The Hematological Disorders - Essay Example

?Discuss the ification of the leukaemias and how this can be used to help treat this group of disorders. Use specific types of leukaemia to illustrate your answer. A group of hematological disorders that are mainly characterized by abnormal proliferation of any lineage of blood cells, usually the white blood cells, is known as leukemia (Wu, 2010). Leukemia occurs due to malignant transformation of blood forming cells which are known as hematopoietic cells. The leukemic cells primarily proliferate in the lymphoid tissues and the bone marrow and then migrate to the peripheral blood. Due to abnormal proliferation, they interfere with the normal hematopoiesis and immunity in both the lymphoid tissue and the bone marrow. After they immigrate into the peripheral blood, through circulation, they infiltrate into other tissues (Wu, 2010). There are several types of leukemia and based on the lineage of cell that is involved, they can be classified as lymphocytic or myeloid. They can further classified as acute or chronic based on the natural history of the disease. Thus, there are basically, four common types of leukemia and they are (Wu, 2010): 1. Acute lymphocytic (or lymphoblastic) leukemia (ALL) 2. Acute myeloid (or myelogenous) leukemia (AML) 3. Chronic lymphocytic (or lymphoblastic) leukemia (CLL) 4. Chronic myeloid (or myelogenous) leukemia (CML) This classification of leukemias is very important from treatment point of view, because; presentation, treatment and prognosis for each group is different. Acute leukemias: ALL and AML ALL and AML share many clinical features and hence they are discussed under the same heading. The presentation of these leukemias is abrupt and within 3 months of onset of malignant changes in the bone marrow and lymphoid tissue. Clinical features of these leukemias is mainly related to malfunctioning of the malignant cells, pancytopenia and leukostasis. Leukostasis is a condition in which the microcirculation in the tissues can get occluded by leukemic blast cells. It mainly occurs when the blast cells counts exceed 100 x 109 per liter.. Decrease in red blood cell counts leads to anemia which manifests as pallor, dysnea on mild exertion and easy fatiguibility. When there is thrombocytopenia or decreased number of circulating platelets, the patient presents as easy bruisability, petechiae and excessive bleeding. More often than not, bleeding is seen from oral mucosa, especially gums and gastrointestinal bleeding. The latter manifests as hematochezia, malena or hematemesis. In girls who are menstruating severe blood loss can occur. When coagulation defects are also concomitant, bleeding is severe warranting hospitalization and blood transfusion. Spontaneous bleeding can also occur in the lungs, central nervous system and other organs. Decrease in the macrophage and granulocyte count can cause increased risk of infection,, especially of the perirectal tissues, skin, gingival tissue, gastrointestinal tract, urinary tract and lungs. Pathogens which frequently contribute to infections in these patients are gram positive cocci, gram negative bacilli and candida species (Wiernik, 2003). Infiltration of lymphnodes, liver and spleen by leukemic cells leads to lymphadenopathy, hepatomegaly and splenomegaly. Organ infiltration is seen more commonly in ALL than in AML. In advanced stages, even other organs can also get infiltrated wtih malignant cells leading to abdominal fullness, nausea, early satiety and loss of appetite. In those with T-cell variant ALL, anterior abdominal mass can be there. Testicular involvement can also occur in ALL. Soft tissue masses of leukemic cells, also known as chloromas can occur in any location in the body. More than 50 percent of patients with acute leukemia present with bone tenderness due to expanding malignant cell mass. Enlargement of the lymph nodes near ureters can cause ureteric obstruction. Other complications include pyelonephritis, nephropathy and renal hemorrhage. Infiltration of leukemic cells into the subarachnoid space may present as leukemic meningitis which can manifest as head ache and nausea. Neurologic involvement in acute leukemias is usually late and presents late especially during relapse. Progression of neurological involvement can lead to cranial nerve palsies, papilledema, altered sensorium and even seizures. The characteristic laboratory features of acute leukemias is failure of cells to mature. Hemogram may reveal anemia with raised or normal Mean corpuscular volume or MCV. The leukocyte counts may vary. They may be very low or very high and can range between 1x109 per liter to 500x109 per liter (Wiernik, 2003). Smears of peripheral blood and bone marrow can reveal blast cells. Platelet count also is very low. On suspicion of the diagnosis of acute leukemia, detailed evaluation of peripheral smear and bone marrow smear must be done using cytogenetics, cytological studies and immunophenotyping. Based on these studies, subtypes of each type of leukemia can be deciphered (Wiernik, 2003). According to the French- American- British Classification, morphological subtypes of ALL include (Wiener, et al, 2008): L1- The cells are significantly small, but homogenous. Their nuclear membrane is regular and they have a small nucleolus. 