Leukemia+(ALL,+AML,+CML)


 * Epidemiology: || Approximately 2500 to 3500 new cases of ALL are diagnosed in children each year in the United States with an incidence of 2.8 cases per 100,000. The peak incidence occurs between 2 and 5 years of age, and it occurs more commonly among boys than girls. In the United States, ALL occurs two times more commonly among white than black children. Certain genetic and immunodeficiency syndromes (eg, Down syndrome, Neurofibromatosis type 1, Bloom syndrome, and ataxia telangiectasia) also place children at higher risk for ALL. An increased risk of ALL associated with higher birth weight has also been noted.

AML is the most common acute leukemia in adults and accounts for approximately 80 percent of cases in this group. In the United States, the incidence has been stable at 3 to 5 cases per 100,000 population. In contrast, AML accounts for less than 10 percent of acute leukemias in children less than 10 years of age. In adults, the median age at diagnosis is approximately 65 years. The incidence increases with age with approximately 1.3 and 12.2 cases per 100,000 population for those under or over 65 years, respectively. The male:female ratio is approximately 5:3.

CML accounts for approximately 15 to 20 percent of leukemias in adults. It has an annual incidence of 1 to 2 cases per 100,000, with a slight male predominance. The median age at presentation is approximately 50 years for patients enrolled on clinical studies, but the actual median age from cancer registry data may be 10 years older. Exposure to ionizing radiation is the only known risk factor. There is no known familial predisposition. The prevalence of CML is steadily increasing in the Western world. It is estimated that there will be >250,000 CML patients living with CML in the US by the year 2040. 7 ||
 * Etiology: || ALL: There is no definite known etiology for ALL. It arises from the accumulation of clonal lymphoblasts in the bone marrow and lymph tissue. There may be a genetic basis.

AML: The etiology for AML is unknown. Genetic, environmental, occupational and drug factors may play a role. Possible environmental factors that have a strong correlation with AML are: exposure to benzene, ionizing radiation, and exposure to chemotherapy. RNA viruses have also been implicated in the etiology of AML specifically HTLV-1 and Epstein Barr Virus.

CML: Exposure to ionizing radiation is well documented as a causative factor in the development of CML. No other risk factors have been identified. 1 || Symptoms of CML can include the following:  AML signs and symptoms  Typically AML comes on suddenly, within days or weeks. Less often, a patient has been ill for a few months. AML makes people sick primarily by interfering with normal bone marrow function. The leukemia cells replace and crowd out the normal cells of the bone marrow, thereby causing low blood cell counts. This insufficient number of red blood cells results in a condition called anemia, which causes a person to be tired and pale. Lack of platelets can make you more susceptible to bleeding and bruising, especially in the skin, nose and gums. Lowered levels of normal white blood cells increase the risk of infection. Although infections can be of any type, typical symptoms include: · Fever · Runny nose · Cough · Chest pain or shortness of breath · Pain with urinating · Diarrhea, occasionally Infections of the bloodstream, called sepsis, and pneumonia are the most dangerous.⁴ ||
 * Signs & Symptoms: || **ALL- ** **SIGN AND SYMPTOMS**
 * Fatigue
 * Weakness
 * Easy bruising or bleeding
 * Pale skin
 * Red, pinhead-sized spots under skin
 * Weight loss
 * Fever
 * Bone or abdominal pain
 * Dyspnea (difficulty breathing) or shortness of breath
 * Frequent infections
 * Swollen lymph nodes (glands)
 * Enlarged liver or spleen⁴
 * weakness
 * fatigue
 * night sweats
 * <span style="color: #ff00ff; font-family: 'Times New Roman','serif';">weight loss
 * <span style="color: #ff00ff; font-family: 'Times New Roman','serif';">fever
 * <span style="color: #ff00ff; font-family: 'Times New Roman','serif';">bone pain
 * <span style="color: #ff00ff; font-family: 'Times New Roman','serif';">an enlarged spleen (felt as a mass under the left side of the ribcage)
 * <span style="color: #ff00ff; font-family: 'Times New Roman','serif';">pain or a sense of "fullness" in the belly
 * <span style="color: #ff00ff; font-family: 'Times New Roman','serif';">feeling full after eating even a small amount of food⁴
 * Diagnostic Procedures: || ALL: History, physical examination, complete blood count, blood chemistries, chest x-ray. A definitive determination of ALL is made from a bone marrow aspirate. A biopsy of the bone marrow should also be performed. Other hematologic and oncologic disorders which may mimic ALL should also be excluded.

