Acute Leukaemia

Essentials of Diagnosis

  1. Weakness, malaise, anorexia, bone and joint pain.
  2. Pallor, fever, petechiae, lymph node swelling, splenomegaly.
  3. Leukocytosis; immature, abnormal white cells in peripheral blood and bone marrow.
  4. Anaemia, thrombocytopenia.

General Considerations

Acute leukaemia is a disorder of the blood-forming tissue characterized by proliferation of abnormal white cells. It is generally considered to be neoplastic, occurs in all races, and may develop at any age. Peak incidence is in the first 5 years of life.

Clinical Findings

A. Symptoms and Signs:

Presenting complaints are often general, consisting of weakness, malaise, anorexia, fever, and purpura. Pain in the joints, lymph node swelling, or excessive bleeding after dental extraction may also be initial complaints.

Petechiae are frequently seen early in the course of the disease. Spleen, liver, and lymph nodes are usually enlarged in acute lymphatic leukaemia but in less than ½ of patients with acute myeloblastic leukaemia. Sternal tenderness is common. Any organ may be involved.

B. Laboratory Findings :

Normochromic, normocytic anaemia occurs early. They platelet count is usually below 100,000/cu mm, while the white count varies from less than 10,000 to over 100,000/cu mm. One-third are leukopenic. On the blood smear immature and abnormal cells may be seen; on a thick or over-stained smear they may be mistaken for lymphocytes.

Auer bodies, redstaining rods in the cytoplasm of myeloblasts or monoblasts, occur in 10-20 per cent and are pathognomonic of acute leukemia. Acute myelocytic leukaemia may be differentiated from acute lymphocytic leukaemia by the presence of perodixase-staining cytoplasmic granules in the former.

There is massive proliferation of primitive malignant cells in the bone marrow even when leukopenia exists.

Skeletal involvement can be seen radiologically in almost all of the children and in half of the adults. Diffuse osteoporosis, periosteal elevation, osteolytic lesions, and radiolucent metaphyseal bands are the most common lesions.

Complications

Fatal gastrointestinal tract hemorrhage, pressure symptoms on the brain stem, brain hemorrhage, and overwhelming infection are the chief causes of death. Intracerebral hemorrhage occurs more frequently in patients with very high white cell counts (over 300,000/cu mm). Bacterial (pseudomonas) infections. fungal (candida and aspergillus) infections, and virus diseases such as disseminated cytomegalic inclusion dis-ease have become the major causes of death.

Differential Diagnosis

The combination of anaemia, thrombocytopenia. and bone marrow proliferation of primitive white cells is found only in leukemia. Leukocytosis may or may -not be present. Among the other features, petechiae may be seen in idiopathic thrombocytopenic purpura or in aplastic anaemia, but there is no enlargement of lymph nodes, liver, or spleen. Enlarged lymph nodes and splenomegaly may be found in infectious mono-nucleosis, Hodgkin's disease, or in lymphosarcoma but the bone marrow and peripheral red cells and platelet are usually normal. Marked lymphocytosis is, often seen in whooping cough and infectious lymphocytosis, but the white cells are mature and red cell and platelet counts are normal. Malignant tumours, eg, neuroblastoma, osteosarcoma, and metastatic cancer, may cause bone pain, anemia, and leukocytosis: if there is marrow invasion, these conditions may resemble leukaemia.

Treatment

A. Acute Lymphatic Leukaemia :

Because it is generally believed that unless every leukaemic cell in the body is destroyed the residual cells will multiply and cause a relapse. attempts are now being made to cure this disease by using multiple agents in an effort to kill all leukaemic cells. It is estimated that the total burden of malignant cells when leukaemia first presents clinically is in the neighborhood of 1012-1013 cells. Initial therapy will reduce that to 109 cells, which results in an apparent clinical and haematologic remission, ie, the marrow will appear normal. Consolidation therapy will reduce the total number of leukaemic cells to 106 or fewer. As the total burden of cells decreases, it becomes more difficult to treat the leukaemic cells without damaging normal cells.

