Pathophysiology: Acute leukemia begins in a single somatic hematopoietic progenitor that transforms to a cell incapable of normal differentiation. Many of these cells no longer possess the normal property of apoptosis, or programmed cell death, thus resulting in a cell with a prolonged life span and unrestricted clonal proliferation.

Leukemogenesis is frequently associated with chromosome abnormalities and gene translocations. Many translocations are characteristic of a particular subtype of acute leukemia and often convey additional prognostic information to the clinician.

Since the transformed cell lacks normal regulatory and growth constraints, it has a favorable competitive advantage at the expense of normal hematopoietic cells. The result is the accumulation of abnormal cells with qualitative defects. A major cause of morbidity and mortality is the deficiency of normal functioning mature hematopoietic cells rather than the presence of numerous malignant cells.

Splenomegaly from leukemic infiltration further contributes to pancytopenia by sequestering and destroying circulating erythrocytes and platelets. As the disease progresses, there are increasing signs and symptoms resulting from anemia, thrombocytopenia, and neutropenia.

Leukemic cells may infiltrate other bodily tissues, causing many significant complications including central nervous system (CNS) involvement, pulmonary dysfunction, or skin and gingival infiltration.

Frequency:

• In the US: Out of approximately 3250 newly diagnosed cases of leukemia in children each year, nearly 20% are AML. While 1 of 3 newly diagnosed infants with leukemia has AML, the ratio of AML to acute lymphoblastic leukemia (ALL) falls rapidly until adolescence, when it increases to account for nearly 50% of all new leukemia diagnoses.

Mortality/Morbidity: The long-term survival rate for pediatric patients with AML is nearly 50%.

Race: While there are some minor geographic variations in the incidence of different AML subtypes, this is a disorder that affects all races equally. As opposed to the incidence of ALL, which affects white children more commonly than black children, the incidence of AML is near equal for all races. One subtype, acute promyelocytic leukemia (APL), does exhibit a slightly greater incidence in the Hispanic population. Some areas of the world having higher than average rates of AML include Shanghai, New Zealand, and areas of Japan.

Sex: Distribution of affected males and females is nearly equal at all ages.

History: Symptoms can be divided into those caused by a deficiency of normal functioning cells, those due to the proliferation and infiltration of the abnormal leukemic cell population, and constitutional symptoms.

• Cytopenia

• Anemia

• This common finding is characterized by pallor, fatigue, tachycardia, and headache.

• The major pathophysiologic mechanism is related to decreased production in the infiltrated bone marrow.

• Bleeding, hemolysis, and sequestration and destruction in an enlarged spleen or liver all may contribute to anemia.

• Hemorrhage from thrombocytopenia

• This is due to decreased production of megakaryocytes in the bone marrow.

• The most common findings will be easy bruising, petechiae, epistaxis, gingival bleeding, and, less often, gastrointestinal or central nervous system hemorrhage.

• The patient with disseminated intravascular coagulation might also have symptoms of hemorrhage or thrombosis, including painful swelling and sharp color demarcation of an extremity.

• Fever

• This is a common presenting complaint in acute leukemia.

• It should always be attributed to infection.

• Depending on the site of infection, symptoms may be pulmonary in nature, as in the case of pneumonias (cough, dyspnea, hypoxia, chest pain); neurologic, as in the case of meningitis (lethargy, emesis, headache); or may cause pain in other sites of involvement, eg, UTI or colitis (bladder and bowel function).

• Mass and infiltrative disease

• The most common extramedullary infiltration by the leukemic cell will occur in the reticuloendothelial system. This may manifest itself as adenopathy, hepatomegaly, or splenomegaly.
• Rarely, a mediastinal mass may cause symptoms of respiratory insufficiency or superior vena cava syndrome.
• Abdominal masses may cause pain or obstruction of the gastrointestinal or urogenital tracts.
• Nodules of myeloblasts, called chloromas, can be found in the skin or central nervous system.
• Monoblastic leukemia often is associated with gingival hyperplasia and CNS infiltration.

