LEUKEMIAS H.A. MWAKYOMA, MD

LEUKEMIAS Background. Leukemias are a group of heterogeneous neoplastic disorders of white blood cells. Based on their origin, myeloid or lymphoid, They can be divided into 2 types. Leukemias traditionally have been designated as acute - Acute leukemias usually present with hemorrhage, anemia, infection, or infiltration of organs OR chronic, based on their untreated course.

LEUKEMIAS- Background---cont Many patients with chronic leukemias are asymptomatic. Other leukemias present with splenomegaly, fever, weight loss, malaise, frequent infections, bleeding, thrombosis, or lymphadenopathy. Some chronic leukemias enter a blast phase where the clinical manifestations are similar to the acute leukemias.

Classification Clinically and pathologically, leukemia is subdivided into a variety of large groups. The first division is between its acute and chronic forms: ACUTE: Acute lymphoblastic leukemia (ALL) Acute myelogenous leukemia (AML) (or myeloblastic) CHRONIC: Chronic lymphocytic leukemia (CLL) Chronic myelogenous leukemia (CML)

Pathophysiology In leukemias, a clone of malignant cells may arise at any stage of maturation, that is, in the lymphoid, myeloid, or pluripotential stage. The cause for this clonal expansion is poorly understood in most cases, but it appears to involve some rearrangement of the DNA. External factors, such as alkylating drugs, ionizing radiation, and chemicals, and internal factors, such as chromosomal abnormalities, lead to DNA changes

Pathophysiology—cont--- Chromosomal rearrangements may alter the structure or regulation of cellular oncogenes. For instance, in the B-cell lymphocytic leukemias, chromosomal translocations may put the genes that normally regulate heavy and light chain immunoglobulin synthesis next to the genes that regulate normal cellular activation and proliferation. This results in proliferation of lymphoblasts.

Pathophysiology—cont--- As the population of cells expands, the bone marrow starts to fail. Pancytopenia is typical and results in part from the physical replacement of normal marrow elements by the immature cells. In addition, the abnormal cells may secrete factors that inhibit normal hematopoiesis.

Pathophysiology—cont--- As the bone marrow becomes replaced, the abnormal cells spill into the circulation and infiltrate other organs, such as the liver, the spleen, and the eye. The ocular manifestations may be secondary to direct infiltration of the leukemic cells, as a result of abnormal systemic hematological parameters, opportunistic infections, or iatrogenic complications arising from chemotherapy.

Acute lymphocytic leukemia (ALL) Is a malignant clonal disorder of the bone marrow lymphopoietic precursor cells. In ALL, progressive medullary and extramedullary accumulations of lymphoblasts are present that lack the potential for differentiation and maturation. An inhibition of the normal development of hematopoietic cell elements occurs.

Acute lymphocytic leukemia (ALL) The clinical presentation is dominated by progressive weakness and fatigue secondary to anemia, infection secondary to leukopenia, and bleeding secondary to thrombocytopenia. When 50% of the bone marrow is replaced, then peripheral blood cytopenias are observed.

Acute lymphoblastic leukemia (ALL) Is the most common type of leukemia in young children. This disease also affects adults, especially those aged 65 and older. Standard treatments involve chemotherapy and radiotherapy. The survival rates vary by age: 85% in children and 50% in adults. Subtypes include: precursor B acute lymphoblastic leukemia, precursor T acute lymphoblastic leukemia, Burkitt's leukemia, and acute biphenotypic leukemia

A Wright's stained bone marrow aspirate smear from a patient with precursor B-cell acute lymphoblastic leukemia

Acute myelogenous leukemia (AML) Is a group of neoplastic disorders of the hematopoietic precursor cells of the bone marrow. AML is subdivided by the French-American-British system into 6 categories depending on the morphology. AML is not a disorder of rapidly proliferating neoplastic cells

Acute myelogenous leukemia (AML) The time for one cell division is prolonged with respect to that of normal bone marrow blast cells. A failure of maturation of the neoplastic cell clone exists. The bone marrow is gradually replaced by blast cells. Therefore, the most important complications are progressive anemia, leukopenia, and thrombocytopenia.

