Leukemias as a Group of Hematological Neoplasms - Research Paper Example

?Leukemia Introduction Leukemias are a group of hematological neoplasms characterized by abnormal proliferation of blood cells, usually white blood cells. This occurs due to malignant transformation of hematopoietic or blood forming cells. The leukemic cells proliferate primary in the bone marrow and the lymphoid tissues and then migrate into the peripheral blood. They interfere with normal hematopoiesis and immunity in the bone marrow and lymphoid tissue and after immigration in to the peripheral blood, they infiltrate other tissues. Classification of Leukemias Leukemias are classified based on the cell types involved (lymphocytic or myeloid) and on the natural history of the disease (acute or chronic). There are four common types of leukemia: 1. Chronic lymphocytic (or lymphoblastic) leukemia (CLL) 2. Chronic myeloid (or myelogenous) leukemia (CML) 3. Acute lymphocytic (or lymphoblastic) leukemia (ALL) 4. Acute myeloid (or myelogenous) leukemia (AML) Epidemiology The incidence of leukemias is about 10 per 100 000 per annum in all types of population. 50% of them are acute leukemias. ALL occurs at an annual rate of approximately 30 to 40 per million. There are approximately 2,400 children and adolescents younger than 20 years diagnosed with ALL each year in the United States (“Leukemia”, US NIHS). The male: female ratio is about 3:2 in acute leukemia, 2:1 in CLL and 1.3:1 in CML. CLL is rare in Chinese and related races. Though acute leukemias occur at all ages, they are lowest amongst the young and highest after 50 years of age. ALL is more incident in young children between 1-5 years. CLL and CML are mainly diseases of middle age and beyond. CML occurs between 30 and 80 years with a peak at 55 years of age. AML is four times more common than ALL in adults. The American Cancer Society (ACS) predicts that about 35,070 new leukemia cases will be diagnosed in the United States in 2006 (“Leukemia Statistics”, Oncology channel). Etiology 1. Genetic factors: There are some families with excessive incidence of leukemias. There is high concordance among identical twins if acute leukemia occurs in the first year of life. Also, the incidence of leukemia is high in various congenital genetic disorders like Down's syndrome, Bloom's Syndrome, Klinefelter's syndrome, etc.  In chronic granulocytic leukemia, an abnormality in the chromosome 21 has been detected. This abnormal chromosome is called Philadelphia chromosome (Ph-1) and is characterized by the absence of a part of one of its long arms (Shafer, 161). 2. Environmental factors: Studies have shown that ionizing radiation causes leukemia in experimental animals. There has been increased incidence of leukemia in the survivors of Japanese bomb explosions and those exposed to occupational radiation. Also, those receiving radiation therapies for various causes including spondylitis may be at increased risk for leukemia. Chromosomal translocations involving the Nucleophosmin gene occur frequently in myeloid and lymphoid cancers. This gene is a multifunctional phosphoprotein to which both tumor-suppressor and oncogenic functions have been attributed (Grisendi, 291- 292). 3. Chemicals: Benzene and other aromatic hydrocarbons, some insecticides, hexachlorcyclohexane, phenyl butazone (Shafer, 162), alkylating agents, and a few chem-therapeutic drugs are known to cause AML. 4. Viruses: Human T-cell Leukemia Virus-I, a human retro virus is known to cause adult T-cell leukemia. 5. Pre-existing disease- Fanconi anemia is a risk factor for developing acute myelogenous leukemia. Those with myeloblastic syndrome also are at risk for acute myelogenous leukemia (“Leukemia”, medicinet.com) Pathophysiology Leukemia results from somatic mutations in the DNA which activate oncogenes or deactivate tumor suppressor genes, because of which there is disruption in the regulation of cell death, differentiation or division. These mutations may occur spontaneously or due to the etiological factors mentioned above. In acute leukemias, there is malignant transformation of a single hematopoietic or lymphoid progenitor. The immature myeloid or lymphoid cells proliferate and the transformed clone expands. There is defect in maturation beyond the myeloblast or promyelocyte level in AML and the lymphoblast in ALL. Since they cannot mature to nonreplicating end cells, they accumulate in the bone marrow and further lead to proliferation. These cells are then released in to the peripheral blood from where they infiltrate in to other tissues such as lymph nodes, liver, spleen, various organs and the central nervous system. Normal cellular blood elements are derived from pluripotent and committed hematopoietic stem cells which reside in the bone marrow. The leukemic transformation of cells can occur at several levels of differentiation. In some, the transformation may involve a pluripotent stem cell and all cell types (granulocytes, macrophages, erythrocytes