[quote=ZoVi,2008 10 16, 17:50]
Turiu klausimėlį apie markerius. Ar man markeris informatyvus, nežinau. Po chemijos buvo 11, po švitinimų 10, rugpjūčio mėn. 12,(3 mėn po švitinimo), o dabar 13,8. (norma 30) Ar reikia sunerimti, ar galimi svyravimai? Gal kas susidūrėt su panašia problemėle?
/quote]
Jūsų markeris normos ribose, o tokie svyravimai gali būti netgi tyrimo paklaida ar
to laikokarpio organizmo būklės svyravimas. Man kilo per mėnesį po 10-15 ir daugiau punktų ir pastoviai aukštyn augančia linija .
QUOTE(V.Z. @ 2008 10 15, 08:38)
mano vyrui priskiria kelias ligas: umine mieloleukoze (cia pagal ligos koda issiaiskinom, kad tokia), o visur dokumentuose raso mieloidine sarkoma. Bet tokios ligos as Lt puslapiuose niekur nerandu. Gal ja isvis Lietuvoje niekas nesirgo Uzsienio saituose randu tik apie sarkoma, o a[ie tokia mieloidine nieko nerandu. Gal nemoku ieskoti Gal kas esate girdeje apie tokia liga?
V.Z., negirdėjau apie tą ligą o ūminę leukemiją apgydė? Kokius tyrimus daro? čiulpų punkcijas turbūt?
QUOTE(Siracusa @ 2008 10 16, 22:38)
V.Z., negirdėjau apie tą ligą o ūminę leukemiją apgydė? Kokius tyrimus daro? čiulpų punkcijas turbūt?
mane labiausiai ir baugina, kad ta liga yra reta ir ja praktiskai Lietuvoj gal tik keli atvejai buvo, o gal ir nei vieno. Daktarai tuo klausimu nesneka su mumis. Ji siuo metu dar gydo. Jo paties kaulu ciulpai yra pazeisti. Po triju labai stipriu citozaro doziu kaulu ciulpuose lyg ir beveik nieko nesimato, bet organizma liga yra apemusi. Jam dar be to yra tas auglys krutineje, kurio negalejo viso isoperuoti. Ispjove tik dali. Dabar vyras namie ir ateinancia arba dar kita savaite vaziuos penktai chemijai. Atrodo ju tiek nedaug kol kas, bet daktarai sake, kad superstipria jam duoda. Citozaro per viena karta gauna 0,6 g. Sake kad tai daug. Bet vyro organizmas stiprus ir pakankamai lengvai jam praeina. Per menesi atsigauna.
Tiesa, tos leukemijos neapgyde. Sake dar gydo... Sake kad ne taip lengvai ji praeina...
V.Z., laikykitės gydymas turbūt bus sunkus ir ilgas, bet viskas ištveriama
tik nesuprantu kaip daktarai nešneka apie ligą - turėtų viską papasakoti ir aptarti
tik nesuprantu kaip daktarai nešneka apie ligą - turėtų viską papasakoti ir aptarti
apie mielodine:
http://www.emedicine...med/topic34.htm
jei neatsidarys:
Background
Acute myelogenous leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow.
Pathophysiology
The underlying pathophysiology consists of a maturational arrest of bone marrow cells in the earliest stages of development. The mechanism of this arrest is under study, but in many cases, it involves the activation of abnormal genes through chromosomal translocations and other genetic abnormalities.
This developmental arrest results in 2 disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. Second, the rapid proliferation of these cells, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, blood, and, frequently, the spleen and liver.
Frequency
United States
Estimates predict 11,960 new cases of AML in the United States in 2005 (6530 men and 5430 women).
International
AML is more commonly diagnosed in developed countries.
Mortality/Morbidity
In 2005, an estimated 9000 deaths will occur in the United States. Of these, 5040 will occur in men and 3960 will occur in women.In adults, treatment results are generally analyzed separately for younger (18-60 y) and older (>60 y) patients.
With current standard chemotherapy regimens, approximately 25-30% of adults younger than 60 years survive longer than 5 years and are considered cured.
Results in older patients are more disappointing, with fewer than 10% of patients surviving long-term.
Race
AML is more common in whites than in other populations.
Sex
AML is more common in men than in women. The difference is even more apparent in older patients. This is likely because myelodysplastic syndromes (MDSs) are more common in men, and advanced MDS frequently evolves into AML. Some have proposed that the increased prevalence of AML in men may be related to occupational exposures.
Age
Prevalence increases with age. The median age of onset is 65 years. However, this disease affects all age groups.
CLINICALSection 3 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
History
Patients present with symptoms resulting from bone marrow failure, organ infiltration with leukemic cells, or both. The time course is variable.
Some patients, particularly younger ones, present with acute symptoms over a few days to 1-2 weeks.
Others have a longer course, with fatigue or other symptoms lasting from weeks to months. A longer course may suggest an antecedent hematologic disorder (AHD) such as myelodysplastic syndrome (MDS).
Symptoms of bone marrow failure are related to anemia, neutropenia, and thrombocytopenia.
The most common symptom of anemia is fatigue. Patients often retrospectively note a decreased energy level over past weeks.
Other symptoms of anemia include dyspnea upon exertion, dizziness, and, in patients with coronary artery disease, anginal chest pain. In fact, myocardial infarction may be the first presenting symptom of acute leukemia in an older patient.
Patients often have decreased neutrophil levels despite an increased total WBC count.
Patients present with fever, which may occur with or without specific documentation of an infection. Patients with the lowest absolute neutrophil counts (ie, <500 cells/µL and especially <100 cells/µL) have the highest risk of infection.
Patients often have a history of upper respiratory infection symptoms that have not improved despite empiric treatment with oral antibiotics.
Patients present with bleeding gums and multiple ecchymoses. Bleeding may be caused by thrombocytopenia, coagulopathy that results from disseminated intravascular coagulation (DIC), or both.
Potentially life-threatening sites of bleeding include the lungs, gastrointestinal tract, and the central nervous system.
Alternatively, symptoms may be the result of organ infiltration with leukemic cells.
The most common sites of infiltration include the spleen, liver, and gums.
Infiltration occurs most commonly in patients with the monocytic subtypes of acute myelogenous leukemia (AML).
Patients with splenomegaly note fullness in the left upper quadrant and early satiety.
Patients with gum infiltration often present to their dentist first. Gingivitis due to neutropenia can cause swollen gums, and thrombocytopenia can cause the gums to bleed.
Patients with markedly elevated WBC counts (>100,000 cells/µL) can present with symptoms of leukostasis (ie, respiratory distress and altered mental status). Leukostasis is a medical emergency that requires immediate intervention.
Patients with a high leukemic cell burden may present with bone pain caused by increased pressure in the bone marrow.
Physical
Physical signs of anemia, including pallor and a cardiac flow murmur, are frequently present.
Fever and other signs of infection can occur, including lung findings of pneumonia.
Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities. Petechiae are small, often punctate, hemorrhagic rashes that are not palpable. Areas of dermal bleeding or bruises (ie, ecchymoses) that are large or present in several areas may indicate a coexistent coagulation disorder such as DIC. Purpura is characterized by flat bruises that are larger than petechiae but smaller than ecchymoses.
Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and, to a lesser degree, lymphadenopathy. Occasionally, patients have skin rashes due to infiltration of the skin with leukemic cells (leukemia cutis). Chloromata are extramedullary deposits of leukemia. Rarely, a bony or soft-tissue chloroma may precede the development of marrow infiltration by AML (granulocytic sarcoma).
Signs relating to leukostasis include respiratory distress and altered mental status.
Causes
Although several factors have been implicated in the causation of AML, most patients who present with de novo AML have no identifiable risk factor.
Antecedent hematologic disorders
The most common risk factor is the presence of an AHD, the most common of which is MDS. MDS is a disease of the bone marrow of unknown etiology that occurs most often in older patients and manifests as progressive cytopenias that occur over months to years.
Patients with low-risk MDS (eg, refractory anemia with normal cytogenetics findings) generally do not develop AML, whereas patients with high-risk MDS (eg, refractory anemia with excess blasts-type 2) frequently do develop AML.
Other AHDs that predispose patients to AML include aplastic anemia, myelofibrosis, paroxysmal nocturnal hemoglobinuria, and polycythemia vera.
Congenital disorders
Some congenital disorders that predispose patients to AML include Bloom syndrome, Down syndrome, congenital neutropenia, Fanconi anemia, and neurofibromatosis.
Usually, these patients develop AML during childhood; rarely, some may present in young adulthood.
More subtle genetic disorders, including polymorphisms of enzymes that metabolize carcinogens, also predispose patients to AML. For example, polymorphisms of NAD(P)H:quinone oxidoreductase (NQO1), an enzyme that metabolizes benzene derivatives, are associated with an increased risk of AML. Particularly increased risk exists for AML that occurs after chemotherapy for another disease or for de novo AML with an abnormality of chromosomes 5, 7, or both. Likewise, polymorphisms in glutathione S-transferase are associated with secondary AML following chemotherapy for other malignancies.
Familial syndromes
Germ-line mutations in the gene AML1 (RUNX1, CBFA2) occur in the familial platelet disorder with predisposition for AML, an autosomal-dominant disorder characterized by moderate thrombocytopenia, a defect in platelet function, and propensity to develop AML.
Mutation of CEBPA (the gene encoding CCAAT/enhancer binding protein, alpha; a granulocytic differentiation factor and member of the bZIP family) was described in a family with 3 members affected by AML.
Some hereditary cancer syndromes, such as Li-Fraumeni syndrome, can manifest as leukemia. However, cases of leukemia are less common than the solid tumors that generally characterize these syndromes.
Environmental exposures
Several studies demonstrate a relationship between radiation exposure and leukemia.
Early radiologists (prior to appropriate shielding) were found to have an increased likelihood of developing leukemia.
Patients receiving therapeutic irradiation for ankylosing spondylitis were at increased risk of leukemia.
Survivors of the atomic bomb explosions in Japan were at a markedly increased risk for the development of leukemia.
Persons who smoke have a small but statistically significant (odds ratio, 1.5) increased risk of developing AML. In several studies, the risk of AML was slightly increased in people who smoked compared with those who did not smoke.
Exposure to benzene is associated with aplastic anemia and pancytopenia. These patients often develop AML. Many of these patients demonstrate M6 morphology.
Prior exposure to chemotherapeutic agents for another malignancy
As more patients with cancer survive their primary malignancy and more patients receive intensive chemotherapy (including bone marrow transplantation [BMT]), the number of patients with AML increases because of exposure to chemotherapeutic agents. For example, the cumulative incidence of acute leukemia in patients with breast cancer who were treated with doxorubicin and cyclophosphamide as adjuvant therapy was 0.2-1.0% at 5 years.
Patients with prior exposure to chemotherapeutic agents can be divided into 2 groups: (1) those with prior exposure to alkylating agents and (2) those with exposure to topoisomerase-II inhibitors.
Patients with a prior exposure to alkylating agents, with or without radiation, often have a myelodysplastic phase prior to the development of AML. Cytogenetics testing frequently reveals -5 and/or -7 (5q- or monosomy 7).
Patients with a prior exposure to topoisomerase-II inhibitors do not have a myelodysplastic phase. Cytogenetics testing reveals a translocation that involves chromosome band 11q23. Less commonly, patients developed leukemia with other balanced translocations, such as inversion 16 or t(15;17).
The typical latency period between drug exposure and acute leukemia is approximately 3-5 years for alkylating agents/radiation exposure but only 9-12 months for topoisomerase inhibitors.
DIFFERENTIALSSection 4 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Acute Lymphoblastic Leukemia
Agnogenic Myeloid Metaplasia With Myelofibrosis
Agranulocytosis
Anemia
Aplastic Anemia
Bone Marrow Failure
Chronic Myelogenous Leukemia
Lymphoma, B-Cell
Lymphoma, Lymphoblastic
Myelodysplastic Syndrome
Myelophthisic Anemia
WORKUPSection 5 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Lab Studies
CBC count with differential demonstrates anemia and thrombocytopenia to varying degrees. Patients with acute myelogenous leukemia (AML) can have high, normal, or low WBC counts.
Prothrombin time/activated partial thromboplastin time/fibrinogen/fibrin degradation products
The most common abnormality is disseminated intravascular coagulation (DIC), which results in an elevated prothrombin time, a decreasing fibrinogen level, and the presence of fibrin split products.
Acute promyelocytic leukemia (APL), also known as M3, is the most common subtype of AML associated with DIC.
Peripheral blood smear
Review of peripheral blood smear confirms the findings of the CBC count.
Circulating blasts are usually seen.
Schistocytes are occasionally seen if DIC is present.
Chemistry profile
Most patients with AML have an elevated lactic dehydrogenase level and, frequently, an elevated uric acid level.
Liver function tests and BUN/creatinine level tests are necessary prior to the initiation of therapy.
Appropriate cultures should be obtained in patients with fever or signs of infection, even in the absence of fever.
