1st order laboratory parameters – obligatory laboratory tests.
- Small blood count [continuous left shift; leukocytosis/increase in white blood cells (leukocytes), erythrocytosis/increase in red blood cells (erythrocytes), thrombocytosis/increase in platelets (thrombocytes)]
- Differential blood count [leukocytosis with basophilia]
- Coagulation parameters – Quick, PTT (partial thromboplastin time).
- Inflammatory parameters – CRP (C-reactive protein).
- Alkaline leukocyte phosphatase (ALP; leukocyte AP) [ALP index: decreased].
- Uric acid [↑]
- LDH [↑]
- Multiplex PCR (polymerase chain reaction) for BCR-ABL transcripts from peripheral blood – to confirm the diagnosis and as a starting point for therapy progression controlsNote: BCR-ABL is responsible for the oncogenic transformation of the affected hematopoietic stem cell.
- Thymidine kinase (TK).
- Cytology with blood smear
- Bone marrow smear – for confirmation of diagnosis as well as confirmation of chronic phase of the disease and cytogenetic findings (Philadelphia chromosome (obsolete Ph1), additional aberrations if necessary).
- Cytology (proportion of blasts and promyelocytes and distribution, eosinophils, basophils).
- Cytogenetics: metaphase analysis
- Bone marrow biopsy [cellularity, fibrosis, blast count and distribution].
- CSF punctate
- Cytogenetic testing and molecular genetics (Philadelphia chromosome (>95% of patients); BCR-ABL translocation) – for early identification of patients with suboptimal response and of relapses (regular follow-up to assess remission status).
Transaminases (alanine aminotransferase ALT, GPT); aspartate aminotransferase (AST; GOT)), electrolytes (sodium, potassium), and renal function parameters (urea, creatinine clearance) should be assessed before starting therapy. Criteria for the accelerated phase are:
- 10-19% blasts in blood or bone marrow; or
- > 20 % basophils in blood or bone marrow or
- Therapy-independent thrombocytopenia (reduction in platelets) < 100,000/μl, not responding to therapy, or
- Additional “major route” clonal chromosomal aberrations of Philadelphia-positive cells (second Philadelphia chromosome, trisomy 8, isochromosome 17q, trisomy 19, complex karyotype, aberrations of chromosomal segment 3q26.2) or
- Newly formed clonal evolution or
- Progressive splenomegaly (increasing splenomegaly) and rising leukocytes unresponsive to therapy.
Definition of blast crisis
- ≥ 30% blasts in peripheral blood or bone marrow or evidence of extramedullary infiltrates (European LeukemiaNet recommendation).
- ≥ 20 % blasts (WHO classification).
Note: Patients with 20-29% blasts have a significantly better prognosis than patients with ≥ 30% blasts.
Tyrosine kinase inhibitors (TKi)
Monitoring of response to tyrosine kinase inhibitors.
Investigation time points | |||||
Investigation | Diagnosis | Within the first 3 months | After 3 months | After 6 months | Later |
Hematological | X | Every 2 weeks until CHR | X | X |
|
Cytogenetic | X | X | X |
|
|
Molecular (Q-RT-PCR) | X multiplex PCR | X | X |
|
Definition of hematologic, cytogenetic, and molecular response.
Method | Remission | Abbreviation | Parameter |
Hematological | Complete | CHR |
|
Cytogenetic | Complete | CCyRa | No Ph+ metaphases |
Partial | PCyRa | 1-35 % Ph+ metaphases | |
Minor | mCyR | 36-65 % Ph+ metaphases | |
Minimal | minCyR | 66-95 % Ph+ metaphases | |
None | None CyR | > 95% Ph+ metaphases | |
Molecular | Major | MMR | BCR-ABL transcripts (IS) ≤ 0.1%b |
Low | MR4 | BCR-ABL transcripts ≤ 0.01% or BCR-ABL transcripts 0 with assay sensitivity > 104 (10,000 ABL transcripts). | |
Low | MR4.5 | BCR-ABL transcripts ≤ 0.0032% or BCR-ABL transcripts 0 with assay sensitivity > 104.5 (32,000 ABL transcripts). |
Definition of inadequate response and resistance to tyrosine kinase inhibitors.
Time after initiation of TKI therapy, months. | Response | |
Hematologic and cytogenetic criteria. | PCR criteria | |
3 | No CHR, no CyR | |
6 | > 35 % Ph+, no PCyR | > 10 % BCR-ABL (IS) |
12 | > 0 % Ph+, no CCyR | > 1 % BCR-ABL (IS) |
Any time |
|
|
Legend
- CCyR: complete cytogenetic remission.
- CHR: complete hematologic remission.
- IS: international standard
- MCyR: majore cytogenetic remission.
- MinCyr: minimal cytogenetic remission
- MMR: majore (good) molecular remission.
- PCyR: partial cytogenetic remission.
- Q-RT-PCR: quantitative polymerase chain reaction.
- TKI: tyrosine kinase inhibitors.
aPCyR and CCyR together constitute majore cytogenetic remission (MCyR)bQuotient of BCR-ABL to control gene ≤ 0.1% by IS (international standard).