AML: History, physical examination, complete blood count, blood chemistries, chest x-ray. A definitive determination of AML is made from a bone marrow aspirate usually taken from the posterior iliac crest. A bone marrow biopsy should be performed.

CML: History, physical examination, complete blood count, blood chemistries, chest x-ray. A definitive determination of CML is made from a bone marrow aspirate usually taken from the posterior iliac crest. A bone marrow biopsy should be performed. 2 ||
 * Histology: || ALL: Characterized by undifferentiated blast cells containing indistinct nucleoli.

AML: Characterized by clonal, hematopoietic stem cells that are in various stages of arrested development. This may occur in any hematopoietic lineage: granulocytic/monocytic, erythrocytic and megakaryocytic.

CML: Characterized by clonal, hematopoietic stem cells that proliferate in bone marrow and in peripheral blood with resulting granulocytosis, thrombocytosis and basophilia. 3 || L1- A small cell with a high nucleus, a regular cytoplasm ratio, or a clefted cell and small, inconspicuous nucleoli L2-Larger blast cells with irregular nuclear membranes, one or more prominent nucleoli, and a relative abundance of cytoplasm. L3- large lymphoblast’s with round to oval prominent nucleoli and basophilic cytoplasm⁴ <span style="color: #ff00ff; font-family: 'Times New Roman','serif'; font-size: 12pt;">Based on the various diagnostic tests, doctors may categorize ALL into six groups. This staging plays a major role in deciding the treatment protocol for affected patients and to also decide on the prognosis.⁵
 * Lymph Node Drainage: || A search of the literature shows no specific lymph node drainage associated with ALL, AML and CML. This is most likely due to the fact that these diseases are systemic and would involve all aspects of the bone marrow, peripheral blood and lymph system. ||
 * Metastatic Spread: || Leukemia can infiltrate the liver, periosteum, and bone. A mediastinal mass may be present in some high risk patients. No other metastatic disease found. ⁵ ||
 * Grading: || A search of the literature shows no specific grade associated with ALL, AML, and CML. ||
 * Staging: || <span style="color: #ff00ff; font-family: 'Times New Roman','serif';">The two major means to classify ALL are based on the morphological appearance and immunological surface markings. The morphological classification used is the FAB ( French-American-British) system. This classification divedes lymphoblastic leukemia into three levels (L1, L2, and L3). These division of ALL are based on the cell size, nuclear shape, number, prominence of nuclei, and amound and appearance of cytoplasm. These levels are as follows:

The stages of ALL include: <span style="color: #ff00ff; font-family: 'Times New Roman','serif'; font-size: 12pt;"> CML is divided into three groups. For this type of leukemia, doctors call these groups "phases" instead of "stages." Chronic phase: Patients in this phase have fewer than 5% blasts and promyelocytes (immature cells that can reproduce) in blood and bone marrow samples. These patients usually have relatively mild symptoms, and usually respond to standard treatments. Accelerated phase: The standard definition of this phase is that bone marrow and blood samples have more than 5% but less than 30% blasts. These patients often have fever, poor appetite, and weight loss. Symptoms and blood counts are not as responsive to treatments as they are during the chronic phase. The leukemic cells have new chromosome changes, in addition to the Philadelphia chromosome. <span style="color: #ff00ff; font-family: 'Calibri','sans-serif'; font-size: 11pt; line-height: 115%;">Bone marrow and/or blood samples from a patient in this phase have more than 30% blasts. The blast cells often spread to tissues and organs beyond the bone marrow. At this point the chronic leukemia has transformed into a very aggressive acute leukemi <span style="font-family: 'Calibri','sans-serif'; font-size: 11pt; line-height: 115%;">. ⁴ <span style="color: #ff00ff; font-family: 'Times New Roman','serif';"> AML- STAGING For a morphological evaluation the FAB system is used. AML is categorized in different maturation states, from M0 (undifferentiated) to M7 (megakaryocytic). They are as follows. M0- minimal evidence of maturation exists. M1- the cells tend to have fine azurophil granules and may have few Auer rods. Minimal evidence exists of differentiation along the rest of the granulocytic or monocytic lineages. M2- the number of blast cells is greater than 30%, and the proportion of monocytic precursors with less than 20% cells have abundant cytoplasm and moderate to marked granularity. M3- the APL predominant cell is heavily granulated with azurophil granulation. Many cells have bundle of Auer rods whose nucleus is often bilobed or kidney shaped. M4- the myeloid precursors or other granulocytic precursors are between 20% and 80% of the nonerythroid nucleated cells. The monocytic cells comprise 20% or more of the nonerythroid nucleated cells. M5- the proportion of granulocyte precursors is less than 20%. M6- fewer than 30% of the cells are of myeloid or monocytic lineage, and more than 50% are megaloblastic erythroid precursors. M7- this state is often associated with extensive marrow fibrosis that has an increase in reticulin or collagen. Other classifying techniques include cytochemical, immunological and chromosomal studies.⁶
 * <span style="color: #ff00ff; font-family: 'Times New Roman','serif'; font-size: 12pt;">Early pre-B ALL
 * <span style="color: #ff00ff; font-family: 'Times New Roman','serif'; font-size: 12pt;">Common ALL
 * <span style="color: #ff00ff; font-family: 'Times New Roman','serif'; font-size: 12pt;">Pre-B-cell ALL
 * <span style="color: #ff00ff; font-family: 'Times New Roman','serif'; font-size: 12pt;">Mature B-cell ALL (Burkitt leukemia)
 * <span style="color: #ff00ff; font-family: 'Times New Roman','serif'; font-size: 12pt;">Pre-T-cell ALL
 * <span style="color: #ff00ff; font-family: 'Times New Roman','serif'; font-size: 12pt;">Mature T-cell ALL⁶

|| More than 75% of patients can expect to experience a complete remission, with the length of remission varying greatly with a number of factors. Age and blood counts are among the most important factors in survival. ALL carriers the worst prognosis in children less than 1 year old, and greater than 10 years old. In adults, younger patients have better survival than older patients, and an initial WBC blood count of less than 10,000/mm is more favorable than a blood count of 20,000/mm or higher. Also poor performance status and evidence of mediastinal mass or organomegaly create a less favorable prognosis.
 * Radiation Side Effects: || Side effects for ALL, AML, and CML are all similar as the treatment modalities are similar to each other. As combination therpay is often used, side effects include nausea, vomiting, diarrhea, weight loss, and malaise. Mucosa of the mouth pharynx, bladder, and rectum may be affected. Bone marrow depression and immunologic suppression may occur. Lhermitte's signs may occur as another acute side effect. Normal secretions are impaired. The integumentary side effects include skin reactions, itching, tingling, bruising, and dry inelastic skin. Alopecia can occur and blanching of the skin. Chronic side effects include sterility and cataracts, growth retardation, and hypothalamic-pituitary dysfunction. 11 ||
 * Prognosis: || **ALL**

Similar prognostic indicators to ALL. Unfavorable signs include age over 50, myelodysplastic syndrome, poor performance status, impairs organ function, and low serum albumin. Children show worse prognosis than those with ALL. Overall, the patients age, tumor extent, and drug sensitivity are more important prognostic factors than cell morphology.
 * AML**

