points is the main factor to predict the outcome
of imatinib treatment. CCR achievement within 18 months protects from disease progression.
- The prognostic relevance of early molecular response to imatinib is currently being assessed.
- In CP-CML patients under second-generation TKIs following imatinib failure, lack of minor
cytogenetic response at 3 months is associated with low probability of major cytogenetic
response by 12 months and lower overall and progression-free survival.

Research agenda

- Biological markers such as gene expression profile, Crkl phosphorylation or imatinib inhibitory
concentration can provide prognostic information.
- Identification of clinicohaematological factors easily available at diagnosis, which allow the
prediction of the outcome to imatinib, is required.

Conflict of interest statement

Francisco Cervantes is member of the Advisory Boards of Novartis and Bristol-Myers Squibb.

References

[1] Minot G, Buckman T, Isaacs R. Chronic myelogenous leukemia. JAMA 1924;82:1489–94.

[2] Hehlmann R, Heimpel H, Hasford J, et al. Randomized comparison of busulfan and hydroxyurea in chronic myelogenous
leukemia: prolongation of survival by hydroxyurea. The German CML Study Group. Blood 1993;82:398–407.
[3] Hehlmann R, Heimpel H, Hasford J, et al. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in
chronic myelogenous leukemia. The German CML Study Group. Blood 1994;84:4064–77.
*[4] The Italian cooperative study group on chronic myeloid leukemia. Interferon alfa-2a as compared with conventional
chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med 1994;330:820–5.
[5] Allan NC, Richards SM, Shepherd PCA, et al. The UK medical research council’s working parties for therapeutic trials in
adult leukaemia. Lancet 1995;345:1392–7.
[6] Chronic myeloid leukemia trialist’ collaborative group. Interferon alfa versus chemotherapy for chronic myeloid
leukemia: a meta-analysis of seven randomized trials. J Natl Cancer Inst 1997;89:1616–20.
[7] Bonifazi F, De Vivo A, Rosti G, et al. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic
responders. Blood 2001;98:3074–81.
[8] Guilhot F, Chastang C, Michallet M, et al. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic
myelogenous leukemia. French chronic myeloid leukemia study group. N Engl J Med 1997;337:223–9.
[9] Baccarani M, Rosti G, De Vivo A, et al. A randomized study of interferon-alpha versus interferon-alpha and low-dose
arabinosyl cytosine in chronic myeloid leukemia. Blood 2002;99:1527–35.
[10] Lee SJ. Chronic myelogenous leukaemia. Br J Haematol 2000;111:993–1009.
*[11] Gratwohl A, Hermans J, Goldman JM, et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic
bone marrow transplantation. Lancet 1998;352:1087–92.
[12] Robin M, Guardiola P, Devergie A, et al. A 10-year median follow-up study after allogeneic stem cell transplantation for
chronic myeloid leukemia in chronic phase from HLA-identical sibling donors. Leukemia 2005;19:1613–20.
[13] Grahtwohl A, Brand R, Apperley J, et al. Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia
in Europe 2006: transplant activity, long term data and current results: an analysis by the chronic leukemia working
party of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica 2006;91:513–21.
 J.C. Hernández-Boluda, F. Cervantes / Best Practice & Research Clinical Haematology 22 (2009) 343–353 351