and megakaryocytes) may be involved, whereas in some others only the committed stem cell may get involved, usually the committed granulocytic-macrophage progenitor, leading to defects in granulocytes and macrophages. Due to defective cells, pancytopenia occurs. Even if the cells are abundant, they are non-functional. Also, the leukemic cells may directly inhibit normal hematopoiesis via cell- mediated or humoral mechanisms leading to hypocellular bone marrow. CLL originates from antigen-stimulated mature B lymphocytes, which either avoid death through the intercession of external signals or die by apoptosis and then they are replenished by proliferating precursor cells (Chiorazzi, 804- 815). Acute leukemias (ALL and AML) Clinical features: Signs and symptoms vary based on the type of leukemia. ALL and AML share many clinical features; the initial symptoms are present for less than 3 months. The clinical features are related to pancytopenia, malfunctioning of the cells and leukostasis1. Anemia may lead to pallor, easy fatigability, and dysnea on mild exertion. Those who develop thrombocytopenia may develop petechiae, easy bruisability and excessive bleeding2. The bleeding commonly occurs from oral mucosa (especially the gums) and gastrointestinal tract. Girls who are menstruating may have excess loss of blood. Even trivial cuts can lead to alarming blood loss. There can be associated coagulation defects which can further worsen the problem. Sometimes spontaneous bleeding can occur in the CNS, lungs and other organs. Due to decreased granulocyte and macrophage counts, there is increased risk of infection3. Infection usually occurs in the skin, gingival, perirectal tissues, gastrointestinal tract, lungs and the urinary tract. The frequent pathogens are gram negative bacilli, gram positive cocci and candida species. Leukemic infiltration of liver, spleen and lymph nodes leads to hepatomegaly, splenomegaly and lymphadenopathy. These are more commonly seen in ALL than in AML. This visceral involvement can cause nausea, abdominal fullness, loss of appetite and early satiety. In patients with T-cell variant of ALL, an anterior mediastinal mass may be present. Testicular involvement is common in males with ALL. Chloromas, which are soft tissue masses of leukemic cells, can develop in any location. Bone pains and sternal tenderness can occur in about 50% patients with acute leukemia, which are due to expanding malignant cell mass. Enlarged lymph nodes or uric acid stones can cause ureteral obstruction. Other complications like urate nephropathy, infections and hemorrhage can also occur. Infiltration of the neoplastic cells in to the sub-arachnoid space may lead to leukemic meningitis which usually manifests as nausea and head ache. Neurologic involvement is usually late and does not occur at the time of diagnosis. It usually presents in relapse. As the disease progresses, papilledema, cranial nerve palsies, seizures and altered sensorium may develop. Laboratory features and diagnosis of ALL: The characteristic feature of acute leukemias is that there is failure of cell maturation. The hemogram may show anemia with normal or raised MCV. Leukocyte counts may be as low as 1x109 per liter to 500x109 per liter (Edwards, 803-813). Peripheral blood smear (PS) and bone marrow smears reveal blast cells. Platelet count also is usually low. Once the diagnosis is suspected on routine PS, bone marrow samples have to be collected to study cytology, cytogenetics and immunological phenotyping. Morphological subtypes of ALL (French- American- British Classification): L1- The cells are small and homogenous. They have a regular nuclear membrane and a small nucleolus. 30% of ALL are of this type. L2- The cells are larger. They have a lower nucleus/cytoplasmic ratio. They typically have one or more prominent nucleoli. 65% of the cases are of this type. L3- The cells have vacuolated cytoplasm and large vesicular basophilic nuclei. This form of ALL is very rare. This has very poor prognosis (“Detailed Guide”, Cancer Reference Information) Most of the leukemic lymphoblasts of ALL contain a nuclear enzyme terminal deoxynucleotidyl transferase (Tdt). It is rarely present in AML and ALL L-3. Leukemic cells from 50% of the patients with ALL react with periodic acid Schiff stain showing block like inclusions of glycogen. Lymphoblasts do not have granulocytic or monocytic enzymes and do not react with cytochemical stains for peroxidase, Sudan Black, and non-specific esterase. Immunological Classification of ALL: 1. Common ALL- 60% of ALL fall in to this category. All the cells are Tdt positive and Common ALL antigen (CALLA) positive. They do not express surface membrane immunoglobulin or T-cell antigens. They are usually derived from B-cell lineage. 