MMH Practical Guideline of Chronic Myeloid Leukemia
2004/7/7
Introduction
Chronic myeloid leukemia (CML) is a clonal stem cell disorder characterized by
increased proliferation of myeloid elements at all stages of differentiation.
The hallmark of CML is the Philadelphia chromosome (Ph), a reciprocal translocation
between the long arms of chromosomes 9 and 22 [i.e., t(9;22)], resulting chimeric
BCR-ABL gene.
Clinical Features
Symptoms
Early chronic phase may have no symptoms.
Fatigue, weight loss, abdominal fullness and anorexia, easy bruising or bleeding,
abdominal pain, or fever.
Signs
The most common finding is splenomegaly, which can be massive (in about 10% of
patients, the spleen is not enlarged, even on splenic scan).
Diagnosis
History and physical examination
CBC, platelets: Morphologic review
Leukocytosis usually > 25,000/ul
Myeloid cells at all stages of maturation in the peripheral smear.
Chemistry profile: MAR
Bone marrow aspirate and biopsy
Leukocyte alkaline phosphatase (LAP) score: markedly diminished.
HBsAg, Anti-HCV Ab
Abdominal echo
Chromosome study: Karyotypic cytogenetics for the detection of the t(9;22)
10% Ph negative: FISH or PCR
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Staging and Prognosis
Stage
Chronic phase
Features/Definitions
<5% blasts and promyelocytes in PB or BM
Accelerated phase Increasing spleen size and increasing WBC count
unresponsive to therapy
Blasts 10-19% of WBCs in peripheral and/or
nucleated BM cells
PB basophils >= 20%
Persistent thrombocytopenia (< 100,000/μL)
Median
survival
5–6 yr
<1 yr
unrelated to therapy, or persistent
thrombocytosis (> 1,000,000/μL) unresponsive
to therapy
Cytogenetic evidence of clonal evolution
Blast crisis
Blasts >= 20% of PB white cells or of nucleated
BM cells
Extramedullary blast proliferation
Large foci or clusters of blasts in the BM biopsy
A few months
PB, peripheral blood; BM, bone marrow.
Primary Treatment for Chronic Phase
Imatinib mesylate (Glivec) 400mg po daily and evaluation every 3 months.
Screen for allogeneic bone marrow transplantation (BMT) (HLA testing) if feasible.
Hematologic remission (at least partial response):
Continue imatinib mesylate.
Monitor cytogenetics or FISH or PCR every 3-6 months after complete hematologic
response.
Not in hematologic remission, or in hematologic relapse:
Increase imatinib mesylate dose (600-800mg/day, if tolerated)
or interferon-α ± cytarabine
or BMT if feasible
or clinical trial
or chemotherapy (e.g. hydroxyurea)
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Treatment Schedule
Drug
Treatment plan
Toxicity
Response Rate
Imatinib mesylate
400 mg p.o. daily,
maximum 800 mg/day
The major
Leukopenia, anemia,
thrombocytopenia, diarrhea, cytogenetic response
was 87.1%.
edema, fluid retention, GI
upset, muscle cramps, rash.
Hydroxyurea
500–2,000 mg p.o. daily (or Leukopenia common,
daily dose of =< 50 mg/kg) anemia, thrombocytopenia,
nausea, rash
90% hematologic
remission; 34–44%
5-yr survival
Interferon α-2a/b
5 × 106 Units/m2 per day
s.c.
Fever, myalgia, rashes,
depression, leukopenia,
19% cytogenetic
responses; 52–79%
anemia, thrombocytopenia
5-yr survival
Interferon α-2a/b +
cytarabine
Interferon α-2a/b, 5 × 10
Units/m2 per day s.c.;
cytarabine, 20 mg/m2 s.c.
single daily dose for 10
days (d 1–10; total
dose/cycle = 200 mg/m2).
Cytarabine cycle is
repeated monthly.
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Nausea, vomiting, diarrhea, 41% cytogenetic
mucositis, weight loss,
response rate; 86%
leukopenia, anemia,
3-yr survival
thrombocytopenia
Discontinue cytarabine
after complete cytogenetic
response is achieved.
Treatment for Blast Crisis
Laboratory studies:
Bone marrow exam, flow cytometry, cytochemistry (peroxidase, TdT), cytogenetics.
Lymphoid: ALL-type induction chemotherapy or clinical trial.
Myeloid: AML-type induction chemotherapy or clinical trial.
Refractory or relapse: Allogeneic BMT (if feasible) or clinical trial.
Supportive Care Strategies for Leukocytosis and Thrombocytosis
Factors to consider when choosing treatment include:
Patient’s age, risk factors for thromboembolic disease, and degree of
thrombocytosis.
Symptomatic leukocytosis:
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e.g. dyspnea, tachypnea, rales, interstitial infiltrates, headaches, blurred vision.
Treatment options include hydroxyurea, apheresis, or imatinib mesylate.
Symptomatic thrombocytosis:
e.g. erythromelalgia, headache, dizziness, visual and acoustic symptoms,
thrombosis or hemorrhage.
Treatment options include hydroxyurea, antiaggregants, anagrelide or apheresis.
Criteria for Hematologic Remission
Complete hematologic response
Complete normalization of peripheral blood counts with leukocyte count < 10,000/μL
Platelet count < 450,000/μL
No immature cells, such as myelocytes, promyelocytes, or blasts in peripheral blood
No signs and symptoms of disease with disappearance of palpable splenomegaly
Partial hematologic response
Same as complete hematologic response, except for:
Presence of immature cells
Platelet count < 50% of the pretreatment count, but > 450,000/μL
Persistent splenomegaly, but < 50% of the pretreatment extent
Criteria for Cytogenetic Remission
Complete: No Ph-positive metaphases
Partial: 1%-34% Ph-positive metaphases
Minor: 35%-90% Ph-positive metaphases
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