[14] Crawley C, Szydlo R, Lalancette M, et al. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an
analysis of prognostic factors from the chronic leukemia working party of the EBMT. Blood 2005;106:2969–76.
*[15] Hochhaus A, Druker B, Sawyers C, et al. Favorable long-term follow-up results over 6 years for response, survival, and
safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-a treatment.
Blood 2008;111:1039–43.
[16] Palandri F, Iacobucci I, Martinelli G, et al. Long-term outcome of complete cytogenetic responders after imatinib 400 mg
in late chronic phase, Philadelphia-positive chronic myeloid leukemia: the GIMEMA Working Party on CML. J Clin Oncol
2008;26:106–11.
*[17] O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed
chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994–1004.
[18] O’Brien SG, Guilhot F, Goldman JM, et al. International Randomized Study of Interferon versus STI571 (IRIS) 7-year follow-
up: sustained survival, low rate of transformation and increased rate of major molecular response in patients with newly
diagnosed chronic myeloid leukemia in chronic phase treated with imatinib. Blood 2008;112 [abstract 186].
[19] Tura S, Baccarani M, Corbelli G, et al. Staging of chronic myeloid leukemia. Br J Haematol 1981;47:105–19.
[20] Cervantes F, Rozman C. A multivariate analysis of prognostic factors in chronic myeloid leukemia. Blood 1982;60:1298–304.
[21] Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in ‘good risk’ chronic granulocytic leukemia. Blood 1984;63:
789–99.
*[22] Sokal JE, Baccarani M, Tura S, et al. Prognostic discrimination among younger patients with chronic granulocytic
leukemia: relevance to bone marrow transplantation. Blood 1985;66:1352–7.
[23] Sokal JE, Gomez GA, Baccarani M, et al. Prognostic significance of additional cytogenetic abnormalities at diagnosis of
Philadelphia chromosome-positive chronic granulocytic leukemia. Blood 1988;72:294–8.
[24] Hasford J, Pfirrmann M, Hehlmann R, et al. A new prognostic score for survival of patients with chronic myeloid leukemia
treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer
Inst 1998;90:850–8.
[25] Sinclair PB, Nacheva EP, Leversha M, et al. Large deletions at the t(9;22) breakpoint are common and may identify a poor-
prognosis subgroup of patients with chronic myeloid leukemia. Blood 2000;95:738–43.
[26] Huntly BJP, Reid AG, Bench AJ, et al. Deletions of the derivative chromosome 9 occur at the time of the Philadelphia
translocation and provide a powerful and independent prognostic indicator in chronic myeloid leukemia. Blood 2001;98:
1732–8.
[27] Kolomietz E, Al-Maghrabi J, Brennan S, et al. Primary chromosomal rearrangements of leukemia are frequently accom-
panied by extensive submicroscopic deletions and may lead to altered prognosis. Blood 2001;97:3581–8.
[28] Kreil S, Pfirrmann M, Haferlach C, et al. Heterogeneous prognostic impact of derivative chromosome 9 deletions in
chronic myelogenous leukemia. Blood 2007;110:1283–90.
[29] Hasford J, Pfirrmann M, Shepherd P, et al. The impact of the combination of baseline risk group and cytogenetic response
on the survival of patients with chronic myeloid leukemia treated with interferon-a. Haematologica 2005;90:335–40.
[30] Hochhaus A, Reiter A, Saussele S, et al. Molecular heterogeneity in complete cytogenetic responders after interferon-
alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing
remission. German CML Study Group and the UK MRC CML Study Group. Blood 2000;95:62–6.
[31] Kluin-Nelemans HC, Buck G, le Cessie S, et al. Randomized comparison of low-dose versus high-dose interferon-alfa in
chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups. Blood 2004;103:
4408–15.
*[32] Iacobucci I, Rosti G, Amabile M, et al. 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. J Clin Oncol 2006;24:454–9.
[33] Marin D, Marktel S, Bua M, et al. Prognostic factors for patients with chronic myeloid leukaemia in chronic phase treated
with imatinib mesylate after failure of interferon alfa. Leukemia 2003;17:1448–53.
[34] Cervantes F, Hernandez-Boluda JC, Steegmann JL, et al. Imatinib mesylate therapy of chronic phase chronic myeloid
leukemia resistant or intolerant to interferon: results and prognostic factors for response and progression-free survival in
150 patients. Haematologica 2003;88:1117–22.
[35] Sneed TB, Kantarjian HM, Talpaz M, et al. The significance of myelosuppression during therapy with imatinib mesylate in
patients with chronic myelogenous leukemia in chronic phase. Cancer 2004;100:116–21.
[36] Kantarjian HM, Cortes JE, O’Brien S, et al. Long-term survival benefit and improved complete cytogenetic and molecular
response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia
after failure of interferon-alpha. Blood 2004;104:1979–88.
[37] Cortes J, Talpaz M, Giles F, et al. Prognostic significance of cytogenetic clonal evolution in patients with chronic
myelogenous leukemia on imatinib mesylate therapy. Blood 2003;101:3794–800.
[38] O’Dwyer ME, Mauro MJ, Blasdel C, et al. Clonal evolution and lack of cytogenetic response are adverse prognostic factors
for hematologic relapse of chronic phase CML patients treated with imatinib mesylate. Blood 2004;103:451–5.
[39] Cortes J, Talpaz M, O’Brien S, et al. Effects of age on prognosis with imatinib mesylate therapy for patients with Phila-
delphia chromosome-positive chronic myelogenous leukemia. Cancer 2003;98:1105–13.
[40] Rosti G, Iacobucci I, Bassi S, et al. Impact of age on the outcome of patients with chronic myeloid leukemia in late chronic
phase: results of a phase II study of the GIMEMA CML working party. Haematologica 2007;92:101–5.
[41] Quintas-Cardama A, Kantarjian H, Talpaz M, et al. Imatinib mesylate therapy may overcome the poor prognostic significance
of deletions of derivative chromosome 9 in patients with chronic myelogenous leukemia. Blood 2005;105:2281–6.
[42] Merx K, Müller MC, Kreil S, et al. Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in
chronic phase CML patients treated with imatinib after failure of interferon a. Leukemia 2002;16:1579–83.
[43] Wang L, Pearson K, Ferguson JE, et al. The early molecular response to imatinib predicts cytogenetic and clinical outcome
in chronic myeloid leukaemia. Br J Haematol 2003;120:990–9.
[44] Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with
accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002;99:1928–37.
352 J.C. Hernández-Boluda, F. Cervantes / Best Practice & Research Clinical Haematology 22 (2009) 343–353

