CML (Chronic myeloid
leukemia)

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Through the use of tyrosine kinase inhibitors, the life expectancy of patients with chronic myeloid leukemia is almost comparable to a healthy control population. Here you can learn more about the classification, diagnosis and prognosis of CML. We also provide links for further reading on the ELTS score and the therapy of chronic myeloid leukemia.

Method:
Anticoagulant:
Recommendation:

Method:

Cytomorphology
Anticoagulant:

EDTA
Recommendation:

obligatory

Method:

Immunophenotyping
Anticoagulant:

EDTA or Heparin
Recommendation:

obligatory*

Method:

Chromosome analysis
Anticoagulant:

Heparin
Recommendation:

obligatory

Method:

FISH
Anticoagulant:

EDTA or Heparin
Recommendation:

facultative

Method:

Molecular genetics
Anticoagulant:

EDTA
Recommendation:

obligatory

* in (suspected) blast crisis

Classification
Diagnostics
Prognosis
Therapy
Overview of clinical studies of the German CML Alliance
Recommendation

CML: Classification

According to the WHO classification, chronic myeloid leukemia (CML) is a myeloproliferative neoplasm and is characterized by the presence of a BCR::ABL1 rearrangement. Untreated, the disease follows a biphasic or triphasic course. According to WHO 2022, the chronic phase (CP-CML) and the blast phase ("blast crisis"; BP-CML) are differentiated as the essential disease phases (WHO 2022).

CML: Diagnostic methods and their significance

Cytomorphology is used for the diagnosis of CML and significantly contributes to the differentiation from other myeloproliferative diseases. Furthermore, it is relevant for the staging of CML. Hematologic remission is assessed by cytomorphologic criteria during follow-up under therapy (see Table 3).

Immunophenotyping is not part of the routine diagnostic CML workflow at initial diagnosis or in remission. However, it is important in the case of blast phase (BP) to differentiate myeloid BP from BP of lymphoid origin (see Table 3).

The presence of a Philadelphia chromosome or rather a BCR::ABL1 rearrangement defines chronic myeloid leukemia.

In 90% of CML patients, a Philadelphia chromosome is present, which results from the reciprocal translocation between the long arm of a chromosome 9 and the long arm of a chromosome 22 (t(9;22)(q34;q11)). The remaining patients show either variant translocations (Marzocchi et al. 2011) or an inconspicuous karyotype (Hagemeijer et al. 1993). Even with an inconspicuous karyotype, a fusion gene of the ABL1 (Abelson) gene (9q34) and the BCR (breakpoint cluster region) gene (22q11) is found at the molecular level.

The presence of additional chromosomal aberrations besides t(9;22) at initial diagnosis or during the disease course can impact the prognosis (see Prognosis in CML). The current recommendations of the European LeukemiaNet (ELN) distinguish between "high-risk" and "low-risk" additional aberrations. The "high-risk" additional aberrations include: Trisomy 8, 17, 19 and 21, additional Philadelphia chromosome, i(17q), -7/del(7q), aberrations of 11q23 and 3q26.2, and a complex karyotype. All other additional aberrations belong to the "low-risk" group. Testing for additional aberrations is indicated at initial diagnosis, treatment failure/resistance, and (suspected) progression (see Table 3) (Cross et al. 2023, Apperley et al. 2025).

The finding of clonal chromosomal aberrations in Philadelphia-negative clones under therapy with tyrosine kinase inhibitors (TKIs) has to be distinguished from the above mentioned additional chromosomal abnormalities. Such alterations appear to be prognostically unfavorable when the Philadelphia-negative clone displays more abnormalities than just a loss of the Y chromosome (Issa et al. 2017). In particular, patients should be monitored closely in the presence of monosomy 7 or the presence of cytopenias or dysplasias, as an association with the development of MDS or AML has been observed in isolated cases (Groves et al. 2011, Issa et al. 2017).