Acute myelogenous leukemia (AML) Occurs more commonly in adults than in children, and more commonly in men than women. AML is treated with chemotherapy. The five-year survival rate is 40%. Subtypes of AML include; acute promyelocytic leukemia, acute myeloblastic leukemia, and acute megakaryoblastic leukemia

acute myeloid leukemia bone marrow showing immature leukemia cells

Chronic myelogenous leukemia (CML) is characterized by an uncontrolled proliferation of granulocytes. An accompanying proliferation of erythroid cells and megakaryocytes is usually present. Many patients are asymptomatic but may present with splenomegaly, weight loss, malaise, bleeding, or thrombosis

Chronic myelogenous leukemia (CML) CML is characterized by a balanced reciprocal translocation between the long arms of chromosomes 9 and 22 [t(9;22)(q34;q11.2)] that occurs in about 90% to 95% of cases. This translocation results in the juxtaposition of the c-abl proto-oncogene from chromosome 9 with a portion of the bcr gene located on chromosome 22, thereby producing a novel bcr/abl fusion gene.

(CML) The gene product results in an 8.5-kb mRNA transcript that generates a 210-kd bcr/abl fusion protein having abnormal tyrosine kinase activity. Through phosphorylation, this enzyme may activate different signal transduction pathways that may result in increased proliferation and decreased apoptosis (programmed cell death) of hematopoietic cells

Leukemia Chronic Myeloid

Chronic myeloid leukemia

Chronic Myelogenous Leukemia

Chronic lymphocytic leukemia (CLL) Represents a monoclonal expansion of lymphocytes. In 95% of cases, CLL is a predominantly malignant clonal disorder of B lymphocytes. The remainder is secondary to a T-cell clone. The neoplastic cell is a hypoproliferative, immunologically incompetent small lymphocyte

Chronic lymphocytic leukemia (CLL) There is primary involvement of the bone marrow and secondary release into the peripheral blood. The recirculating lymphocytes selectively infiltrate the lymph nodes, the spleen, and the liver. Most patients are asymptomatic at diagnosis. As the disease progresses, lymphadenopathy, splenomegaly, and hepatomegaly develop. A secondary immune deficiency with hypogammaglobulinemia exists

Chronic lymphocytic leukemia (CLL) most often affects adults over the age of 55. It sometimes occurs in younger adults, but it almost never affects children. Two-thirds of affected people are men. The five-year survival rate is 75%. It is incurable, but there are many effective treatments. One subtype is B-cell prolymphocytic leukemia, a more aggressive disease

Chronic lymphocytic leukemia (CLL)

Chronic lymphocytic leukemia (CLL), on the other hand, does not usually form tumor masses. . increased proportion of large or atypical lymphocytes in the blood .

B-cell chronic lymphocytic leukemia

Causes No single known cause for any of the different types of leukemia exists. The known causes, which are not generally factors within the control of the average person, account for relatively few cases Among adults, the known causes are natural and artificial ionizing radiation,

Causes a few viruses such as human T-lymphotropic virus(HTLV-1), cause adult T-cell leukemia and some chemicals, notably benzene and alkylating chemotherapy agents for previous malignancies. Use of tobacco is associated with a small increase in the risk of developing acute myeloid leukemia in adults.

Causes Some people have a genetic predisposition towards developing leukemia people with chromosomal abnormalities or certain other genetic conditions have a greater risk of leukemia. For example, people with Down syndrome have a significantly increased risk of developing forms of acute leukemia (especially acute myeloid leukemia), and Fanconi anemia is a risk factor for developing acute myeloid leukemia.

EPIDEMIOLOGY: Age Most childhood leukemias are acute. ALL is the most common malignancy in children, especially affecting those aged 2-10 years. ALL is seen in only 20% of adult acute leukemias and behaves more aggressively than the childhood type. AML constitutes 15-20% of acute leukemias in children.

EPIDEMIOLOGY: Age Incidence of AML increases with age; in persons younger than 65 years, the incidence is 1.3, and in persons older than 65 years, the incidence is 12.2. CML constitutes less than 5% of childhood leukemias. The incidence of CML increases slowly with age until the middle 40s, when the incidence starts to rise rapidly.

EPIDEMIOLOGY: Sex Generally is more common in males and than females. The breakdown of new cases of leukemia by gender and category is as follows: CLL: male > females CML: male > females ALL: males> females; childhood ALL demonstrates a notable male predominance. AML: males > females

Mortality/Morbidity When all leukemias are lumped together, the global 5-year survival is 20%. In developed countries, 31% survive for 5 or more years, compared with 15% in developing countries. This underscores the lack of access to high-tech treatment in the developing world

Diagnosis Diagnosis is usually based on repeated complete blood counts and a bone marrow examination following observations of the symptoms, A lymph node biopsy can be performed as well in order to diagnose certain types of leukemia in certain situations

Treatment Most forms of leukemia are treated with pharmaceutical medication, typically combined into a multi-drug chemotherapy regimen. Some are also treated with radiation therapy. In some cases, a bone marrow transplant is useful