• Constitutional and miscellaneous symptoms

• Unexplained persistent fevers are sometimes the only presenting symptom of leukemia. Unlike in adults, weight loss and cachexia are unusual findings in children with leukemia. These effects can result from a combination of increased catabolic nutritional state and decreased caloric intake from anorexia.
• Orthopedic symptoms
  • Bone pain, although less common than in patients with ALL, may be caused by periosteal elevation by leukemic cell infiltrates or bone infarctions.
  • Occasionally, the weakened bony cortex leads to pathologic fractures of the extremity, with resultant pain and decreased mobility, or vertebral compression fractures after minimal trauma, causing back pain and lower extremity dysfunction (weakness, loss of bladder and bowel function).
• Central nervous system involvement
  • Although uncommon at initial diagnosis, it can appear at any time during follow-up and is associated with a variety of symptoms.
  • The most common signs and symptoms are related to signs of elevated intracranial pressure, including headache, nausea and emesis, lethargy, irritability, and visual complaints.
  • Cranial nerve involvement, most often facial (Bell palsy) and abducens (esotropia), may appear as an isolated finding or in combination with other manifestations.
  • In addition to leukemic cell infiltration and proliferation with mass effect, intracranial hemorrhage and CNS infections can cause similar devastating CNS complications.
  • Spinal lesions are rare, although in AML blast cells periodically form large aggregates leading to epidural compression.
  • Extreme leukocytosis with white blood cell counts greater than 200,000 cells/mm³ often is associated with hyperviscosity, intracerebral leukostasis, and intracerebral hemorrhage early in the course of the disease.

   

• Ocular manifestations
  • In rare cases, leukemic cells infiltrate all parts of the eye. The retina and iris are the most common sites affected.
  • Iritis often will cause photophobia, pain, and increased lacrimation; whereas, retinal involvement, often accompanied by hemorrhage, can lead to loss of vision.

• While most patients are diagnosed after a relatively brief duration of symptoms, a small group of patients may present with myelodysplasia, a more indolent disorder characterized by a slowly progressive anemia or thrombocytopenia. This disorder can exist for many months and even years before ultimately converting into AML.

Physical:

• Pancytopenia

• Pallor with tachycardia is observed to different degrees, proportional to the severity of anemia. With more severe anemia, lethargy, heart murmur, and signs of congestive heart failure may appear.

• Bleeding manifestations most commonly are observed in the skin and include petechiae, purpuric lesions, and ecchymoses.

• Gastrointestinal bleeding may indicate erosions or perforation.

• Signs of infection may include fever, gingivitis, hypotension, or respiratory distress, depending on the site of infection.

• Signs of leukemic infiltration and proliferation

• Adenopathy, at times generalized, is less common than in ALL.

• Splenomegaly at times can be massive, particularly in the young child.

• On occasion, pronounced organomegaly can result in respiratory embarrassment in infants due to decreased diaphragmatic excursion.

• CNS findings may include lethargy, cranial nerve dysfunction (particularly esotropia and facial palsy), or papilledema.

• Typhlitis can present with acute lower-quadrant pain mimicking appendicitis.

• Signs of perforation include hypotension, abdominal distension, and decreased bowel sounds. Clinical deterioration is rapid if the condition is not recognized.

Causes: Although the cause of AML in most patients is unknown, several factors are associated with its development. Despite these correlations, most people exposed to the same factors do not develop leukemia. This would suggest that these factors trigger a cell's malignant transformation, perhaps through the action of one or more oncogenes.

• Radiation exposure

• A great deal of evidence has implicated radiation in leukemogenesis in many patients, as evidenced from Japan following the release of radiation from atomic explosions at Hiroshima and Nagasaki. While younger children had a higher risk of developing ALL, teens and adults were more likely to contract AML. The latent period was from 2-15 years after the exposure, depending on the proximity to the radiation.

• Reports of increased risk of leukemia in patients living close to nuclear plants are currently under investigation, but data are lacking. Likewise, early reports of strong electromagnetic fields as a risk factor for acute leukemia have not been corroborated.