Perform HLA or DNA typing in patients who are potential candidates for allogeneic transplantation.
Bone marrow aspiration
A blast count can be performed with bone marrow aspiration. Historically, by French-American-British (FAB) classification, AML was defined by the presence of more than 30% blasts in bone marrow. In the newer World Health Organization (WHO) classification, AML is defined as the presence of greater than 20% blasts in the marrow.
The bone marrow aspirate also allows evaluation of the degree of dysplasia in all cell lines.
Flow cytometry (immunophenotyping) can be used to help distinguish AML from acute lymphocytic leukemia (ALL) and further classify the subtype of AML. The immunophenotype correlates with prognosis in some instances.
Cytogenetic studies performed on bone marrow provide important prognostic information and are useful to confirm a diagnosis of APL, which bears the t(15;17) and is treated differently.
Recently, several molecular abnormalities that are not detected with routine cytogenetics have been shown to have prognostic importance in patients with AML. When possible, the bone marrow should be evaluated for the following abnormalities:
Fms-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene in persons with AML and is constitutively activated in one third of AML cases. Internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3 exist in 25% of AML cases. In other cases, mutations exist in the activation loop of FLT3. Most studies demonstrate that patients with AML and FLT3 mutations have a poor prognosis.
Mutations in CEBPA are detected in 15% of patients with normal cytogenetics findings and are associated with a longer remission duration and longer overall survival.
Mutations in nucleophosmin (NPM) are associated with increased response to chemotherapy in patients with a normal karyotype.
Gene-expression profiling is a research tool that allows a comprehensive classification of AML based on the expression pattern of thousands of genes.
Imaging Studies
Chest radiographs help assess for pneumonia and signs of cardiac disease.
Multiple gated acquisition (MUGA) scan is needed once the diagnosis is confirmed because many chemotherapeutic agents used in treatment are cardiotoxic.
Other Tests
Electrocardiography should be performed prior to treatment.
Procedures
Bone marrow aspiration and biopsy are the definitive diagnostic tests.
Aspiration slides are stained for morphology with either Wright or Giemsa stain.
To determine the FAB type of the leukemia, slides are also stained with myeloperoxidase (or Sudan black), terminal deoxynucleotidyl transferase (TdT) (unless performed by another method [eg, flow cytometry]), and double esterase (see Histologic Findings).
Bone marrow samples should also be sent for cytogenetics testing and flow cytometry.
Patients with APL should have their marrow evaluated for the PML/RARa genetic rearrangement.
When possible, the bone marrow should be evaluated for FLT3 mutations.
Histologic Findings
The older, more traditional, FAB classification is as follows:
M0 - Undifferentiated leukemia
M1 - Myeloblastic without differentiation
M2 - Myeloblastic with differentiation
M3 - Promyelocytic
M4 - Myelomonocytic
M4eo - Myelomonocytic with eosinophilia
M5 - Monoblastic leukemia
M5a - Monoblastic without differentiation
M5b - Monocytic with differentiation
M6 - Erythroleukemia
M7 - Megakaryoblastic leukemia
The newer WHO classification is as follows:
AML with recurrent genetic abnormalities
AML with t(8;21)(q22;q22), (AML1/ETO)
AML with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13)(q22), (CBFB/MYH11)
APL with t(15;17)(q22;q12), (PML/RARa) and variants
AML with 11q23 (MLL) abnormalities
AML with multilineage dysplasia
Following myelodysplastic syndrome (MDS) or MDS/myeloproliferative disease (MPD)
Without antecedent MDS or MDS/MPD but with dysplasia in at least 50% of cells in 2 or more lineages
AML and MDS, therapy related
Alkylating agent or radiation-related type
Topoisomerase II inhibitor type
Others
AML, not otherwise classified
AML, minimally differentiated
AML, without maturation
AML, with maturation
Acute myelomonocytic leukemia
Acute monoblastic or monocytic leukemia
Acute erythroid leukemia
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis and myelofibrosis
Myeloid sarcoma
Table 1. Common Cytogenetic Abnormalities in AML
Abnormality Genes Involved Morphology Response
t(8;21)(q22;q22) AML/ETO M2 Good
inv(16)(p13;q22) CBFb/MYH11 M4eo Good
Normal Multiple Varies Intermediate
-7 Multiple Varies Poor
-5 Multiple Varies Poor
+8 Multiple Varies Intermediate-poor
11q23 MLL Varies Intermediate-poor
Miscellaneous Multiple Varies Intermediate-poor
Multiple complex* Multiple Varies Poor
*Refers to 3-5 different cytogenetic abnormalities, depending on the classification used
Table 2. Cytogenetic Abnormalities in APL
Translocation Genes Involved All-Trans-Retinoic Acid Response
t(15;17)(q21;q11) PML/RARa Yes
t(11;17)(q23;q11) PLZF/RARa No
t(11;17)(q13;q11) NuMA/RARa Yes
t(5;17)(q31;q11) NPM/RARa Yes
t(17;17) stat5b/RARa Unknown
Table 3. Immunophenotyping of AML Cells
Marker Lineage
CD13 Myeloid
CD33 Myeloid
CD34 Early precursor
HLA-DR Positive in most AML, negative in APL
CD11b Mature monocytes
CD14 Monocytes
CD41 Platelet glycoprotein IIb/IIIa complex
CD42a Platelet glycoprotein IX
CD42b Platelet glycoprotein Ib
CD61 Platelet glycoprotein IIIa
Glycophorin A Erythroid
TdT Usually indicates acute lymphocytic leukemia, however, may be positive in M0 or M1
CD11c Myeloid
CD117 (c-kit) Myeloid/stem cell
CD56 NK-cell/stem cell
TREATMENTSection 6 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Medical Care
Current standard chemotherapy regimens cure only a minority of patients. As a result, evaluate all patients for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy as described below.
Treatment of acute myelogenous leukemia (excluding acute promyelocytic leukemia)
Induction therapy: Various acceptable induction regimens are available.
The most common approach is called "3 and 7," which consists of 3 days of a 15- to 30-minute infusion of an anthracycline (idarubicin or daunorubicin) or anthracenedione (mitoxantrone), combined with 100 mg/m2 of arabinosylcytosine (araC) as a 24-hour infusion daily for 7 days. Idarubicin is given at a dose of 12 mg/m2/d for 3 days, daunorubicin at 45-60 mg/m2/d for 3 days, or mitoxantrone at 12 mg/m2/d for 3 days.
These regimens require adequate cardiac, hepatic, and renal function.
Using these regimens, approximately 50% of patients achieve remission with one course. Another 10-15% enter remission following a second course of therapy.
Alternatively, high-dose araC combined with idarubicin, daunorubicin, or mitoxantrone can be used as induction therapy in younger patients. The use of high-dose araC outside the setting of a clinical trial is considered controversial. However, 2 studies demonstrated improved disease-free survival rates in younger patients who received high-dose araC during induction.
Consolidation therapy in younger patients: In patients aged 60 years or younger, treatment options for consolidation therapy include high-dose araC, autologous stem cell transplantation, or allogeneic stem cell transplantation.
High-dose araC therapy: Mayer et al conducted a randomized study of 3 different doses of araC in patients with acute myelogenous leukemia (AML) who achieved remission after standard "3 and 7" induction chemotherapy. Patients received 4 courses of araC at one of the following doses: (1) 100 mg/m2/d by continuous infusion for 5 days, (2) 400 mg/m2/d by continuous infusion for 5 days, or (3) 3 g/m2 in a 3-hour infusion every 12 hours on days 1, 3, and 5. The probability of remaining in continuous complete remission (CR) after 4 years in patients aged 60 years or younger was 24% in the 100-mg group, 29% in the 400-mg group, and 44% in the 3-g group (P = .002). The outcome in older patients did not differ. Based on this study, high-dose araC for 4 cycles is a standard option for consolidation therapy in younger patients.
Stem cell transplantation
In order to define the best postremission therapy for young patients, several large, randomized studies have compared allogeneic bone marrow transplantation (BMT), autologous BMT, and chemotherapy without BMT. Unfortunately, the results of these studies are conflicting.
Some studies suggest an advantage to BMT.
In a Dutch study, patients received either allogeneic BMT or autologous BMT based on the availability of a sibling donor matched via human leukocyte antigen (HLA). This study demonstrated a decreased rate of relapse at 3 years for patients receiving allogeneic BMT versus autologous BMT (34% vs 60%, respectively; P = .03) and an increased overall survival rate at 3 years for patients receiving allogeneic BMT versus autologous BMT (66% vs 37%, respectively; P = .05). However, the median age of patients who received allogeneic BMT was 10 years younger that those who received autologous BMT.
In the Medical Research Council AML 10 trial, patients without an HLA-matched donor received 4 courses of intensive chemotherapy followed by either no further treatment or autologous BMT. In this study, the number of relapses was lower for patients receiving autologous BMT versus no further treatment (37% vs 58%, respectively; P <.001), and the rate of disease-free survival at 7 years was improved for patients receiving autologous BMT versus no further treatment (53% vs 40%, respectively; P = .04). However, no improvement in the overall survival rate at 7 years was observed for autologous BMT versus no further treatment (57% vs 45%, respectively; P = .2).
In a European Organization for Research and Treatment of Cancer/Gruppo Italiano Malattie Ematologiche Maligne dell'Adul study, patients with an HLA-identical sibling underwent allogeneic BMT. Other patients randomly received either autologous BMT or a second course of intensive chemotherapy with high-dose araC and daunorubicin. The disease-free survival rate at 4 years was 55% for patients who received allogeneic BMT, 48% for patients who received autologous BMT, and 30% for patients who received intensive chemotherapy (P = .04). Again, the overall survival rate was similar in all 3 groups because patients who relapsed after chemotherapy had a response to subsequent autologous BMT.
Several other studies have failed to show any advantage to BMT.
In a study by Groupe Ouest Est Leucemies Aigues Myeloblastiques, patients as old as 40 years with a matched donor received allogeneic BMT. All other patients received a course of consolidation chemotherapy with high-dose araC and an anthracycline and then randomly received either a second course of consolidation chemotherapy or autologous BMT. In this study, the type of postremission therapy had no effect on outcome.
In a US Intergroup study, patients in remission with a matched donor received allogeneic BMT. Other patients randomly received either autologous BMT or one additional course of high-dose araC. In this study, the survival rate was better for patients receiving chemotherapy without BMT compared with the other groups
In view of these conflicting results, the following recommendations can be made:
Patients with good-risk AML, ie, t(8;21) and inversion of chromosome 16(inv16), have a good prognosis following consolidation with high-dose araC and should be offered such therapy. This is given as araC at 3 g/m2 twice a day on days 1, 3, and 5 of each cycle, repeated monthly (after recovery from the previous cycle) for 4 consolidation cycles. Transplantation should be reserved for patients who relapse.
Patients with high-risk cytogenetics findings are rarely cured with chemotherapy and should be offered transplantation in first remission. However, these patients also are at high risk for relapse following transplantation.
The best approach for patients with intermediate-risk cytogenetics findings is controversial. Some refer patients in first remission for transplantation, whereas others give consolidation chemotherapy with high-dose araC for 4 courses and reserve transplantation for patients who relapse.
Prior to referral for allogeneic transplantation, a suitable donor must be identified. Ideally, this is a fully HLA-matched sibling; however, most patients do not have such a donor. In these patients, alternatives include transplantation using a matched unrelated donor or using cord blood. Newer studies are examining the possibility of transplanting across HLA barriers (ie, with haploidentical-related donors) via intensive conditioning regimens and high doses of infused CD34+ donor cells.
Consolidation therapy in older patients: No standard consolidation therapy exists for patients older than 60 years. Options include a clinical trial, high-dose araC in select patients, or repeat courses of standard-dose anthracycline and araC (2 and 5; ie, 2 d of anthracycline and 5 d of araC). Select patients can be considered for autologous stem cell transplantation or nonmyeloablative allogeneic transplantation.
Nonmyeloablative allogeneic transplantation
Although allogeneic stem cell transplantation is a potentially curative treatment option for patients with AML, all age groups have a significant risk of death from the procedure. The risk of death increases with age, particularly in patients older than age 40 years. However, the median age of patients with AML is 65 years; therefore, only a small percentage of patients with AML are candidates for such aggressive therapy.
Following ablative allogeneic transplantation, death occurs due to sepsis, hemorrhage, direct organ toxicity (particularly affecting the liver; ie, venoocclusive disease [VOD]), and graft versus host disease. In an attempt to reduce these toxicities, several investigators have developed new, less toxic conditioning regimens known as nonmyeloablative transplants or mini-transplants. These transplants use conditioning drugs that are immunosuppressive to allow engraftment of donor cells with less direct organ toxicity than that of standard transplants. Patients who receive these transplants often also have less severe acute graft versus host disease than patients who receive standard transplants. These two factors result in a day 100 mortality rate of less than 10%.