It is not clear whether the body's own immunologic defenses can cope with this residue or whether additional aggressive chemotherapy is required. Multiple drug therapy attacks the leukaemic cells in different phases of the mitotic cycle. Vincristine arrests cells in mitosis, prednisone lyses lymphoblasts in their resting phases or prevents their entry into DNA synthesis, mercaptopurine inhibits DNA synthesis, and methotrexate inhibits DNA, RNA, and protein synthesis. Use of these drugs sequentially or in combination also avoids drug resis-tance to a large extent and improves the chances of destroying the leukemic cells that are in a "resting phase" (ie, nondividing) and are usually relatively insensitive to chemotherapy. Finally, prophylactic therapy to the CNS eradicates foci of malignant cells in "sanctuaries" not reached by systemic therapy.

The current schemes of multiple drug therapy and prophylactic CNS treatment as compared to single drug treatment have a considerably higher morbidity, are more costly, and often remove patients from their home environment for longer periods of time. In deciding which approach to use, the physician must weigh these problems against the chance of prolonging survival.

The following regimen incorporates most of the above considerations:

  1. For rapid initial remission-

    a. Vincristine (Oncovin®), 0.05 mg/kg (2 mg/sq m) IV once a week for 4 weeks, plus--
    b. Prednisone, 1 mg/kg (40 mg/sq m) orally daily.

  2. For consolidation and further distribution of drug- Methotrexate, 15 mg/sq m orally twice a week.
  3. To destroy residual leukaemic blood in CNS- Radiation to cerebrospinal axis, 2400 r.
  4. Prolonged maintenance- Mercaptopurine, 2.5 mg/kg daily orally, or methotrexate, 15 mg/sq m twice a week orally, or cyclophosphamide, 200 mg/sq m weekly orally.
  5. Management of relapses- Acute relapses may be treated with vincristine and prednisone, above, or cytarabine (Cytosat®), 50-100 mg daily IV for 4 days, or daunomycin, 1 mg/kg IV daily for 4 days.

B. Acute Myeloblastic Leukaemia:

This is usually a disease of adults. The objective of therapy is prolonged remission since cure is not possible at present. The reasons for multiple drug therapy are similar to those that justify similar treatment of acute lymphatic leuke-mia, but the effective agents are different. Many schemes have been used. Intermittent therapy is in favor at present because it appears to minimize toxic suppression of normal cells. The following 2 regimens are most widely used in current practice:

1 . Cytarabine and Thioguanine

a. Cytarabine, 2-3 mg/kg IV daily in 2 divided doses 12 hours apart for 4 days, plus- -

b. Thioguanine, 2.5 mg/kg orally daily in 2 divid-ed doses 12 hours apart for 4 days; repeat every 2 weeks.

2. "COAP"- This is a very vigorous regimen used in some centers. Give cyclophosphamide (Cytoxan®), 100 mg/sq m orally daily for 4 days; vincristine (Onco-vin®), 2 mg IV once only; cytarabine (Cytosar®, Ara-C), 100 mg/sq m orally daily for 4 days; and prednisone, 200 mg orally daily. Cycles are repeated every 2 weeks.

3. Other agents- Other agents that have been used in the treatment of acute myeloblastic leukemia in-clude mercaptopurine (Purinethol®), 2.5 mg orally daily; vincristine (Oncovin®), 0.05 mg IV once a week; daunomycin, 1-2 mg/kg orally daily for 4 days; and cyclophosphamide (Cytoxan®), 100-150 mg/sq m IV daily for 4 days. For maintenance, one may use mercaptopurine, 2.5 mg/kg orally daily.

