Chronic myeloid
leukemia (CML)

  • 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 or Heparin
  • Recommendation:
    obligatory

* in blast crisis

The incidence of CML is 1.5 per 100,000 cases per year with a median age at diagnosis of 55-60 years. Due to improved treatment options and the availability of targeted tyrosine kinase inhibitors (TKI) against BCR-ABL1, the survival rate and thus the prevalence of the disease has been continuously increasing.

Classification of CML

According to the WHO classification 2017, CML is a myeloproliferative neoplasm and is characterized by the presence of a BCR-ABL1 rearrangement. Based on clinical and hematological criteria, three phases can be distinguished in CML: the chronic phase (CP-CML), the accelerated phase (AP-CML) and the blast phase ("blast crisis"; BP-CML).


CML WHO Classification 2017
(Swerdlow et al. 2017)

Myeloproliferative neoplasm

Chronic myeloid leukemia (CML), BCR-ABL1-positive

Table 1 compares the criteria for defining the accelerated phase and blast crisis according to WHO 2017 and ELN (European LeukemiaNet) 2013 & 2020.

Table 1: Comparison of criteria for the definition of the accelerated phase and blast crisis according to WHO 2017

(Swerdlow et al. 2017) and ELN 2013 (Baccarani et al. 2013), the latter are also valid in the updated ELN recommendation (Hochhaus et al. 2020)

 

Accelerated phase

Blast phase

WHO 2017

ELN 2013

WHO 2017

ELN 2013

Spleen

Persistent or increasing splenomegaly, unresponsive to therapy

-

-

-

Leukocytes

Persistent or increasing high white blood cell count (>10 x109/l), unresponsive to therapy

-

-

-

Blast in PB or BM

10-19%

15-29% or
blasts + promyelocytes ≥30% with blasts <30%

≥20%

≥30%

Basophils im PB

≥20%

≥20%

-

-

Thrombozytosis / Thrombocytopenia

>1000 x109/l, unresponsive to therapy
<100 x 109/l, unrelated to therapy

<100 x 109/l, unrelated to therapy

-

-

Clonal chromosomal abnormalities in Ph+ cells at diagnosis

+

+

-

-

Extramedullary blast proliferation, apart from spleen

-

-

+

+


Diagnostics of CML

Prognosis of CML

Clinical prognosis scores

In each era of CML therapy, risk assessment scores based purely on clinical parameters have been developed; Table 3 provides an overview.

Table 3: Comparison of different clinical scores for risk stratification in CML 

 

Score

Sokal (1984)

Hasford (1998)

EUTOS (2011)

ELTS (2016)

 

Treatment era

Busulfan/Splenectomy +
intensive chemotherapy

Interferon alpha

Imatinib

Imatinib

Prediction for

Survival

Survival

Achievement of complete cytogenetic remission within 18 months

CML caused mortality

Risk groups

3

3

2

3

Clinical parameter

Age

x

x

-

x

Spleen size

x

x

x

x

Platelet count (/nl)

x

x

-

x

Blasts in peripheral blood (%)

x

x

-

x

Blood basophils (%)

-

x

x

-

Blood eosinophils (%)

-

x

-

-


The EUTOS long term survival (ELTS) score described in 2016 has the greatest prognostic relevance in the current era of tyrosine kinase inhibitors (Geelen et al. 2018) and should therefore be used for risk stratification according to the ELN's recommendation (Hochhaus et al. 2020). The ELTS score differs from the Socal score, which uses the same parameters for risk classification, in the weighting of the parameters (Hochhaus et al. 2020).

The ELTS score is based on a study by Pfirrmann et al. that examined CML-related mortality under first-line imatinib therapy. Age, spleen size, blasts in the blood and platelet count were identified as prognostic factors for CML-related mortality. The stratification based on the specially developed ELTS score allowed the classification of the 2205 evaluable study participants into three risk groups, the majority of patients (61%) were in the low risk group, 12% were assigned to the high risk group. The probability of CML-related deaths over an 8-year period was 11% (high risk), 6% (intermediate risk), and 2% (low risk). Stratification according to the ELTS score also had prognostic relevance with regard to overall survival; the 8-year survival probability was 81% for patients in the high risk group, 84% for patients with intermediate risk and 93% in the low risk group (Pfirrmann et al. 2016).


Calculation of prognosis

Here you get to the prognosis calculation of the ELTS score.


Additional cytogenetic abnormalities are sometimes associated with a less favourable prognosis

In up to 10% of patients, additional cytogenetic abnormalities are observed in addition to the Philadelphia translocation at the time of initial diagnosis. The proportion of patients with additional abnormalities increases in the course of the disease and amounts to approx. 30% in the accelerated phase (Cortes et al. 2003) and 60-80% in the blast crisis (Anastasi et al. 1995, Johansson et al. 2002, Chen et al. 2017, Hehlmann et al. 2020).

