ACUTE LEUKEMIAS

The leukemias are heterogeneous hematologic malignancies characterized by unregulated proliferation of the blood-forming cells of the bone marrow. These immature proliferating leukemia cells (blasts) physically “crowd out” or inhibit normal cellular maturation in bone marrow, resulting in anemia, neutropenia, and thrombocytopenia. Leukemic blasts may also infiltrate a variety of tissues such as lymph nodes, skin, liver, spleen, kidney, testes, and the central nervous system. leukemia has been classified as acute or chronic based on differences in cell of origin and cell line maturation, clinical presentation, rapidity of progression of the untreated disease, and response to therapy. Four major leukemias are recognized: acute lymphocytic (or lymphoblastic) leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). Undifferentiated immature cells that proliferate autonomously characterize acute leukemias. Chronic leukemias also proliferate autonomously, but the cells are more differentiated and mature.1 Untreated, the acute leukemias are rapidly progressive, resulting in death within 2 to 3 months.

Etiology:-

Clinical Conditions Associated with an Increased Frequency of Acute Leukemia:-

Drugs                                                                          Chemical

Alkylating agents                                                        Benzene

Epidophyllotoxins                                                       Radiation

Genetic conditions                                                     Ionizing radiation

Down’s syndrome                                                       Virus

Bloom’s syndrome                                                      Epstein-Barr Virus

Fanconi’s anemia                                                        Human T-lymphocyte virus

Klinefelter’s syndrome                                               (HTLV-1 and HTLV-2)

Ataxia telangiectasia                                                   Social habits

Langerhans cell histiocytosis                                      Cigarette smoking

Shwachman’s syndrome                                             Maternal marijuana use

Severe combined

immunodeficiency syndrome

Maternal ethanol use

Kostmann’s syndrome

Neurofibromatosis type 1

Familial monosomy 7

Diamond-Blackfan anemia

PATHOPHYSIOLOGY:-

Normal hematopoiesis consists of multiple well-orchestrated steps of cellular development. A pool of pluripotent stem cells undergoes differentiation, proliferation, and maturation, to form the mature blood cells seen in the peripheral circulation. These pluripotent stem cells initially differentiate to form two distinct stem cell pools. The myeloid stem cell gives rise to six types of blood cells (erythrocytes, platelets, monocytes, basophils, neutrophils, and eosinophils), while the lymphoid stem cell differentiates to form circulatingBandTlymphocytes. Leukemia may develop at any stage and within any cell line. Two features are common to both AML and ALL: first, both arise from a single leukemic cell that expands and acquires additional mutations, culminating in a monoclonal population of leukemia cells. Second, there is a failure to maintain a relative balance between proliferation and differentiation, so that the cells do not differentiate past a particular stage of hematopoiesis. Cells (lymphoblasts or myeloblasts) then proliferate uncontrollably. Proliferation, differentiation, and apoptosis are under genetic control, and leukemia can occur when the balance between these processes is altered.

AML probably arises from a defect in the pluripotent stem cell or a more committed myeloid precursor, resulting in partial differentiation and proliferation of immature precursors of the myeloid blood-forming cells. In older patients, trilineage leukemic involvement is common, suggesting that the cell of origin is probably a stem or very early progenitor cell. In younger patients, a more differentiated progenitor becomes malignant, allowing maturation of some granulocytic and erythroid populations. These two forms of AML exhibit different patterns of resistance to chemotherapy, with resistance more evident in the older adults with AML. ALL is a disease characterized by proliferation of immature lymphoblasts. In this type of acute leukemia, the defect is probably at the level of the lymphopoietic stem cell or a very early lymphoid precursor.1 Leukemic cells have growth and/or survival advantages over normal cells, leading to a “crowding out” phenomenon in the bone marrow. This growth advantage is not caused by more rapid proliferation as compared with normal cells. Some studies suggest that it is caused by factors produced by leukemic cells that either inhibit normal cellular proliferation and differentiation, or reduce apoptosis as compared with normal blood cells. The types of genetic alterations that lead to leukemia have only recently become evident. The genetic defects may include (1) activation of a normally suppressed gene (protooncogene) to create an oncogene that produces a protein product that signals increased proliferation; (2) loss of signals for the blood cell to differentiate; (3) loss of tumor suppressor genes that control normal proliferation; and (4) loss of signals for apoptosis. Most normal cells are programmed to die eventually through apoptosis, but the appropriate programmed signal is often interrupted in cancer cells, leading to continued survival, replication, and drug resistance. Signal transduction, RNA transcription, cell-cycle control factors, cell differentiation, and programmed cell death may all be affected. One example of a genetic defect leading to acute leukemia is abnormal activation of the ras gene.7 These genes produce G proteins (guanine nucleotide-binding proteins) that couple activation of  outer cell membrane receptors to activation of signal transduction. The abnormal activation of these signal transduction pathways can lead to increased cell proliferation. Point mutations in the ras gene lead to unregulated proliferation and differentiation. Defects in this gene are present in 25% to 44% ofAMLpatients, and in 6% to 18% of ALL patients. Disruption of ras signaling also creates a useful target for therapeutic intervention. The investigational agents called farnesyl transferase inhibitors (such as tipifarnib [R115777, Zarnestra] or lonafarnib [Sarasar]) block an early part of the ras pathway, and are undergoing evaluation in various types of cancer, including leukemias.

CLASSIFICATION:--

The French-American-British (FAB) classification system identifies eight different subtypes of AML based on granulocytic differentiation and maturation  and this system is used to determine prognosis and choice of therapy.