The tolerability of these regimens allows patients aged 70 years or younger to undergo transplantation. However, patients who receive nonmyeloablative transplants still develop significant chronic graft versus host disease, which can be fatal. In addition, relapse rates following nonmyeloablative transplants appear to be higher than those following standard transplants. Further studies are ongoing to determine the best role for these transplants in patients with AML.
Treatment of acute promyelocytic leukemia
Acute promyelocytic leukemia (APL) is a special subtype of AML. APL differs from other subtypes of AML in that patients are, on average, younger (median age 40 y) and most often present with pancytopenia rather than with elevated WBC counts. In fact, WBC counts higher than 5000 cells/µL at presentation are associated with a poor prognosis.
APL is the subtype of AML that is most commonly associated with coagulopathy due to disseminated intravascular coagulation (DIC) and fibrinolysis. Therefore, aggressive supportive care is an important component of the treatment of APL. Platelets should be transfused to maintain a platelet count of at least 30,000/µL (and preferably 50,000/µL). Administer cryoprecipitate to patients whose fibrinogen level is less than 100 g/dL.
The bone marrow demonstrates the presence of more than 30% blasts resembling promyelocytes. These cells contain large dense cytoplasmic granules along with varying numbers of Auer rods.
Although the initial diagnosis is based on morphology, the diagnosis is confirmed based on cytogenetic and molecular studies. Do not delay treatment pending the results of confirmatory tests.
In more than 95% of cases, cytogenetics testing reveals t(15;17)(q21;q11). Molecular studies reveal the PML/RARa rearrangement. Patients with either t(15;17) or the PML/RARa rearrangement respond well to all-trans-retinoic acid (ATRA) and chemotherapy.
A small percentage of patients have other cytogenetic abnormalities, including t(11;17)(q23;q11), t(11;17)(q13;q11), t(5;17)(q31;q11), or t(17;17). Patients with t(11;17)(q23;q11) are resistant to ATRA. Older studies using standard chemotherapy regimens without ATRA showed that approximately 70% of patients achieved CR and 30% were disease free at 5 years. Induction failures were due to deaths resulting from hemorrhage caused by DIC, with few actual resistant cases.
In the 1980s, reports from China, France, and the United States demonstrated that most patients with APL could enter remission with ATRA as the single agent. Unfortunately, in the absence of further therapy, these remissions were short-lived. In addition, a new toxicity, the retinoic acid syndrome, was discovered. The retinoic acid syndrome results from differentiation of leukemic promyelocytic cells into mature polynuclear cells and is characterized by fever, weight gain, pleural and pericardial effusions, and respiratory distress. The syndrome occurs in approximately 25% of patients, and, in the past, was fatal in 9%.
Subsequently, the early addition of chemotherapy resulted in a reduction of deaths caused by retinoic acid syndrome. Studies have also demonstrated that the addition of chemotherapy (idarubicin and araC) to ATRA results in remissions in more than 90% of patients. As many as 70% of these patients are long-term survivors.
Currently, the most standard approach is the combination of ATRA and anthracycline-based chemotherapy. Chemotherapy is most effective when added early in induction (ie, day 3) rather than after attainment of CR. Initiate chemotherapy on day 1 of therapy for patients with high WBC counts (eg, >5000/µL). Once patients with APL are in remission, the standard approach is consolidation therapy with 2 courses of idarubicin and araC. Maintenance therapy with ATRA, 6-MP, and methotrexate is effective in preventing relapses compared with no maintenance therapy; however, the optimal schedule of this therapy is not yet determined.
Patients who relapse can be retreated with chemotherapy plus ATRA, depending on the duration of their first remission and cardiac status. Arsenic trioxide is also highly active. Arsenic trioxide induces CR in 85% of patients. Toxicities include the APL differentiation syndrome (similar to that seen with ATRA), leukocytosis, and abnormalities found on ECG. Evaluate patients in second remission for allogeneic or autologous stem cell transplantation.
Newer studies are examining the need for araC (ie, treatment with idarubicin and ATRA alone) in newly diagnosed patients. For example, the GIMEMA AIDA regimen (ie, idarubicin 12 mg/m2 on days 2, 4, 6, and 8 combined with ATRA 45 mg/m2 daily until remission) yields remissions in 95% of patients.
Another trend is the development of risk-adapted approaches to consolidation therapy. In the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) study, patients with intermediate and high risks of relapse (ie, whose baseline WBC count was >10,000/µL or platelet count was <40,000/µL) received 3 courses of consolidation therapy with ATRA and increased doses of anthracyclines (idarubicin month 1, mitoxantrone month 2, idarubicin month 3).
Other areas of investigation include the use of arsenic in front-line therapy (with or without chemotherapy) and the use of gemtuzumab ozogamicin as consolidation therapy.
Treatment of relapsed acute myelogenous leukemia
Patients with relapsed AML have an extremely poor prognosis. Most patients should be referred for investigational therapies. Young patients who have not previously undergone transplantation should be referred for such therapy.
Estey et al reported that the chances of obtaining a second remission with chemotherapy correlate strongly with the duration of the first remission. Patients with an initial CR duration of longer than 2 years had a 73% CR rate with initial salvage therapy. Patients with an initial CR duration of 1-2 years had a CR rate of 47% with initial salvage therapy. Patients with an initial CR duration of less than 1 year or with no initial CR had a 14% CR rate with initial salvage therapy. Patients with an initial CR duration of less than 1 year (or no initial CR) who had no response to first-salvage therapy and received a second or subsequent salvage therapy had a response rate of 0%. These data stress the need to develop new treatment options for these patients.
Newer therapies
Gemtuzumab ozogamicin
Gemtuzumab ozogamicin is a monoclonal antibody against CD33 (a molecule present on most AML cells but not on normal stem cells) conjugated to calicheamicin (a potent chemotherapy molecule). Gemtuzumab ozogamicin is currently approved by the Food and Drug Administration in the United States for the treatment of patients with CD33-positive AML in first relapse who are aged 60 years or older and who are not considered candidates for other cytotoxic chemotherapy.
Sievers reported the results of gemtuzumab ozogamicin administration in 142 patients with AML who were in their first relapse and who had no history of an antecedent hematologic disorder (AHD). Sixteen percent of patients obtained a formal complete response. An additional 13% of patients met criteria for complete response but did not have the required platelet recovery. Toxicity included infusion reactions, myelosuppression, and hepatic toxicity.
Later studies have shown that use of gemtuzumab ozogamicin either prior to or following stem cell transplantation is associated with an increased risk of VOD. Additional studies have demonstrated that VOD occurs in patients who receive gemtuzumab ozogamicin but do not undergo stem cell transplantation. Newer studies are investigating the use of gemtuzumab ozogamicin in combination with other chemotherapy agents and in patients with newly diagnosed AML. Although gemtuzumab ozogamicin is an active drug, the response rate is lower than that obtained with standard "3 and 7" chemotherapy.
Investigational therapies
A number of new drugs are currently in clinical trials. The two most promising areas are farnesyl transferase inhibitors and drugs that target FLT3.
Farnesyl transferase inhibitors target ras, a molecule that is involved in the pathophysiology of various hematologic malignancies. Two drugs of this type, tipifarnib and lonafarnib, are currently undergoing clinical trials. Early results have demonstrated responses in 15-30% of patients with minimal toxicity.
Drugs that target FLT3, such as MLN518 and PKC412, are also currently being studied.
Supportive care
Replacement of blood products
Patients with AML have a deficiency in the ability to produce normal blood cells and, therefore, need replacement therapy. The addition of chemotherapy temporarily worsens this deficiency. All blood products should be irradiated to prevent transfusion-related graft-versus-host disease that is almost invariably fatal.
Packed red blood cells are given to patients with a hemoglobin level of less than 7-8 g/dL or at a higher level if the patient has significant cardiovascular or respiratory compromise.
Platelets should be transfused if the level is less than 10,000-20,000 cells/µL. Patients with pulmonary or gastrointestinal hemorrhage should receive platelet transfusions to maintain a value greater than 50,000 cells/µL. Patients with CNS hemorrhage should be transfused until they achieve a platelet count of 100,000 cells/µL. Patients with APL should have their platelet count maintained at more than 50,000 cells/µL, at least until evidence of DIC has resolved.
Fresh frozen plasma should be given to patients with a significantly prolonged prothrombin time, and cryoprecipitate should be given if the fibrinogen level is less than 100 g/dL.
Antibiotics
Intravenous antibiotics should be given to all febrile patients.
At minimum, antibiotics should include broad-spectrum coverage such as that provided by a third-generation cephalosporin with or without vancomycin.
In addition to this minimum, additional antibiotics should be given to treat specific documented or suspected infections.
Patients with persistent fever after 3-5 days of antibacterial antibiotics should receive antifungal antibiotics. In the past, amphotericin was the standard antifungal antibiotic. Patients with fever but without a focus of infection received amphotericin at a dose of 0.5 mg/kg. Patients with sinopulmonary symptoms received 1 mg/kg. In the past few years, a number of other antifungal agents have become available. These include the lipid-preparation amphotericins (Abelcet and AmBisome), newer azoles (voriconazole), and the echinocandins (caspofungin and micafungin). These drugs have varying roles in the treatment of neutropenic patients with either suspected or proven fungal infections.
The use of prophylactic antibiotics in neutropenic patients who are not febrile is controversial; however, many clinicians prescribe them to patients undergoing induction therapy. A commonly used regimen is ciprofloxacin at 500 mg orally twice daily, fluconazole (Diflucan) at 200 mg orally daily, and acyclovir at 200 mg orally 5 times a day.
Once patients receiving these antibiotics become febrile, the regimen is changed to intravenous antibiotics as indicated above.
Allopurinol at 300 mg should be given 1-3 times a day during induction therapy until clearance of blasts and resolution of hyperuricemia. For patients who cannot tolerate oral medications, intravenous drugs such as rasburicase are an option.
Use of growth factors as supportive care
Several randomized studies have been performed that attempted to determine the effect of growth factors on induction therapy.
In an early Japanese study, patients with poor-risk acute leukemia randomly received either granulocyte colony-stimulating factor (G-CSF) derived from Escherichia coli or no drug. Patients in the G-CSF group had a faster neutrophil recovery than those receiving no drug (20 d vs 28 d, respectively), decreased febrile days (3 d vs 7 d, respectively), and fewer documented infections. No significant difference in response rate or remission duration was observed between the 2 groups.
In a French study of G-CSF, the duration of neutropenia was shorter (21 d vs 27 d, respectively) and the CR rate higher (70% vs 47%, respectively); however, the overall survival rate was unaffected.
In a Southwestern Oncology Group study, a decrease was observed in the time to neutrophil recovery and days with fever; however, no difference in CR rate and overall survival rate was observed for patients receiving G-CSF versus no drug.
Other groups have studied the effect of granulocyte macrophage colony-stimulating factor (GM-CSF) on induction therapy.
In an Eastern Cooperative Oncology Group study of yeast-derived GM-CSF in elderly patients with AML, no significant increase in response rate was observed; however, a significant decrease in the death rate from pneumonia and fungal infection was observed. Neutrophil recovery rate was increased in the GM-CSF group (14 d vs 21 d, respectively), and overall survival was significantly improved (323 d vs 145 d, respectively; P = .048).
In a study by the Cancer and Leukemia Group B of GM-CSF that was derived from E coli, no difference was observed in response rates for the 2 groups. The risk of severe infection and resistant leukemia was similar in the 2 groups. However, in a European Organization for Research and Treatment of Cancer study using GM-CSF derived from E coli, patients who randomly received GM-CSF after induction had a significantly lower CR rate compared to patients who did not receive GM-CSF (48% vs 77%, respectively).
These data suggest that G-CSF and yeast-derived GM-CSF accelerate neutrophil recovery and decrease the risk of infection in patients with AML undergoing induction therapy. For this reason, most clinicians use either of these growth factors in patients who are at high risk for complications from infection.
Surgical Care
Placement of a central venous catheter (eg, triple lumen, Broviac, Hickman) is necessary.
Diet
Patients should be on a neutropenic diet (ie, no fresh fruits or vegetables). All foods should be cooked. Meats should be cooked completely (ie, well done).
Activity
Patients should limit their activity to what is tolerable, with no strenuous activities (eg, lifting, exercise).
MEDICATIONSection 7 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Medications cause severe bone marrow depression. Only physicians specifically trained in their use should use them. In addition, access to appropriate supportive care (ie, blood banking) is required.
Drug Category: Antineoplastics
These agents are used for induction or consolidation therapy.
Drug Name Cytosine arabinoside, cytarabine (Cytosar-U)
Description Antimetabolite specific for cells in the S-phase of the cell cycle. Acts through inhibition of DNA polymerase and cytosine incorporation into DNA and RNA.