• Toxins and drugs

• Exposure to toxic chemicals that cause damage to bone marrow, such as benzene and toluene used in the leather, shoe, and dry cleaning industries, has been associated with leukemia in adults. Direct evidence of this effect in children has not been established. Likewise, exposure to pesticides has been noted to increase the risk of AML in some studies.

• A more compelling association has been seen after treatment with antineoplastic cytotoxic agents, particularly alkylating agents such as procarbazine, the nitrosoureas, cyclophosphamide, melphalan, and, most recently, epipodophyllotoxins etoposide and teniposide. Patients treated with these agents for malignancies such as Hodgkin lymphoma especially if the agents are administered in conjunction with radiation therapy, have a significantly greater risk of developing a preleukemic syndrome that ultimately transforms into overt AML.

• Genetics and syndromes

• Children with Down syndrome (trisomy 21) have a greater than 15-fold risk of developing leukemia over the general population, most commonly acute megakaryoblastic leukemia. Children with Down syndrome who experience the transient myeloproliferative syndrome as neonates, a condition often indistinguishable from acute leukemia, also have a greater risk of developing acute leukemia in subsequent years.

• Approximately 8% of children with Fanconi anemia develop AML in their adolescent years.

• Patients with other inherited disorders, such as Shwachman, Bloom, and Diamond-Blackfan syndromes, also have a greater risk of leukemia. These syndromes share features of poor DNA repair that are believed to predispose affected individuals to leukemogenic stimuli. Children with neurofibromatosis and Kostmann neutropenia also appear to be a higher risk of developing AML.

Lab Studies:

• Blood count and blood smear

• The hallmark of leukemia is the reduction or absence of normal hematopoietic elements.

• Anemia usually is normocytic, with a lower than expected reticulocyte count for the level of the hemoglobin. The decrease in hemoglobin levels can range from minimal to profound.

• Platelet counts are usually low and generally are commensurate with the degree of bleeding. Patients with spontaneous petechiae usually have platelet counts less than 20,000/mm³.

• White cell counts may be decreased or elevated. On occasion, hyperleukocytosis with white cell counts greater than 100,000 can be observed, with higher numbers conferring a white color to the blood specimen. The white cell differential is usually the key to suspected leukemia, with primitive granulocyte or monocyte precursors observed on peripheral smear.

• Mature neutrophils usually are diminished.

• Auer rods, characteristic cytoplasmic inclusions, can be found in specimens of circulating blood of many AML patients on careful examination of the blood smear.

• Chemistries

• Both serum uric acid and lactic dehydrogenase levels are frequently elevated as a consequence of increased cell proliferation and destruction.

• Other signs of tumor lysis, including hyperkalemia, hypocalcemia, and lactic acidosis, may be present.

• Serum muramidase (lysozyme) levels usually are increased in patients with monocytic leukemias.

• Bone marrow examination

• This establishes a definitive diagnosis.

• Bone marrow aspirate and biopsy demonstrate the characteristic replacement of normal marrow elements with the monotonous sheets of leukemic blasts.

• Acute myelogenous leukemia is subdivided into different subtypes, some having characteristic clinical pictures. The French-American-British classification system recognizes 7 primary AML types (M1-M7), which can usually be established with additional marrow studies. The World Health Organization recently has classified Acute Myeloid Leukemias into groups that include the following:
  • AML with recurrent cytogenetic translocations, eg, promyelocytic leukemia with typical t(15;17)
  • AML with multilineage dysplasia
  • AML and myelodysplasia syndromes secondary to therapy (eg, those following alkylating agents)
  • AML not otherwise categorized (including erythroid leukemias, monocytic leukemias and others)

• Cytogenetic markers, histochemical stains, and immunophenotyping

• Leukemia cells demonstrate clonal cytogenetic abnormalities in more than 85% of patients. These are often unique to the subtype; for example, the t(15;17) translocation is nearly always found in patients with acute promyelocytic leukemia, while t(8;21) is more commonly found in myeloblastic leukemia.