Morphologic (FAB) Classification of Acute Myeloid Leukemia:-

	Subtype	Adult	Children <2yr	Children>2 yr
M0	Acute myeloblastic leukemia without maturation	5	LOW	LOW
M1	Acute myeloblastic leukemia minimal maturation	15	17	25
M2	Acute myeloblastic leukemia with  maturation	25		27
M3	Acute promyelocytic leukemia	10		5
M4	Acute myleomonocytic leukemia	25	30	26
M5a	Acute myleomonocytic leukemia poor differentiation	5	52	16
M5b	Acute myleomonocytic leukemia well differentiation	5
M6	Acute erythro leukemia	5		2
M7	Acute mega karyoblastic	10		5-7

CLINICAL PRESENTATION:-

Morphologic and immunophenotype Classification of ALL:-

subtype	Cell of origin	Adult%	Children%
L1	Early pre B cell, pre B cell,B cell , T cell	30	85
L2	Early pre-B cell , Pre-B cell B cell ,T cell.	60	14
L3	B cell	10	1

PRESENTATION OF ACUTE MYELOID LEUKEMIA(AML)

GENERAL

Typically a 1- to 3-month history of vague symptoms such as tiredness, lack of exercise tolerance, chest pain, and “feeling unwell,” but in no obvious distress.

SYMPTOMS

The patient may report weight loss, malaise, fatigue, and palpitations and dyspnea on exertion. They may also present with fever, chills, and rigors suggestive of infection; bruising (excessive vaginal bleeding, epistaxis, ecchymoses, and petechiae); gum hypertrophy (AML M4 and AML M5 subtypes); bone pain; seizures, headache, and diplopia.

SIGNS

Temperature may be elevated due to low neutrophil count; petechiae

LABORATORY TESTS

Complete blood cell count (with differential). Anemia is usually present and is normochromic and normocytic (without

a compensatory increase in reticulocytes). Thrombocytopenia (severe, less than 50,000/mm3 platelets) is present in approximately 50% of cases. Leukopenia/leukocytosis: approximately 20% of patients will present with an elevated white blood cell (WBC) count, 20% with a low WBC count, and the rest with normal counts. Even patients with elevated counts can be considered functionally neutropenic. Uric acid is elevated in 50% of patients due to rapid

cellular turnover (more common in patients presenting with elevated WBC counts). Electrolytes: potassium and phosphate are usually elevated. Coagulation: elevated prothrombin time, partial thromboplastin time, D-dimers; hypofibrinogenemia.

OTHER DIAGNOSTIC TESTS

Bone marrow biopsy and aspirate: send for morphologic examination, cytochemical staining, immunophenotyping, and cytogenetic (chromosome) analysis. At diagnosis the marrow is typically hypercellular, with normal erythropoiesis being replaced by leukemic blasts. To be diagnosed with AML, there needs to be more than 20% blasts.

For patients presenting with CNS signs, a diagnostic lumbar puncture should be performed. CNS involvement is common with AML M4 and M5 subtypes.

PRESENTATION OF ACUTE LYMPHOBLASTIC LEUKEMIA(ALL)

GENERAL

Typically a 1- to 3-month history of vague symptoms such as tiredness, lack of exercise tolerance, chest pain, and “feeling unwell,” but in no obvious distress.

SYMPTOMS

The patient may report weight loss, malaise, fatigue, and palpitations and dyspnea on exertion. They may also present with fever, chills, and rigors suggestive of infection; bruising (excessive vaginal bleeding, epistaxis, ecchymoses, and petechiae); bone pain; seizures, headache, and diplopia.

SIGNS

Temperaure may be elevated due to low neutrophil count; petechiae; splenomegaly, hepatomegaly, and lymphadenopathy.

LABORATORY TESTS

Complete blood cell count (with differential). Anemia is usually present and is normochromic and normocytic (without

a compensatory increase in reticulocytes). Thrombocytopenia (severe, less than 50,000/mm3 platelets) is present in approximately 50% of cases. Leukopenia/leukocytosis: approximately 20% patients will present with an elevated white blood cell (WBC) count, 20% with a low WBC count, and the rest with normal counts. Even patients with elevated counts can be considered functionally neutropenic. Uric acid is elevated in 50% of patients due to rapid

cellular turnover (more common in patients presenting with elevated WBC counts). Electrolytes: potassium and phosphate are usually elevated.

OTHER DIAGNOSTIC TESTS

Bone marrow biopsy and aspirate: send for morphologic examination, cytochemical staining, immunophenotyping, and cytogenetic (chromosome) analysis. CNS involvement is common in all ALL patients, and

is a common cause of relapse. All patients should have a screening lumbar puncture performed.

CHRONIC LEUKEMIA

Chronic leukemia includes at least four disease types: chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), prolymphocytic leukemia, and hairy cell leukemia. It differs from acute leukemia in that its clinical course is indolent. Most patients with chronic leukemia survive for several years after their initial diagnosis, even without treatment.

CHRONIC MYLOGENOUS LEUKEMEIA:-

CML is one of a group of hematologic cancers known as myeloproliferative disorders and results from the malignant transformation of a pluripotent stem cell. This malignant transformation leads to the clonal proliferation and accumulation of both progenitor and mature myeloid cells.The clinical course of CML has three phases: it begins with an indolent chronic phase in which signs and symptoms can be controlled with well-tolerated low-intensity chemotherapy; next is a transition phase known as the accelerated phase, in which low-intensity chemotherapy no longer controls the white blood cell (WBC) count; and, finally, there is a terminal phase, also known as a blast crisis, which is similar to acute leukemia and leads to rapid clinical deterioration and death of the patient.