Adult Dose 100 mg/m2/d IV as a 24-h continuous infusion for 7 d
3 g/m2/d IV as a 3-h infusion bid on d 1, 3, and 5
Pediatric Dose 100-200 mg/m2/d IV for 5-10 d
Contraindications Documented hypersensitivity; relatively contraindicated in pregnancy; dose reduction may be required in patients with hepatic insufficiency
Interactions Decreases effects of gentamicin and flucytosine; other alkylating agents and radiation increase cytarabine toxicity
Pregnancy D - Unsafe in pregnancy
Precautions Should be administered only by physicians specifically trained to prescribe antineoplastic agents; if a significant increase in bone marrow suppression occurs, reduce number of days of treatment; patients with hepatic or renal insufficiencies are at a higher risk for CNS toxicity after a high dose; exercise caution with these patients by reducing the dose
Drug Name Daunorubicin (Cerubidine)
Description Topoisomerase-II inhibitor. Inhibits DNA and RNA synthesis by intercalating between DNA base pairs.
Adult Dose 45-60 mg/m2/d IV as a 15- to 30-min infusion for 3 d
Pediatric Dose 35-45 mg/2/d IV for 3 d
Contraindications Documented hypersensitivity; congestive heart failure or reduced ejection fraction; relatively contraindicated in pregnancy
Interactions None reported
Pregnancy D - Unsafe in pregnancy
Precautions Should be administered only by physicians specifically trained to prescribe antineoplastic agents; extravasation may occur, resulting in severe tissue necrosis; caution with patients with impaired hepatic, renal, or biliary function; significant dose reduction required in hepatic or renal insufficiency
Drug Name Idarubicin (Idamycin)
Description Topoisomerase-II inhibitor. Inhibits cell proliferation by inhibiting DNA and RNA polymerase.
Adult Dose 12 mg/m2/d IV as a 15- to 30-min infusion for 3 d
Pediatric Dose 10-12 mg/m2/d IV for 3 d and repeat q3wk
Contraindications Documented hypersensitivity; patients with congestive heart failure or reduced ejection fraction; relatively contraindicated in pregnancy
Interactions None reported
Pregnancy D - Unsafe in pregnancy
Precautions Should be administered only by physicians specifically trained to prescribe antineoplastic agents; extravasation can result in severe tissue necrosis; caution in preexisting cardiac disease and impaired hepatic function; significant dose reduction required in hepatic or renal insufficiency
Drug Name Mitoxantrone (Novantrone)
Description Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II.
Adult Dose 12 mg/m2/d IV as a 15- to 30-min infusion for 3 d
Pediatric Dose 18-20 mg/m2 IV q3-4wk
Contraindications Documented hypersensitivity; relatively contraindicated in pregnancy; significant dose reduction required in hepatic or renal insufficiency; congestive heart failure or a reduced ejection fraction
Interactions None reported
Pregnancy D - Unsafe in pregnancy
Precautions Caution in impaired hepatic function and preexisting cardiac disease (cardiotoxicity commonly observed after cumulative dose of 120-160 mg/m2); perform baseline and follow-up cardiac function tests (2-d echo and ejection fraction measurements)
Drug Name Gemtuzumab ozogamicin (Mylotarg)
Description Chemotherapy agent composed of a recombinant humanized IgG4, k antibody against CD33 conjugated with a cytotoxic antitumor antibiotic, calicheamicin. After binding to the cell, the released calicheamicin derivative binds to DNA in the minor groove, resulting in DNA double-strand breaks and cell death.
Adult Dose 9 mg/m2 IV over 2 h; give total of 2 doses 14 d apart; full hematologic recovery not necessary for administration of second dose; administer 50 mg diphenhydramine PO and 650-1000 mg acetaminophen PO 1 h prior to administration of each dose; may consider leukoreduction with hydroxyurea or leukapheresis to reduce peripheral WBC count to <30,000/µL prior to administration of Mylotarg; full recovery from hematologic toxicities not a requirement for administration of second dose
Pediatric Dose Not established
Contraindications Documented hypersensitivity to drug or calicheamicin derivatives; presence of anti-CD33 antibody
Interactions None reported; potential for drug-drug interaction with drugs affected by cytochrome P450 enzymes may not be ruled out
Pregnancy D - Unsafe in pregnancy
Precautions Postinfusion reactions include hypotension, fever, chills, or dyspnea (acetaminophen, intravenous fluids, and diphenhydramine may be administered to reduce incidence); severe myelosuppression occurs in all patients at recommended dosages; caution in patients with renal and hepatic impairment; tumor lysis may occur (risk may be reduced by administering allopurinol prophylactically and maintaining adequate hydration); should be administered under supervision of physicians experienced in treatment of acute leukemia and in facilities equipped to monitor and treat patients with leukemia; Mylotarg administration can result in severe hypersensitivity reactions (including anaphylaxis) and other infusion-related reactions, which may include severe pulmonary events (infrequently, hypersensitivity reactions and pulmonary events have been fatal); in most cases, infusion-related symptoms occurred during infusion or within 24 h of administration of Mylotarg and resolved; infusion should be interrupted for patientswho
experience dyspnea or clinically significant hypotension; monitor patients until signs and symptoms completely resolve; consider discontinuation of treatment for patients who develop anaphylaxis, pulmonary edema, or acute respiratory distress syndrome
Since patients with high peripheral blast counts may be at greater risk for pulmonary events and tumor lysis syndrome, physicians should consider leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral white count to <30,000/µL prior to administration of Mylotarg; hepatotoxicity, including severe hepatic venoocclusive disease (VOD), has been reported in association with use of Mylotarg as single agent, as part of a combination chemotherapy regimen, and in patients without history of liver disease or hematopoietic stem cell transplantation (HSCT); patients who receive Mylotarg either before or after HSCT, patients with underlying hepatic disease or abnormal liver function, and patients who receive Mylotarg in combinations with other chemotherapy are at increased risk for developing VOD, including severe VOD; death from liver failure and from VOD have been reported in patients who received Mylotarg; monitor for symptoms of hepatotoxicity, particularly VOD, which include rapid weight gain,right upper quadrant pain, hepatomegaly, ascites, elevations in bilirubin and liver enzymes
Drug Name Arsenic trioxide (Trisenox)
Description Used in patients with relapsed APL. The mechanism of action of Trisenox is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML-RAR alpha.
Adult Dose Induction: 0.15 mg/kg/d IV until bone marrow remission occurs; maximum induction is 60 doses
Consolidation: 0.15 mg/kg/d IV starting 3-6 wk after completion of induction therapy; maximum consolidation is 25 doses over 5 wk
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions Electrolyte abnormalities may occur if used concomitantly with diuretics or amphotericin B; concurrent use with QTc-prolonging agents (type Ia and type II antiarrhythmic agents, cisapride, thioridazine, selected quinolones) may increase risk of potentially fatal arrhythmias
Pregnancy D - Unsafe in pregnancy
Precautions Correct electrolyte abnormalities prior to treatment and monitor potassium and magnesium levels during therapy; may prolong QT interval; discontinue therapy and hospitalize patient if QTc >500 ms or if syncope or irregular heartbeats develop during therapy; may lead to torsade de pointes or complete AV block (risk factors include congestive heart failure, history of torsade de pointes, preexisting QT interval prolongation, use of potassium-wasting diuretics, conditions that cause hypokalemia or hypomagnesemia)
FOLLOW-UPSection 8 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Further Inpatient Care
Patients require readmission for consolidation chemotherapy or for the management of toxic effects of chemotherapy.
Further Outpatient Care
Patients should come to the office for monitoring of disease status and chemotherapy effects.
Transfer
Patients are best treated at a center whose staff has significant experience in the treatment of leukemia. Patients should be transferred to an appropriate (generally tertiary care) hospital if they are admitted to hospitals without appropriate blood product support, leukapheresis capabilities, or physicians and nurses familiar with the treatment of leukemia patients.
Deterrence/Prevention
While receiving chemotherapy, patients should avoid exposure to crowds and people with contagious illnesses, especially children with viral infections.
Complications
Death may occur because of uncontrolled infection or hemorrhage. This may happen even after use of appropriate blood product and antibiotic support.
The most common complication is failure of the leukemia to respond to chemotherapy. The prognosis for these patients is poor because they usually do not respond to other chemotherapy regimens.
Prognosis
Prognosis relies on several factors.
Increasing age is an adverse factor because older patients more frequently have a prior antecedent hematologic disorder (AHD) along with comorbid medical conditions that compromise the ability to give full doses of chemotherapy.
Prior AHD is associated with a poor outcome to therapy. The most common AHD is myelodysplastic syndrome (MDS).
Cytogenetic analysis of the bone marrow is one of the most important prognostic factors. Patients with t(8;21), t(15;17) or inversion 16 have the best prognosis, with long-term survival rates of approximately 65%. Patients with normal cytogenetics findings have an intermediate prognosis and have a long-term survival rate of approximately 25%. Patients with poor-risk cytogenetics findings (especially -7, -5) have a poor prognosis, with a long-term survival rate of less than 10%.
Other cytogenetic abnormalities, including +8, 11q23, and miscellaneous, have been reported to be intermediate-risk in some series and poor-risk in others.
The presence of an FLT3 mutation is associated with a poorer prognosis. Mutations in CEBPA are associated with a longer remission duration and longer overall survival. Mutations in NPM are associated with an increased response to chemotherapy.
Patient Education
Patients should be instructed to call immediately if they are febrile or have signs of bleeding.
For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education articles Leukemia and Bruises.
MISCELLANEOUSSection 9 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Medical/Legal Pitfalls
The most important medical legal pitfall is the failure to rapidly distinguish a patient with acute leukemia from patients with less urgent hematologic disorders. Pancytopenia, for example, can be caused by a large variety of diseases of varying severity, including vitamin deficiencies and autoimmune disease. However, pancytopenia due to acute promyelocytic leukemia (APL) is a life-threatening emergency that must be aggressively treated immediately. The easiest way to avoid misdiagnosis is to review the peripheral blood smear at the time of initial evaluation of all patients with hematologic disorders.
A second pitfall is failure to immediately treat a patient with neutropenic fever or infection with broad spectrum antibiotics.
A third pitfall is failure to give appropriate transfusion support to a patient with acute leukemia. This includes transfusion of platelets and clotting factors (fresh frozen plasma, cryoprecipitate) as guided by the patient's blood test results and bleeding history. Blood products must be irradiated to prevent transfusion-associated graft versus host disease.
2006 metų
http://www.emedicine...med/topic34.htm
jei neatsidarys:
Background
Acute myelogenous leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow.
Pathophysiology
The underlying pathophysiology consists of a maturational arrest of bone marrow cells in the earliest stages of development. The mechanism of this arrest is under study, but in many cases, it involves the activation of abnormal genes through chromosomal translocations and other genetic abnormalities.
This developmental arrest results in 2 disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. Second, the rapid proliferation of these cells, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, blood, and, frequently, the spleen and liver.
Frequency
United States
Estimates predict 11,960 new cases of AML in the United States in 2005 (6530 men and 5430 women).
International
AML is more commonly diagnosed in developed countries.
Mortality/Morbidity
In 2005, an estimated 9000 deaths will occur in the United States. Of these, 5040 will occur in men and 3960 will occur in women.In adults, treatment results are generally analyzed separately for younger (18-60 y) and older (>60 y) patients.
With current standard chemotherapy regimens, approximately 25-30% of adults younger than 60 years survive longer than 5 years and are considered cured.
Results in older patients are more disappointing, with fewer than 10% of patients surviving long-term.
Race
AML is more common in whites than in other populations.
Sex
AML is more common in men than in women. The difference is even more apparent in older patients. This is likely because myelodysplastic syndromes (MDSs) are more common in men, and advanced MDS frequently evolves into AML. Some have proposed that the increased prevalence of AML in men may be related to occupational exposures.
Age
Prevalence increases with age. The median age of onset is 65 years. However, this disease affects all age groups.
CLINICALSection 3 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
History
Patients present with symptoms resulting from bone marrow failure, organ infiltration with leukemic cells, or both. The time course is variable.
Some patients, particularly younger ones, present with acute symptoms over a few days to 1-2 weeks.
Others have a longer course, with fatigue or other symptoms lasting from weeks to months. A longer course may suggest an antecedent hematologic disorder (AHD) such as myelodysplastic syndrome (MDS).
Symptoms of bone marrow failure are related to anemia, neutropenia, and thrombocytopenia.
The most common symptom of anemia is fatigue. Patients often retrospectively note a decreased energy level over past weeks.
Other symptoms of anemia include dyspnea upon exertion, dizziness, and, in patients with coronary artery disease, anginal chest pain. In fact, myocardial infarction may be the first presenting symptom of acute leukemia in an older patient.
Patients often have decreased neutrophil levels despite an increased total WBC count.
Patients present with fever, which may occur with or without specific documentation of an infection. Patients with the lowest absolute neutrophil counts (ie, <500 cells/µL and especially <100 cells/µL) have the highest risk of infection.
Patients often have a history of upper respiratory infection symptoms that have not improved despite empiric treatment with oral antibiotics.
Patients present with bleeding gums and multiple ecchymoses. Bleeding may be caused by thrombocytopenia, coagulopathy that results from disseminated intravascular coagulation (DIC), or both.
Potentially life-threatening sites of bleeding include the lungs, gastrointestinal tract, and the central nervous system.