Such additional chromosomal changes are a sign of disease progression. In addition to point mutations in the ABL1 kinase domain, they also represent a possible cause of TKI resistance. Additional abnormalities can be observed even before the clinical symptoms of a blast crisis appear (Marin et al. 2008). The time interval between the occurrence of additional abnormalities and the beginning of the blast phase depends on the type of additional aberration (Gong et al. 2017). For the high-risk abnormalities described by Gong et al. (isochromosome 17q (i(17q)), aberrations of chromosome 7 (-7/del(7q)), 3q26 rearrangements, complex karyotype (≥ 2 aberrations besides t(9;22)) a rapid progress was described, so that in these patients a blast crisis occurred in the median ~2 months after the occurrence of the additional abnormalities (Gong et al. 2017).

A classification of the additional abnormalities can be made according to their frequency. A distinction is made between additional abnormalities of the so-called "major route" (trisomies of chromosomes 8 and 19, i(17q), additional Philadelphia chromosome) and the "minor route" (e.g. -7, -17, +17, +21, -Y and t(3;21)). The occurrence of "major route" additional abnormalities was associated with a worse prognosis and a higher rate of progression to the acceleration phase or blast crisis (Fabarius et al. 2011).

However, more recent data allow a classification of the individual cytogenetic additional abnormalities on the basis of their prognostic significance (Wang et al. 2016, Gong et al. 2017, Hehlmann et al. 2020). On this basis the ELN recommends a distinction between "high-risk" and "low-risk" additional abnormalities. The "high-risk" additional abnormalities are counted as "high-risk": Trisomy 8 and 19, additional Philadelphia chromosome, i(17q), -7/del(7q), aberrations of 11q23 and 3q26.2 and a complex karyotype. All other additional abnormalities belong to the "low-risk" group (Hochhaus et al. 2020). "High-risk" additional abnormalities predict a worsened response to therapy as well as an increased risk of progression (Hochhaus et al. 2020), they are therefore taken into account in therapy planning (see Therapy).


Indication of worsening of prognosis in the presence of Philadelphia negative clones

Philadelphia-negative clones can be detected in cytogenetic remission in 5-10% of patients during therapy for CML with tyrosine kinase inhibitors (Abruzzese et al. 2007, Deininger et al. 2007, Jabbour et al. 2007, Baccarani et al. 2013). The most frequent cytogenetic changes in chronic myeloid leukemia are the loss of the Y chromosome (-Y) and trisomy 8 (+8). The significance of such Philadelphia-negative clones has long been considered largely unclear (Abruzzese et al. 2007, Deininger et al. 2007, Jabbour et al. 2007, Marin et al. 2008, Groves et al. 2011). However, more recent data indicate a less favourable prognosis for these patients if the Philadelphia negative clone does not only show a loss of the Y chromosome (Issa et al. 2017).

In individual cases, an association with the development of MDS or AML has been described for the occurrence of Philadelphia negative clones - especially in the presence of monosomy 7 or the existence of cytopenia or dysplasia (Groves et al. 2011, Issa et al. 2017). The occurrence of chromosome 7 abnormalities or dysplasias was also associated with a deteriorated deep molecular response to TKI (Bidet et al. 2019).


Quality of response after 3 months
predictive of deep molecular remission

The depth of the molecular response after three months is a prognostic factor for whether CML patients achieve deep molecular remission (MR4.5) after 18 months. According to ELN criteria, patients should optimally have achieved a good molecular response with BCR-ABL1/ABL1 after IS of ≤10% after 3 months. If this is not the case, TKI resistance may be caused by one or more BCR-ABL1 mutations and may require a change of TKI depending on the mutation status (Hochhaus et al. 2020). Achieving deep molecular remissions minimizes the risk of losing complete cytogenetic remission or MMR. However, it has not yet been conclusively clarified whether deeper molecular remission is associated with longer survival in chronic myeloid leukemia (Falchi et al. 2013, Hehlmann et al. 2014, Kantarjian & Cortes 2014).

Therapy of CML

In addition to the disease phase, therapy planning for CML also takes into account potential comorbidities as well as the possibility of a TKI discontinuation. A continuous diagnostic monitoring allows the assessment of therapy response - and therapeutic intervention in case of insufficient response, resistance, intolerance or progression. In the following, various aspects of the CML therapy algorithm are described in further detail; an overview of therapeutic decision making is also depicted in Figure 1. (Note: Click on the figure to enlarge it.)

Figure 1: Decision making in CML therapy, according to Onkopedia Leitlinie CML 2018, Cortes 2020 and Hochhaus et al. 2020.


Molecular response is crucial for the course of therapy in CML

The molecular genetic analysis of the BCR-ABL1 transcripts plays a key role in therapy monitoring. At initial diagnosis, the determination of the present transcript type is obligatory (Hochhaus et al. 2020). This is a prerequisite for molecular monitoring in the course of therapy using RQ-PCR, which is now the standard in CML diagnostics (see Table 4 and Diagnostics of CML, molecular genetics). The molecular response to TKI therapy is a decisive prognostic parameter with consequences for further therapy planning (see Table 5 and Figure 1).

Table 4: Diagnosis of CML

according to European LeukemiaNet (ELN) (with modifications to Hochhaus et al. 2020)

Method

Time of investigation

 

At diagnosis

during the course

Therapy failure / resistance

(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 lymphatic blasts

Chromosome analysis
(bone marrow)

x

-

x

Proof/Exclusion of additional aberrations

x

Proof/Exclusion of additional aberrations

FISH

(x) in Ph-negative cases

(x) for atypical BCR-ABL1 transcript

-

-

Molecular genetics

x

Qualitative PCR to detect the BCR-ABL1 fusion and determine the transcript type; optional: RQ-PCR

x

RQ-PCR every 3 months, even after reaching MMR

x

Mutation analysis of the ABL1 kinase domain

x

Mutation analysis of the ABL1 kinase domain

Definition of the molecular response to tyrosine kinase inhibitors (TKI)

The definition of optimal response to treatment for CML with a TKI or therapy failure is shown in Table 5 and Figure 1. Between optimal response and treatment failure lies a warning range in which patients require close monitoring. In the event of therapy failure, the ELN recommends that a change in therapy to an alternative TKI should be considered. A change of therapy should always be preceded by a BCR-ABL1 mutation analysis in order to be able to make the optimal choice for an alternative TKI, depending on the type of point mutation in the ABL1 kinase domain (Baccarani et al. 2013, Hochhaus et al. 2020). Mutation analysis is also recommended in case of repeated doubling of the BCR-ABL1/ABL1 value (in %), suboptimal response or primary resistance.


Risk-based classification of additional chromosomal abnormalities important for therapy planning

The occurrence of "high-risk" additional chromosomal abnormalities after ELN (cf. prognosis) is considered a warning signal at the initial diagnosis and in the course of the treatment as a failure (cf. Table 5 and Figure 1). The ELN recommends treating these patients as high-risk patients, which requires close monitoring and possibly a change or intensification of therapy (Hochhaus et al. 2020) (see Table 5 and Figure 1). For "low-risk" patients, the ELN recommendations require the same procedure as for patients without additional chromosomal abnormalities.

Table 5: Definition of the response to TKI

(according to Hochhaus et al. 2020)
Time
Failure
Warning (close monitoring necessary)

Optimal

Baseline

 

High-risk ELTS-Score

"high-risk" ACA*

 

3 months

>10% BCR-ABL1/ABL1
if confirmed within 1-3 months

>10% BCR-ABL1/ABL1

≤10% BCR-ABL1/ABL1

6 months

 >10% BCR-ABL1/ABL1

 >1-10% BCR ABL1/ABL1

≤1% BCR-ABL1/ABL1

12 months

 >1% BCR-ABL1/ABL1

 >0,1-1% BCR-ABL1/ABL1

≤0,1% BCR-ABL1/ABL1

Any time

 >1% BCR-ABL1/ABL1

Resistance mutations

"high-risk" ACA*

>0,1-1% BCR-ABL1/ABL1

Loss of  ≤0.1% BCR-ABL1/ABL1 (MMR)

≤0,1% BCR-ABL1/ABL1

*"high-risk" additional chromosomal abnormalities after ELN: +8, + 19, additional Philadelphia chromosome, i(17q), -7/del(7q), 11q23 aberrations, 3q26.2 aberrations, complex karyotype

Therapy-free remission

Several studies have shown that discontinuation of TKI treatment (TKI stop) is possible and safe after achieving and maintaining deep molecular remission (Campiotti et al. 2017, Narra et al. 2017, Saussele et al. 2018). Depending on the study, 40-55% of patients remained in molecular remission, although the factors predicting recurrence are still the subject of current research (Hochhaus et al. 2019). In the updated ELN recommendations, criteria for a TKI stop are given (Table 6 and Figure 1).

Table 6: Requirements  for tyrosine kinase inhibitor discontinuation  

(according to Hochhaus et al. 2020)

Mandatory

Minimal (TKI stop allowed)

Optimal (stop recommended for consideration)

Patient in first chronic phase

First-line therapy or second-line if intolerance was the only reason for changing TKI

Duration of TKI therapy >5 years

Motivated patient with structured communication

Typical e13a2 or e14a2 BCR–ABL1 transcripts

Duration of DMR > 3 years if MR4

Access to high quality quantitative PCR using the International Scale (IS) with rapid turn-around of PCR test results

Duration of TKI therapy >5 years (>4 years for 2GTKI)

Duration of DMR > 2 years if MR4.5

Patient’s agreement to more frequent monitoring after stopping treatment. This means monthly for the first 6 months, every 2 months for months 6–12, and every 3 months thereafter

Duration of DMR (MR4 or better) >2 years

 

 

No prior treatment failure

 

Recurrences after TKI stop is basically possible and usually occurs within the first 6-8 months after TKI stop (Saußele et al. 2016, Hochhaus et al. 2020). The loss of the major molecular response (MMR) is considered a recurrence (Rousselot et al. 2014). In this case, treatment should be resumed. By reinitiating therapy with the same TKI, a molecular response could be achieved again in the vast majority (90-95%) of patients (Hochhaus et al. 2020).

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.

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