30% of ALL are of L1 type. L2- The cells are significantly larger. The nucleus/cytoplasmic ratio is smaller. The cells have one or more nucleoli that are prominent. 65% of ALL are of L2 type. L3- The cells have large vesicular basophilic nuclei and vacuolated cytoplasm. Practically, this form of ALL is very rare and is associated with poor prognosis. ALL leukemic lymphoblasts possess a nuclear enzyme called terminal deoxynucleotidyl transferase (Tdt). This enzyme is not present in ALL L-3 and AML. This is one of the differentiating points between L1, L2 from L3 and also from AML. On the other hand, lymphoblasts are unlikely to have monocytic or granylocytic enzymes and are non-reactive to cytochemical stains like Sudan Black, peroxidase or non-specific esterase. More than 50 percent patients with ALL have periodic Schiff stain reaction suggestive of glycogen body inclusions. ALL can also be classified immunologically as follows (Wiener, et al, 2008): 1. Common ALL- More than 60% of ALL cases fall under this category. All the cells are for Tdt and also for Common ALL antigen (CALLA) . The cells do not express T-cell antigens or surface membrane immunoglobulin. Cells are mainly derived from the B-cell lineage. 2. T-cell ALL- 20% of ALL belong to this category. The cells areboth Tdt and acid phosphatase positive. However, they are CALLA negative. The cells are from the T-cell lineage and express antigens pertaining to T-cell including E-rosette receptor. This type of ALL is mainly seen in adolescent males. Another characteristic feature of this ALL is that the leukocyte count is very high and many patients present with a mediastinal mass. 3. B-cell ALL- The cells are mainly from B-cell lineage and less than 5% of cases of ALL belong to this category. Most of them have L3 morphology. Since the cells are of B-cell lineage, they produce a monoclonal immunoglobulin which is bound to the cell's surface membrane. This type is commonly known as Burkitt’s lymphoma and is frequently associated with t(8;14) chromosomal anomaly (Harris, 2495-2498). 4. Null cell ALL- Only 15% of ALL cases fall in to this category. The cells do not have any CALLA antigens or B-cell or T-cell antigens. Hence they are known as null cells. the lineage of these cells is poorly understood. Treatment of ALL is mainly focused on controlling the bone marrow disease and the systemic disease and also to prevent infiltration at other sites, especially the central nervous system. Treatment is mainly chemotherapy and is divided into 3 phases: induction phase, consolidation phase and maintenance phase. In the induction phase, chemotherapeutic agents are given to bring about induction. Several chemotherapeutic agents are useful for the treatment of ALL and combination of more than one drug is often used achieve induction. the combinations are called regimens. The standard regimen includes vincristine, prednisolone and an anthracycline drug. In some centers, the regimens also include vincristine, L-asparagianse and prednisolone. In children with high risk, daunorubicin must be give along with these. The main aim of induction therapy is to destroy the bulk of the tumor (Wiener, et al, 2008). The next phase of treatment is the consolidation phase and the aim of this treatment is to destroy any residual tumor that is left behind after induction therapy. Drugs used in this phase are cytosine, etoposide, duanorubicin, 6-mercaptopurine and methotrexate. The choice of drug depends on the levels of risk. The duration of consolidation therapy in adults is 1-3 months and that in children is 4-8 months. In T-cell leukemia, prophylaxis of the central nervous system in this stage includes cranial irradiation and administration of intrathecal methotrexate. In others, only methotrexate may be given either intrathecal or systemic or both. Consolidation phase is followed by the maintenance phase and the aim of this phase is prevention of the recurrence of the disease. This treatment is started only after remission. Drugs that are administered for remission are vincristine, prednisolone, doxorubicin, cyclophosphamide, 6-mercaptopurine and methotrexate. patients with B-cell ALL usually do not respond to standard regimens and hence more often than not they are treated with cyclophosphamide regimens. Those with Ph1 positivity