Alternatively, symptoms may be the result of organ infiltration with leukemic cells.
The most common sites of infiltration include the spleen, liver, and gums.
Infiltration occurs most commonly in patients with the monocytic subtypes of acute myelogenous leukemia (AML).
Patients with splenomegaly note fullness in the left upper quadrant and early satiety.
Patients with gum infiltration often present to their dentist first. Gingivitis due to neutropenia can cause swollen gums, and thrombocytopenia can cause the gums to bleed.
Patients with markedly elevated WBC counts (>100,000 cells/µL) can present with symptoms of leukostasis (ie, respiratory distress and altered mental status). Leukostasis is a medical emergency that requires immediate intervention.
Patients with a high leukemic cell burden may present with bone pain caused by increased pressure in the bone marrow.
Physical
Physical signs of anemia, including pallor and a cardiac flow murmur, are frequently present.
Fever and other signs of infection can occur, including lung findings of pneumonia.
Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities. Petechiae are small, often punctate, hemorrhagic rashes that are not palpable. Areas of dermal bleeding or bruises (ie, ecchymoses) that are large or present in several areas may indicate a coexistent coagulation disorder such as DIC. Purpura is characterized by flat bruises that are larger than petechiae but smaller than ecchymoses.
Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and, to a lesser degree, lymphadenopathy. Occasionally, patients have skin rashes due to infiltration of the skin with leukemic cells (leukemia cutis). Chloromata are extramedullary deposits of leukemia. Rarely, a bony or soft-tissue chloroma may precede the development of marrow infiltration by AML (granulocytic sarcoma).
Signs relating to leukostasis include respiratory distress and altered mental status.
Causes
Although several factors have been implicated in the causation of AML, most patients who present with de novo AML have no identifiable risk factor.
Antecedent hematologic disorders
The most common risk factor is the presence of an AHD, the most common of which is MDS. MDS is a disease of the bone marrow of unknown etiology that occurs most often in older patients and manifests as progressive cytopenias that occur over months to years.
Patients with low-risk MDS (eg, refractory anemia with normal cytogenetics findings) generally do not develop AML, whereas patients with high-risk MDS (eg, refractory anemia with excess blasts-type 2) frequently do develop AML.
Other AHDs that predispose patients to AML include aplastic anemia, myelofibrosis, paroxysmal nocturnal hemoglobinuria, and polycythemia vera.
Congenital disorders
Some congenital disorders that predispose patients to AML include Bloom syndrome, Down syndrome, congenital neutropenia, Fanconi anemia, and neurofibromatosis.
Usually, these patients develop AML during childhood; rarely, some may present in young adulthood.
More subtle genetic disorders, including polymorphisms of enzymes that metabolize carcinogens, also predispose patients to AML. For example, polymorphisms of NAD(P)H:quinone oxidoreductase (NQO1), an enzyme that metabolizes benzene derivatives, are associated with an increased risk of AML. Particularly increased risk exists for AML that occurs after chemotherapy for another disease or for de novo AML with an abnormality of chromosomes 5, 7, or both. Likewise, polymorphisms in glutathione S-transferase are associated with secondary AML following chemotherapy for other malignancies.
Familial syndromes
Germ-line mutations in the gene AML1 (RUNX1, CBFA2) occur in the familial platelet disorder with predisposition for AML, an autosomal-dominant disorder characterized by moderate thrombocytopenia, a defect in platelet function, and propensity to develop AML.
Mutation of CEBPA (the gene encoding CCAAT/enhancer binding protein, alpha; a granulocytic differentiation factor and member of the bZIP family) was described in a family with 3 members affected by AML.
Some hereditary cancer syndromes, such as Li-Fraumeni syndrome, can manifest as leukemia. However, cases of leukemia are less common than the solid tumors that generally characterize these syndromes.
Environmental exposures
Several studies demonstrate a relationship between radiation exposure and leukemia.
Early radiologists (prior to appropriate shielding) were found to have an increased likelihood of developing leukemia.
Patients receiving therapeutic irradiation for ankylosing spondylitis were at increased risk of leukemia.
Survivors of the atomic bomb explosions in Japan were at a markedly increased risk for the development of leukemia.
Persons who smoke have a small but statistically significant (odds ratio, 1.5) increased risk of developing AML. In several studies, the risk of AML was slightly increased in people who smoked compared with those who did not smoke.
Exposure to benzene is associated with aplastic anemia and pancytopenia. These patients often develop AML. Many of these patients demonstrate M6 morphology.
Prior exposure to chemotherapeutic agents for another malignancy
As more patients with cancer survive their primary malignancy and more patients receive intensive chemotherapy (including bone marrow transplantation [BMT]), the number of patients with AML increases because of exposure to chemotherapeutic agents. For example, the cumulative incidence of acute leukemia in patients with breast cancer who were treated with doxorubicin and cyclophosphamide as adjuvant therapy was 0.2-1.0% at 5 years.
Patients with prior exposure to chemotherapeutic agents can be divided into 2 groups: (1) those with prior exposure to alkylating agents and (2) those with exposure to topoisomerase-II inhibitors.
Patients with a prior exposure to alkylating agents, with or without radiation, often have a myelodysplastic phase prior to the development of AML. Cytogenetics testing frequently reveals -5 and/or -7 (5q- or monosomy 7).
Patients with a prior exposure to topoisomerase-II inhibitors do not have a myelodysplastic phase. Cytogenetics testing reveals a translocation that involves chromosome band 11q23. Less commonly, patients developed leukemia with other balanced translocations, such as inversion 16 or t(15;17).
The typical latency period between drug exposure and acute leukemia is approximately 3-5 years for alkylating agents/radiation exposure but only 9-12 months for topoisomerase inhibitors.
DIFFERENTIALSSection 4 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Acute Lymphoblastic Leukemia
Agnogenic Myeloid Metaplasia With Myelofibrosis
Agranulocytosis
Anemia
Aplastic Anemia
Bone Marrow Failure
Chronic Myelogenous Leukemia
Lymphoma, B-Cell
Lymphoma, Lymphoblastic
Myelodysplastic Syndrome
Myelophthisic Anemia
WORKUPSection 5 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Lab Studies
CBC count with differential demonstrates anemia and thrombocytopenia to varying degrees. Patients with acute myelogenous leukemia (AML) can have high, normal, or low WBC counts.
Prothrombin time/activated partial thromboplastin time/fibrinogen/fibrin degradation products
The most common abnormality is disseminated intravascular coagulation (DIC), which results in an elevated prothrombin time, a decreasing fibrinogen level, and the presence of fibrin split products.
Acute promyelocytic leukemia (APL), also known as M3, is the most common subtype of AML associated with DIC.
Peripheral blood smear
Review of peripheral blood smear confirms the findings of the CBC count.
Circulating blasts are usually seen.
Schistocytes are occasionally seen if DIC is present.
Chemistry profile
Most patients with AML have an elevated lactic dehydrogenase level and, frequently, an elevated uric acid level.
Liver function tests and BUN/creatinine level tests are necessary prior to the initiation of therapy.
Appropriate cultures should be obtained in patients with fever or signs of infection, even in the absence of fever.
Perform HLA or DNA typing in patients who are potential candidates for allogeneic transplantation.
Bone marrow aspiration
A blast count can be performed with bone marrow aspiration. Historically, by French-American-British (FAB) classification, AML was defined by the presence of more than 30% blasts in bone marrow. In the newer World Health Organization (WHO) classification, AML is defined as the presence of greater than 20% blasts in the marrow.
The bone marrow aspirate also allows evaluation of the degree of dysplasia in all cell lines.
Flow cytometry (immunophenotyping) can be used to help distinguish AML from acute lymphocytic leukemia (ALL) and further classify the subtype of AML. The immunophenotype correlates with prognosis in some instances.
Cytogenetic studies performed on bone marrow provide important prognostic information and are useful to confirm a diagnosis of APL, which bears the t(15;17) and is treated differently.
Recently, several molecular abnormalities that are not detected with routine cytogenetics have been shown to have prognostic importance in patients with AML. When possible, the bone marrow should be evaluated for the following abnormalities:
Fms-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene in persons with AML and is constitutively activated in one third of AML cases. Internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3 exist in 25% of AML cases. In other cases, mutations exist in the activation loop of FLT3. Most studies demonstrate that patients with AML and FLT3 mutations have a poor prognosis.
Mutations in CEBPA are detected in 15% of patients with normal cytogenetics findings and are associated with a longer remission duration and longer overall survival.
Mutations in nucleophosmin (NPM) are associated with increased response to chemotherapy in patients with a normal karyotype.
Gene-expression profiling is a research tool that allows a comprehensive classification of AML based on the expression pattern of thousands of genes.
Imaging Studies
Chest radiographs help assess for pneumonia and signs of cardiac disease.
Multiple gated acquisition (MUGA) scan is needed once the diagnosis is confirmed because many chemotherapeutic agents used in treatment are cardiotoxic.
Other Tests
Electrocardiography should be performed prior to treatment.
Procedures
Bone marrow aspiration and biopsy are the definitive diagnostic tests.
Aspiration slides are stained for morphology with either Wright or Giemsa stain.
To determine the FAB type of the leukemia, slides are also stained with myeloperoxidase (or Sudan black), terminal deoxynucleotidyl transferase (TdT) (unless performed by another method [eg, flow cytometry]), and double esterase (see Histologic Findings).
Bone marrow samples should also be sent for cytogenetics testing and flow cytometry.
Patients with APL should have their marrow evaluated for the PML/RARa genetic rearrangement.
When possible, the bone marrow should be evaluated for FLT3 mutations.
Histologic Findings
The older, more traditional, FAB classification is as follows:
M0 - Undifferentiated leukemia
M1 - Myeloblastic without differentiation
M2 - Myeloblastic with differentiation
M3 - Promyelocytic
M4 - Myelomonocytic
M4eo - Myelomonocytic with eosinophilia
M5 - Monoblastic leukemia
M5a - Monoblastic without differentiation
M5b - Monocytic with differentiation
M6 - Erythroleukemia
M7 - Megakaryoblastic leukemia
The newer WHO classification is as follows:
AML with recurrent genetic abnormalities
AML with t(8;21)(q22;q22), (AML1/ETO)
AML with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13)(q22), (CBFB/MYH11)
APL with t(15;17)(q22;q12), (PML/RARa) and variants
AML with 11q23 (MLL) abnormalities
AML with multilineage dysplasia
Following myelodysplastic syndrome (MDS) or MDS/myeloproliferative disease (MPD)
Without antecedent MDS or MDS/MPD but with dysplasia in at least 50% of cells in 2 or more lineages
AML and MDS, therapy related
Alkylating agent or radiation-related type
Topoisomerase II inhibitor type
Others
AML, not otherwise classified
AML, minimally differentiated
AML, without maturation
AML, with maturation
Acute myelomonocytic leukemia
Acute monoblastic or monocytic leukemia
Acute erythroid leukemia
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis and myelofibrosis
Myeloid sarcoma
Table 1. Common Cytogenetic Abnormalities in AML
Abnormality Genes Involved Morphology Response
t(8;21)(q22;q22) AML/ETO M2 Good
inv(16)(p13;q22) CBFb/MYH11 M4eo Good
Normal Multiple Varies Intermediate
-7 Multiple Varies Poor
-5 Multiple Varies Poor
+8 Multiple Varies Intermediate-poor
11q23 MLL Varies Intermediate-poor
Miscellaneous Multiple Varies Intermediate-poor
Multiple complex* Multiple Varies Poor
*Refers to 3-5 different cytogenetic abnormalities, depending on the classification used
Table 2. Cytogenetic Abnormalities in APL
Translocation Genes Involved All-Trans-Retinoic Acid Response
t(15;17)(q21;q11) PML/RARa Yes
t(11;17)(q23;q11) PLZF/RARa No
t(11;17)(q13;q11) NuMA/RARa Yes
t(5;17)(q31;q11) NPM/RARa Yes
t(17;17) stat5b/RARa Unknown
Table 3. Immunophenotyping of AML Cells
Marker Lineage
CD13 Myeloid
CD33 Myeloid
CD34 Early precursor
HLA-DR Positive in most AML, negative in APL
CD11b Mature monocytes
CD14 Monocytes
CD41 Platelet glycoprotein IIb/IIIa complex
CD42a Platelet glycoprotein IX
CD42b Platelet glycoprotein Ib
CD61 Platelet glycoprotein IIIa
Glycophorin A Erythroid
TdT Usually indicates acute lymphocytic leukemia, however, may be positive in M0 or M1
CD11c Myeloid
CD117 (c-kit) Myeloid/stem cell
CD56 NK-cell/stem cell
TREATMENTSection 6 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Medical Care
Current standard chemotherapy regimens cure only a minority of patients. As a result, evaluate all patients for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy as described below.
Treatment of acute myelogenous leukemia (excluding acute promyelocytic leukemia)
Induction therapy: Various acceptable induction regimens are available.
