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Acute Leukemia

Most adults with acute leukemia have the non-lymphocytic type (85%) with a minority being lymphocytic. This contrasts with the pediatric experience where most children have acute lymphocytic leukemia. The distinction between the types of leukemia is based on classical morphological features supplemented by analysis of cell-surface antigens and of genetic alterations acute leukemia, lukemia

Acute Non-lymphocytic Leukemia

1) FAB Classification

Cases of non-lymphocytic leukemia are usually classified according to the FAB system (French-American-British). The seven categories are:

M1 - Undifferentiated myeloblasts

M2 - Myeloblasts with differentiation

M3 - Promyelocytic leukemia

M4 - Myelomonocytic leukemia

M5 - Monocytic leukemia

M6 - Erythroleukemia

M7 - Megakaryocytic leukemia

Some of the FAB subtypes have characteristic clinical features. For example, M3 (acute promyelocytic leukemia) is associated with disseminated intravascular coagulation due to release of procoagulant materials from the abundant cytoplasmic granules. Patients with M5 (acute monocytic leukemia) may have infiltration of tissues with monoblasts. One typical site is the gums which give a picture of gingival hyperplasia.

2) Genetic Abnormalities

Genetic abnormalities are a common feature of acute leukemia and are considered to be of etiological significance. About 25 % of cases of acute myeloid leukemia will have point mutations of the k-ras oncogene in the malignant cells. Chromosomal abnormalities can be identified in the leukemic cells of a high percentage of patients and in some cases are associated with characteristic clinical features. Patients with M3 leukemia have a

Recently investigators have reported that the section of chromosome 16 involved in the inversion contains a gene for multi-drag resistance, suggesting that inactivation of this gene makes the leukemia cells more sensitive to chemotherapy. Deletions of chromosome 5q and 7q are particularly common

3) Clinical Features

The common clinical features of acute leukemia are due to bone marrow failure. Anemia is frequent and may be dealt with easily on a short-term basis with packed red cell transfusions. More difficult problems develop due to thrombocytopenia and granulocytopenia.

a) Infections

The incidence of bacterial infections is directly related to the level of the granulocyte count. With more than 1,000 granulocytes per mm3 patients do not have an increased incidence of infections. However, as the granulocyte count falls below that threshold, the frequency of infection rises. Patient who become febrile in the setting of leukopenia require a careful history, a physical examination with emphasis on subtle signs of 

b) Coagulopathies

As noted above, patients with M3 leukemia (acute promyelocytic) may have DIC. However, most leukemic patients have bleeding complications related to the decreased number of platelets. The bleeding time should be normal with a platelet count of over 100,000/dL, assuming normal platelet

c) Leukostasis

Patients who have marked leukocytosis (greater than 100,000 blast cells/dL) may develop a leukostasis syndrome due to sludging of the blast cells in the microcirculation. Complications of the syndrome include intracranial hemorrhage and respiratory failure. Leukostasis is a medical ontology

4) Therapy

Patients with acute non-lymphocytic leukemia are commonly treated with induction therapy consisting of an anthracycline (daunorubicin or idarubicin) and cytosine arabinoside. Most patients will go into a complete remission after one or two cycles of therapy. Once the patient is in complete remission, additional therapy is usually administered in an effort to prolong the disease free period. Different programs can be employed including additional courses of daunorubicin and cytosine arabinoside, high dose cytosine arabinoside, or high dose chemotherapy followed by autologous or allogeneic stem cell reinfusion. Allogeneic transplantation is generally limited to younger patients (under 40) who have an HLA matched sibling. The ideal form of consolidation therapy is still under evaluation. The five year survival for younger patients (under 60) with acute leukemia is about 20%. The results in treating older patients (over 60) are generally poor with a high death rate during intensive induction and

