Chronic Myelogenous Leukemia (CML)

Background:

10-15% of all leukemias
Male/Female: 1.5
Median age of 65 years old
Ionizing radiation is the only known causative factor (usually within 6 to 8 years of exposure)
No known genetic factors determine susceptibility to CML

Pathophysiology:

>95% of CML patients have Philadelphia chromosome (Ph) in the marrow.
- Contains BCR-ABL1 fusion gene (translocation between BCR on chromosome 22 and ABL1 on chromosome 9)
  - BCR-ABL1 oncoprotein has tyrosine kinase activity.
BCR-ABL1 is found in all cells of the myeloid lineage and B cells but not in T cells.
At diagnosis, it is usually a mixed population of Ph-positive and negative cells in the bone marrow. With time, normal stem cells are replaced by BCR-ABL1 positive clones.
Genomic instability:
- Usually starts with chronic and relatively benign phase
- May evolves to a more aggressive phase with additional chromosomal abnormalities and 10-20% blasts
Neutrophil function is preserved → Does not present with bacterial or fungal infections.

Diagnosis:

High leukocyte count with basophilia and a hypercellular marrow is pathognomonic of CML.
Eosinophilia is also common.
Chromosome analysis shows t(9;22) translocation.
Leukocyte alkaline phosphatase is low in CML.
It is important to distinguish CML presenting as acute leukemia from de novo (Ph-negative) acute leukemia because the treatment approaches are distinct.

→ pre-B ALL: TdT-positive, CD10+, CD19+, CD33±, CD34±

→ undifferentiated AML: peroxidase weak-positive, CD33+, CD34+, CD13±

Chloromas often respond poorly to chemotherapy, the best treatment option is radiotherapy.

Prognostic factors:

CML phases:

Chronic phase (CP):
- >80% of patients
Accelerated phase (AP):
- Peripheral blood myeloblast 15-30%
- Peripheral blood myeloblast + promyelocytes ≥30%
- Peripheral blood basophil >20%
- Plt count <100k unrelated to therapy
- Additional chromosome abnormalities in Ph+ cells
Blastic phase (BP):
- ≥30% blasts in blood or BM
- Extramedullary infiltration of leukemic cells

Treatment:

If WBC >80,000 → Tx: Hydroxyurea 0.5-2.5 g daily + Allopurinol 300 mg daily (until normal WBC)
Once CML is confirmed and WBC count is controlled → Treatment with TKI

Treatment response:

Hematologic response (HR):
- Complete HR: Normal WBC
Cytogenetic response (CR):
- Minor CR: 35-85% Ph
- Major CR: 5-35% Ph
- Complete CR: 0% Ph
Molecular response (MR):
- Major MR: <0.1% BCR-ABL1
- Complete MR: undetectable BCR-ABL1

- Chronic Phase (CP):

Standard first-line treatment for CP:
- Low risk CP:
  - 1st generation TKI:
    - Imatinib 400 mg daily
  - 2nd generation TKI:
    - Dasatinib 100 mg daily
    - Nilotinib 300 mg BID
  - 3rd generation TKI:
    - Bosutinib 400 mg daily
Intermediate and high risk CP:
- Same dose Dasatinib, Nilotinib and Bosutinib (2nd and 3rd gen)
If failure to first-line TKI: Alternative TKI is indicated.
BCR-ABL1 kinase domain mutations (such as T315I) are highly resistant to imatinib, dasatinib and nilotinib (1st and 2nd gen).
- Treatment for T315I: ponatinib is preferred.
Tx: first-line TKI → if resistant to first-line TKI (BCR-ABL1 >10% after 3 months of treatment) → Tx: alternative TKI + check BCR-ABL1 kinase domain mutation status → if resistant to treatment → Tx: another alternate TKI (including Ponatinib) based on mutation analysis result → if resistant to treatment → Tx: allo-HSCT
- If patient is not suitable for HSCT → Tx: Cytosine arabinoside (ARA-C) + IFN-α
HSCT can be the first line of treatment for CP only if the patient is <30 years old with low probability of morbidity and mortality.

- Accelerated Phase (AP):

Treatment options:
- Dasatinib, Nilotinib, Ponatinib (2nd and 3rd gen)
- Omacetaxine mepesuccinate (If resistance to ≥2 TKIs)
- allo-HSCT
- ARA-C + IFN-α
de-novo AP can be initially managed like CP with a single agent TKI (2nd or 3rd gen) followed by evaluation for allo-HSCT.
Doses of TKIs used for treatment of AP are higher than CP.

- Blastic Phase (BP):

Tyrosine Kinase Inhibitors:

Dasatinib:
- Dasatinib compared to Imatinib caused higher CR and MR rate and lower rate or progression to BP and AP but did not change overall survival. (DASISION)
- Crosses the blood–brain barrier/ effective for CNS disease.
- Patients with significant lung disease should avoid dasatinib.
- Up to 30% of patients develop pleural effusions.
  - May require dose reduction, diuretics or corticosteroids.
- Side effects: cytopenia, diarrhea, pleural effusion, heart failure, prolonged QT
- Dasatinib 140 mg daily is better tolerated than divided doses of 70 mg twice daily.
Nilotinib:
- Reduce the incidence of progression to BP.
- Avoid Nilotinib in significant atherosclerotic disease or diabetes.
- It can cause elevated liver enzymes, electrolyte abnormalities and pancreatitis.
- FDA black box warning: prolonged QT interval, arrhythmia and sudden cardiac death
  - Check QT interval at baseline and one week after initiation of Nilotinib
Ponatinib:
- Efficacious against T315I mutations (31% HR in such CML BP patients).
- Increase risk of arterial and venous thrombosis, pancreatitis, heart failure and TLS.

Monitoring response to treatment:

CBC q2 weeks until complete HR which should be confirmed on two subsequent occasions.
BMBx q6 months until complete CR (0% Ph) which should be confirmed on two subsequent occasions, then BMBx q12 months.
Quantitative PCR for BCR-ABL1 transcripts in the blood q3 months
Reduction of BCR-ABL1 transcripts by 3 or more logs below the baseline is associated with good outcome.
After allo-HSCT, quantitative PCR should be monitored q3 months for 2 years and then q3-6 months.

Failure of TKI treatment:

If TKI fails → Check kinase domain mutation analysis

Pregnancy:

TKIs are contraindicated in pregnancy. Women on TKI should not breastfeed.
Female patients are advised to have optimal control of CML before conceiving and stop TKI at least 3 months before conception.
Male patients can continue TKI during conception.
Leukapheresis is performed if there is significant leukocytosis off treatment.
Hydroxyurea and IFN-α have also been used in pregnancy without complications.

Criteria for TKI discontinuation:

Chronic Phase CML with no history of AP or BP
On an approved TKI therapy for at least 3 years
Stable molecular response (BCR-ABL1 ≤ 01%) for ≥2 years as documented on at least four tests, performed at least 3 months apart
Access to a reliable quantitative PCR test with a sensitivity of detection BCR-ABL1 ≤ 0.0032%

Related Posts