C. Treatment of Complications:

  1. Local manifestations- Severe bone pain, massive lymph node enlargement interfering with respirations and swallowing, and CNS involvement with signs of increased intracranial pressure may be treated successfully with local irradiation. Intrathecal methotrexate. 5 mg dissolved in 10 ml of spinal fluid adminis-tered every 3 days until the spinal fluid is clear, may be a valuable adjunct to oral or intramuscular methotrex-ate.
  2. Fever- In adult patients with leukemia, bacterial infection is ultimately proved in 75 per cent, of cases to be the cause of febrile episodes. Septicemia and infections of the throat, lungs, skin, urinary tract, and anorectal area are the usual causes. Gram-negative organisms- especially pseudomonas, but also Escherichia coli, klebsiella, proteus, and bacteroides-are frequently identified. In a patient with adequate circulating granu-locyte levels, one may use gentamicin, 3-5 mg/kg/day every 8 hours IM or IV, plus cephalothin (Keflin®), 20-80 mg/kg/day every 6 hours IV. In patients with significant granulocytopenia, one may use carbenicillin, 20 gm/sq m/day given every 4 hours 1V, plus cephalothin, 20-80 mg/kg/day every 6 hours IV. These drugs can be, mixed in the intravenous infusion bottle and should be given over periods of one-half to 1 hour. Fungal infections and infections with Pneumocystis carinii may also occur in the compromised host and call for specific management.
  3. Hemorrhage- For patients with severe throm-bocytopenia and bleeding, platelet concentrates should be given to raise the platelet count to at least 60,000/cu mm. To estimate dosage, assume that 1 unit will raise the count of a 70 kg subject by 10,000/cu mm.
  4. Hyperuricemia - Allopurinol, which inhibits the formation of uric acid, should be administered to patients with high uric acid or high white count along with chemotherapy. A high fluid intake is also impor-tant. The usual dose of allopurinol (Zyloprim®) is 100 mg 3-4 times daily. The dose of mercaptopurine must be reduced to 25-35 per cent of the usual dose when allo-purinol is being given.

Prognosis

A. Acute Lymphatic Leukemia:

Over 90 per cent of patients under 20 years of age treated as above can be brought into a state of remission. The mean duration of remissions is 1-3 years. Using the above approach or some variation of it, survival for several years can now be achieved in 15 -25 per cent of all patients.

B. Acute Myeloblastic Leukaemia:

Up to 50 per cent of patients with acute myeloblastic leukaemia will achieve remissions on the above 2 regimens. The median duration of remissions is 1 year or less, but survivals of several years occur occasionally.

Chronic Myelocytic Leukaemia

Essentials of Diagnosis

General Considerations

Chronic leukaemia is characterized by proliferation of abnormal white cells, which invade the blood stream and may infiltrate any part of the body to cause local symptoms. It is inevitably fatal.

In addition to their immaturity, leukaemic cells have certain distinguishing biochemical characteristics. Leukaemic neutrophilic cells have less glycogen and alkaline phosphatase than normal or polycythemia white cells, whereas their histamine content is higher. Many of the immature myeloid cells in blood and marrow characteristically show the so-called Philadelphia chromosome, an abnormally small autosome.

Chronic myelocytic leukaemia is primarily a disease of young adults, but it may be found at any age.

Clinical Findings

A. Symptoms and Signs:

Pallor, weakness, sternal tenderness, fever, purpura, skin nodules, and retinal haemorrhages or exudate may be seen. There may be abdominal discomfort secondary to splenomegaly. Gum bleeding after dental extraction, or large ecchymoses or muscle bleeding after traumapre manifestations of thrombasthenia-may be the presenting sign.

Some patients are diagnosed accidentally before the onset of symptoms when a high white count is found during a routine examination.

B. Laboratory Findings:

The white count may ex-ceed 500,000/cu mm, but fewer than 5 per cent of the cells are "blasts." Nonfilamented neutrophils, metamyelo-cytes, and myelocytes predominate; the neutrophils are alkaline phosphatase negative; basophils, eosinophils, and platelets are increased; and a few normoblasts may be seen. Some degree of anaemia is common. The marrow shows complete replacement of fat by cellular elements, mostly granulocytes, but few blasts.

Differential Diagnosis

In leukaemoid reactions due to infection or metastatic cancer, eosinophils and basophils are decreased rather thawr increased, the leukocyte alkaline phosphatase is strongly positive, and the marrow is only moderately hyperplastic. In myelofibrosis, the spleen may be quite large but leukocytosis only moderate; the marrow is fibrotic, the granulocytes are usually alkaline phosphatase positive; and the Philadelphia chromosome is not seen.

Complications

Probably no part of the body is exempt from leukemic infiltration. Complications will depend upon the area infiltrated, eg, pressure symptoms or hemorrhage if the CNS is infiltrated. The spleen may become very large and painful. Half of the patients die in a "blastic" crisis.