2. T-cell ALL- About 20% of ALL are this type. The cells are Tdt and acid phosphatase positive. Most of them are CALLA negative. The cells arise from T-cell lineage and express T-cell antigens including E-rosette receptor. This type of ALL typically occurs in adolescent males. The leukocyte count is very high and the patients usually have an anterior mediastinal mass. 3. B-cell ALL- Less than 5% of ALL cases are this type. The cells are from B-cell lineage. Most of them have L3 morphology. The cells produce a monoclonal immunoglobulin which is bound to the surface membrane. This type is also known as Burkitt’s lymphoma and is associated with t(8;14) chromosomal anomaly (Harris, 2495-2498). 4. Null cell ALL- About 15% of ALL cases fall in to this category. The cells do not have any CALLA antigens or B-cell or T-cell antigens. Treatment of ALL: The focus of treatment is to control bone marrow and systemic disease and prevent infiltration at other sites, especially the central nervous system. Phases of treatment: 1. Induction phase- Induction is brought about by chemo-therapeutic agents. Various combinations of drugs have been in use. These combinations are called regimens. The standard regimen includes prednisolone, vincristine and an anthracycline drug. L-aspariginase or cyclophosphamide may also be included. In children with low risk ALL, the regimen containing prednisolone, L-asparaginase and vincristine. High risk children may need daunorubicin along with these. The aim is to destroy the bulk of tumor. 2. Consolidation therapy- The aim is to eradicate any residual tumor. Daunorubicin, cytosine, etoposide, methotrexate and 6-mercaptopurine are used in this phase based on the risk level. The duration is 1-3 months inadults and 4-8 months in children. Central nervous system prophylaxis is given at this stage which includes cranial irradiation and intra-thecal (IT) methotrexate (especially in those with T-cell leukemia) or just systemic and IT methotrexate or only IT methotrexate. 3. Maintainence therapy- The aim of this phase is to prevent disease recurrence. It is started only after remission. It may be given for about 2 years on out-patient basis and then stopped and observed. Drugs suitable for this phase are prednisolone, vincristine, cyclophosphamide, doxorubicin, methotrexate and 6-mercaptopurine. Those with B-cell ALL may not respond to standard regimens and may require cyclophosphamide based regimens. Those who are positive to Ph1 may have worse prognosis; allogeneic bone marrow transplantation may be recommended in them. Those with recurrent ALL may need re-induction chemotherapy, allogeneic bone marrow transplantation, immune system agents, new chemotherapeutic agents and even low dose radiotherapy. Supportive treatment- This involves treatment of infections, taking care of diet and nutrition (IV nutrition if required), blood component transfusions as required, fluid and electrolyte management, monitoring liver and kidney functions, managing side effects of chemo-therapeutic agents, psychological support, emotional support, financial support and developmental support in children (“Leukemia”, US NIHS). Prognosis of ALL: Median survival is 30 months. About 80% of adults less than 60 years of age go into remission (“Leukemia”, US NIHS) Laboratory features and diagnosis of AML: Bone marrow samples have to be studied for cytology, cytogenetics and phenotyping. The leukemic cells are larger than those in ALL and have a lower nuclear-cytoplasmic ratio. The presence of Auer rods and abnormal primary granules in the cytoplasm of leukemic cells is diagnostic of AML. Sub type Leukemia name % of AML Morphology Peroxidase Sudan Black NSE PAS M1 AML without maturation 20 Few azurophilic granules +/- +/- - M2 AML with maturation 30 Blasts+ Auer rods+/- +++ +/- + M3 Promyelocytic leukemia 5 Promyeloctes (hypergranular) Auer rods++ +++ + + M4 Acute myelomonocytic leukemia 30 Monocytoid cells Serum lysosyme+ ++ +++ ++/+ M5 Acute monocytic leukemia 10 Monocytes Serum lysozyme+ +/- +++ ++/+ M6 Acute erythroleukemia 5 Erythroblasts+ - - ++ M7 Acute megakaryocytic leukemia 5 Undifferentiated blasts+ Platelet peroxidase+ Reaction with anti-platelet ab + - +/- + French-American-British group Classification of AML (Wilson, 1554) Treatment of AML: The treatment is similar to ALL except for the fact that there is no need for maintainence phase. Thedrugs used for induction therapy are daunorubicin, cytosine arabinoside, etoposide and thioguanine. For consolidation, cytosine arabinoside, amsacrine and mitozantrone may be used. Prognosis of AML: Median survival is 13 months. Chronic Leukemias: The clinical features in CLL are different from the acute leukemias. In these conditions, maturation of cells is fairly normal. In more that 25% of those with CLL, the disease is discovered incidentally during a routine hemogram for some other problem; the patient may not have any symptoms at all. Some patients may develop anemia and related symptoms, lymphadenopathy and intercurrent infections. On examination, these patients have splenomegaly and mild hepatomegaly. As the disease progresses, features of pancytopenia may ensue. About 20% of those with CLL go on to develop autoimmune