clinical recommendations Annals of Oncology 20 (Supplement 4): iv105–iv107, 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. Seràgnoli’, University of Bologna, S. Orsola–Malpighi Hospital, Bologna, Italy; 2Department of Medicine III, University
Hospital Grosshadern, LMU Munich, Germany

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

thrombocytopenia unrelated to therapy, or clonal cytogenetic
The incidence of chronic myeloid leukemia (CML) is reported evolution. Similarly, the BP/BC of the disease is characterized
between 1 and 2 cases/100 000/year, without major geographic by ‡30% blasts in blood or bone marrow or extramedullary
differences. Median age at diagnosis is close to 60 years. blastic infiltration.
Prognostic scores based on age, spleen size, blood cell counts
diagnosis and differential have been established in the pre-imatinib era
and allow the discrimination of risk groups with a different
Diagnosis is based on blood counts (leukocytosis and response rate, progression-free survival and overall survival.
frequently also thrombocytosis) and differential (immature The degree and time points of hematologic, cytogenetic and
granulocytes, from the metamyelocyte to the myeloblast, and molecular responses provide very important prognostic
basophilia). Splenomegaly is present in >50% of cases of CML information as time-dependent variables (Table 1).
in the initial chronic phase, but 50% of patients are
asymptomatic.
Proof of diagnosis is attained by demonstration of the treatment
Philadelphia (Ph) chromosome (22q–) resulting from the
balanced translocation t(9; 22) (q34;q11), and/or the BCR–ABL Imanitib is the current standard approach. On the basis of
rearrangement in peripheral blood or bone marrow cells. In a randomized trial of imatinib, a selective ABL tyrosine kinase
some cases (5%) a Ph chromosome cannot be detected and inhibitor (TKI), versus interferon (IFN)-a and low-dose
confirmation of diagnosis rests on molecular genetic methods, arabinosyl cytosine (IRIS study), imatinib 400 mg daily has
e.g. fluorescence in situ hybridization or reverse transcription– been established as standard front-line treatment of all patients
polymerase chain reaction (RT–PCR). Screening for with CP CML. The update of the IRIS study reported
BCR–ABL KD mutations is especially recommended in a progression-free survival of 84% and an overall survival of
acceleration and/or blast crisis (for definition see below). 88% after 6 years. Other comparisons of imatinib with IFN-a
provide clear evidence of the superiority of imatinib also
with regard to survival.
staging and risk assessment Outcome after allogeneic stem cell transplantation (SCT) in
More than 90% of patients are diagnosed in chronic phase the first-line therapy is inferior because of transplant-related
(CP). The typical clinical course is triphasic: CP, accelerated mortality. Thus, initial allogeneic SCT cannot be recommended
phase (AP) and blastic phase (BP) or blast crisis (BC). The anymore.
most accepted definition of AP is 15%–29% blasts in blood or 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
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L. imatinib is also superior in the elderly.
Taddei 4, CH-6962 Viganello-Lugano, Switzerland;
E-mail: [email protected]

Approved by the ESMO Guidelines Working Group: August 2003, last update response evaluation
December 2008. This publication supercedes the previously published version—Ann
Oncol 2008; 19 (Suppl 2): ii63–ii64. The response to imatinib (standard dose, 400 mg daily) may fall
into three categories, namely optimal, suboptimal and failure
Conflict of interest: Prof. Baccarani has reported that he received honoraria for
(Table 1):
participation in advisory boards and educational events, as well as research support, by
Novartis Pharma, Bristol-Myers Squibb, Merck–Sharp & Dhome and Wyeth–Lederle. In case of ‘optimal response’, imatinib should be continued
Prof. Dreyling has reported no conflicts of interest. indefinitely. The patients who achieve a complete molecular

ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected]
clinical recommendations Annals of Oncology

Table 1. Definition of response to imatinib (modified, from ref. 1) a major molecular response (MMolR) has been achieved and
confirmed.
Optimal Suboptimal Failure Once a CCgR and a MMolR have been achieved and
3 Months CHR < CHR No HR confirmed, cytogenetics can be performed every 12 months and
6 Months ‡ PCgR < PCgR No CGR RT-Q-PCR every 6 months. If the patients was high risk by
12 Months CCgR < CCgR < PCgR Sokal, or was a suboptimal responder, more frequent
18 Months ‡ MMolR < MMolR < CCgR monitoring is advisable.
Anytime No response Loss of Loss of CHR Screening for BCR–ABL KD mutations is recommended only
loss MMolR Mutationsa Loss of CCgR in case of failure or suboptimal response.
Mutationsb Measuring imatinib blood concentration may be important
in all patients and is recommended in case of suboptimal
a
BCR–ABL KD mutations still sensitive to imatinib. response, failure, dose-limiting toxicity or adverse events.
b
BCR–ABL KD mutations insensitive to imatinib. Standardization of molecular monitoring and of imatinib blood
CHR, complete hematologic response (white blood cells <10 · 109/l,
concentration assays is underway in Europe, based on a
differential with no immature granulocytes and <5% basophils, platelets
project of the European Leukemia Network (The European
<450 · 109/l, spleen non-palpable); PCgR, partial cytogenetic response (Ph+
Treatment and Outcome Study of CML).
metaphases 1%–35%); CCgR, complete cytogenetic response (Ph+
metaphases absent); MMolR, major molecular response (BCR–ABL:ABL
<0.10% by International Scale on RT-Q-PCR). note
Levels of evidence [I–V] and grades of recommendation [A–D]
as used by the American Society of Clinical Oncology are
response [BCR–ABL undetectable by real-time, quantitative given in square brackets. Statements without grading were
PCR (RT-Q-PCR)] can be eligible for prospective trials of considered justified standard clinical practice by the experts and
treatment discontinuation or of immunotherapy with IFN-a or the ESMO faculty.
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 literature
can be continued on imatinib at a higher dose, but is also 1. Baccarani M, Saglio G, Goldman J et al. Evolving concepts in the management
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Annals of Oncology clinical recommendations
12. Kantarjian HM, Giles F, Gattermann N et al. Nilotinib (formerly AMN107), a highly 14. Heaney NB, Copland M, Stewart K et al. Complete molecular responses are
selective BCR–ABL tyrosine kinase inhibitor, is effective in patients with achieved after reduced intensity stem cell transplantation and donor
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