[45] Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with
chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002;99:3530–9.
*[46] Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia.
N Engl J Med 2006;355:2408–17.
[47] Huntly BJP, Guilhot F, Reid AG, et al. Imatinib improves but may not fully reverse the poor prognosis of patients with CML
with derivative chromosome 9 deletions. Blood 2003;102:2205–12.
[48] Kim DH, Popradi G, Sriharsha L, et al. No significance of chromosome 9 deletion on the clearance kinetics of BCR/ABL
fusion transcripts, cytogenetic or molecular response, loss of response, or treatment failure to imatinib mesylate therapy
for chronic myeloid leukemia. Cancer 2008;113:772–81.
[49] Castagnetti F, Marzocchi G, Luatti S, et al. Deletions of the derivative chromosome 9 do not influence response to imatinib of
early chronic phase chronic myeloid leukemia patients. A GIMEMA working party analysis. Blood 2006;108 [abstract 2112].
[50] Müller MC, Gattermann N, Lahaye T, et al. Dynamics of BCR-ABL mRNA expression in first-line therapy of chronic
myelogenous leukemia patients with imatinib or interferon a/araC. Leukemia 2003;17:2392–400.
[51] Zheng C, Haak M, Brors B, et al. Gene expression profiling of CD34þ cells identifies a molecular signature of chronic
myeloid leukemia blast crisis. Leukemia 2006;20:1028–34.
[52] Radich JP, Dai H, Mao M, et al. Gene expression changes associated with progression and response in chronic myeloid
leukemia. Proc Natl Acad Sci USA 2006;103:2794–9.
[53] Frank O, Brors B, Fabarius A, et al. Gene expression signature of primary imatinib-resistant chronic myeloid leukemia
patients. Leukemia 2006;20:1400–7.
[54] Yong ASM, Szydlo RM, Goldman JM, et al. Molecular profiling of CD34þ cells identifies low expression of CD7, along with
high expression of proteinase 3 or elastase, as predictors of longer survival in patients with CML. Blood 2006;107:205–12.
[55] Mohty M, Yong ASM, Szydlo RM, et al. The polycomb group BMI1 gene is a molecular marker for predicting prognosis of
chronic myeloid leukemia. Blood 2007;110:380–3.
[56] Mc Lean LA, Gathmann I, Capdeville R, et al. Pharmacogenomic analysis of cytogenetic response in chronic myeloid
leukemia patients treated with imatinib. Clin Cancer Res 2004;10:155–65.
[57] Villuendas R, Steegmann JL, Pollan M, et al. Identification of genes involved in imatinib resistance in CML: a gene-
expression profiling approach. Leukemia 2006;20:1047–54.
[58] Crossman LC, Mori M, Hsieh YC, et al. In chronic myeloid leukemia white cells from cytogenetic responders and non-
responders to imatinib have very similar gene expression signatures. Haematologica 2005;90:459–64.
[59] White D, Saunders V, Lyons AB, et al. In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive
of molecular response in patients with de novo CML. Blood 2005;106:2520–6.
[60] White DL, Saunders V, Dang P, et al. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib
but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood 2006;108:
697–704.
[61] White DL, Saunders V, Dang P, et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1
activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood 2007;110:4064–72.
[62] Mahon FX, Belloc F, Lagarde V, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell
line models. Blood 2003;101:2368–73.
[63] Dulucq S, Bouchet S, Turcq B, et al. Multidrug resistance gene (MDR1) polymorphisms are associated with major
molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2008;112:2024–7.
[64] Kantarjian H, Talpaz M, O’Brien S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chro-
mosome-positive chronic phase chronic myeloid leukemia. Blood 2004;103:2873–8.
[65] Hughes TP, Branford S, White DL, et al. Impact of early dose intensity on cytogenetic and molecular responses in chronic-
phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood 2008;112:3965–73.
[66] Cortes J, Baccarani M, Guilhot F, et al. A phase III, randomized, open-label study of 400 mg versus 800 mg of imatinib
mesylate in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using
molecular endpoints: 1-year results of TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity) study. Blood 2008;
112 [abstract 335].
*[67] de Lavallade H, Apperley JF, Khorashad JS. Imatinib for newly diagnosed patients with chronic myeloid leukemia: inci-
dence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008;26:3358–63.
[68] Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus
cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003;349:1423–32.
[69] Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recom-
mendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006;108:1809–20.
[70] Marin D, Milojkovic D, Olavarria E, et al. European LeukemiaNet criteria for failure or suboptimal response reliably
identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood 2008;
112:4437–44.
[71] Hughes TP, Hochhaus A, Branford S, et al. Reduction of BCR-ABL transcript levels at 6, 12, and 18 months (mo) correlates
with long-term outcomes on imatinib at 72 mo: an analysis from the International Randomized Study of Interferon
versus STI571 (IRIS) in patients with chronic phase chronic myeloid leukemia. Blood 2008;112 [abstract 334].
[72] Branford S, Lawrence R, Grigg A, et al. Long term follow up of patients with CML in chronic phase treated with first-line
imatinib suggests that earlier achievement of a major molecular response leads to greater stability of response. Blood
2008;112 [abstract 2113].
[73] Branford S, Rudzki Z, Harper A, et al. Imatinib produces significantly superior molecular responses compared to inter-
feron alfa plus cytarabine in patients with newly-diagnosed chronic myeloid leukemia in chronic phase. Leukemia 2003;
17:2401–9.
[74] Hughes T, Branford S. Molecular monitoring of BCR-ABL as a guide to clinical management in chronic myeloid leukaemia.
Blood Rev 2006;20:29–41.
[75] Press RD, Love Z, Tronnes AA, et al. BCR-ABL mRNA levels at and after the time of a complete cytogenetic response (CCR)
predict the duration of CCR in imatinib mesylate-treated patients. Blood 2006;107:4250–6.
 J.C. Hernández-Boluda, F. Cervantes / Best Practice & Research Clinical Haematology 22 (2009) 343–353 353