The most common approach is called "3 and 7," which consists of 3 days of a 15- to 30-minute infusion of an anthracycline (idarubicin or daunorubicin) or anthracenedione (mitoxantrone), combined with 100 mg/m2 of arabinosylcytosine (araC) as a 24-hour infusion daily for 7 days. Idarubicin is given at a dose of 12 mg/m2/d for 3 days, daunorubicin at 45-60 mg/m2/d for 3 days, or mitoxantrone at 12 mg/m2/d for 3 days.
These regimens require adequate cardiac, hepatic, and renal function.
Using these regimens, approximately 50% of patients achieve remission with one course. Another 10-15% enter remission following a second course of therapy.
Alternatively, high-dose araC combined with idarubicin, daunorubicin, or mitoxantrone can be used as induction therapy in younger patients. The use of high-dose araC outside the setting of a clinical trial is considered controversial. However, 2 studies demonstrated improved disease-free survival rates in younger patients who received high-dose araC during induction.
Consolidation therapy in younger patients: In patients aged 60 years or younger, treatment options for consolidation therapy include high-dose araC, autologous stem cell transplantation, or allogeneic stem cell transplantation.
High-dose araC therapy: Mayer et al conducted a randomized study of 3 different doses of araC in patients with acute myelogenous leukemia (AML) who achieved remission after standard "3 and 7" induction chemotherapy. Patients received 4 courses of araC at one of the following doses: (1) 100 mg/m2/d by continuous infusion for 5 days, (2) 400 mg/m2/d by continuous infusion for 5 days, or (3) 3 g/m2 in a 3-hour infusion every 12 hours on days 1, 3, and 5. The probability of remaining in continuous complete remission (CR) after 4 years in patients aged 60 years or younger was 24% in the 100-mg group, 29% in the 400-mg group, and 44% in the 3-g group (P = .002). The outcome in older patients did not differ. Based on this study, high-dose araC for 4 cycles is a standard option for consolidation therapy in younger patients.
Stem cell transplantation
In order to define the best postremission therapy for young patients, several large, randomized studies have compared allogeneic bone marrow transplantation (BMT), autologous BMT, and chemotherapy without BMT. Unfortunately, the results of these studies are conflicting.
Some studies suggest an advantage to BMT.
In a Dutch study, patients received either allogeneic BMT or autologous BMT based on the availability of a sibling donor matched via human leukocyte antigen (HLA). This study demonstrated a decreased rate of relapse at 3 years for patients receiving allogeneic BMT versus autologous BMT (34% vs 60%, respectively; P = .03) and an increased overall survival rate at 3 years for patients receiving allogeneic BMT versus autologous BMT (66% vs 37%, respectively; P = .05). However, the median age of patients who received allogeneic BMT was 10 years younger that those who received autologous BMT.
In the Medical Research Council AML 10 trial, patients without an HLA-matched donor received 4 courses of intensive chemotherapy followed by either no further treatment or autologous BMT. In this study, the number of relapses was lower for patients receiving autologous BMT versus no further treatment (37% vs 58%, respectively; P <.001), and the rate of disease-free survival at 7 years was improved for patients receiving autologous BMT versus no further treatment (53% vs 40%, respectively; P = .04). However, no improvement in the overall survival rate at 7 years was observed for autologous BMT versus no further treatment (57% vs 45%, respectively; P = .2).
In a European Organization for Research and Treatment of Cancer/Gruppo Italiano Malattie Ematologiche Maligne dell'Adul study, patients with an HLA-identical sibling underwent allogeneic BMT. Other patients randomly received either autologous BMT or a second course of intensive chemotherapy with high-dose araC and daunorubicin. The disease-free survival rate at 4 years was 55% for patients who received allogeneic BMT, 48% for patients who received autologous BMT, and 30% for patients who received intensive chemotherapy (P = .04). Again, the overall survival rate was similar in all 3 groups because patients who relapsed after chemotherapy had a response to subsequent autologous BMT.
Several other studies have failed to show any advantage to BMT.
In a study by Groupe Ouest Est Leucemies Aigues Myeloblastiques, patients as old as 40 years with a matched donor received allogeneic BMT. All other patients received a course of consolidation chemotherapy with high-dose araC and an anthracycline and then randomly received either a second course of consolidation chemotherapy or autologous BMT. In this study, the type of postremission therapy had no effect on outcome.
In a US Intergroup study, patients in remission with a matched donor received allogeneic BMT. Other patients randomly received either autologous BMT or one additional course of high-dose araC. In this study, the survival rate was better for patients receiving chemotherapy without BMT compared with the other groups
In view of these conflicting results, the following recommendations can be made:
Patients with good-risk AML, ie, t(8;21) and inversion of chromosome 16(inv16), have a good prognosis following consolidation with high-dose araC and should be offered such therapy. This is given as araC at 3 g/m2 twice a day on days 1, 3, and 5 of each cycle, repeated monthly (after recovery from the previous cycle) for 4 consolidation cycles. Transplantation should be reserved for patients who relapse.
Patients with high-risk cytogenetics findings are rarely cured with chemotherapy and should be offered transplantation in first remission. However, these patients also are at high risk for relapse following transplantation.
The best approach for patients with intermediate-risk cytogenetics findings is controversial. Some refer patients in first remission for transplantation, whereas others give consolidation chemotherapy with high-dose araC for 4 courses and reserve transplantation for patients who relapse.
Prior to referral for allogeneic transplantation, a suitable donor must be identified. Ideally, this is a fully HLA-matched sibling; however, most patients do not have such a donor. In these patients, alternatives include transplantation using a matched unrelated donor or using cord blood. Newer studies are examining the possibility of transplanting across HLA barriers (ie, with haploidentical-related donors) via intensive conditioning regimens and high doses of infused CD34+ donor cells.
Consolidation therapy in older patients: No standard consolidation therapy exists for patients older than 60 years. Options include a clinical trial, high-dose araC in select patients, or repeat courses of standard-dose anthracycline and araC (2 and 5; ie, 2 d of anthracycline and 5 d of araC). Select patients can be considered for autologous stem cell transplantation or nonmyeloablative allogeneic transplantation.
Nonmyeloablative allogeneic transplantation
Although allogeneic stem cell transplantation is a potentially curative treatment option for patients with AML, all age groups have a significant risk of death from the procedure. The risk of death increases with age, particularly in patients older than age 40 years. However, the median age of patients with AML is 65 years; therefore, only a small percentage of patients with AML are candidates for such aggressive therapy.
Following ablative allogeneic transplantation, death occurs due to sepsis, hemorrhage, direct organ toxicity (particularly affecting the liver; ie, venoocclusive disease [VOD]), and graft versus host disease. In an attempt to reduce these toxicities, several investigators have developed new, less toxic conditioning regimens known as nonmyeloablative transplants or mini-transplants. These transplants use conditioning drugs that are immunosuppressive to allow engraftment of donor cells with less direct organ toxicity than that of standard transplants. Patients who receive these transplants often also have less severe acute graft versus host disease than patients who receive standard transplants. These two factors result in a day 100 mortality rate of less than 10%.
The tolerability of these regimens allows patients aged 70 years or younger to undergo transplantation. However, patients who receive nonmyeloablative transplants still develop significant chronic graft versus host disease, which can be fatal. In addition, relapse rates following nonmyeloablative transplants appear to be higher than those following standard transplants. Further studies are ongoing to determine the best role for these transplants in patients with AML.
Treatment of acute promyelocytic leukemia
Acute promyelocytic leukemia (APL) is a special subtype of AML. APL differs from other subtypes of AML in that patients are, on average, younger (median age 40 y) and most often present with pancytopenia rather than with elevated WBC counts. In fact, WBC counts higher than 5000 cells/µL at presentation are associated with a poor prognosis.
APL is the subtype of AML that is most commonly associated with coagulopathy due to disseminated intravascular coagulation (DIC) and fibrinolysis. Therefore, aggressive supportive care is an important component of the treatment of APL. Platelets should be transfused to maintain a platelet count of at least 30,000/µL (and preferably 50,000/µL). Administer cryoprecipitate to patients whose fibrinogen level is less than 100 g/dL.
The bone marrow demonstrates the presence of more than 30% blasts resembling promyelocytes. These cells contain large dense cytoplasmic granules along with varying numbers of Auer rods.
Although the initial diagnosis is based on morphology, the diagnosis is confirmed based on cytogenetic and molecular studies. Do not delay treatment pending the results of confirmatory tests.
In more than 95% of cases, cytogenetics testing reveals t(15;17)(q21;q11). Molecular studies reveal the PML/RARa rearrangement. Patients with either t(15;17) or the PML/RARa rearrangement respond well to all-trans-retinoic acid (ATRA) and chemotherapy.
A small percentage of patients have other cytogenetic abnormalities, including t(11;17)(q23;q11), t(11;17)(q13;q11), t(5;17)(q31;q11), or t(17;17). Patients with t(11;17)(q23;q11) are resistant to ATRA. Older studies using standard chemotherapy regimens without ATRA showed that approximately 70% of patients achieved CR and 30% were disease free at 5 years. Induction failures were due to deaths resulting from hemorrhage caused by DIC, with few actual resistant cases.
In the 1980s, reports from China, France, and the United States demonstrated that most patients with APL could enter remission with ATRA as the single agent. Unfortunately, in the absence of further therapy, these remissions were short-lived. In addition, a new toxicity, the retinoic acid syndrome, was discovered. The retinoic acid syndrome results from differentiation of leukemic promyelocytic cells into mature polynuclear cells and is characterized by fever, weight gain, pleural and pericardial effusions, and respiratory distress. The syndrome occurs in approximately 25% of patients, and, in the past, was fatal in 9%.
Subsequently, the early addition of chemotherapy resulted in a reduction of deaths caused by retinoic acid syndrome. Studies have also demonstrated that the addition of chemotherapy (idarubicin and araC) to ATRA results in remissions in more than 90% of patients. As many as 70% of these patients are long-term survivors.
Currently, the most standard approach is the combination of ATRA and anthracycline-based chemotherapy. Chemotherapy is most effective when added early in induction (ie, day 3) rather than after attainment of CR. Initiate chemotherapy on day 1 of therapy for patients with high WBC counts (eg, >5000/µL). Once patients with APL are in remission, the standard approach is consolidation therapy with 2 courses of idarubicin and araC. Maintenance therapy with ATRA, 6-MP, and methotrexate is effective in preventing relapses compared with no maintenance therapy; however, the optimal schedule of this therapy is not yet determined.
Patients who relapse can be retreated with chemotherapy plus ATRA, depending on the duration of their first remission and cardiac status. Arsenic trioxide is also highly active. Arsenic trioxide induces CR in 85% of patients. Toxicities include the APL differentiation syndrome (similar to that seen with ATRA), leukocytosis, and abnormalities found on ECG. Evaluate patients in second remission for allogeneic or autologous stem cell transplantation.
Newer studies are examining the need for araC (ie, treatment with idarubicin and ATRA alone) in newly diagnosed patients. For example, the GIMEMA AIDA regimen (ie, idarubicin 12 mg/m2 on days 2, 4, 6, and 8 combined with ATRA 45 mg/m2 daily until remission) yields remissions in 95% of patients.
Another trend is the development of risk-adapted approaches to consolidation therapy. In the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) study, patients with intermediate and high risks of relapse (ie, whose baseline WBC count was >10,000/µL or platelet count was <40,000/µL) received 3 courses of consolidation therapy with ATRA and increased doses of anthracyclines (idarubicin month 1, mitoxantrone month 2, idarubicin month 3).
Other areas of investigation include the use of arsenic in front-line therapy (with or without chemotherapy) and the use of gemtuzumab ozogamicin as consolidation therapy.
Treatment of relapsed acute myelogenous leukemia
Patients with relapsed AML have an extremely poor prognosis. Most patients should be referred for investigational therapies. Young patients who have not previously undergone transplantation should be referred for such therapy.
Estey et al reported that the chances of obtaining a second remission with chemotherapy correlate strongly with the duration of the first remission. Patients with an initial CR duration of longer than 2 years had a 73% CR rate with initial salvage therapy. Patients with an initial CR duration of 1-2 years had a CR rate of 47% with initial salvage therapy. Patients with an initial CR duration of less than 1 year or with no initial CR had a 14% CR rate with initial salvage therapy. Patients with an initial CR duration of less than 1 year (or no initial CR) who had no response to first-salvage therapy and received a second or subsequent salvage therapy had a response rate of 0%. These data stress the need to develop new treatment options for these patients.
Newer therapies
Gemtuzumab ozogamicin
Gemtuzumab ozogamicin is a monoclonal antibody against CD33 (a molecule present on most AML cells but not on normal stem cells) conjugated to calicheamicin (a potent chemotherapy molecule). Gemtuzumab ozogamicin is currently approved by the Food and Drug Administration in the United States for the treatment of patients with CD33-positive AML in first relapse who are aged 60 years or older and who are not considered candidates for other cytotoxic chemotherapy.
Sievers reported the results of gemtuzumab ozogamicin administration in 142 patients with AML who were in their first relapse and who had no history of an antecedent hematologic disorder (AHD). Sixteen percent of patients obtained a formal complete response. An additional 13% of patients met criteria for complete response but did not have the required platelet recovery. Toxicity included infusion reactions, myelosuppression, and hepatic toxicity.
Later studies have shown that use of gemtuzumab ozogamicin either prior to or following stem cell transplantation is associated with an increased risk of VOD. Additional studies have demonstrated that VOD occurs in patients who receive gemtuzumab ozogamicin but do not undergo stem cell transplantation. Newer studies are investigating the use of gemtuzumab ozogamicin in combination with other chemotherapy agents and in patients with newly diagnosed AML. Although gemtuzumab ozogamicin is an active drug, the response rate is lower than that obtained with standard "3 and 7" chemotherapy.
Investigational therapies
A number of new drugs are currently in clinical trials. The two most promising areas are farnesyl transferase inhibitors and drugs that target FLT3.
Farnesyl transferase inhibitors target ras, a molecule that is involved in the pathophysiology of various hematologic malignancies. Two drugs of this type, tipifarnib and lonafarnib, are currently undergoing clinical trials. Early results have demonstrated responses in 15-30% of patients with minimal toxicity.
Drugs that target FLT3, such as MLN518 and PKC412, are also currently being studied.
Supportive care
Replacement of blood products
Patients with AML have a deficiency in the ability to produce normal blood cells and, therefore, need replacement therapy. The addition of chemotherapy temporarily worsens this deficiency. All blood products should be irradiated to prevent transfusion-related graft-versus-host disease that is almost invariably fatal.
Packed red blood cells are given to patients with a hemoglobin level of less than 7-8 g/dL or at a higher level if the patient has significant cardiovascular or respiratory compromise.
Platelets should be transfused if the level is less than 10,000-20,000 cells/µL. Patients with pulmonary or gastrointestinal hemorrhage should receive platelet transfusions to maintain a value greater than 50,000 cells/µL. Patients with CNS hemorrhage should be transfused until they achieve a platelet count of 100,000 cells/µL. Patients with APL should have their platelet count maintained at more than 50,000 cells/µL, at least until evidence of DIC has resolved.
Fresh frozen plasma should be given to patients with a significantly prolonged prothrombin time, and cryoprecipitate should be given if the fibrinogen level is less than 100 g/dL.
Antibiotics
Intravenous antibiotics should be given to all febrile patients.
At minimum, antibiotics should include broad-spectrum coverage such as that provided by a third-generation cephalosporin with or without vancomycin.
In addition to this minimum, additional antibiotics should be given to treat specific documented or suspected infections.
Patients with persistent fever after 3-5 days of antibacterial antibiotics should receive antifungal antibiotics. In the past, amphotericin was the standard antifungal antibiotic. Patients with fever but without a focus of infection received amphotericin at a dose of 0.5 mg/kg. Patients with sinopulmonary symptoms received 1 mg/kg. In the past few years, a number of other antifungal agents have become available. These include the lipid-preparation amphotericins (Abelcet and AmBisome), newer azoles (voriconazole), and the echinocandins (caspofungin and micafungin). These drugs have varying roles in the treatment of neutropenic patients with either suspected or proven fungal infections.
The use of prophylactic antibiotics in neutropenic patients who are not febrile is controversial; however, many clinicians prescribe them to patients undergoing induction therapy. A commonly used regimen is ciprofloxacin at 500 mg orally twice daily, fluconazole (Diflucan) at 200 mg orally daily, and acyclovir at 200 mg orally 5 times a day.
Once patients receiving these antibiotics become febrile, the regimen is changed to intravenous antibiotics as indicated above.
Allopurinol at 300 mg should be given 1-3 times a day during induction therapy until clearance of blasts and resolution of hyperuricemia. For patients who cannot tolerate oral medications, intravenous drugs such as rasburicase are an option.
Use of growth factors as supportive care
Several randomized studies have been performed that attempted to determine the effect of growth factors on induction therapy.
In an early Japanese study, patients with poor-risk acute leukemia randomly received either granulocyte colony-stimulating factor (G-CSF) derived from Escherichia coli or no drug. Patients in the G-CSF group had a faster neutrophil recovery than those receiving no drug (20 d vs 28 d, respectively), decreased febrile days (3 d vs 7 d, respectively), and fewer documented infections. No significant difference in response rate or remission duration was observed between the 2 groups.
In a French study of G-CSF, the duration of neutropenia was shorter (21 d vs 27 d, respectively) and the CR rate higher (70% vs 47%, respectively); however, the overall survival rate was unaffected.
In a Southwestern Oncology Group study, a decrease was observed in the time to neutrophil recovery and days with fever; however, no difference in CR rate and overall survival rate was observed for patients receiving G-CSF versus no drug.
Other groups have studied the effect of granulocyte macrophage colony-stimulating factor (GM-CSF) on induction therapy.
In an Eastern Cooperative Oncology Group study of yeast-derived GM-CSF in elderly patients with AML, no significant increase in response rate was observed; however, a significant decrease in the death rate from pneumonia and fungal infection was observed. Neutrophil recovery rate was increased in the GM-CSF group (14 d vs 21 d, respectively), and overall survival was significantly improved (323 d vs 145 d, respectively; P = .048).
In a study by the Cancer and Leukemia Group B of GM-CSF that was derived from E coli, no difference was observed in response rates for the 2 groups. The risk of severe infection and resistant leukemia was similar in the 2 groups. However, in a European Organization for Research and Treatment of Cancer study using GM-CSF derived from E coli, patients who randomly received GM-CSF after induction had a significantly lower CR rate compared to patients who did not receive GM-CSF (48% vs 77%, respectively).
These data suggest that G-CSF and yeast-derived GM-CSF accelerate neutrophil recovery and decrease the risk of infection in patients with AML undergoing induction therapy. For this reason, most clinicians use either of these growth factors in patients who are at high risk for complications from infection.
Surgical Care
Placement of a central venous catheter (eg, triple lumen, Broviac, Hickman) is necessary.
Diet
Patients should be on a neutropenic diet (ie, no fresh fruits or vegetables). All foods should be cooked. Meats should be cooked completely (ie, well done).
Activity
Patients should limit their activity to what is tolerable, with no strenuous activities (eg, lifting, exercise).
MEDICATIONSection 7 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Medications cause severe bone marrow depression. Only physicians specifically trained in their use should use them. In addition, access to appropriate supportive care (ie, blood banking) is required.
Drug Category: Antineoplastics
These agents are used for induction or consolidation therapy.
Drug Name Cytosine arabinoside, cytarabine (Cytosar-U)
Description Antimetabolite specific for cells in the S-phase of the cell cycle. Acts through inhibition of DNA polymerase and cytosine incorporation into DNA and RNA.
Adult Dose 100 mg/m2/d IV as a 24-h continuous infusion for 7 d
3 g/m2/d IV as a 3-h infusion bid on d 1, 3, and 5
Pediatric Dose 100-200 mg/m2/d IV for 5-10 d
Contraindications Documented hypersensitivity; relatively contraindicated in pregnancy; dose reduction may be required in patients with hepatic insufficiency
Interactions Decreases effects of gentamicin and flucytosine; other alkylating agents and radiation increase cytarabine toxicity
Pregnancy D - Unsafe in pregnancy
Precautions Should be administered only by physicians specifically trained to prescribe antineoplastic agents; if a significant increase in bone marrow suppression occurs, reduce number of days of treatment; patients with hepatic or renal insufficiencies are at a higher risk for CNS toxicity after a high dose; exercise caution with these patients by reducing the dose
Drug Name Daunorubicin (Cerubidine)
Description Topoisomerase-II inhibitor. Inhibits DNA and RNA synthesis by intercalating between DNA base pairs.
Adult Dose 45-60 mg/m2/d IV as a 15- to 30-min infusion for 3 d
Pediatric Dose 35-45 mg/2/d IV for 3 d
Contraindications Documented hypersensitivity; congestive heart failure or reduced ejection fraction; relatively contraindicated in pregnancy
Interactions None reported
Pregnancy D - Unsafe in pregnancy
Precautions Should be administered only by physicians specifically trained to prescribe antineoplastic agents; extravasation may occur, resulting in severe tissue necrosis; caution with patients with impaired hepatic, renal, or biliary function; significant dose reduction required in hepatic or renal insufficiency
Drug Name Idarubicin (Idamycin)
Description Topoisomerase-II inhibitor. Inhibits cell proliferation by inhibiting DNA and RNA polymerase.
Adult Dose 12 mg/m2/d IV as a 15- to 30-min infusion for 3 d
Pediatric Dose 10-12 mg/m2/d IV for 3 d and repeat q3wk
Contraindications Documented hypersensitivity; patients with congestive heart failure or reduced ejection fraction; relatively contraindicated in pregnancy
Interactions None reported
Pregnancy D - Unsafe in pregnancy
Precautions Should be administered only by physicians specifically trained to prescribe antineoplastic agents; extravasation can result in severe tissue necrosis; caution in preexisting cardiac disease and impaired hepatic function; significant dose reduction required in hepatic or renal insufficiency
Drug Name Mitoxantrone (Novantrone)
Description Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II.
Adult Dose 12 mg/m2/d IV as a 15- to 30-min infusion for 3 d
Pediatric Dose 18-20 mg/m2 IV q3-4wk
Contraindications Documented hypersensitivity; relatively contraindicated in pregnancy; significant dose reduction required in hepatic or renal insufficiency; congestive heart failure or a reduced ejection fraction
Interactions None reported
Pregnancy D - Unsafe in pregnancy
Precautions Caution in impaired hepatic function and preexisting cardiac disease (cardiotoxicity commonly observed after cumulative dose of 120-160 mg/m2); perform baseline and follow-up cardiac function tests (2-d echo and ejection fraction measurements)
Drug Name Gemtuzumab ozogamicin (Mylotarg)
Description Chemotherapy agent composed of a recombinant humanized IgG4, k antibody against CD33 conjugated with a cytotoxic antitumor antibiotic, calicheamicin. After binding to the cell, the released calicheamicin derivative binds to DNA in the minor groove, resulting in DNA double-strand breaks and cell death.
Adult Dose 9 mg/m2 IV over 2 h; give total of 2 doses 14 d apart; full hematologic recovery not necessary for administration of second dose; administer 50 mg diphenhydramine PO and 650-1000 mg acetaminophen PO 1 h prior to administration of each dose; may consider leukoreduction with hydroxyurea or leukapheresis to reduce peripheral WBC count to <30,000/µL prior to administration of Mylotarg; full recovery from hematologic toxicities not a requirement for administration of second dose
Pediatric Dose Not established
Contraindications Documented hypersensitivity to drug or calicheamicin derivatives; presence of anti-CD33 antibody
Interactions None reported; potential for drug-drug interaction with drugs affected by cytochrome P450 enzymes may not be ruled out
Pregnancy D - Unsafe in pregnancy
Precautions Postinfusion reactions include hypotension, fever, chills, or dyspnea (acetaminophen, intravenous fluids, and diphenhydramine may be administered to reduce incidence); severe myelosuppression occurs in all patients at recommended dosages; caution in patients with renal and hepatic impairment; tumor lysis may occur (risk may be reduced by administering allopurinol prophylactically and maintaining adequate hydration); should be administered under supervision of physicians experienced in treatment of acute leukemia and in facilities equipped to monitor and treat patients with leukemia; Mylotarg administration can result in severe hypersensitivity reactions (including anaphylaxis) and other infusion-related reactions, which may include severe pulmonary events (infrequently, hypersensitivity reactions and pulmonary events have been fatal); in most cases, infusion-related symptoms occurred during infusion or within 24 h of administration of Mylotarg and resolved; infusion should be interrupted for patientswho
experience dyspnea or clinically significant hypotension; monitor patients until signs and symptoms completely resolve; consider discontinuation of treatment for patients who develop anaphylaxis, pulmonary edema, or acute respiratory distress syndrome
Since patients with high peripheral blast counts may be at greater risk for pulmonary events and tumor lysis syndrome, physicians should consider leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral white count to <30,000/µL prior to administration of Mylotarg; hepatotoxicity, including severe hepatic venoocclusive disease (VOD), has been reported in association with use of Mylotarg as single agent, as part of a combination chemotherapy regimen, and in patients without history of liver disease or hematopoietic stem cell transplantation (HSCT); patients who receive Mylotarg either before or after HSCT, patients with underlying hepatic disease or abnormal liver function, and patients who receive Mylotarg in combinations with other chemotherapy are at increased risk for developing VOD, including severe VOD; death from liver failure and from VOD have been reported in patients who received Mylotarg; monitor for symptoms of hepatotoxicity, particularly VOD, which include rapid weight gain,right upper quadrant pain, hepatomegaly, ascites, elevations in bilirubin and liver enzymes
Drug Name Arsenic trioxide (Trisenox)
Description Used in patients with relapsed APL. The mechanism of action of Trisenox is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML-RAR alpha.
