Chronic Myeloid Leukemia: Laboratory Evaluation

Chronic Myeloid Leukemia: Laboratory Evaluation

This Test Guide provides an overview of tests that assist with the diagnosis, classification, prognosis, and management of chronic myeloid leukemia (CML).

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Chronic Myeloid Leukemia: Laboratory Evaluation

Test Guide

 

Chronic Myeloid Leukemia

Laboratory Evaluation

Chronic myeloid leukemia, formerly called chronic myelogenous leukemia (CML), is a hematopoietic stem cell cancer characterized by uncontrolled expansion of myeloid cells.1 In 90% to 95% of cases, CML is caused by a characteristic translocation1 between chromosomes 9 and 22. This translocation results in an abnormally short chromosome 22—the Philadelphia chromosome (Ph)—and formation of the BCR-ABL1 fusion gene.1 The fusion gene in turn produces a constitutively active tyrosine kinase that causes CML.1 The remaining 5% to 10% of cases have a translocation involving 3 or 4 chromosomes o r a cryptic translocation that cannot be detected by karyotyping.1

CML has 2 phases of progression: the initial chronic phase and the blast phase.1 When blood morphology findings suggest CML, the diagnosis is confirmed by identifying Ph using karyotyping and/or by detecting the BCR-ABL1 fusion gene with polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) tests.1,2 Once CML is diagnosed, determining disease phases (chronic or blast phase) can help assess prognosis and select therapy.1,2 Figure 1 shows criteria that can be used in laboratory diagnosis and determining the phases of CML.

CML treatments mainly include therapy with a tyrosine kinase inhibitor (TKI) (eg, bosutinib, dasatinib, imatinib, or nilotinib) and allogeneic hematopoietic stem cell transplantation.2 TKI therapies have dramatically improved treatment outcomes in CML, and bosutinib, dasatinib, imatinib, and nilotinib are now first-line therapies for chronic-phase CML.2 Laboratory tests that assess hematologic, cytogenetic, and molecular disease levels can be used to monitor response to TKI therapy (Table 1 and Figure 2).2-4 Although these therapies induce durable responses in most patients with chronic-phase CML, some patients fail to respond (primary resistance) or lose their response (secondary resistance) to therapy.5 The most common cause of resistance is mutation in the ABL1 kinase domain.5 Laboratory tests that evaluate ABL1 kinase domain mutations may help guide treatment change when patients develop primary or secondary resistance to TKI therapy (Figure 3).2 ABL1 kinase domain mutation analysis is also recommended to help select initial treatment for patients with blast-phase CML (Figure 3).2

Figure 1. Use of Laboratory Testing to Diagnose CML and Determine Disease Phase
Figure 2. Use of Laboratory Tests to Monitor Response to TKI Therapy in CML Patients
Figure 3. Uses of ABL1 Kinase Domain Mutation Analysis

Table 1. Classification of Treatment Response

Type of treatment response

Criteria

Complete hematologic response2

All of the following:

  • Complete normalization of PB counts
  • WBC count <109/L
  • Platelet count <450x109/L
  • No immature cells in PB
  • No disease signs or symptoms

Cytogenetic response2
  • Complete
 No Ph+ metaphase cellsa
  • Major
 0%-35% Ph+ metaphase cellsa
  • Partial
 1%-35% Ph+ metaphase cellsa
  • Minor
 >35%-65% Ph+ metaphase cellsa

Molecular response2
  • Deep

BCR-ABL1/ABL1 ratio of≤0.01% IS (MR 4.0) or BCR-ABL1/ABL1 ratio of ≤0.0032% IS (MR 4.5) by PCR
  • Major

BCR-ABL1/ABL1 ratio of ≤0.1% ISb
  • Early

BCR-ABL1/ABL1 ratio of ≤10% IS at 3 and 6 months
IS, international scale; MR, molecular response; PB, peripheral blood; PCR, polymerase chain reaction; Ph+, positive for the Philadelphia chromosome; WBC, white blood cell.
a Out of ≥20 metaphase cells.
b Corresponds to a ≥3-log decrease in BCR-ABL1 transcript levels from standardized baseline.

 

Table 2 provides an overview of the types of laboratory tests used for diagnosing CML and recognizing CML phases, determining prognosis, and monitoring treatment response. It is provided for informational purposes only and is not intended as medical advice. Test selection and interpretation, diagnosis, and patient management decisions should be based on the physician’s education, clinical expertise, and assessment of the patient.

Table 2. Laboratory Tests Useful for CML Diagnosis, Classification, Prognosis, and Monitoring of TKI Treatment Response

Test code

Test name

Clinical use

Hematology, morphology, and comprehensive tests

6399

CBC (Includes Differential and Platelets)

Diagnosis, classification, prognosis, and monitoring of treatment response.

17734(X)a

Comprehensive Hematopathology Report

IIncludes morphology evaluation; may include chromosome analysis, BCR-ABL1 PCR test, BCR-ABL1 FISH test, and/or ABL1 kinase domain mutation analysis.