• In addition to the standard Wright-Giemsa stain, histochemical stains help differentiate the various acute leukemias. Periodic acid-Schiff positivity indicates acute biphenotypic leukemia or undifferentiated leukemia with lymphoblastic features. Most AML cells yield strongly positive reactions to myeloperoxidase and Sudan black stains. Esterase stains usually can help differentiate myeloid from monocytic leukemia.

• Monoclonal antibodies specific for different cell lineages and stages of development are routinely used to further characterize the leukemic cell. The most common myeloid markers include CD13, CD14, CD15, and CD33, with more than 90% of leukemic cells demonstrating positivity to some of these antigens. CD34 marker is also frequently found in AML blasts.

• Lumbar puncture and cerebrospinal fluid examination
  • While less frequently involved than in patients with ALL, leukemic infiltration can occur in patients with AML.
  • CSF should be obtained prior to beginning any therapy.
  • Send fluid for cytology evaluation in addition to the usual cell count and chemistries.
  • Intrathecal chemotherapy is administered at the same time and repeated on an intermittent basis to treat or prevent CNS involvement.
• HLA typing: Following successful remission induction, patients with human leukin antigen (HLA)-matched donors usually undergo high-dose myeloablative chemotherapy followed by bone marrow (or hematopoietic stem cell) rescue. At the time of diagnosis, it is important to begin the donor screening process by obtaining blood for HLA matching from the patient and immediate family members.

Imaging Studies:

• Radiographic studies

• While not helpful in confirming the diagnosis, these can be important when there is suspicion of leukemic complications.

• A routine chest radiograph should be done to rule out the presence of a mediastinal mass, particularly in the presence of respiratory symptoms or suspicion of a superior vena cava syndrome.

• If the patient has abdominal pain and distention, an abdominal film can often detect free air suggestive of a perforation.

• Radiograph examination of the extremities may show findings such as metaphyseal bands at the distal femurs (more commonly observed in young children with ALL), periosteal new bone formation, focal lytic lesions, or pathologic fractures.

• Computed tomography and magnetic resonance imaging

• If the patient has abdominal pain and suspicion of possible large bowel infection, a computed tomography (CT) scan may reveal thickening and edema of the bowel wall suggestive of typhlitis.

• If a patient has neurologic symptoms, a CT scan or magnetic resonance imaging (MRI) of the head is mandatory to rule out intracranial hemorrhage of infiltrative disease.

• CT scanning also may allow early detection of asymptomatic sinusitis that might cause persistent unexplained fevers.

• Sonography

• Since serious infections that affect heart function are routinely observed in this patient population, periodic cardiac monitoring is important.

• Perform an echocardiogram prior to chemotherapy.

• Most treatment regimens use anthracyclines, such as daunomycin and idarubicin, which may cause significant cardiomyopathy.

• Radionuclide imaging

• This is often used to detect occult infection that cultures and other imaging modalities fail to identify.

• Technetium bone scans often help localize an occult osteomyelitis.

• Whole body gallium scanning often detects an occult deep tissue infection and can help with appropriate antibiotic management.

Procedures:

• Bone marrow aspirate and biopsy

• Bone marrow examination is necessary to establish the diagnosis of AML.

• The preferred site is the iliac crest, either anterior or posterior. In infancy, the tibia is often a better source of marrow for diagnostic purposes. On rare occasion, a sternal biopsy is necessary.

• While bone marrow aspirate is often sufficient to establish the diagnosis and follow disease progress, a core biopsy is often necessary for "packed" marrows or dry taps (usually heavily infiltrated marrows that do not yield enough diagnostic materials).

• A biopsy is necessary to gauge the cellularity of a marrow specimen during follow-up for making subsequent therapeutic decisions.

• Lumbar puncture

• This is necessary for diagnostic and therapeutic reasons.

• Even if marrow is not involved at the time of diagnosis, CNS seeding can occur later; therefore, periodic surveillance lumbar punctures with the administration of intrathecal chemotherapy are necessary.