Adult Dose Induction: 0.15 mg/kg/d IV until bone marrow remission occurs; maximum induction is 60 doses
Consolidation: 0.15 mg/kg/d IV starting 3-6 wk after completion of induction therapy; maximum consolidation is 25 doses over 5 wk
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions Electrolyte abnormalities may occur if used concomitantly with diuretics or amphotericin B; concurrent use with QTc-prolonging agents (type Ia and type II antiarrhythmic agents, cisapride, thioridazine, selected quinolones) may increase risk of potentially fatal arrhythmias
Pregnancy D - Unsafe in pregnancy
Precautions Correct electrolyte abnormalities prior to treatment and monitor potassium and magnesium levels during therapy; may prolong QT interval; discontinue therapy and hospitalize patient if QTc >500 ms or if syncope or irregular heartbeats develop during therapy; may lead to torsade de pointes or complete AV block (risk factors include congestive heart failure, history of torsade de pointes, preexisting QT interval prolongation, use of potassium-wasting diuretics, conditions that cause hypokalemia or hypomagnesemia)
FOLLOW-UPSection 8 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Further Inpatient Care
Patients require readmission for consolidation chemotherapy or for the management of toxic effects of chemotherapy.
Further Outpatient Care
Patients should come to the office for monitoring of disease status and chemotherapy effects.
Transfer
Patients are best treated at a center whose staff has significant experience in the treatment of leukemia. Patients should be transferred to an appropriate (generally tertiary care) hospital if they are admitted to hospitals without appropriate blood product support, leukapheresis capabilities, or physicians and nurses familiar with the treatment of leukemia patients.
Deterrence/Prevention
While receiving chemotherapy, patients should avoid exposure to crowds and people with contagious illnesses, especially children with viral infections.
Complications
Death may occur because of uncontrolled infection or hemorrhage. This may happen even after use of appropriate blood product and antibiotic support.
The most common complication is failure of the leukemia to respond to chemotherapy. The prognosis for these patients is poor because they usually do not respond to other chemotherapy regimens.
Prognosis
Prognosis relies on several factors.
Increasing age is an adverse factor because older patients more frequently have a prior antecedent hematologic disorder (AHD) along with comorbid medical conditions that compromise the ability to give full doses of chemotherapy.
Prior AHD is associated with a poor outcome to therapy. The most common AHD is myelodysplastic syndrome (MDS).
Cytogenetic analysis of the bone marrow is one of the most important prognostic factors. Patients with t(8;21), t(15;17) or inversion 16 have the best prognosis, with long-term survival rates of approximately 65%. Patients with normal cytogenetics findings have an intermediate prognosis and have a long-term survival rate of approximately 25%. Patients with poor-risk cytogenetics findings (especially -7, -5) have a poor prognosis, with a long-term survival rate of less than 10%.
Other cytogenetic abnormalities, including +8, 11q23, and miscellaneous, have been reported to be intermediate-risk in some series and poor-risk in others.
The presence of an FLT3 mutation is associated with a poorer prognosis. Mutations in CEBPA are associated with a longer remission duration and longer overall survival. Mutations in NPM are associated with an increased response to chemotherapy.
Patient Education
Patients should be instructed to call immediately if they are febrile or have signs of bleeding.
For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education articles Leukemia and Bruises.
MISCELLANEOUSSection 9 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous References
Medical/Legal Pitfalls
The most important medical legal pitfall is the failure to rapidly distinguish a patient with acute leukemia from patients with less urgent hematologic disorders. Pancytopenia, for example, can be caused by a large variety of diseases of varying severity, including vitamin deficiencies and autoimmune disease. However, pancytopenia due to acute promyelocytic leukemia (APL) is a life-threatening emergency that must be aggressively treated immediately. The easiest way to avoid misdiagnosis is to review the peripheral blood smear at the time of initial evaluation of all patients with hematologic disorders.
A second pitfall is failure to immediately treat a patient with neutropenic fever or infection with broad spectrum antibiotics.
A third pitfall is failure to give appropriate transfusion support to a patient with acute leukemia. This includes transfusion of platelets and clotting factors (fresh frozen plasma, cryoprecipitate) as guided by the patient's blood test results and bleeding history. Blood products must be irradiated to prevent transfusion-associated graft versus host disease.
2006 metų
Sveiki,
trumpai as su jumis cia bendravau, ne menesio nera, o mamytes jau neturiu lygiai savaite. Visgi toks zaibiskas greitumas buvo netiketas net ir man, kur apie liga zinojau viska.... ka padarysi, stengiuos gyvent toliau, nes asarotu akiu ir sirdies negaliu, o ir nenoriu rodyt savo dar mazom atzalelem.
O jums linkiu kuo dziugesniu ziniu, tyrimu rezultatu, sveikatos
trumpai as su jumis cia bendravau, ne menesio nera, o mamytes jau neturiu lygiai savaite. Visgi toks zaibiskas greitumas buvo netiketas net ir man, kur apie liga zinojau viska.... ka padarysi, stengiuos gyvent toliau, nes asarotu akiu ir sirdies negaliu, o ir nenoriu rodyt savo dar mazom atzalelem.
O jums linkiu kuo dziugesniu ziniu, tyrimu rezultatu, sveikatos
QUOTE(ausrap @ 2008 10 17, 23:47)
Sveiki,
trumpai as su jumis cia bendravau, ne menesio nera, o mamytes jau neturiu lygiai savaite. Visgi toks zaibiskas greitumas buvo netiketas net ir man, kur apie liga zinojau viska.... ka padarysi, stengiuos gyvent toliau, nes asarotu akiu ir sirdies negaliu, o ir nenoriu rodyt savo dar mazom atzalelem.
O jums linkiu kuo dziugesniu ziniu, tyrimu rezultatu, sveikatos
trumpai as su jumis cia bendravau, ne menesio nera, o mamytes jau neturiu lygiai savaite. Visgi toks zaibiskas greitumas buvo netiketas net ir man, kur apie liga zinojau viska.... ka padarysi, stengiuos gyvent toliau, nes asarotu akiu ir sirdies negaliu, o ir nenoriu rodyt savo dar mazom atzalelem.
O jums linkiu kuo dziugesniu ziniu, tyrimu rezultatu, sveikatos
Mieloji, ausrap,
Nuoširdi Jums užuojauta. Tikrai, staigus posūkis Jūsų šeimos kelyje. Stiprybės Jums ir Jūsų šeimai. Gyvenimas tęsiasi - vieniems čia, kitiems - tenai. Mamytė niekur nedingo. Ji Jūsų širdyse. Tegul Ją globoja angelai , o Ji globos Jus.
QUOTE(ausrap @ 2008 10 17, 22:47)
Sveiki,
trumpai as su jumis cia bendravau, ne menesio nera, o mamytes jau neturiu lygiai savaite. Visgi toks zaibiskas greitumas buvo netiketas net ir man, kur apie liga zinojau viska.... ka padarysi, stengiuos gyvent toliau, nes asarotu akiu ir sirdies negaliu, o ir nenoriu rodyt savo dar mazom atzalelem.
O jums linkiu kuo dziugesniu ziniu, tyrimu rezultatu, sveikatos
trumpai as su jumis cia bendravau, ne menesio nera, o mamytes jau neturiu lygiai savaite. Visgi toks zaibiskas greitumas buvo netiketas net ir man, kur apie liga zinojau viska.... ka padarysi, stengiuos gyvent toliau, nes asarotu akiu ir sirdies negaliu, o ir nenoriu rodyt savo dar mazom atzalelem.
O jums linkiu kuo dziugesniu ziniu, tyrimu rezultatu, sveikatos
Mieloji, nuosirdi uzuojauta
Sveikos, Mergaitės, šį ramų, tykų ir tylų mūsų forume savaitgalį. Tikriausiai visos jaučiatės gerai ir tvirtai, na , o jeigu kas turit kokią problemėlę, tai linkiu kuo lengviau ir greičiau ją išspręsti.
Atrodo, kad visos tos TIESOS yra puikiai žinomos, bet skaitai jas dar kartą ir dar kartą...ir vis kyla klausimų, abejonių, pamąstymų. Kad krūties vėžį sukelia pakaitinė hormonų terapija, aš tikrai sutinku. Mano mamytė 2 metus juos vartojo, kol suprato, kad jie ne padeda, o kad daro kažką ne taip. Prasidėjo dar didesni širdamušiai, begalinis prakaitavimas, o visa kaltė buvo suversta menopauzei. Niekas nepasiūlė išsitirti skydliaukės, o ir pati nepagalvojo, nes juk "tai menopauzė". Kai išsityrė , pasirodo hormoninė sistema visiškai išsiderinusi. Pradėjo gerti vaistukus - viskas taip susitvarkė, kad mamytė sakėsi taip gerai senai nesijautusi. Deja, tas džiaugsmas truko neilgai.
Arba - kontraceptikai ( turiu omenyje tabletes). Juk juos kiša bet kada. Aišku, kai kurias ligeles kiek aptvarko, bet koks jų poveikis bus po kiek laiko - klausimas. Bandžiau ginekologei sakyti apie tai, ir kad mamytė serga. Pasakė, mažiau gilinkitės, ką ten rašo. O kiek moterų juos naudoja metai iš metų.
Visiems aišku, kad judėjimas ir normalus svoris - sveikata, bet ar visiems tai galioja? Juk kiek ir šiame forume mergaičių, kurios rūpindavosi sveika mityba ir sportu, o liga neaplenkė. Vienareikšmio atsakymo čia nėra ir būti negali.
Manau, kad tai yra TOKS laikmetis, kliuvęs būtent mums. Ir jis yra tarsi trumputė akimirka didelėje visatos istorijoje. Gal būt tai, kas teigiama šiandien kaip sveikatos prevencija (kad ir tie patys kontraceptikai), po daugelio metų bus paneigta. Juk kiek ligų yra, kada nežinomos kilmės priežastys , ir gydytojas negali paaiškinti, kodėl susergama. Manau, kad naujovės įdiegiamos tiek, kiek naujo apie mūsų organizmą sužino mokso atstovai, nes kaip kažkada sakiau, kad žmogus begaliniai sudėtingas mechanizmas. Tai , kas šiandien atrodo aiškų, rytoj gali sukelti abejonių.
Neabejotina tik viena - kad mylėti save ir savimi rūpintis reikia būtinai.Ne visiems tai išeina, o kai kurie net ir nemokame to daryti. TOKS LAIKMETIS.
Ramaus visoms vakaro.
QUOTE(Tai aš @ 2008 10 19, 14:59)
Atrodo, kad visos tos TIESOS yra puikiai žinomos, bet skaitai jas dar kartą ir dar kartą...ir vis kyla klausimų, abejonių, pamąstymų. Kad krūties vėžį sukelia pakaitinė hormonų terapija, aš tikrai sutinku. Mano mamytė 2 metus juos vartojo, kol suprato, kad jie ne padeda, o kad daro kažką ne taip. Prasidėjo dar didesni širdamušiai, begalinis prakaitavimas, o visa kaltė buvo suversta menopauzei. Niekas nepasiūlė išsitirti skydliaukės, o ir pati nepagalvojo, nes juk "tai menopauzė". Kai išsityrė , pasirodo hormoninė sistema visiškai išsiderinusi. Pradėjo gerti vaistukus - viskas taip susitvarkė, kad mamytė sakėsi taip gerai senai nesijautusi. Deja, tas džiaugsmas truko neilgai.
Arba - kontraceptikai ( turiu omenyje tabletes). Juk juos kiša bet kada. Aišku, kai kurias ligeles kiek aptvarko, bet koks jų poveikis bus po kiek laiko - klausimas. Bandžiau ginekologei sakyti apie tai, ir kad mamytė serga. Pasakė, mažiau gilinkitės, ką ten rašo. O kiek moterų juos naudoja metai iš metų.
Visiems aišku, kad judėjimas ir normalus svoris - sveikata, bet ar visiems tai galioja? Juk kiek ir šiame forume mergaičių, kurios rūpindavosi sveika mityba ir sportu, o liga neaplenkė. Vienareikšmio atsakymo čia nėra ir būti negali.
Manau, kad tai yra TOKS laikmetis, kliuvęs būtent mums. Ir jis yra tarsi trumputė akimirka didelėje visatos istorijoje. Gal būt tai, kas teigiama šiandien kaip sveikatos prevencija (kad ir tie patys kontraceptikai), po daugelio metų bus paneigta. Juk kiek ligų yra, kada nežinomos kilmės priežastys , ir gydytojas negali paaiškinti, kodėl susergama. Manau, kad naujovės įdiegiamos tiek, kiek naujo apie mūsų organizmą sužino mokso atstovai, nes kaip kažkada sakiau, kad žmogus begaliniai sudėtingas mechanizmas. Tai , kas šiandien atrodo aiškų, rytoj gali sukelti abejonių.
Neabejotina tik viena - kad mylėti save ir savimi rūpintis reikia būtinai.Ne visiems tai išeina, o kai kurie net ir nemokame to daryti. TOKS LAIKMETIS.
Ramaus visoms vakaro.