Contributed by Rajendra Persad, MDFINAL DIAGNOSIS: CHRONIC MYELOID LEUKEMIA IN ACCELERATED PHASE.
DISCUSSION:
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized hematologically by marked leukocytosis, basophilia, and eosinophilia; the leukocytosis is due primarily to an increase in mature and immature neutrophils. CML is a clonal disorder associated in virtually all cases with a t(9;22)chromosome usually manifest as the Philadelphia (Ph) chromosome, and/or molecular evidence of the translocation of the abl (Ableson leukemia virus) oncogene from chromosome 9 to the breakpoint cluster region (bcr) of chromosome 22.
Epidemiology:
The incidence of CML is 1-1.5/ 100 000 population, constituting 15-20 % of all leukemias, making it the commonest of the chronic myeloproliferative disorders. The incidence has remained unchanged in the last 50 years. It is primarily a disease of adults, with a median age of 53years; approximately one third of patients are older than 60 years. CML is uncommon in childhood, accounting for approximately 5% of childhood leukemias. There is a slight male predominance.
Familial cases of CML are rare, and no geographic or ethnic predisposition has been reported. Radiation exposure remains the only recognized predisposing factor; there is no known association with viruses, drugs or other chemicals.
Clinical findings:
A large minority of patients are asymptomatic, and are discovered incidentally during routine blood testing. Fatigue and loss of energy are the most common symptoms. Dyspnea, anorexia, weight loss LUQ discomfort, bloating and early satiety are less common. Symptoms due to hyperviscosity are uncommon.
Splenomegaly is seen in ~50 % of patients. Other physical findings include pallor, hepatomegaly, lymphadenopathy and evidence of spontaneous bleeding.
Laboratory findings:
Peripheral blood leukocytosis is characteristic, the majority having white cell counts greater than 50,000 x 106/L. Absolute basophilia is critical to the diagnosis(though the percentage may be low), and is more specific than eosinophilia or monocytosis.
The differential count shows a predominance of myelocytes and polymorphs. The myelocytes outnumber the more mature metamyelocytes (the myelocyte bulge).
Mild to moderate normochromic normocytic anemia and mild thrombocytosis are usually noted. Typically there is normal morphology of RBC and WBC. Leukocyte alkaline phosphatase is decreased in CML, a finding of importance in distinguishing leukemoid reactions. Serum B12 and B12 binding capacity are increased as a result of elevated transcobalamins. Hyperuricemia and hyperuricosuria are also noted.
The bone marrow is hypercellular with increased neutrophils and neutrophil precursors (especially myelocytes). The myeloid to erythroid ratio is increased. Dyspoietic changes are more commonly seen following treatment with chemotherapy. Megakaryocytosis with small hypolobated forms in clusters or uniformly distributed may also be seen. Abnormal macrophages containing crystals, pseudo-Gaucher cells and sea-blue histiocytes may also be found.
Marrow fibrosis is seen in up to 50% of patients, and has been associated with shortened survival when significantly increased.
Flow cytometry is useful in delineating and immunophenotyping the blast transformation and the accelerated phases of CML.
Blast transformation often occurs 3 -4 years after diagnosis of the chronic phase, but may be abrupt without an intervening accelerated phase, and can be seen at presentation. The presence of >20% blasts in the peripheral blood or marrow is diagnostic of CML in blast crisis.
The marrow may be focally involved by the blast process and may only be recognized in biopsy sections. Extramedullary involvement is also seen (any site, but usually LN or spleen). Blasts may show lymphoid or myeloid differentiation morphologically and immunophenotypically ( 70% are myeloid). Biphenotypic transformation is also seen.
Accelerated phase is characterized by one or more of the following: Increase in blasts < 20%; Myelofibrosis; Basophilia > 20%, Hb < 7.0 g/dL; Thrombocytopenia <100 x109/L; and Karyotypic evolution.
The clinical course of the accelerated phase is more prolonged and unpredictable than with blastic transformation
Cytogenetics/molecular:
bcr/abl, t(9;22)(q34;q11).
In 90 -95% of cases the Ph chromosome can be demonstrated by classical cytogenetics. This represents a balanced reciprocal translocation between the long arms of chromosomes 9 and 22. The derivative chromosome 22 is the Philadelphia chromosome; in the remaining 5%, the bcr/abl translocation can be demonstrated by FISH, Southern blot or reverse transcriptase-PCR methods. In some of these cases the translocation may be complex (involving other chromosomes).
The chimeric bcr/abl gene produces a fusion protein with dysregulated tyrosine kinase activity. This protein can phosphorylate several substrates resulting in the activation of multiple signal transduction pathways affecting the growth and differentiation of cells; similar to the action of cytokines on normal hematopoiesis. However the bcr/abl signal is constitutive and the affected cells escape the normal constraints of growth and differentiation.
The translocation is found in all myeloid lineage cells, but NOT in marrow fibroblasts or somatic cells.
Progression of CML to the accelerated or blast phase is often accompanied by additional karyotypic abnormalities. They include a second Philadelphia chromosome; Trisomy 8; Isochromosome for long arm of 17 {i (17q)}; Trisomy 19; and less commonly -7, -17, +17, +21, -Y, t(3;21).
Differential diagnosis
Leukemoid reactions usually have lesser degree of leucocytosis and lack the myelocyte bulge seen in CML. Additionally there is an absence of basophilia. Leukocyte alkaline phosphatase is usually elevated in leukemoid reactions, and toxic granulations and Dohle bodies are noted.
Polycythemia Vera also has a lesser degree of leukocytosis, with an increase in red cell mass and hematocrit. The Philadelphia chromosome is absent in Polycythemia vera.
Idiopathic myelofibrosis may be more difficult to distinguish from CML; but helpful features include: lack of basophilia; lesser leukocytosis and abnormal red cell morphology are more typical of idiopathic myelofibrosis.
Normoblastemia, atypical platelets and micromegakaryocytes are more frequent in the blood of patients with myelofibrosis.
Treatment and Prognosis:
Chemotherapy: Busulfan was first drug to be effective in producing hematologic remission. Hydroxyurea is equally effective but less mutagenic and has a more favorable toxicity profile than Busulfan.
Interferon: Interferon-a can produce hematologic remission, and can also eliminate the Philadelphia positive clone when assessed by classical cytogenetics. This drug is also used in combination with cytarabine.
Hematopoietic cell transplantation: This treatment modality is employed following high dose chemotherapy, and can result in long-term complete remission and a possible cure. However the number of patients who can benefit from this method is limited by the availability of suitable donors and age limits.
New Therapy: The recent introduction of STI 571 (signal transduction inhibitor) has been widely reported and has gained considerable public attention. This molecule binds to the bcr/abl protein and results in the prevention of phosphorylation of any substrate. This drug has high potency with a mild toxicity profile and is administered orally.
With conventional therapy median survival is 60 to 65 months. CML terminates in blast/accelerated phase in the majority of patients. They are treated similar to the acute leukemias, but only 30% respond, with median survival of 7 months. Non-responders survive a median of 3 months. Patients with lymphoblastic crisis have a more favorable prognosis than those with myeloblastic transformation.
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Contributed by Rajendra Persad, MD
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