Definition, Etiology, Pathogenesis Top
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm involving clonal proliferation of a malignant multipotential hematopoietic stem cell. As a result of reciprocal translocation of the long arms of chromosomes 9 and 22, the Philadelphia (Ph) chromosome is formed, and the subsequent fusion of the BCR and ABL1 genes leads to the development of a new mutant BCR-ABL1 gene. This gene encodes the bcr-abl fusion protein, which due to its tyrosine kinase activity causes an increased clonal proliferation of hematopoietic stem cells, inhibition of apoptosis, and impaired adhesion of leukemic cells to the bone marrow matrix.
Clinical Features And Natural History Top
Clinical manifestations of hyperleukocytosis (>200,000-300,000/microL in 10% patients) include weight loss, leukostasis (abnormalities of microcirculation), altered mental status, visual disturbances, headache, symptoms of hypoxemia, priapism, and manifestations of splenomegaly (left upper quadrant pain, early satiety [a late symptom]) and hepatomegaly.
In ~40% of patients, CML is an incidental finding in a complete blood count (CBC) performed for other reasons. The chronic phase of CML always progresses—sometimes rapidly—to blastic transformation (blast crisis). The progression usually follows through an intermediate accelerated phase (triphasic course) or less often it may be direct (biphasic course). In patients with blast crisis, peripheral blood or bone marrow blast counts increase to >20%, as in acute leukemia (in ~50% of patients, CML transforms into myeloid leukemia; in ~30%, into lymphoblastic leukemia; in ~10%, into megakaryoblastic leukemia; and in the remaining cases, blast crisis has features of myelofibrosis). The accelerated phase and blast crisis in CML are characterized by multiple cytogenetic abnormalities, resistance to treatment, and a poor prognosis.
1. CBC: White blood cell (WBC) counts are elevated in all patients with CML, with mature and immature granulocytes at all stages of development, thrombocytosis (in a third of patients), and basophilia. Differential blood count reveals a left shift that may extend to blasts and includes promyelocytes, myelocytes, metamyelocytes, less frequently erythroblasts. Hemoglobin levels at diagnosis are usually normal. Platelet counts may be elevated.
2. Bone marrow examination: Bone marrow aspiration and trephine biopsy usually reveal increased bone marrow cellularity with an elevated proportion of cells of neutrophilic (similar to that observed in peripheral blood) and megakaryopoietic lineages.
3. Cytogenetic and molecular studies of bone marrow (Ph chromosome) and peripheral blood are performed both to establish the diagnosis and to monitor minimal residual disease and response to treatment.
The diagnosis is based, at all stages, on the documented presence of the Ph chromosome using cytogenetic studies or the BCR-ABL1 gene using molecular studies.
1. The World Health Organization (WHO) diagnostic criteria of accelerated phase (≥1 feature must be present):
1) 10% to 19% blasts in peripheral blood or bone marrow.
2) ≥20% of basophils in peripheral blood.
3) Sustained thrombocytopenia <100,000/microL (unrelated to treatment).
4) Clonal cytogenetic evolution (emergent chromosomal aberrations) during treatment.
5) Progressive splenomegaly or leukocytosis not responding to treatment.
2. The WHO diagnostic criteria of blast crisis (≥1 feature must be present):
1) ≥20% blasts in peripheral blood or bone marrow.
2) Extramedullary blastic infiltrates (in organs other than spleen).
3) Large aggregates or clusters of blasts in bone marrow.
1. Conditions associated with elevated neutrophil counts:
1) Other myeloproliferative and myelodysplastic-myeloproliferative neoplasms.
2) Leukemoid reaction: Infection (WBC count ≤100,000/microL), particularly in patients with bacterial pneumonia, meningitis, diphtheria, tuberculosis, or fungal infections.
3) Other neoplasms that produce granulocyte growth factors: Small cell lung cancer, ovarian cancer, melanoma, Hodgkin lymphoma.
4) Other conditions (WBC count, 30,000-40,000/microL): Tissue necrosis, myocardial infarction, myositis, acute hemorrhage, glucocorticoid therapy.
5) Exogenous administration of granulocyte colony-stimulating factor or granulocyte and macrophage colony-stimulating factor.
1. Long-term treatment with tyrosine kinase inhibitors (TKIs):
1) Imatinib 400 mg orally once daily.
2) Dasatinib 100 mg orally once daily; this is effective in all patients with resistance to imatinib caused by BCR-ABL1 gene mutations except for T315I/A, F317L, and V299L mutations.
3) Nilotinib 300 mg orally bid; this is effective in all patients with resistance to imatinib caused by BCR-ABL1 gene mutations except for T315I, Y253H/F, E255V/K, and F359V mutations.
4) Bosutinib 500 mg orally once daily.
5) Ponatinib 45 mg orally once daily (first-line therapy); this is effective in patients with the T315I mutation.
The first-line agents include imatinib, nilotinib, and dasatinib. In the case of imatinib resistance or intolerance, dasatinib, nilotinib (800 mg/d), or bosutinib may be used. No significant data in favor of any of these agents are available, except for the BCR-ABL1 mutations causing resistance to any one of them. The choice of the agent should be based on the availability, cost, drug’s toxicity profile, as well as patient’s comorbidities and possible interactions with other administered drugs.
Criteria of the optimal response to treatment:
1) A major hematologic response (MCyR) (≤35% of Ph+ cells on cytogenetic examination) and/or achieving ≤10% of BCR-ABL1 transcript in real-time quantitative polymerase chain reaction after 3 months of treatment.
2) A complete cytogenetic response (CCyR) (no Ph+ cells on cytogenetic examination) and/or <1% of BCR-ABL1 transcript up to 6 months after diagnosis.
3) A major molecular response (MMR) (<0.1% of BCR-ABL1 transcript) up to 12 months from diagnosis or anytime afterwards.
2. Allogeneic hematopoietic stem cell transplantation (HSCT) should be considered in patients in the chronic phase with the T315I mutation of BCR-ABL1 or after the failure of first-line dasatinib or nilotinib treatment. Allogeneic HSCT is recommended in all transplant-eligible patients in chronic phase after failure of or intolerance to 2 TKIs.
3. Interferon alpha is used in pregnant women (monotherapy) and in patients with TKI treatment failure who are not eligible for allogeneic HSCT (in combination with cytarabine or another agent).
4. Hydroxyurea (INN hydroxycarbamide) is used as a short-term treatment to reduce WBC counts prior to confirming the diagnosis. It has no disease-modifying effect and no influence on survival.
5. Treatment of accelerated phase and blast crisis requires higher doses of TKIs. In patients with disease progression in the course of treatment, switch to another TKI (see above). Achieving remission may frequently require concomitant chemotherapy, as in acute leukemia. In every patient in accelerated phase/blast crisis, allogeneic HSCT should be performed if possible, optimally after achieving a chronic phase. The only exception is TKI-naive patients with an accelerated phase diagnosed de novo in whom the optimal response to TKI treatment has been achieved.
The response to TKI treatment is the most important prognostic factor. In patients treated with imatinib, 7-year rates of progression-free survival and survival free of accelerated phase/blast transformation are 81% and 93%, respectively. In patients undergoing allogeneic HSCT (from a related donor), the 3-year survival rate is reported as up to 76%.Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to the selective nature of the observed cohort. www.bloodcell.transplant.hrsa.gov