[76] Cortes J, Talpaz M, O’Brien S, et al. Molecular response in patients with chronic myelogenous leukemia in chronic phase
treated with imatinib mesylate. Clin Cancer Res 2005;11:3425–32.
[77] Larson RA, Druker BJ, Guilhot F, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-
phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 2008;111:4022–8.
[78] Picard S, Titier K, Etienne G, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular
responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007;109:3496–9.
[79] Guilhot F, Hughes TP, Cortes J, et al. Imatinib pharmacokinetic exposure and its correlation with clinical outcome in
patients with chronic-phase chronic myeloid leukemia for 400 mg and 800 mg daily doses (Tyrosine Kinase Dose
Optimization Study [TOPS]). Blood 2008;112 [abstract 447].
[80] White D, Saunders V, Grigg A, et al. Measurement of in vivo BCR-ABL kinase inhibition to monitor imatinib-induced
target blockage and predict response in chronic myeloid leukemia. J Clin Oncol 2007;25:4445–51.
[81] Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic
myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 2008;22:1200–6.
[82] Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase
inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase
following imatinib resistance and intolerance. Blood 2007;110:3540–6.
*[83] Tam CS, Kantarjian H, Garcia-Manero G, et al. Failure to achieve a major cytogenetic response by 12 months defines
inadequate response in patients receiving nilotinib or dasatinib as second or subsequent line therapy for chronic myeloid
leukemia. Blood 2008;112:516–8.
[84] Milojkovic D, Bua M, Apperley JF, et al. Prediction of cytogenetic response to second generation TKI therapy in CML
chronic phase patients who have failed imatinib therapy and early identification of factors that influence survival. Blood
2008;112 [abstract 332].