hemolytic anemia. Those with CML have a mild or chronic course initially during which the disease responds to treatment, followed by an accelerated phase, in which the disease control becomes very difficult and then by an intense phase called the ‘blastic’ or ‘leukemic’ phase when the disease turns in to acute leukemia(ALL and AML) and the situation is out of control. There is marked splenomegaly. The blastic phase is sudden and bizarre. Most patients die in this phase. Laboratory features and diagnosis of CLL: The white cell count is very high and it ranges from 15x109 to 200x109 per liter. The colony- forming cells are also increased to ten thousand times normal. There is predominance of mature appearing lymphocytes. In advanced disease there may be anemia, granulocytopenia and thrombocytopenia. Clinical Staging- Stage A- No anemia or thrombocytopenia. Less than 3 areas of lymphoid enlargement. Stage B- No anemia or thrombocytopenia. 3 or more than 3 areas of lymphoid enlargement. Stage C- Anemia and/or thrombocytopenia exists. Treatment of CLL: Actually it is difficult to cure CLL and most patients do not require any treatment. Most of them are observed during the initial stages. Patients in Stage A and asymptomatic Stage B may not require any treatment. Those in Stage B who are symptomatic may need chemotherapy with chlorambucil. The distressing local lymph nodes may be dealt with radiotherapy. Stage 3 disease may need an aggressive combination of chemotherapy. This stage needs supportive therapy to deal with anemia and infections. Bone marrow failure has to be treated with prednisolone. Those who develop autoimmune hemolytic anemia or large spleen may need splenectomy. Prognosis of CLL: Median survival is 6 years. Laboratory features and diagnosis of CML: About 11% are asymptomatic at the time of diagnosis. Peripheral blood smear reveals normocytic normochromic anemia. The most prominent laboratory finding is leukocytosis. There are 2 peaks in the distribution of neutrophils. One peak is due to polymorphonuclear neutrophils. The second one is due to myelocytes or metamyelocytes. This differentiates from leukemoid reactions. Platelet morphology and function is normal. Basophilia may be prominent. It is typical of myeloproliferative disorders4. There is marked elevation of serum Vit. B12 levels. Leukocytic alkaline phosphatase5 is markedly reduced. The marrow as well as spleen of these patients may contain glycolipid laden phagocytes. Increased cell turn over may lead to hyperuricemia. The mature granulocyte in this condition is morphologically and functionally normal. Chromosome mapping reveals Ph-1 chromosome in more than 95% of the patients. Bone marrow sampling is a must for chromosomal analysis, because prognosis of those with Ph1 is poor. Treatment of CML: There is no need to start an asymptomatic patient on treatment. Those who are symptomatic and have high leukocyte counts need chemotherapy with busulphan or hydroxyurea. Those with Ph1 or with a possibility to worsen may be given alpha interferon to improve survival. Allogeneic bone marrow transplantation also may be considered. In the accelerated phase, hydroxyurea and cytosine arabinoside may be tried. Blast crisis should be managed based on the type of acute leukemia that has ensued. This has to be confirmed by bone marrow cytology and immunological studies. Prognosis of CML: Median survival is 3 years. There is 15% risk of death in the first year. Other Leukemias Hairy cell leukemia is a lymphoproliferative chronic B cell disorder. There are characteristic hairy cells in the bone marrow and PS. Acid phosphatase staining of cells is resistant to tartarate. Alpha interferon is the treatment of choice. Prolymphocytic Leukemia is a variant of CLL. The characteristic cell is a large lymphocyte with a prominent nucleolus. Prognosis is very poor. Leucophoresis may be necessary for high counts. References Chiorazzi, Nicholas, Rai Kanti and Ferrarini Manlio. “Chronic Lymphocytic Leukemia.” The New England Journal of Medicine 352. 8(2005): 804-815. Davidson’s Principles and Practice of Medicine. Eds. Edwards, Christopher, Boucher Ian, Haslett Christopher and Chilvers Edwin. Great Britain: ELBS publishers, 1995. Detailed Guide: Leukemia. Cancer Reference Information. 18th April, 2012. Grisendi, Silvia and Pandolfi, Pier. “NPM Mutations in Acute Myelogenous Leukemia.” 353. 3(2005): 291-292. Harris, Nancy and Horning, Sandra. “Burkitt’s lymphoma- the message from Microarrays.” The New England Journal of Medicine 354. 23 (2006): 2495-2498. Harrison’s Principles of Internal Medicine. Eds. Wilson, Jean et al. New York: Mc Graw Hill, 1991. Leukemia. National Comprehensive Cancer Network. 18th April, 2012. Leukemia. U.S. National Institutes of health. 18th April, 2012. < http://www.cancer.gov/cancertopics/types/leukemia> Leukemia Statistics. Oncology Channel. 18th April, 2012. Shafer, William. "Etiology of leukemia-A Review." California Medicine 104. 3 (1966): 161-165. Read More