Patients with M3 (acute promyelocytic) leukemia may go into remission when treated with all-trans retinoic acid. This agent appears to cause maturation of the immature myeloid cells. Available studies indicate that remissions induced with all-tram retinoic acid alone are of brief duration due to development of tolerance to the agent. Thus, conventional chemotherapy should also be employed. Current clinical trials are evaluating the optimal method for combining the two therapies. Marked leukocytosis may occur following initiation of treatment with all-tram retinoic acid and result in the "retinoic acid syndrome" which can include respiratory failure. Early therapy with corticosteroids may help prevent the development of this

Secondary Acute Myeloid Leukemia

With the increasing use of cancer chemotherapeutic agents, more complications are being observed. A significant, and frequently lethal one is acute myeloid leukemia. Two patterns of leukemia have been observed. Patients who were treated with alkylating agents (eg, cyclophosphamide) may develop an M6 or M7 form of acute leukemia after a latency period of four to six years. Frank leukemia may be preceded by a period of myelodysplasia. Cytogenetic studies demonstrate deletions involving chromosome 5q and 7q. Patients who were treated with topoisomerase directed drugs (eg, etoposide, anthracyclines) may develop a monocytic leukemia (M4 or M5) without a period of myelodysplasia within one to

Acute Lymphocytic Leukemia

The minority of cases of acute leukemia in adults are of lymphocytic origin.

1) FAB Classification

The FAB system is also applied to classifying lymphocytic leukemia with three groups being identified:

L1 - Small cells with high nuclear to cytoplasmic ratio and small or no nucleoli. Monomorphic population.

L2 - Larger cells with lower nuclear to cytoplasmic ratio and prominent nucleolus. Heterogenous population.

4) Therapy

Treatment in the induction phase of ALL usually includes daunorubicin, vincristine and prednisone. Some protocols include L-asparaginase and other chemotherapeutic agents. Prophylactic treatment to prevent central nervous system relapse is usually administered, especially to patients deemed at high risk for this complication. Most regimens incorporate intrathecal methotrexate. Patients usually receive remission maintenance therapy. The

Chronic Leukemia

Chronic Granulocytic Leukemia

Chronic granulocytic leukemia is one of the myeloproliferative disorders. The peak incidence is in middle-age.

1) Genetic Abnormalities

A cardinal feature of chronic granulocytic leukemia is the presence of a reciprocal translocation between chromosome 9 and 22 ("Philadelphia chromosome"). The involved area on chromosome 9 codes for the abl oncogene while the region on chromosome 22 is called the "breakpoint cluster region" usually abbreviated as "bcr." As a result of the translocation, a messenger RNA is transcribed that contains of information from both genes. The protein product is a tyrosine kinase of molecular weight 210 kilodaltons. It is likely that this abnormal protein kinase has a pathophysiological role in the development of CML. This is suggested by experiments in which the gene produced by this translocation is transfected into mouse hematopoietic stem cells and then these cells transplanted back into the mice. A proportion of the mice develop an illness that is similar to CML in humans. The translocation between chromosomes 9 and 22 is also seen in acute lymphoblastic leukemia (see above section) with the translocation involving a different section of the bcr gene. The result is a tyrosine kinase of molecular weight 185 kilodaltons. Its role in the development of leukemia is being explored.

2) Clinical Features

Patients with chronic granulocytic leukemia may present with:

1. Leukocytosis discovered on an "incidental" blood count.

2. Non-specific symptoms such as night sweats, fatigue or weight loss.

3. Left upper quadrant fullness, pain or discomfort.

Almost all patients will have splenomegaly on physical examination. They have a leukocytosis with the differential white count showing a shift to the left ("bone marrow in the blood") and an increase in basophils and eosinophils. The cells have a decrease in alkaline phosphatase.

3) Therapy

Chronic myelogenous leukemia is not cured with standard therapy. Most patients respond to chemotherapy (usually hydroxyurea) with a resolution in symptoms, decrease in spleen size, decrease in white cell count and increase in hematocrit. However, stem cells containing the Philadelphia chromosome continue to be present in the bone marrow. Randomized controlled trials have demonstrated an improved survival by combining chemotherapy with alpha-interferon.

