clinical recommendations

Annals of Oncology 20 (Supplement 4): iv105iv107, 2009

doi:10.1093/annonc/mdp143

Chronic myelogenous leukemia: ESMO Clinical

Recommendations for diagnosis, treatment and
follow-up
M. Baccarani1 & M. Dreyling2
On behalf of the ESMO Guidelines Working Group*
1

Department of Hematology and Oncology L. and A. Sera`gnoli, University of Bologna, S. OrsolaMalpighi Hospital, Bologna, Italy; 2Department of Medicine III, University
Hospital Grosshadern, LMU Munich, Germany

The incidence of chronic myeloid leukemia (CML) is reported

between 1 and 2 cases/100 000/year, without major geographic
differences. Median age at diagnosis is close to 60 years.

diagnosis
Diagnosis is based on blood counts (leukocytosis and
frequently also thrombocytosis) and differential (immature
granulocytes, from the metamyelocyte to the myeloblast, and
basophilia). Splenomegaly is present in >50% of cases of CML
in the initial chronic phase, but 50% of patients are
asymptomatic.
Proof of diagnosis is attained by demonstration of the
Philadelphia (Ph) chromosome (22q) resulting from the
balanced translocation t(9; 22) (q34;q11), and/or the BCRABL
rearrangement in peripheral blood or bone marrow cells. In
some cases (5%) a Ph chromosome cannot be detected and
confirmation of diagnosis rests on molecular genetic methods,
e.g. fluorescence in situ hybridization or reverse transcription
polymerase chain reaction (RTPCR). Screening for
BCRABL KD mutations is especially recommended in
acceleration and/or blast crisis (for definition see below).

staging and risk assessment

More than 90% of patients are diagnosed in chronic phase
(CP). The typical clinical course is triphasic: CP, accelerated
phase (AP) and blastic phase (BP) or blast crisis (BC). The
most accepted definition of AP is 15%29% blasts in blood or
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L.
Taddei 4, CH-6962 Viganello-Lugano, Switzerland;
E-mail: clinicalrecommendations@esmo.org
Approved by the ESMO Guidelines Working Group: August 2003, last update
December 2008. This publication supercedes the previously published versionAnn
Oncol 2008; 19 (Suppl 2): ii63ii64.
Conflict of interest: Prof. Baccarani has reported that he received honoraria for
participation in advisory boards and educational events, as well as research support, by
Novartis Pharma, Bristol-Myers Squibb, MerckSharp & Dhome and WyethLederle.
Prof. Dreyling has reported no conflicts of interest.

bone marrow, >20% basophils in blood, thrombocytosis or

thrombocytopenia unrelated to therapy, or clonal cytogenetic
evolution. Similarly, the BP/BC of the disease is characterized
by 30% blasts in blood or bone marrow or extramedullary
blastic infiltration.
Prognostic scores based on age, spleen size, blood cell counts
and differential have been established in the pre-imatinib era
and allow the discrimination of risk groups with a different
response rate, progression-free survival and overall survival.
The degree and time points of hematologic, cytogenetic and
molecular responses provide very important prognostic
information as time-dependent variables (Table 1).

treatment
Imanitib is the current standard approach. On the basis of
a randomized trial of imatinib, a selective ABL tyrosine kinase
inhibitor (TKI), versus interferon (IFN)-a and low-dose
arabinosyl cytosine (IRIS study), imatinib 400 mg daily has
been established as standard front-line treatment of all patients
with CP CML. The update of the IRIS study reported
a progression-free survival of 84% and an overall survival of
88% after 6 years. Other comparisons of imatinib with IFN-a
provide clear evidence of the superiority of imatinib also
with regard to survival.
Outcome after allogeneic stem cell transplantation (SCT) in
the first-line therapy is inferior because of transplant-related
mortality. Thus, initial allogeneic SCT cannot be recommended
anymore.
IFN-a is currently tested in combination with imatinib in
phase III prospective studies. Hydroxyurea is recommended
only for initial cytoreduction or therapeutic palliation, since
imatinib is also superior in the elderly.

