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Clinical Manifestations, Diagnosis And The Treatment Plan Of Chronic Myeloid Leukemia (CML)

Updated on January 21, 2014

Splenomegaly In Leukemia

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Clinical Features And Complications

Clinical features

The disease is insidious in onset and it is almost impossible to assess the duration of illness when the patient comes up for examination. Some asymptomatic cases are picked up by routine blood tests. Majority of cases present with the feeling of a mass and dull ache in the abdomen caused by splenomegaly. The spleen is grossly enlarged in over 95% of cases. The total leukocyte count and the size of the spleen generally correspond with each other. Gross splenomegaly is associated with episodes of splenic infarction which present as painful episodes. Some cases reveal bone tenderness. Pallor, exertional dyspnea, andtachycardia may occur due to moderate or severe anemia. Hypermetabolism leads to loss of weight, lassitude and night sweats.

With advancement of the disorder, the abdomen becomes distended due to hepatosplenomegaly. Nutritional deficiencies, cachexia and intercurrent infections complicate the picture. When the leukocyte count is high, the ocular fundus shows hyperemia of the disc, venous engorgement and occasionally hemorrhages.

Complications

Complications may occur from time to time. These are infections, anemia, trauma, infarction of the spleen and secondary gout. Thrombotic tendencies develop resulting in deep venous thrombosis and priapism. Hemorrhagic complications may also occur.

The most serious and inescapable complication is the development of blastic transformation after periods ranging from months to years after diagnosis. Blastic transformation is heralded by unresponsiveness to conventional treatment and the development of severe anemia, fever, infections, lymphadenopathy and rapid deterioration of general health. In 75% of cases, the blood picture is myeloid and in 25%, lymphatic leukemia. Extramedullary tumours, consisting of myeloblasts may develop especially in the bones, lymph node and skin. The peripheral blood count and the proportion of blast cells increase. The blast crisis is brought about by the proliferation of a genetically altered clone of neoplastic cells derived from the Ph’ cells. Additional chromosomal abnormalities such as aneuploidy may develop. In the blastic stage, the prognosis is that of AML, but response to therapy is less satisfactory than primary AML. Response of ALL to treatment is more satisfactory. A few cases may develop secondary myelosclerosis.

Diagnosed Of Leukemia

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Diagnosis

CML should be suspected when there is gross leukocytosis with splenomegaly in the presence of a reasonably good general health. Other causes of splenomegaly such as portal hypertension, chronic malaria, leishmaniasis, thalassemias and hemolytic anemias should be considered in the differential diagnosis, but blood smear examination excludes them. Leukemoid reactions should be excluded. When the diagnosis is in doubt, demonstration of the Ph’ chromosome is diagnostic of CML. Leukocyte alkaline phosphatase score is low in CML, whereas in leukemoid reactions, it is high. Myelofibrosis may have to be distinguished from CML. Myelofibrosis is characterized by gross splenomegaly and a leuko-erythroblastic picture. Bone marrow is scanty and trephine biopsy reveals fibrosis.

Course And Prognosis

Chronic myeloid leukemia runs a relentless course to end fatally in all cases. Unlike as in acute leukemia, medical therapy does not bring about a cure. Untreated, the average period of survival is 2-3 years. Treatment given early in the disease brings about clinical relief and clears the blood picture, but the disease is not eradicated and therefore relapse is the rule. About 20% patients survive up to 10 years. Death is due to blastic transformation, infection, hemorrhage or rarely drug toxicity. Presence of Philadelphia chromosome confers a better prognosis. Philadelphia positive cases do better and live longer with an average period of survival of 4 years whereas, Philadelphia negative cases invariably run a downhill course and die within one year. Philadelphia chromosome negative cases have been termed as atypical CML and most of these occur in children.

Radiation Therapy In Leukemia Treatment

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Radiation Therapy

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Leukemia Drugs

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Treatment

Since conventional medical therapy does not eradicate the disease, the aim is to relieve symptoms and bring about clinical normalcy. The high leucocyte count and organomegaly subside completely with treatment and the patient becomes asymptomatic though a few abnormal cells and the Philadelphia chromosomes persist.

Drugs

Drug of choice is busulphan (myeleran) which is an alkylating agent belonging to the group of sulphur mustards. It is given orally in the dose of 2-8 mg/day. Blood counts are done at weekly intervals. By 2-3 weeks, the total leucocyte count starts falling. At this stage, the dose is reduced and continued till the total leukocyte count falls below 10,000/cmm and the splenomegaly disappears. In the majority of cases, this is achieved when the total dose reaches 200-220 mg of busulphan. Once the leukocyte count fall below 10,000/cmm, busulphan is withdrawn to avoid marrow depression. Further treatment is indicated when the total leukocyte count goes above 50,000/cmm. Busulphan is effective in over 75% of cases. Relapses also respond to busulphan, but with the passage of time, the response becomes less satisfactory and the duration of clinical remission progressively shortens. Adverse side effects include bone marrow aplasia, allergic manifestations and pigmentation resembling Addison’s disease, but without the endocrine abnormalities. Busulphan rarely produces extrinsic alveolitis and interstitial pulmonary fibrosis (busulphan lung). This is in absolute contraindication for further busulphan therapy.

Another drug which is also used widely is hydroxyurea given in a dose of 0.5- 1g/day orally. The fall in leukocyte count is slow but steady. The drug has to be given continuously. Since drug therapy serves only to bring about clinical relief without significantly improving the course and final outcome, other more intensive regimen have been devised. These include 6-mercaptopurine (6MP), 50 mg or 6-thioguanine, 80 mg/daily along with busulphan 2 mg/day. Another regimen is to give busulphan in intermittent high doses given for 5 days in a week. This brings down the leukocyte count rapidly. Other regimen including drugs like dibromomannitol are under trial. Since busulphan is not so available freely, melphalan has been tried. Results are comparable to that of busulphan.

Splenic Irradiation

This is a time-honoured modality of therapy for CML. Irradiation with a total dose of 100-200 rads brings about clinical and hematological relief. As in the case of busulphan therapy, the patient remains asymptomatic for a few months to a few years to relapse again. Further irradiation is effective.

Splenectomy

This procedure has been suggested in CML to prolong the average period of survival and make the patient responsive to treatment, but the results are equivocal. Leucapheresis using a cell separator may be temporarily beneficial in hyperviscosity state and may be required when the total leukocyte count exceeds 300- 400,000/cmm. The procedure may also bring about temporary remission.

Bone marrow transplantation (autologous blood or marrow)

This is now being tried in a larger number of patients who are in clinical remission and are less responsive to conventional therapy. The patient’s own leukocytes and stem cells can be collected when he is in the CML phase and preserved over several years, to be reinfused when he gets into acute transformation and becomes refractory to treatment. Another method is to infuse homologous bone marrow from HLA matched donors. Results of transplantation are encouraging and this modality is being extended to more cases at present. Best results are obtained when transplantation is done in the chronic phase itself.

© 2014 Funom Theophilus Makama

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