FISH analysis can confirm or exclude the presence of a BCR::ABL1 rearrangement within 24 hours, making it a valuable screening tool. Using FISH on interphase nuclei, 100 to 200 cells can be checked for the presence of a BCR::ABL1 rearrangement. FISH analyses can also be useful for the diagnosis and monitoring of patients without the Philadelphia chromosome (Ph-) or with rare or atypical transcripts (Apperley et al. 2025). FISH can also be used to specifically screen for certain “high-risk” additional aberrations; the panel includes probes for the detection of trisomies 8, 19, and 21, isochromosome 17q, deletion of chromosome 7 or 7q31, as well as MECOM rearrangement (3q26) and KMT2A rearrangement (11q23). However, a complex karyotype cannot be reliably detected with this method.

Molecular genetics with the methods of PCR and sequencing plays the central role in CML diagnostics. In addition to diagnosis (detection of the BCR::ABL1 fusion gene and determination of the transcript type), these diagnostic methods are now routinely used both to monitor therapy response and to identify resistance mutations in case of therapy failure.

ASXL1 mutations, which occur in approximately 10% of patients, are associated with a poorer response to TKIs and/or a shortened event-free survival time, but have not yet been shown to affect overall survival (Apperley et al. 2025).

Monitoring of therapy response

The key method for quantifying treatment response is the highly sensitive (10^-5) real-time PCR. BCR::ABL1 expression is quantified relative to a reference gene (usually ABL1). For standardization and comparability, results are expressed as % BCR::ABL1/ABL1 according to the International Scale (IS). This allows the assessment of molecular response (MR) and the establishment of defined milestones such as the major molecular response (MMR) (see Table 1) (Cross et al. 2023). A deep molecular response is achieved starting at MR4 (Cross et al. 2023, Apperley et al. 2025).

Table 1: Molecular response criteria (according to

Apperley et al. 2025, Cross et al. 2023)

Response	*% BCR::ABL1/ABL1* (International scale)**	Log reduction based on the IRIS baseline	*Minimum number of ABL1* copies (sensitivity)**
MMR	≤0.1000	3	10 000 *
MR4	≤0.0100	4	10 000 *
MR4.5	≤0.0032	4.5	32 000
MR5	≤0.001	5	100 000

* Each value of the duplicate measurement must be at least 10,000, otherwise no MR status may be assigned.

The molecular response criteria are crucial for therapy planning, which today also includes the possibility of therapy-free remission. A prerequisite for a TKI discontinuation is a preceding deep molecular remission lasting more than two years; further criteria are given in the ELN recommendations (Cross et al. 2023, Apperley et al. 2025). Approximately 40-50% of patients can remain without treatment after stopping TKI (White et al. 2022, Apperley et al. 2025).

Mutation analysis in case of therapy resistance

Under TKI treatment, there is a risk of TKI resistance in case BCR::ABL1 expression increases again. In this situation, sequencing for BCR::ABL1 mutations should be performed. Given that certain mutations confer resistance to individual tyrosine kinase inhibitors while other TKIs may continue to be effective, the precise definition of the mutation is important for further treatment decisions (including Apperley et al. 2025). Therefore, molecular genetic services include testing for possible BCR::ABL1 mutations in case of resistance to competitive TKIs (such as imatinib) as well as the allosteric TKI asciminib.

CML: Prognosis

Additional chromosomal abnormalities are partly associated with a poorer prognosis

In up to 10% of patients, additional chromosomal abnormalities besides the Philadelphia translocation are observed at initial diagnosis (see above). The proportion of patients with additional alterations increases during the course of the disease and is approximately 60-80% in blast crisis (Anastasi et al. 1995, Johansson et al. 2002, Chen et al. 2017, Hehlmann et al. 2020, Hehlmann et al. 2022). Such additional chromosomal abnormalities are indicative of disease progression. In addition to point mutations in the ABL1 kinase domain, they also represent a potential cause of TKI resistance.

"High-risk" additional abnormalities are predictive for a reduced response to therapy as well as for an increased risk of progression. Accordingly, they are relevant for therapy planning. High-risk additional aberrations include trisomies 8, 17, 19, and 21, an additional Philadelphia chromosome, isochromosome 17q, monosomy 7 or deletion (7q), 11q23 aberrations, 3q26.2 changes, and a complex karyotype (Clark et al. 2021, Apperley et al. 2025).