• Central venous catheter placement

• Because of intense chemotherapy and supportive care needs, guaranteed venous access is critical. An indwelling central venous catheter with at least 2 lumens usually is placed prior to beginning therapy. This provides access for chemotherapy infusions, intravenous nutritional support, transfusions, antibiotics, and other supportive care medications, as well as allowing blood withdrawal for required testing.

• Families are taught catheter care, including sterile technique and preventive maintenance to avoid catheter clotting and infection.

• Subcutaneous ports and peripheral indwelling central catheters placed in the cubital area are less commonly used.

Histologic Findings: Bone marrow examination usually shows characteristic hyperplastic marrow with monotonous replacement with leukemia cells. Patients with myelodysplasia might show a small percentage of blast cells, with megaloblastic features and a decrease in the normal hematopoietic cell population. Pronounced fibrosis often is observed, particularly in the acute megakaryoblastic subtype (M7).

Medical Care: Treatment for patients with acute myelogenous leukemia involves intensive chemotherapy regimens used to destroy the leukemic cell population as rapidly as possible and prevent the emergence of a resistant clone and simultaneous supportive care to sustain the patient until the bone marrow has achieved a hematologic remission and is once again producing normal hematopoietic cells.

• Chemotherapy

• Virtually all of the chemotherapeutic drug regimens use some combination of an anthracycline, either daunomycin or idarubicin, in conjunction with cytosine arabinoside. Additional drugs sometimes include etoposide, dexamethasone, 6-thioguanine, cyclophosphamide, and mitoxantrone.

• Most children in the United States are treated with chemotherapy protocols developed by 2 national pediatric cancer groups, These protocols have resulted in improved results with intensified therapy, often beginning the next myelosuppressive cycle of treatment before there is recovery from the previous course of treatment. While prolonging the period of pancytopenia, induction failures have been fewer and disease-free survival has improved significantly.
• The Children's Cancer Group has piloted DCTER or IDA-DCTER induction therapy (infusions of daunomycin or idarubicin, cytosine arabinoside, and etoposide along with oral 6-thioguanine and Decadron) with "intensive timing" (two 4-day courses of treatment given with a 6-day rest period in between, regardless of blood counts). The Pediatric Oncology Group has used a similar approach of intensive timing with one cycle of daunomycin, cytosine arabinoside, and 6-thioguanine, followed several days later by high dose cytosine arabinoside.
• Following remission induction, the CCG regimen uses additional consolidation therapy with either DCTER or fludarabine/cytosine arabinoside. POG consolidation utilizes daunomycin/high dose cytosine arabinoside/asparaginase.
• Several studies have demonstrated a clear survival benefit for patients who are treated with allogeneic bone marrow transplant, with no advantage of autologous transplant over chemotherapy intensification. As a result, for CCG patients with HLA identical marrow matches, patients are nonrandomly treated with busulfan/cyclophosphamide with marrow transplantation. For those without a matched donor, intensification treatment with high dose cytosine arabinoside/asparaginase is used as the final aggressive therapy.
• The proposal for the new combined Children's Oncology Group protocol most likely will use a combination of these approaches, with the addition of anti-CD33 antibody and a postintensification course using mitoxantrone and cytosine arabinoside.

• Acute promyelocytic leukemia
  • The discovery of effective maturation agents has altered the approach to treating APL.
  • Transretinoic acid (TRA) can effectively induce most newly diagnosed APL patients into remission, with the myelosuppressive effects of chemotherapy. The current treatment approach is to begin therapy with TRA if the white cell count is below 10,000/mm³ for several days, and then administer chemotherapy to induce remission. This approach has significantly reduced the incidence and severity of disseminated intravascular coagulation and tumor lysis syndrome.
  • TRA is used during intensification phases of therapy, as well as a prolonged maintenance therapy to prevent disease recurrence.
  • If the initial white cell count is greater than 10,000/mm³, chemotherapy is used first to decrease the cell count before beginning TRA, reducing the risk of a potentially serious retinoic acid syndrome (characterized by fever, respiratory distress, diffuse pulmonary infiltrates, and hypoxia).

