Chronic Myeloid Leukemia
Chronic myeloid leukemia (CML), also known as chronic myelogenous leukemia, is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate.
In chronic myeloid leukemia (CML) there is a malignant transformation of the multipotential hematopoietic stem cells (pluripotent stem cells). There are excessive cells in the granulocytic series, primarily in the bone marrow but also in extramedullary sites (e.g. spleen, liver), although these malignant cells do differentiate nearly normally.
Although granulocyte production predominates, the neoplastic clone includes RBCs, megakaryocytes, monocytes, and even some T and B cells.
The term “chronic” in chronic myelogenous leukemia indicates that this cancer tends to progress more slowly than acute forms of leukemia.
CML accounts for about 15% of all adult leukemias. CML can strike at any age although it is uncommon before age 10, and the median age at diagnosis is 45 to 55. CML may occur in either sex.
Most cases of CML appear to be induced by a translocation known as the Philadelphia (Ph) chromosome, which is demonstrable in 95% of patients. It is a reciprocal translocation t(9;22) in which a piece of chromosome 9 containing the oncogene c-abl is translocated to chromosome 22 and fused to the gene BCR. The fusion gene BCR-ABL is important in the pathogenesis and expression of CML and results in the production of a specific tyrosine kinase.
CML has 3 phases:
- Chronic phase: An initial indolent period that may last months to years.
- Accelerated phase: Treatment failure with increasing malaise, infections and fevers, bone pain, worsening anemia, progressive thrombocytopenia or thrombocytosis, persistent or worsening splenomegaly, clonal evolution, increasing blood basophils, and increasing marrow or blood blasts.
- Blast phase: Accumulation of blasts in extramedullary sites (eg, bone, CNS, lymph nodes, skin), blasts in blood or marrow increased to > 20%. These are usually myeloblasts but lymphoid blast crisis occurs in about 20% of cases. A myelofibrotic crisis occurs in some. The blast phase leads to fulminant complications resembling those of acute leukemia, including sepsis and bleeding. Some patients progress directly from the chronic to the blast phase.
Clinical features of chronic phase CML:
There is an insidious onset of:
- Anorexia and weight loss.
- Symptoms of anemia.
- Night sweats.
- Easy bleeding.
- Splenomegaly which may be massive ± spleen pain.
- FBC reveals raised white cell count with immature forms in the blood and often increased eosinophils and basophils. Total WBC count 20,000-60,000 cells/μL.
- The Hb is often initially normal and then falls. Anemia is usually normochromic and normocytic.
- Platelet count up or down.
- The neutrophil alkaline phosphatase score is very low to absent in most cells.
- Marrow hypercellular with gross myeloid hyperplasia. Megakaryocytes are prominent and may be increased. Mild fibrosis in the reticulin stain.
- Diagnosis is confirmed by finding the Philadelphia chromosome in samples examined with cytogenetic or molecular studies, although it is absent in 5% of patients. Philadelphia chromosome (translocation of the long arm of 22 to the long arm of 9) present in 95% of cases. This results in activation of a hybrid bcr-abl proto-oncogene which can be detected by reverse transcriptase polymerase chain reaction.
The goals of treatment of chronic myelogenous leukemia (CML) are threefold and have changed markedly in the past 10 years. They are as follows:
Hematologic remission (normal FBC and physical examination ie, no organomegaly).
Cytogenetic remission (normal chromosome returns with 0% Philadelphia chromosome–positive (Ph+) cells).
Molecular remission (negative polymerase chain reaction [PCR] result for the mutational BCR/ABL mRNA), which represents an attempt for cure and prolongation of patient survival.
Treatment of CML includes the following measures:
- Supportive treatment: transfusions, treatment of infections, Allopurinol for gout.
- A Tyrosine Kinase Inhibitor (TKI), sometimes with chemotherapy.
- Sometimes stem cell transplantation.
Except when stem cell transplantation is successful, treatment is not known to be curative.
However, since the advent of tyrosine kinase inhibitors (TKIs), chronic myeloid leukemia (CML) has been transformed from a disease that was usually fatal into one in which patients have a close-to-normal life expectancy. When TKIs are used, survival is prolonged and maximum overall survival has not been reached. Some patients may be able to discontinue tyrosine kinase inhibitors and remain in remission. The durability of these remissions is as yet not known.
Imatinib (Gleevec) and several newer drugs e.g. Dasatinib (Sprycel), Nilotinib (Tasigna), Bosutinib (Bosulif) and Ponatinib (Iclusig) inhibit the specific tyrosine kinase that results from the BCR-ABL gene product.
Imatinib (Gleevec) was the first drug to specifically target the BCR-ABL tyrosine kinase protein, and it quickly became the standard treatment for CML patients. Because it was the first TKI, imatinib is known as a first generation tyrosine kinase inhibitor.
Almost all CML patients respond to treatment with imatinib, and most of these responses seem to last for many years. This drug doesn’t seem to make the leukemia go away and stay away, so patients need to take it indefinitely (or until it stops working). Imatinib is taken by mouth as a pill with food, usually once a day. Common side effects can include diarrhea, nausea, muscle pain, and fatigue. These are generally mild. About 30% of people taking the drug have itchy skin rashes. Most of these symptoms can be treated effectively, if needed. Another common side effect is fluid buildup around the eyes, feet, or abdomen. In rare cases, the fluid may collect in the lungs or around the heart, which can cause trouble breathing.
Imatinib also is superior to other treatments in the accelerated and blast phases. In the blast phase, combinations of chemotherapy with imatinib have a higher response rate than does therapy with either approach alone.
Tyrosine kinase inhibitors (TKIs) are dramatically effective in achieving complete clinical and cytogenetic remissions of Ph chromosome–positive CML and are clearly superior to other regimens (eg, interferon with or without cytarabine).
Treatment tolerance is excellent. The high level of durable complete remissions associated with TKI therapy has led to the prospect of a cure for the disease. However, the gene products of some BCR-ABL mutations are resistant to current TKIs and remain very difficult to control.
Older chemotherapy regimens are reserved for BCR-ABL negative patients, patients who relapse after receiving a TKI, and patients in the blast phase. The main agents are busulfan, hydroxyurea, and interferon. Hydroxyurea is easiest to manage and has the fewest adverse effects.
Allogeneic stem cell transplantation can be useful for patients refractory to therapy.
Although splenic radiation is rarely used, it may be helpful in refractory cases of CML or in patients with terminal disease and marked splenomegaly.
Splenectomy may alleviate abdominal discomfort, lessen thrombocytopenia, and relieve transfusion requirements when splenomegaly cannot be controlled with chemotherapy or irradiation. Splenectomy does not play a significant role during the chronic phase of CML.
CML in childhood:
This may resemble adult disease, but classical “Juvenile CML” is Philadelphia chromosome negative, and is characterized by a prominent monocytosis and a high HbF level.
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