Quality of response is predictive for the further course

According to ELN criteria, patients should have achieved a molecular response of BCR::ABL1 ≤10% after 3 months (favorable response). If this is not the case, TKI resistance due to one or more BCR::ABL1 mutations may be underlying and may require a change of TKI depending on the mutation status. However, a change in TKI should not be made solely based on a single BCR::ABL1 value of ≤10%. Patients who initially fail to achieve a specific treatment goal may still show a delayed but favorable response (“late responders”) if subsequent measurements show continuously decreasing BCR::ABL1 values. In addition, the kinetics of RT-qPCR reactions, comorbidities, any dose adjustments, and/or lack of/inadequate compliance should be considered (Apperley et al. 2025). An early molecular response to first-line therapy with TKI inhibitors (TKIs) is an effective indicator of long-term progression-free survival and overall survival (Shah et al. 2024).

Achieving a major molecular response (MMR, BCR::ABL1 ≤ 0.1%) is predictive of a CML-specific survival rate approaching 100% (Hochhaus et al. 2020). Achieving MMR at 12 months is associated with a very low probability of subsequent loss of response and a high probability of subsequent deep molecular remission (DMR, BCR::ABL1 ≤0.01%), which may facilitate discontinuation of TKI therapy (Shah et al. 2024).

Thanks to modern CML therapy, the life expectancy of patients with chronic-phase CML is approaching that of the general population, but according to current registry data and studies, it remains slightly below it, also in terms of quality-adjusted lifetime (Apperley et al. 2025, Chen et al. 2025).

Clinical prognosis scores

Scores for risk assessment based on clinical parameters have been developed in each CML therapy era (Table 2).

Table 2: Comparison of different clinical scores for risk stratification in CML

Score	(Sokal et al. 1984)	(Hasford et al. 1998)	EUTOS (2011) (Hasford et al. 2011)	ELTS (2016) (Pfirrmann et al. 2016)
Therapy era	Busulfan/splenectomie + intensive chemotherapie	Interferon alpha	Imatinib	Imatinib
parameters considered:
Age	x	x		x
Spleen size	x	x	x	x
Thrombocytes	x	x		x
Blasts in PB	x	x		x
Basophils in PB		x	x
Eosinophils in PB		x

The EUTOS long-term survival (ELTS) score, described in 2016, is recommended by the current ELN guidelines as the standard for risk stratification and enables a targeted prediction of the risk of CML-related death during TKI therapy (Geelen et al. 2018, Apperley et al. 2025).

A new prognostic model enables a targeted assessment of the risk of treatment failure under TKI in CML patients in the chronic phase. It is based on six clinical factors and divides patients into three risk groups with clearly different probabilities of failure (Zhang et al. 2024).

Prognosis calculation

This link takes you to an ELTS score online calculator for prognosis estimation.

CML: Therapy

The German guidelines for CML therapy can be found on the Onkopedia website. Further treatment guidelines are provided by the National Comprehensive Cancer Network (Shah et al. 2024) and an overview by Jabbour et al. (Jabbour & Kantarjian 2024).

Overview of clinical studies of the German CML Alliance

The linked PDF document from the University Hospital of Jena provides an overview of currently recruiting clinical studies for adult CML patients of the German CML Alliance. Currently, the information is only available in German.

CML: Recommendation

Table 3 provides an overview of which diagnostic methods are recommended by the European LeukemiaNet at which time point.

Table 3: CML diagnostics according to ELN recommendations (according to Apperley et al. 2025 and Cross et al. 2023)

Method	Time point
	At diagnosis	Follow-up	Therapy failure/Resistence	(suspected) progression
Cytomorphology	x	x every 2 weeks until complete hematological remission, more often in case of hematological toxicity	-	x determination of blast percentage
Immunophenotyping	-	-	-	Differentiation between myeloid and lymphoid blasts
Chromosome analysis (Bone marrow)	x detection of philadelphia chromosome, detection/exclusion of additional chromosomal abnormalities	-	x detection/exclusion of additional chromosomal abnormalities	x detection/exclusion of additional chromosomal abnormalities
FISH	x and in Ph-negative cases	(x) for atypical BCR::ABL1 transcripts	-	-
Molecular genetics	x qualitative PCR to detect the BCR::ABL1 fusion and determination of the transcript type; optional: RQ-PCR	x RQ-PCR every 3 months, in stable MMR every 4-6 months if necessary	x mutation analysis of the ABL1 kinase domain	x mutation analysis of the ABL1 kinase domain
WGS / WES / Panel-NGS	Recommended in BP	-	According to individual indication	Recommended for BP / in cases of unclear progression

Status: October 2025

Anastasi J et al. The relationship between secondary chromosomal abnormalities and blast transformation in chronic myelogenous leukemia. Leukemia 1995;9(4):628-633.