have worst prognosis and in such patients bone marrow transplantation is recommended. In those with recurrent ALL, re-induction chemotherapy many be needed and these also benefit from immune system agents, bone marrow transplantation, newer chemotherapeutic agents and low dose radiotherapy. Also with chemotherapy patients also need supportive treatment like treatment of infections, diet and nutrition, blood transfusions, fluid and electrolyte management, managing side effects of cancer therapies, monitoring of organ dysfunctions due to cancer therapy, emotion support and developmental support (Wiener, et al, 2008). The presence of Auer rods and abnormal primary granules in the cytoplasm of is diagnostic of AML. Leukemic cells of AML are larger than the ALL leukemic cells and have lower nuclear-cytoplasmic ratio. Based on cytogenetics, cytology and phenotyping on bone marrow samples, the following classification can be established for AML. This is based on French-American-British group Classification (Wiener, et al, 2008). 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 (Wiener, et al, 2008). Treatment of AML is similar to ALL, but without a maintenance phase. The drugs used for induction therapy are cytosine arabinoside, daunorubicin, etoposide and thioguanine. For consolidation, cytosine arabinoside, amsacrine and mitozantrone may be used (Wiener, et al, 2008). Chronic leukemias: CML and CLL Clinical presentation of chronic leukemias is much different when compared to acute leukemias. The maturation of the cells is normal and in more than 25 percent cases the diagnosis is made during routine tests for some other purpose. Some of the common clinical features include anemia, lymphadenopathy, intercurrent infections, hepatomegaly and splenomegaly. In advanced stages pancytopnenia and clinical features pertaining to it will ensue. In 20 percent of CLL cases, autoimmune hemolytic anemia ensues. Patients with CML have a chronic or a mild course in the initial stage. response to treatment is excellent in this stage. This stage then enters an accelerated stage when treatment is very difficult to be administered. This is followed by a blastic or leukemic phase which mimics acute leukemia. Most patients succumb in this stage. In CLL, the leukocyte count is very high and ranges from 15x109 to 200x109 per liter. The picture is dominated by mature appearing lymphocytes. Even colony- forming cells are also increased to ten thousand times normal. In advanced disease, there may be anemia, granulocytopenia and thrombocytopenia. CLL can be staged clinically as below (Chiorazzi et al, 2005): Stage A- No anemia or thrombocytopenia. Lymphoid enlargement in less than 3 areas. Stage B- No anemia or thrombocytopenia. Lymphoid enlargement in 3 or more than 3 areas. Stage C- Anemia with or without thrombocytopenia. CLL is difficult to treat and most patients do not require any treatment. Only those in advanced stage B may need chlorambucil therapy. Local lymph nodes that are distressing may need radiotherapy. Bone marrow failure responds to prednisolone. Supportive therapy must be given in all stages (Chiorazzi et al, 2005). The most predominant laboratory finding in CML is leukocytosis. About 11% are asymptomatic at the time of diagnosis. Peripheral blood smear reveals normocytic normochromic anemia. 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 is the main differentiating point from leukemoid reaction. The morphology and functioning of platelets is normal. Basophilia is usually prominent and this is is typical of myeloproliferative disorders. There is also elevation of serum Vit. B12 levels. Leukocytic alkaline phosphatase2 is however reduced. The marrow and spleen of CML patients usually contains glycolipid laden phagocytes. Increased cell turn contributes 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 (Wiernik, 2003). Asymptomatic patients usually do not require any 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. Bone marrow transplantation also may be considered in rare cases. In the accelerated phase, hydroxyurea and cytosine arabinoside may be useful. 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 (Wiernik, 2003). Thus, the treatment of leukemias is based on the type and stage of leukemia. References Chiorazzi, N., Rai, K. and Ferrarini, M. (2005). Chronic Lymphocytic Leukemia. The New England Journal of Medicine, 352, 8, 804-815. Wiener, C., Fauci, A., Braunwald, E., Kasper, D., Hauser, S., Longo, D., Jameson, J., and Loscalzo, J. (2008). Leukemias. In: Harrison's Principles of Internal Medicine. London: McGrawHill Wiernik, P.H. (2003). Neoplastic diseases of blood. Cambridge: Cambridge University Press Wu, L.(2010). Leukemias. Medscape Reference. Retrieved from http://emedicine.medscape.com/article/1201870-overview Read More