response evaluation
The response to imatinib (standard dose, 400 mg daily) may fall
into three categories, namely optimal, suboptimal and failure
(Table 1):
In case of optimal response, imatinib should be continued
indefinitely. The patients who achieve a complete molecular

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incidence

clinical recommendations
Table 1. Definition of response to imatinib (modified, from ref. 1)

3 Months
6 Months
12 Months
18 Months
Anytime

Optimal

Suboptimal

Failure

CHR
PCgR
CCgR
MMolR
No response
loss

< CHR
< PCgR
< CCgR
< MMolR
Loss of
MMolR Mutationsa

No HR
No CGR
< PCgR
< CCgR
Loss of CHR
Loss of CCgR
Mutationsb

response [BCRABL undetectable by real-time, quantitative

PCR (RT-Q-PCR)] can be eligible for prospective trials of
treatment discontinuation or of immunotherapy with IFN-a or
vaccines, to eliminate minimal residual disease.
In case of suboptimal response to imatinib, the best
treatment option is still a matter of investigation. The patient
can be continued on imatinib at a higher dose, but is also
eligible for a second generation TKI.
In case of failure, second-line treatment is based on second
generation TKI, namely dasatinib and nilotinib. About 50% of
CP patients resistant or intolerant of imatinib achieve
a complete cytogenetic response (CCgR) with either agent, but
both agents are ineffective in case of a T315I BCRABL kinase
domain (KD) mutation. The response to either agent is usually
rapid and within 6 months it may be possible to decide to
continue with the second generation TKI or to move to
allogeneic SCT, if the patient is eligible. Currently, the eligibility
criteria for SCT have been expanded by the extended use of
reduced conditioning or non-myeloablative procedures and by
the availability of alternative stem cell sources, including
cord blood.
Once a patient has progressed to AP or BP/BC, treatment
depends on prior treatment and may include other TKIs, other
experimental targeted agents (e.g. homoharringtonine) or
cytotoxic chemotherapy. An allogeneic SCT consolidation
should be performed whenever possible.

follow-up (monitoring)
Monitoring is essential for treatment optimization and a costeffective outcome. During the first 3 months, clinical,
biochemical and hematologic monitoring is recommended
every 2 weeks. From month 3 on, cytogenetics (chromosome
banding analysis of marrow cell metaphases) is recommended
at least every 6 months until a CCgR has been achieved and
confirmed.
Real-time, quantitative PCR (RT-Q-PCR) (BCRABL:ABL
%, on blood cells) is recommended every 3 months until

iv106 | Baccarani & Dreyling

a major molecular response (MMolR) has been achieved and

confirmed.
Once a CCgR and a MMolR have been achieved and
confirmed, cytogenetics can be performed every 12 months and
RT-Q-PCR every 6 months. If the patients was high risk by
Sokal, or was a suboptimal responder, more frequent
monitoring is advisable.
Screening for BCRABL KD mutations is recommended only
in case of failure or suboptimal response.
Measuring imatinib blood concentration may be important
in all patients and is recommended in case of suboptimal
response, failure, dose-limiting toxicity or adverse events.
Standardization of molecular monitoring and of imatinib blood
concentration assays is underway in Europe, based on a
project of the European Leukemia Network (The European
Treatment and Outcome Study of CML).

note
Levels of evidence [IV] and grades of recommendation [AD]
as used by the American Society of Clinical Oncology are
given in square brackets. Statements without grading were
considered justified standard clinical practice by the experts and
the ESMO faculty.

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BCRABL KD mutations still sensitive to imatinib.

BCRABL KD mutations insensitive to imatinib.
CHR, complete hematologic response (white blood cells <10 109/l,
differential with no immature granulocytes and <5% basophils, platelets
<450 109/l, spleen non-palpable); PCgR, partial cytogenetic response (Ph+
metaphases 1%35%); CCgR, complete cytogenetic response (Ph+
metaphases absent); MMolR, major molecular response (BCRABL:ABL
<0.10% by International Scale on RT-Q-PCR).
b

Annals of Oncology

Annals of Oncology

clinical recommendations

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Volume 20 | Supplement 4 | May 2009

doi:10.1093/annonc/mdp143 | iv107