Apperley JF et al. 2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia. Leukemia 2025;39(8):1797-1813.

Chen EY et al. Loss in Overall and Quality-Adjusted Life Expectancy for Patients With Chronic-Phase Chronic Myeloid Leukemia. Eur J Haematol 2025;114(2):334-342.

Chen Z et al. Cytogenetic landscape and impact in blast phase of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Leukemia 2017;31(3):585-592.

Clark RE et al. Additional chromosomal abnormalities at chronic myeloid leukemia diagnosis predict an increased risk of progression. Blood Adv 2021;5(4):1102-1109.

Cross NCP et al. European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia. Leukemia 2023;37(11):2150-2167.

Geelen IGP et al. Validation of the EUTOS long-term survival score in a recent independent cohort of "real world" CML patients. Leukemia 2018;32(10):2299-2303.

Groves MJ et al. Factors influencing a second myeloid malignancy in patients with Philadelphia-negative -7 or del(7q) clones during tyrosine kinase inhibitor therapy for chronic myeloid leukemia. Cancer Genet 2011;204(1):39-44.

Hagemeijer A et al. Translocation of BCR to chromosome 9: a new cytogenetic variant detected by FISH in two Ph-negative, BCR-positive patients with chronic myeloid leukemia. Genes Chromosomes. Cancer 1993;8(4):237-245.

Hasford J et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 2011;118(3):686-692.

Hasford J 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(11):850-858.

Hehlmann R et al. Impact of emerging ACA on survival in chronic myeloid leukemia (CML). Leukemia 2022;

Hehlmann R et al. High-risk additional chromosomal abnormalities at low blast counts herald death by CML. Leukemia 2020;34(8):2074-2086.

Issa GC et al. Clonal chromosomal abnormalities appearing in Philadelphia chromosome-negative metaphases during CML treatment. Blood 2017;130(19):2084-2091.

Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2025 update on diagnosis, therapy, and monitoring. Am J Hematol 2024;99(11):2191-2212.

Johansson B et al. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol 2002;107(2):76-94.

Marzocchi G et al. Variant Philadelphia translocations: molecular-cytogenetic characterization and prognostic influence on frontline imatinib therapy, a GIMEMA Working Party on CML analysis. Blood 2011;117(25):6793-6800.

Onkopedia Leitlinie „Chronische Myeloische Leukämie (CML)“; DGHO 2025.

Pfirrmann M et al. Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia. Leukemia 2016;30(1):48-56.

Shah NP et al. Chronic Myeloid Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2024;22(1):43-69.

Sokal JE et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 1984;63(4):789-799.

White HE et al. Standardization of molecular monitoring of CML: results and recommendations from the European treatment and outcome study. Leukemia 2022;36(7):1834-1842.

WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2022. (WHO classification of tumours series, 5th ed.; vol. 11). Available from: https://tumourclassification.iarc.who.int/chapters/63.

Zhang X et al. A predictive model for therapy failure in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy. Blood 2024;144(18):1951-1961.

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CML (Chronic myeloid leukemia)

CML: Classification

CML: Diagnostic methods and their significance

Cytomorphology

Immunophenotyping

Chromosome analysis

Fluorescence in situ hybridisation (FISH)

Molecular genetics

Table 1: Molecular response criteria (according to

Apperley et al. 2025, Cross et al. 2023)

Mutation analysis in case of therapy resistance

CML: Prognosis

Additional chromosomal abnormalities are partly associated with a poorer prognosis

Quality of response is predictive for the further course

Clinical prognosis scores

Table 2: Comparison of different clinical scores for risk stratification in CML

Prognosis calculation

CML: Therapy

Overview of clinical studies of the German CML Alliance

CML: Recommendation

Table 3: CML diagnostics according to ELN recommendations (according to Apperley et al. 2025 and Cross et al. 2023)

You may also be interested in

CML (Chronic myeloid
leukemia)