• Children with Down syndrome
  • As opposed to the trend towards more intense therapy for the majority of children diagnosed with AML, it has been shown that children with Down syndrome fare better with less intense therapy, with a clearly greater likelihood of long-term disease-free remission. Many children with trisomy 21 have had transient myeloproliferative disease as infants, a picture that resembles AML in many ways but usually disappears with supportive care only; many of the children who experience this syndrome as neonates go on to develop true AML requiring chemotherapy.
  • Children with Down syndrome also seem to have more significant complications of intense therapy. As a result, the treatment for children with trisomy 21 uses lower doses of induction chemotherapy (daunomycin, cytosine arabinoside, and 6-thioguanine) with longer periods between treatments. Rather than bone marrow transplant, these children receive chemotherapy intensification with high dose cytosine arabinoside.
• Radiation therapy

  This treatment primarily is used to treat chloromas and other masses that are pressing on a vital structure and may cause imminent irreversible damage. Examples include spinal cord compression and mediastinal masses causing superior vena cava syndrome or airway compromise, although corticosteroids and early administration of chemotherapy can effectively relieve most of these complications.

  • Persistent CNS leukemia usually requires craniospinal radiation as well.
  • Most pretransplant myeloablative regimens in children in first complete remission have replaced radiation with busulfan to decrease the incidence of long-term adverse effects.
• Blood and marrow transplantation
  • A myeloablative combination of chemotherapy and radiation, followed by rescue with infusion of HLA-matched bone marrow to reconstitute the patient's own bone marrow has been shown to be an effective approach to curing patients with AML. In several randomized studies, allogeneic transplantation has been demonstrated to produce a higher overall and disease-free survival. However, this option is not available to most patients since an HLA-matched donor can only be found for approximately 25% of patients.
  • Options have increased significantly with the availability of international HLA registries that can help locate unrelated HLA matches. In addition, the use of both purged or unpurged autologous stem cells have been undergoing clinical trials, with the advantages of availability and avoidance of GVHD. However, randomized studies to date have not shown an advantage for autologous stem cell transplantation compared to chemotherapy in pediatric studies.
  • The increased storage of immunotolerant umbilical cord blood, rich in stem cells, has further expanded the availability of stem cells, since less well-matched cord stem cells can be used without incurring major GVHD. Success rates for stem cell transplants have also increased due to decreasing morbidity because of better GVHD prophylaxis and the use of different combinations of methotrexate, cyclosporine, and corticosteroids.
  • The incidence of veno-occlusive disease of the liver, a complication that is often fatal, has decreased with the use of prophylactic heparin infusions.