Treatment

A. General Measures:

The aim of therapy is pallia-tion of symptoms and correction of anemia. Initial manifestations and each exacerbation should treated promptly. Specific treatment of the anemia is unnecessary, as it is usually corrected by treatment directed at the leukemic process. Blood counts are checked weekly at first and then once or twice a month until a satisfactory remission is obtained. During remission patients are encouraged to resume normal activity, but follow-up visits are necessary every 1-3 months. The nature of the disease should be explained to the patient and the necessity for periodic -observation and lifelong treatment should be impressed upon him.

B. Irradiation :

X-ray therapy consists of total body irradiation or local therapy to the spleen, liver, or local infiltrates. (X-ray therapy localized to the spleen has a beneficial general effect on the hematopoietic system by mechanisms which are still unknown. Localized high-voltage x-ray over the spleen in doses of 50-100 R daily until a total of 600 R has been given is usually sufficient for clinical hematologic remission.) X-ray therapy (by a radiologist) is given over a period of a few weeks. X-ray is most effective in the treatment of local manifestations.

The results of treatment with radiophosphorus (32P) are comparable to those of total body irradiation; it is less effective in the treatment of local manifestations. There is no radiation sickness. The dosage of 32P depends upon the degree of leukocytosis. One mCi (millicurie) is equivalent to 15 R. If the white count is above 50,000/cu mm, the initial dosage of 32P is 1-2.5 mCi IV; 2 weeks later. 1-1.5 mCi are given. Similar doses are given every 2 weeks until the white count is less than 20.000. During remission patients are seen every 1-3 months. When the white count rises above 25,000, an additional 1-1.5 mCi are given.

C. Chemotherapy:

Busulfan (Myleran®), an alkyl-ating agent, is the drug of choice. Initial dosage is 2 mg 2-4 times daily, continued until the white count is less than 10,000/cu mm. As a rule the white count begins to drop within a week and normal values are reached in 4-6 weeks. When the white count reaches about 10,000/cu mm the drug may be discontinued, or administered intermittently. Remissions may last for several months to more than a year. When relapse occurs, a course of busulfan may be repeated. Overtreatment results in general depression of myelopoiesis; irreversible thrombocytopenia may develop. Since thrombo-cytopenia may occur before any significant drop in hemoglobin, platelet counts should always be done as part of the routine count. The drug should be withheld if platelet values are below normal.

Melphalan (Alkeran®) is also quite effective. Mer-captopurine (Purinethol®) is used for blastic crises.

Prognosis

The average life expectancy in chronic myelocytic leukemia is about 3-4 years. With appropriate therapy the course is frequently remittent, with periods of months during which the patient is free of symptoms.

Chronic Lymphatic Leukemia

Essentials of Diagnosis

General Considerations

This disorder involves progressive accumulation of aged, small lymphocytes which have lost the capacity to divide. The life span of these metabolically abnormal cells may be considerably lengthened to several years; the total body lymphocyte mass expands considerably, and may reach enormous proportions. The cells, which originate in lymph nodes, aggregate chiefly in the lymph nodes, spleen, blood, and marrow. The decline in levels of immunoglobulins commonly observed during the course of the disease may represent the replacement of normal, immunologic competent cells by cells that are functionally inert and have lost the ability to react to antigenic stimuli. These lymphocytes have a strikingly low mitotic rate.

The disorder may remain relatively quiescent for several years, free of symptoms and signs and with relatively stable lymphocyte counts; or it may become progressive, with various clinical manifestations and a rising blood count.

Chronic lymphatic leukemia is rare under the age of 30 and extremely rare in Orientals.

Clinical Findings


A. Symptoms and Signs:

The onset is insidious, and the diagnosis is usually made accidentally during routine examination. Weakness and symptoms of hypermetabolism may be present. Enlarged lymph nodes may cause pressure symptoms (eg, tracheal compression with respiratory difficulty). The spleen, liver, and lymph nodes are not tender.

B. Laboratory Findings:

At the time of diagnosis, the hemoglobin may be normal. Anemia develops as the disease progresses. Lymphocytosis usually precedes the rise in total white count. Eventually, the white count rises and may reach 100-500 thousand/cu mm. Over 90 per cent of the cells are mature lymphocytes; "smudge" cells are common. The platelet count tends to be below normal. Early in the disease, the marrow architecture may be normal; lymphocytes make up more than 30 per cent of cells.

Differential Diagnosis

Similar lymph node enlargement may be seen in lymphosarcoma and infectious mononucleosis. Differentiation is usually readily made on the basis of the blood smear.

Lymphocyte counts of 50-100 thousand/cu mm may be seen in children with whooping cough or infectious lymphocytosis. Lymphatic leukemoid reactions of moderate degree (with white counts of 20-30 thousand/cu mm) are occasionally seen with tuberculosis. Diffuse lymph gland enlargement may be found in lymphosarcoma and infectious mononucleosis, and rarely in tuberculosis, syphilis, carcinomatosis, hyperthyroidism, brucellosis, lupus erythematosus, and toxoplasmosis. In Hodgkin's disease, lymph node enlargement is usually asymmetric or only in a single site.

Complications

Severe hemolytic anemia, frequently with a positive Coombs test, develops in one-third of the patients. Thirty percent of patients have hypogammaglobu-linemia and may be susceptible to infection.

Treatment

A. General Measures:

It may be desirable to with-hold therapy until clinical manifestations appear or until hematologic complications develop. Many older patients with this disorder remain relatively asymptomatic despite high leukocyte levels. All symptomatic patients and all patients with anemia or thrombocytopenia must be treated.

B. Irradiation:

As for chronic myelocytic leukaemia, but systemic control with splenic radiation is less frequent.

C. Chemotherapy:

  1. Chlorambucil (Leukeran®) is widely used. The dosage is 0.1-0.2 mg/kg daily in divided doses after meals. Clinical and hematologic improvement may not be evident for 3-4 weeks and maximum improvement may not be achieved for 2-4 months. When the white count falls below 25,000/cu mm, the dose should be reduced, usually to a maintenance level of 2-4 mg daily. The drug should be discontinued when the white count falls to 5000-10,000/cu mm. Side effects are relatively uncommon, although gastrointestinal irritation occurs. Pancytopenia may develop, but recovery usually occurs when the drug is discontinued.
  2. Triethylenemelamine (TEM), 2.5-5 mg in a single dose on an empty stomach with 1-2 gm of sodium bicarbonate, is a useful alkylating agent. It has the advantage of simplicity of administration, but the effects are less predictable than with other agents.
  3. Cyclophosphamide (Cytoxan®), 50-100 mg orally 1-3 times daily, causes less platelet depression than other agents and may be used when other agents have produced thrombocytopenia.

D. Corticosteroids:

Some patients respond well to relatively small doses of corticosteroids. Initially one may give prednisone (or equivalent), 40 mg daily until a response occurs; maintenance may be as little as 10-20 mg every 48 hours.

E. Treatment of Complications:

  1. Anaemia- Anaemia is caused by a combination of 2 factors: increased rate of red cell destruction and inadequate bone marrow compensation. It often fails to respond to antileukemic therapy and transfusions have to be given. Prednisolone (or equivalent), 10-20 mg 4 times daily, is usually required. With remission of the anemia, corticosteroids may be gradually withdrawn. With severe hemolytic anemia and splenic sequestration of the red cells, splenectomy may have to be considered. Intercurrent anemia due to blood loss and iron deficiency is treated with iron.
  2. Haemorrhage- Abnormal bleeding in leukemia is usually due to thrombocytopenia, which may be sec-ondary to either the Ieukemic process or to therapy. If due to the leukemia, it may be improved by appropriate chemotherapy; if due to chemotherapy, the marrow-depressing drugs must be discontinued and corticosteroid therapy instituted until the marrow has had a chance to recover.
  3. Infections- Infections are treated with specific antibiotics. Prophylactic use of antibiotics is not recommended. Some patients develop low levels of gamma globulin. with gamma globulin levels of 0.7 gm/100 ml or less, prophylactic gamma globulin is needed. Initially, 0.3 ml/lb is given in divided doses of 5 ml each; a maintenance dose of half this amount is administered once or twice a month.

Prognosis

The average life expectancy in chronic lymphatic leukemia is about 3-4 years. Most patients respond well to chemotherapy or x-ray therapy, and long periods of remission are the rule.

There is a group of patients with this disorder, usually the more elderly ones, in whom the disease remains relatively inactive without treatment, sometimes for many years.

Adopted form the Clinical Management of Leukemia, Hant A wintrobe MM.

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