There is no consistent treatment cure. The prognosis is affected by spleen size, platelet count, hematocrit, gender, and percentage of blood myeloblasts. Survival also depends on the phase of the disease at diagnosis. In the accelerated phase, survival is 1 year or less, and after blast formation, individuals only live a few months. A patient in the active phase has a median survival time of 2 years, and 4-6 years in the chronic phase. 1 1 || __Bone Marrow Transplant__ This is the treatment of choice. Bone marrow is harvested from a healthy donor. The marrow is transferred to the patient after their marrow has been ablated by chemotherapy or Total Body Irradiation. Identical twins are the most desirable donors __Chemotherapy__ Usually given as a combination of prednisone, dexamethasone, vincristine, L-asparaginase, methotrexate, and etoposide __Radiation Therapy__ Four possible treatment methods: 1) Whole brain - used to encompass meninges. Dose is 18 Gy in 2 Gy fractions. 2) Craniospinal - consists of a whole brain field, and a spine field. the whole brain field is treated to 2400 cGy in 150 cGy fractions the spine is treated to 1500 cGy in 150 cGy fractions The spine field may need to be treated in two parts to cover the whole spine. Gap calculations must be done between any adjacent fields to ensure proper matching of the fields at treatment depth. Traditionally, the patient is treated in the prone position but this not mandatory. 3) Testis field - 400 cGy in a single fraction and may be added to TBI treatement 4) Total Body Irradiation (TBI) - Total dose is 1200 cGy given in three days. Treatments are given at 200 cGy, twice per day. The field size 40 x 40cm and the patient is positioned across the room in a reclined lateral position. Compensators are used to reduce the dose to the head, and below the knees. Treatment is given equally to both sides of the patient by rotating the patient halfway through the procedure. TLDs (Thermoluminescent dosimeters) should be used at some point during the treatment to confirm the dose that is actually received by the patient. They are often placed between the knees, ankles, and thighs to measure dose at midline.
 * CML**
 * Treatments: || **ALL**

__Bone Marrow Transplant__ This is the treatment of choice. Bone marrow is harvested from a healthy donor. The marrow is transferred to the patient after their marrow has been ablated by chemotherapy or Total Body Irradiation. Identical twins are the most desirable donors __Chemotherapy__ Usually given as a combination of cytosine arabinoside, combined with an anthracycline antibiotic such as daunorubicin, doxorubicin or idarubicin __Radiation Therapy__ As with ALL, there are four possible treatment methods: 1) Whole brain - used to encompass meninges. Dose is 18 Gy in 2 Gy fractions. 2) Craniospinal - consists of a whole brain field, and a spine field. the whole brain field is treated to 2400 cGy in 150 cGy fractions the spine is treated to 1500 cGy in 150 cGy fractions The spine field may need to be treated in two parts to cover the whole spine. Gap calculations must be done between any adjacent fields to ensure proper matching of the fields at treatment depth. Traditionally, the patient is treated in the prone position but this not mandatory. 3) Testis field - 400 cGy in a single fraction and may be added to TBI treatement 4) Total Body Irradiation (TBI) - Total dose is 1200 cGy given in three days. Treatments are given at 200 cGy, twice per day. The field size 40 x 40cm and the patient is positioned across the room in a reclined lateral position. Compensators are used to reduce the dose to the head, and below the knees. Treatment is given equally to both sides of the patient by rotating the patient halfway through the procedure. TLDs (Thermoluminescent dosimeters) should be used at some point during the treatment to confirm the dose that is actually received by the patient. They are often placed between the knees, ankles, and thighs to measure dose at midline.
 * AML**