Younger patients (generally under age 50) with an HLA matched donor should be offered bone marrow transplantation as an

Chronic Lymphoid Leukemias

Chronic Lymphocytic Leukemia

Patients with chronic lymphocytic leukemia have a persistent lymphocytosis (often defined as a monoclonal population of more than 5,000 lymphocytes/dL). Morphologically the peripheral blood smear shows a uniform population of cells which appear to be "mature" small lymphocytes. Immunophenotyping studies demonstrate that almost all cases involve B lymphocytes with a characteristic surface membrane structure including positivity to CD5 monoclonal antibodies.

1) Staging

Several staging systems have been proposed. One which is commonly used in the United States is called the Rai system.

Stage 0 - Lymphocytosis only.

Stage I - Lymphocytosis and lymphadenopathy

Stage II - Hepatosplenomegaly

Stage III - Anemia

Stage IV - Thrombocytopenia

The prognosis becomes progressively worse as the stage advances with a median survival of more than ten years for patients in Stage 0 to less than two years for Stage IV.

2) Genetic Abnormalities

Chromosomal abnormalities are common in patients with CLL. Trisomy of chromosome 12 is the most frequent f'mding, being present in over half of the patients. Breakpoints involving chromosomes 13q and 14q have been described. The significance in terms of the genes involved is being addressed. The prognosis is better for patients who have no chromosomal abnormalities.

3) Clinical Features

Clinical problems develop due to the effects of lymphadenopathy as well as complications from anemia and thrombocytopenia. The mechanisms for anemia and thrombocytopenia may be marrow failure from infiltration by CLL cells or immune mediated from antibody formation. Infections with bacteria such as Strep. pneumoniae and Hemophilus influenzae result from hypogammaglobulinemia which is another complications of CLL. Intravenous immunoglobulin has not been beneficial on a routine basis.

Patients with CLL may develop other malignancies. In some patients, a non-Hodgkins lymphoma occurs (Richter's syndrome). In other patients prolymphocytic leukemia, lymphoblastic lymphoma or multiple myeloma, may supervene.

4) Therapy

CLL is not a curable type of leukemia. Since the goals of therapy are primarily palliative, the timing of the initiation of therapy is controversial. It is probably reasonable to start therapy when lymphadenopathy causes symptoms or unacceptable cosmetic effects. Patients are usually treated once

T-Cell Leukemia-Lymphoma

Infection with HTLV-1 is related to the etiology of T-cell leukemia-lymphoma. Endemic areas include the Caribbean basin and southern Japan. Only a small percentage of patients who have evidence of a previous infection develop this malignancy. The clinical features include fever, skin rashes and hypercalcemia with lytic bone lesions. The latter complication is due to production of PTHrP by the malignant cells. Abnormal lymphoid cells with a lobulated nucleus may be identified in the peripheral blood. Patients in the leukemic or lymphoma phase of the illness respond poorly to conventional chemotherapy. Recent reports have described better responses with a combination of AZT and interferon.

Prolymphocytic Leukemia

Clinical features of prolymphocytic leukemia include marked splenomegaly, and leukocytosis with cells that are larger than those in CLL and have a prominent nucleolus. The course is shorter than CLL and the patients do not respond to chlorambucil and require combination chemotherapy. Some patients respond to fludarabine.

Hairy Cell Leukemia

Hairy cell leukemia occurs in older men. Symptoms result from splenomegaly and cytopenia. Characteristically the cells in the peripheral blood have lymphoid nuclei with fine cytoplasmic projections ("hairs"). They contain tartrate resistant acid phosphatase. The cells are in the B cell lineage. Bone marrow aspiration may be unsuccessful because the marrow is packed with malignant cells. In these cases a biopsy is necessary to assess marrow