Diagnosis, classification, prognosis, and monitoring of treatment response.

Cytogenetic and FISH tests

14600

Chromosome Analysis, Hematologic Malignancy

Diagnosis, classification, prognosis, and monitoring of treatment response.

12070b

FISH, CML/ALL, BCR/ABL, Translocation 9,22

Diagnosis (alternative to karyotyping)

Molecular tests

91065b

BCR-ABL1 Gene Rearrangement, Quantitative PCR

Diagnosis, prognosis, and monitoring of treatment response.

16029b

ABL Kinase Domain Mutation in CML, Cell-based

Treatment selection for patients with blast-phase CML and those with primary or secondary TKI resistance (predicts resistance to bosutinib, dasatinib, imatinib, or nilotinib)
BM, bone marrow; CBC, complete blood count; CML, chronic myeloid leukemia; FISH, fluorescence in situ hybridization; PB, peripheral blood; PCR, polymerase chain reaction; RT, room-temperature; TKI, tyrosine kinase inhibitor.
a Test results are reviewed by a hematopathologist and, if deemed medically necessary for evaluation, additional tests are performed at an additional charge. CPT codes vary depending on the specific tests ordered. Test code 17734 includes an interpretive report issued by a hematopathologist.
b This test was developed and its analytical performance characteristics have been determined by Quest Diagnostics. It has not been cleared or approved by the US Food and Drug Administration. This assay has been validated pursuant to the CLIA regulations and is used for clinical purposes.

 

References

  1. Apperley JF, Godley LA, Radich J, et al. Chronic myeloid leukaemia. In: Chan J, ed. The World Health Organization Classification of Haematolymphoid Tumours. 5 Beta ed. IARC Press; 2022:chap 2. Accessed October 18, 2022. https://tumourclassification.iarc.who.int
  2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Chronic myeloid leukemia. Version 1.2023. Updated August 5, 2022. https://www.nccn.org
  3. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-884. doi:10.1182/blood-2013-05-501569
  4. Hochhaus A, Saussele S, Rosti G, et al. Chronic myeloid leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv261. doi:10.1093/annonc/mdy159
  5. Patel AB, O'Hare T, Deininger MW. Mechanisms of resistance to ABL kinase inhibition in chronic myeloid leukemia and the development of next generation ABL kinase inhibitors. Hematol Oncol Clin North Am. 2017;31(4):589-612. doi:10.1016/j.hoc.2017.04.007
     

Content reviewed 11/2022

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This Test Guide provides an overview of tests that assist with the diagnosis, classification, prognosis, and management of chronic myeloid leukemia (CML).

Test Guide List

Chronic Myeloid Leukemia: Laboratory Evaluation

Test Guide

 

Chronic Myeloid Leukemia

Laboratory Evaluation

Chronic myeloid leukemia, formerly called chronic myelogenous leukemia (CML), is a hematopoietic stem cell cancer characterized by uncontrolled expansion of myeloid cells.1 In 90% to 95% of cases, CML is caused by a characteristic translocation1 between chromosomes 9 and 22. This translocation results in an abnormally short chromosome 22—the Philadelphia chromosome (Ph)—and formation of the BCR-ABL1 fusion gene.1 The fusion gene in turn produces a constitutively active tyrosine kinase that causes CML.1 The remaining 5% to 10% of cases have a translocation involving 3 or 4 chromosomes o r a cryptic translocation that cannot be detected by karyotyping.1

CML has 2 phases of progression: the initial chronic phase and the blast phase.1 When blood morphology findings suggest CML, the diagnosis is confirmed by identifying Ph using karyotyping and/or by detecting the BCR-ABL1 fusion gene with polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) tests.1,2 Once CML is diagnosed, determining disease phases (chronic or blast phase) can help assess prognosis and select therapy.1,2 Figure 1 shows criteria that can be used in laboratory diagnosis and determining the phases of CML.

CML treatments mainly include therapy with a tyrosine kinase inhibitor (TKI) (eg, bosutinib, dasatinib, imatinib, or nilotinib) and allogeneic hematopoietic stem cell transplantation.2 TKI therapies have dramatically improved treatment outcomes in CML, and bosutinib, dasatinib, imatinib, and nilotinib are now first-line therapies for chronic-phase CML.2 Laboratory tests that assess hematologic, cytogenetic, and molecular disease levels can be used to monitor response to TKI therapy (Table 1 and Figure 2).2-4 Although these therapies induce durable responses in most patients with chronic-phase CML, some patients fail to respond (primary resistance) or lose their response (secondary resistance) to therapy.5 The most common cause of resistance is mutation in the ABL1 kinase domain.5 Laboratory tests that evaluate ABL1 kinase domain mutations may help guide treatment change when patients develop primary or secondary resistance to TKI therapy (Figure 3).2 ABL1 kinase domain mutation analysis is also recommended to help select initial treatment for patients with blast-phase CML (Figure 3).2

Figure 1. Use of Laboratory Testing to Diagnose CML and Determine Disease Phase
Figure 2. Use of Laboratory Tests to Monitor Response to TKI Therapy in CML Patients
Figure 3. Uses of ABL1 Kinase Domain Mutation Analysis

Table 1. Classification of Treatment Response

Type of treatment response

Criteria

Complete hematologic response2

All of the following:

  • Complete normalization of PB counts
  • WBC count <109/L
  • Platelet count <450x109/L
  • No immature cells in PB
  • No disease signs or symptoms

Cytogenetic response2
  • Complete
 No Ph+ metaphase cellsa
  • Major
 0%-35% Ph+ metaphase cellsa
  • Partial
 1%-35% Ph+ metaphase cellsa
  • Minor
 >35%-65% Ph+ metaphase cellsa

Molecular response2
  • Deep

BCR-ABL1/ABL1 ratio of≤0.01% IS (MR 4.0) or BCR-ABL1/ABL1 ratio of ≤0.0032% IS (MR 4.5) by PCR
  • Major

BCR-ABL1/ABL1 ratio of ≤0.1% ISb
  • Early

BCR-ABL1/ABL1 ratio of ≤10% IS at 3 and 6 months
IS, international scale; MR, molecular response; PB, peripheral blood; PCR, polymerase chain reaction; Ph+, positive for the Philadelphia chromosome; WBC, white blood cell.
a Out of ≥20 metaphase cells.
b Corresponds to a ≥3-log decrease in BCR-ABL1 transcript levels from standardized baseline.

 

Table 2 provides an overview of the types of laboratory tests used for diagnosing CML and recognizing CML phases, determining prognosis, and monitoring treatment response. It is provided for informational purposes only and is not intended as medical advice. Test selection and interpretation, diagnosis, and patient management decisions should be based on the physician’s education, clinical expertise, and assessment of the patient.

Table 2. Laboratory Tests Useful for CML Diagnosis, Classification, Prognosis, and Monitoring of TKI Treatment Response

Test code

Test name

Clinical use

Hematology, morphology, and comprehensive tests

6399

CBC (Includes Differential and Platelets)

Diagnosis, classification, prognosis, and monitoring of treatment response.

17734(X)a

Comprehensive Hematopathology Report

IIncludes morphology evaluation; may include chromosome analysis, BCR-ABL1 PCR test, BCR-ABL1 FISH test, and/or ABL1 kinase domain mutation analysis.

Diagnosis, classification, prognosis, and monitoring of treatment response.

Cytogenetic and FISH tests

14600

Chromosome Analysis, Hematologic Malignancy

Diagnosis, classification, prognosis, and monitoring of treatment response.

12070b

FISH, CML/ALL, BCR/ABL, Translocation 9,22

Diagnosis (alternative to karyotyping)

Molecular tests

91065b

BCR-ABL1 Gene Rearrangement, Quantitative PCR

Diagnosis, prognosis, and monitoring of treatment response.

16029b

ABL Kinase Domain Mutation in CML, Cell-based

Treatment selection for patients with blast-phase CML and those with primary or secondary TKI resistance (predicts resistance to bosutinib, dasatinib, imatinib, or nilotinib)
BM, bone marrow; CBC, complete blood count; CML, chronic myeloid leukemia; FISH, fluorescence in situ hybridization; PB, peripheral blood; PCR, polymerase chain reaction; RT, room-temperature; TKI, tyrosine kinase inhibitor.
a Test results are reviewed by a hematopathologist and, if deemed medically necessary for evaluation, additional tests are performed at an additional charge. CPT codes vary depending on the specific tests ordered. Test code 17734 includes an interpretive report issued by a hematopathologist.
b This test was developed and its analytical performance characteristics have been determined by Quest Diagnostics. It has not been cleared or approved by the US Food and Drug Administration. This assay has been validated pursuant to the CLIA regulations and is used for clinical purposes.

 

References

  1. Apperley JF, Godley LA, Radich J, et al. Chronic myeloid leukaemia. In: Chan J, ed. The World Health Organization Classification of Haematolymphoid Tumours. 5 Beta ed. IARC Press; 2022:chap 2. Accessed October 18, 2022. https://tumourclassification.iarc.who.int
  2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Chronic myeloid leukemia. Version 1.2023. Updated August 5, 2022. https://www.nccn.org
  3. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-884. doi:10.1182/blood-2013-05-501569
  4. Hochhaus A, Saussele S, Rosti G, et al. Chronic myeloid leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv261. doi:10.1093/annonc/mdy159
  5. Patel AB, O'Hare T, Deininger MW. Mechanisms of resistance to ABL kinase inhibition in chronic myeloid leukemia and the development of next generation ABL kinase inhibitors. Hematol Oncol Clin North Am. 2017;31(4):589-612. doi:10.1016/j.hoc.2017.04.007
     

Content reviewed 11/2022

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