__Bone Marrow Transplant__ This is the treatment of choice. Bone marrow is harvested from a healthy donor. The marrow is transferred to the patient after their marrow has been ablated by chemotherapy or Total Body Irradiation. Identical twins are the most desirable donors __Chemotherapy__ Drugs used are alpha-interferon, busulfan, and hydroxyurea. __Radiation Therapy__ Consists of two possible procedure: 1) Spleen field: The spleen field is traditionally a clinical setup. The field must encompass the entire spleen with a 1cm margin around the organ. Field setup is done through palpation or fluoroscopy. Simulation is needed to localize the spleen and ensure that the kidney is out of the treatment field. 2) Total Body Irradiation (TBI) - Total dose is 1200 cGy given in three days. Treatments are given at 200 cGy, twice per day. The field size 40 x 40cm and the patient is positioned across the room in a reclined lateral position. Compensators are used to reduce the dose to the head, and below the knees. Treatment is given equally to both sides of the patient by rotating the patient halfway through the procedure. TLDs (Thermoluminescent dosimeters) should be used at some point during the treatment to confirm the dose that is actually received by the patient. They are often placed between the knees, ankles, and thighs to measure dose at midline. 1 1 || TD 5/5 for CarnioSpinal and TBI Treatment 8  || Figure 1 Prophalactic Whole Brain 9
 * CML**
 * TD5/5: || [[image:CNS_and_Medullo.jpg width="448" height="207"]]

Figure 2 TBI Techniques 10

Figure 3 Craniospinal Fields for ALL 10

1. Scigliano E, Vlachos A, Najfeld V, et. al.The leukemias. In: Rubin P, ed. //Clinical Oncology: A Multidisciplinary Approach// //for Physicians and Students//. 8th ed.Philadelphia, PA: W.B. Saunders Company; 2001:565-590. 2. Scigliano E, Vlachos A, Najfeld V, et. al.The leukemias. In: Rubin P, ed. //Clinical Oncology: A Multidisciplinary Approach// //for Physicians and Students//. 8th ed.Philadelphia, PA: W.B. Saunders Company; 2001:565-590. 3. Scigliano E, Vlachos A, Najfeld V, et. al.The leukemias. In: Rubin P, ed. //Clinical Oncology: A Multidisciplinary Approach// //for Physicians and Students//. 8th ed.Philadelphia, PA: W.B. Saunders Company; 2001:565-590. <span style="color: fuchsia; font-family: 'Arial','sans-serif'; font-size: 10pt; line-height: 115%;">4. <span style="color: green; font-family: 'Arial','sans-serif'; font-size: 10pt; line-height: 115%;"> [|www.cancer.net/Cancer+Types/Leukemia.com] <span style="color: fuchsia; font-family: 'Arial','sans-serif'; font-size: 10pt; line-height: 115%;">Accessed Febuary 12, 2010 <span style="color: #ff00ff; font-family: 'Times New Roman','serif'; font-size: 10pt; line-height: 115%;">5. Washington, M. Charles, Leaver T. Dennis. Principles and Practice of Radiation Therapy: Practical Applications. 1 <span style="color: #ff00ff; font-family: 'Times New Roman','serif'; font-size: 9pt; line-height: 115%;">st <span style="color: #ff00ff; font-family: 'Times New Roman','serif'; font-size: 90%; line-height: 115%;"> edition, St.Louis, Missouri, Mosby, 1997. pgs 86-95 <span style="color: #f41fe0; font-family: 'Arial','sans-serif'; font-size: 10pt;">6. Lenhard,E. Raymond. Jr.,MD., Osteen, T. Robert, Gansler,Ted,.MD. The American Cancer Society's Clinical Oncology. 1st edition. Atlanta,GA. 2001.pg 530 7. [] Accessed February 18, 2010 8. Wikibooks en.wikibooks.org TD5/5 adapted from Emami 1991 9. SCTRC 01/14/10 10. Chao KS, Perez CA., Brady LW. //Radiation Oncology - Management Decisions//. 2nd ed. Philadelphia, PA: Lippincott, Williams & 11. Washington CM, Leaver D. // Principles and Practice of Radiation Therapy //. 2nd ed. St. Louis, MO: Mosby. 2004
 * __References__**