• Transfusion support
  • Because the treatment regimens are intensive, expeditious transfusion support is critical.
  • Throughout the long periods of pancytopenia, platelet and red cell transfusions are necessary to correct anemia and thrombocytopenia until a remission is achieved.
  • On occasion, plasma must be administered to correct coagulopathies, particularly in patients with disseminated intravascular coagulation. All transfused products must be irradiated to prevent graft versus host disease (GVHD) in this heavily immunosuppressed patient.
  • Support from the blood bank is mandatory in patients who present with hyperleukocytosis and a great risk of stroke and heart failure from hyperviscosity. These patients are best served with leukophoresis or double volume exchange transfusion to decrease the leukemic cell burden rapidly and more safely, without contributing to metabolic abnormalities. This procedure also allows a more rapid correction of anemia, which would otherwise have been prohibitive due to viscosity constraints.
  • Rarely, granulocyte transfusions are administered to treat serious infections that do not respond to appropriate antibiotic therapy. This is particularly useful for gram-negative sepsis and serious intra-abdominal infections.
• Metabolic management
  • The patient who presents with a large leukemic cell burden, either a high circulating white count or massive organomegaly, is at risk for severe, often life-threatening metabolic derangements.
  • Prior to beginning cytoreduction, correct any existing abnormalities and take preventive measures to avoid new ones.
  • Hyperkalemia and hyperphosphatemia with associated hypocalcemia result from rapid cell turnover and cell destruction.
  • Treat elevated potassium levels promptly by using measures such as Kayexalate, insulin and glucose combination, and sometimes hemodialysis.
  • Calcium replacement is often necessary to correct severe hypocalcemia.
  • Prevention is key to avoiding most serious metabolic complications. The combination of vigorous hydration, administration of allopurinol (a xanthine oxidase inhibitor to prevent uric acid formation), and alkalinization of urine with sodium bicarbonate is usually successful in preventing serious tumor lysis syndromes.
• Antibiotics
  • Infection is a major cause of morbidity and mortality.
  • Patients with fever, particularly if they are severely neutropenic, are presumed to have serious infection until proven otherwise.
  • Empiric broad-spectrum antibacterial antibiotics are administered when a patient is febrile with an absolute neutrophil count below 750-1000/mm³. The choice of antibiotics depends on the typical pathogens found in the community and hospital but usually is some combination of an aminoglycoside and a cephalosporin or semisynthetic penicillin with beta lactamase inhibitor until culture results are available.
  • When tunnel infections around a central venous catheter are suspected, vancomycin should be administered. At certain institutions, line removal is also recommended.
  • If a patient presents with abdominal or gastrointestinal symptoms, antibiotic choice should include anaerobic coverage.
  • With more prolonged periods of neutropenia, particularly after treatment with broad-spectrum antibacterial agents, fungal disease becomes a great concern.
  • Empiric use of amphotericin is indicated in patients with persistent fever.
  • Often CT scanning is necessary to detect subtle abscesses in the lungs, liver, spleen, kidneys, or brain.
  • Prophylactic antibiotics have helped to decrease the incidence of a number of infections. Sulfamethoxazole/trimethoprim has dramatically reduced the incidence of Pneumocystis carinii pneumonia. Prophylactic penicillin in some centers has decreased the incidence serious systemic streptococcal sepsis that develops in patients with severe mucositis. Acyclovir has been useful in preventing herpes simplex infections, particularly in patients who have undergone bone marrow transplant.
  • Vigilance is most important in the AML patient with persistent fever, and frequent cultures of possible sites of infection should be performed.
  • To facilitate proper diagnosis, bronchoscopy, lung biopsy, and imaging studies are often necessary.
• Biologic response modifiers
  • Granulocyte colony-stimulating factor (G-CSF) and granulocyte monocyte colony-stimulating factor (GM-CSF) shorten the period of chemotherapy-induced neutropenia, allowing the use of more intense chemotherapy regimens. But their role in the treatment of patients with leukemia has not been definitively established since there has been no improvement in survival demonstrated.
  • The role for synthetic erythropoietin and, more recently, platelet growth factor has yet to be elucidated. Clinical trials are in progress to determine whether the administration of these agents will diminish the need for transfusion support.

Surgical Care: The role of surgery is limited.

• Initial central venous catheter insertion is necessary to initiate treatment and manage all aspects of chemotherapy and transfusion support.

• Biopsy or aspiration of tissue for culture is often necessary for the febrile patient with possible abscess.

• The acute abdomen in this patient population often presents the clinician with serious complications, such as typhlitis, that requires expeditious surgical intervention.

Consultations:

• Urology consultation: Consider this consultation for male teenagers who will be undergoing intense chemotherapy that may cause oligospermia and fertility problems in the future. While this condition is usually temporary, it is a more significant problem for patients who undergo high-dose chemotherapy as preparation for blood or marrow transplant. It is a major problem for patients who may be receiving total body radiation. Encourage sperm banking, preferably before beginning any treatment that will affect the quality of the sperm being banked.

• Psychologic support: The intense treatment and frequent prolonged hospitalizations for chemotherapy and resulting complications (especially for patients undergoing stem cell transplant), as well as the very real possibility of life-threatening complications, place major stresses on the patient and family. Psychologic support, with educational information and numerous meetings and updates, are very important for the psychologic well being of the family.

Diet:

• Careful attention must be directed towards adequate nutrition. Because of prolonged periods of neutropenia with infections that blunt a patient's appetite, along with recurrent episodes of chemotherapy-induced mucositis, high calorie oral supplements are often helpful for maintaining weight, allowing the patient to better tolerate therapy. Most patients require intravenous total parenteral nutrition.

• For patients receiving a blood or marrow transplant, low-bacteria diets often are instituted to decrease the incidence of posttransplant infections resulting from profound immunosuppression. Emphasis is to initially avoid uncooked fresh vegetables and fruits.

Activity:

• Minimal limits on activity are necessary. Patients should avoid crowds and exposure to potentially contagious disorders when neutropenic or immunosuppressed after transplant.

• When thrombocytopenic, potentially traumatic physical sports activities need to be curtailed to avoid serious hemorrhage. Medications that can potentiate bleeding, such as antiplatelet agents, including aspirin and other nonsteroidal anti-inflammatory drugs, should be avoided.

Treatment is directed towards 2 goals, destroying the leukemic cells and supporting the patient through long periods of pancytopenia.

Chemotherapy meets the first goal, but many classes of drugs also must be included in treatment, including broad-spectrum antibacterial, antiviral, and antifungal antibiotics, biologic response modifiers, and other classes of supportive medications.
 

Drug Category: Chemotherapeutic agents -- While many chemotherapeutic agents are active, most current regimens use combinations of an anthracycline and cytosine arabinoside. All chemotherapy agents destroy myeloblasts using a variety of mechanisms.

Drug Category: Colony-stimulating factors -- Acts as a hematopoietic growth factor that stimulates the development of granulocytes. Used to treat or prevent neutropenia when receiving myelosuppressive cancer chemotherapy and to reduce the period of neutropenia associated with bone marrow transplantation. Also used to mobilize autologous peripheral blood progenitor cells for bone marrow transplantation and in the management of chronic neutropenia. Part of supportive care, these medications can help shorten the period of cytopenia with the resultant decrease in serious adverse effects of the chemotherapy treatment.

Drug Category: Antibiotics, prophylactic -- Infections remain the biggest problem. The use of prophylactic medications can help prevent several of these often life-threatening infections.

Drug Category: Antiemetic agents -- Antineoplastic induced vomiting is stimulated through the chemoreceptor trigger zone (CTZ), which then stimulates the vomiting center (VC) in the brain. Increased activity of central neurotransmitters, dopamine in CTZ or acetylcholine in VC appears to be a major mediator for inducing vomiting. Following administration of antineoplastic agents, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With serotonin release and subsequent binding to 5-HT3-receptors, vagal neurons are stimulated and transmit signals to the VC, resulting in nausea and vomiting.

Emesis is a significant problem in patients receiving high-dose chemotherapy. The resultant nutritional, metabolic, and fluid derangements can be unpleasant enough that patients may refuse further life-saving therapy. It is important to use these drugs prophylactically.

Further Inpatient Care:

• Hospitalizations are necessary for chemotherapy and treating complications related to the disease and its treatment, usually infections or febrile neutropenic episodes. Some hospitalizations can be quite lengthy, with numerous antibiotic changes necessary until the infections and the patient's neutropenia resolve.

• Following transplant, most febrile episodes require in-patient treatment and observation until the profound neutropenia is clear and there is no significant infection.

Further Outpatient Care:

• Since early intervention prevents cytopenic complications, blood counts must be monitored carefully during and between phases of treatment.

• Following all planned therapy, careful physical examinations and blood work are important to ensure continued hematologic remission.

In/Out Patient Meds:

• Most supportive medications can be discontinued when chemotherapy is completed, including prophylactic antibiotics, nutritional support (eg, appetite stimulants), and antiemetics.

• Patients usually require prolonged immunosuppressive therapy with prednisone and cyclosporine following transplant. Penicillin, antifungal medications, acyclovir, and trimethoprim/sulfamethoxazole are continued until all immunosuppressive medications are discontinued.

Transfer:

• Transfer to a pediatric cancer center is usually necessary for initial diagnostic studies and management of both chemotherapy and treatment-related complications.

• For patients with suitable donors, transfer to a center capable of performing blood and marrow transplants usually are necessary.

Deterrence/Prevention: