eMedicine Specialties > Pediatrics: General Medicine > Oncology

Acute Myelocytic Leukemia: Treatment & Medication

Author: Mark E Weinblatt, MD, Chief, Division of Pediatric Hematology/Oncology, Professor of Clinical Pediatrics, Department of Pediatrics, Winthrop University Hospital
Contributor Information and Disclosures

Updated: Jul 15, 2009

Treatment

Medical Care

Treatment for patients with acute myeloid leukemia (AML) involves intensive chemotherapy to destroy the leukemic cell population as rapidly as possible and to prevent the emergence of a resistant clone. Patients are simultaneously given supportive care until their bone marrow achieves hematologic remission and is again producing normal hematopoietic cells.

• Chemotherapy
  • Virtually all chemotherapeutic drug regimens include some combination of an anthracycline (most often daunomycin) with cytosine arabinoside. Other drugs that have been administered include etoposide, amsacrine, dexamethasone, 6-thioguanine, cyclophosphamide, and mitoxantrone.
  • For many years, most children in the United States were treated with chemotherapy protocols developed by the Children’s Cancer Group and the Pediatric Oncology Group. These protocols, which used different multiagent chemotherapies, were associated with improved results as therapy was intensified. Although these treatments prolonged pancytopenia, they decreased induction failures and substantially improved disease-free survival.
  • After the 2 national groups merged to form the Children's Oncology Group (COG), the recommended regimen,³ based on the Medical Research Council acute myeloid leukemia trials, was adapted; this consisted of 2 cycles of induction therapy with infusions of daunomycin, cytosine arabinoside, etoposide (ADE therapy). Gemtuzumab ozogamicin, an anti-CD33 antibody linked to an antitumor antibiotic, is currently under investigation in a COG pediatric national trial.
  • After remission is induced, postinduction treatment is necessary because more than 90% of patients otherwise relapse without additional treatment. In patients without human leukocyte antigen (HLA)-matched donors from their family, sequential cycles of chemotherapy are administered by using combinations of cytosine arabinoside and etoposide, mitoxantrone and cytosine arabinoside, and, finally, high-dose cytosine arabinoside with L-asparaginase.
  • Allogeneic bone marrow transplantation has been shown to reduce relapse rates but does not always improve overall survival because of treatment-related mortality. Autologous bone marrow transplantation has also been shown to reduce relapse rates but does not improve overall survival compared with chemotherapy alone because of treatment-related mortality. 
  • In the COG trials, transplants are not recommended for "low-risk acute myeloid leukemia," which is characterized by chromosome inv(16) and t(8;21) abnormalities; these patients receive additional "consolidation" chemotherapy and are only transplanted in second remission. Allogeneic bone marrow transplantation from an HLA-matched sibling or parent is recommended during the first complete remission (ie, after 3 cycles of chemotherapy) for other patients (ie, those with standard-risk acute myeloid [normal cytogenetics] who enter remission with 2 induction courses and those with high-risk acute myeloid leukemia [abnormal karyotypes, including monosomy 7, trisomy 3, 5q- or complex karyotypes]). Transplantation is reserved for the second remission after a relapse for patients with Down syndrome and acute myeloid leukemia. Patients with acute promyelocytic leukemia (APL) should not receive a transplant during the first remission. 
  • Upon relapse and the achievement of a molecular remission in a child treated with chemotherapy only, stem cell transplantation offers the best chance of cure. If an HLA-matched family donor is not available, the use of unrelated matched donors and autologous bone marrow transplant are options that have shown promise. See the section on stem cell transplant below.
  • Other approaches have met with success in other parts of the world. Nordic and Japanese researches have reported promising results using multiple cycles of high-dose cytosine arabinoside.^4,5
• Treatment for APL⁶
  • The discovery of effective maturation agents has altered the approach to treating APL.
  • All-trans retinoic acid (ATRA) can effectively induce remission in most newly diagnosed APLs with the myelosuppressive effects of chemotherapy. The current treatment approach is to begin therapy with ATRA, followed with several days with an anthracycline to induce remission. For patients with a WBC count of more than 10 X 10⁹ (>10 X 10³/microliter), concomitant ATRA and anthracycline are used.
  • Additional cycles of this combination are used as consolidation chemotherapy. Randomized trials have shown an advantage of maintenance therapy for all patients with ATRA and, particularly, high-risk patients with ATRA in combination with 6-mercaptopurine and methotrexate.
  • Another approach that is being investigated in clinical trials is the use of arsenic trioxide, which is highly active in both newly diagnosed and relapsing APL. It effectively induces remissions in 85% of patients who have a relapse. In a North American Intergroup Study, the introduction of arsenic in consolidation was shown to significantly improve overall outcomes in adults with APL.   
  • Gemtuzumab ozogamicin (Mylotarg), or anti-CD33 calicheamicin, is also being tested in patients with APL. The hope is that both arsenic and gemtuzumab ozogamicin may reduce exposure to anthracyclines without sacrificing efficacy. The COG is planning on piloting a trial that will replace an anthracycline course of chemotherapy with arsenic trioxide plus ATRA in order to reduce the anthracycline exposure from an estimated 650 mg/m² to 350 mg/m² in standard-risk patients and to 450 mg/m² in high-risk patients. 
  • Patients with APL and high WBC counts at presentation should not undergo leukophoresis because of an increased risk of bleeding due to activation and degranulation of promyelocytes. Instead, hydration and hydroxyurea can be used, followed by rapid initiation of induction chemotherapy.
• Treatment for children with Down syndrome
  • Unlike most children with acute myeloid leukemia who should receive intense therapy, young children (<4 y) with Down syndrome fare best with reduced-intensity therapy, which results in an improved likelihood of long-term, disease-free remission. Many children with trisomy 21 have had transient myeloproliferative disease as infants. This picture resembles acute myeloid leukemia in many ways, but it usually disappears with only supportive care. About 20-30% of the children who had this syndrome as neonates develop true acute myeloid leukemia requiring chemotherapy.
  • Children with Down syndrome also seem to have marked complications of intense therapy. As a result, treatment for children with trisomy 21 involves lowered doses of induction chemotherapy (daunomycin, cytosine arabinoside, and 6-thioguanine) with prolonged periods between treatments. These children receive intensified chemotherapy high-dose cytosine arabinoside rather than bone marrow transplantation. Consolidation and intensification courses of therapy with high-dose cytosine arabinoside do not cause increased toxicity or mortality in patients with Down syndrome. 
  • Age has been shown to be an important prognostic factor for children with Down Syndrome; children younger than 2 years have the best outlook. A COG study (A2971) has shown that the 2-year-old to 4 year-old age group does as well as those younger than 2 years. Older children with Down syndrome continue to have a worse outlook than children younger than 4 years.
• Radiation therapy
  • Radiation treatment is primarily used to treat chloromas and other masses that are pressing on a vital structure and that may imminently cause irreversible damage. Examples include spinal cord compression and superior vena cava syndrome or airway compromise due to mediastinal masses. Corticosteroids and early administration of chemotherapy can effectively relieve most of these complications.
  • Persistent CNS leukemia usually requires craniospinal irradiation.
  • Most pretransplantation myeloablative regimens given to children in their first complete remission have replaced total body irradiation with busulfan to decrease the incidence of some long-term adverse effects. Although busulfan is associated with significant potential short-term and long-term adverse effects (including seizures and infertility), the incidence of second malignancies is lower than that associated with total body radiation.
• Blood and marrow transplantation
  • A myeloablative combination of chemotherapy and irradiation followed by rescue with an infusion of HLA-matched stem cells to reconstitute the patient's bone marrow is an effective approach to cure acute myeloid leukemia.⁷ In several randomized studies, allogeneic transplantation raised overall and disease-free survival rates.⁸ However, this option is not available to most patients because HLA-matched donors are found for only approximately 25%. In addition, for good-risk patients, transplantation is reserved for a second remission because the salvage rate is quite high for such patients. 
  • Options have substantially increased with the availability of international HLA registries that can help in locating HLA-matched unrelated donors (MUD). Results with MUD are virtually equivalent to HLA-matched family donors and have become more available with the development of large international HLA registries. Umbilical cord blood, which is rich in stem cells, has further expanded the availability of donor stem cells because increased HLA mismatch appears to be better tolerated with such donor cells in terms of the development of high-grade graft versus host disease (GVHD).
  • In addition, the use of both purged or unpurged autologous stem cells, which offer the advantages of availability and avoidance of graft versus host disease, are under investigation in clinical trials. However, to date, randomized studies in pediatric patients have not shown an overall survival advantage for autologous stem cell transplantation compared with chemotherapy. 
  • Success rates for stem cell transplants have also increased because of improved GVHD prophylaxis and treatment, using different combinations of methotrexate, cyclosporine, tacrolimus, mycophenolate, and corticosteroids to lower mortality rates.
  • Veno-occlusive disease (also termed sinusoidal obstructive syndrome) of the liver, a complication that can be fatal, has shown excellent responses to defibrotide in early phase clinical trials.
  • The substitution of busulfan-cyclophosphamide for regimens involving total-body irradiation has reduced long-term problems related to growth retardation and the increased risk of brain tumors. However, the risk of sterility, second malignancies, and neurocognitive abnormalities (especially in young children) remain a significant problem in survivors. 
• Transfusion support
  • Because treatment regimens are intensive, expeditious blood product transfusion support is critical.
  • Throughout long periods of pancytopenia, platelet and RBC transfusions are necessary to correct anemia and thrombocytopenia until remission is achieved.
  • Fresh frozen plasma is occasionally required to correct coagulopathies, particularly in patients with disseminated intravascular coagulation. All transfused products must be irradiated to prevent GVHD in heavily immunosuppressed patients.
  • Support from the blood bank is mandatory when patients present with hyperleukocytosis and are at high risk for stroke and heart failure due to hyperviscosity. These patients are best treated with leukophoresis or double-volume exchange transfusion to rapidly and safely decrease the leukemic cell burden without contributing to metabolic abnormalities. This procedure also facilitates rapid correction of anemia, which viscosity constraints would otherwise have prohibited.
  • In rare cases, granulocyte transfusions are administered to treat serious infections that do not respond to appropriate antibiotic therapy. This approach may be most appropriate for gram-negative sepsis, serious intra-abdominal infections, and, sometimes, fungal infections, although the efficacy of this approach as not been definitively proven.  
• Metabolic management
  • Patients who present with a large leukemic cell burden, either a high circulating WBC count or massive organomegaly, are at risk for severe, often life-threatening metabolic derangements.
  • Before beginning cytoreduction, correct any existing abnormalities and take measures to prevent new ones.
  • Hyperkalemia and hyperphosphatemia with associated hypocalcemia result from rapid cell turnover and destruction.
  • Promptly treat elevated potassium levels by using measures such as sodium polystyrene sulfonate (Kayexalate), an 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 the formation of uric acid), and alkalinization of the urine with sodium bicarbonate is usually successful in preventing serious tumor lysis syndromes. For patients at high risk for tumor lysis syndrome, those with renal dysfunction, or those whose uric acid levels are already elevated, rasburicase directly lyses uric acid and can rapidly reduce its levels.
• Antibiotic therapy
  • Infection is a major cause of morbidity and mortality.
  • Patients with fever, particularly if they have severe neutropenia, are presumed to have serious infection until proven otherwise.
  • Empiric broad-spectrum antibacterial antibiotics are administered when a patient is febrile and has an absolute neutrophil count of less than 7.5-10 X 10⁹/L  (<750-1000/μL). The choice of antibiotics depends on the typical pathogens found in the community and hospital. It is usually 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, removal of the intravenous line is also recommended.
  • If a patient presents with abdominal or GI symptoms, the antibiotic chosen should cover anaerobes.
  • When neutropenia is prolonged, particularly after treatment with broad-spectrum antibacterial agents, fungal disease becomes a great concern.
  • Empiric use of antifungal therapy is indicated in patients with persistent fever 3-5 days of initiation of broad spectrum antibiotics and negative bacterial cultures. Although amphotericin has been the standard treatment for many years, other agents, such as voriconazole, are increasingly used.
  • CT scanning is often 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. In some centers, prophylactic penicillin has decreased the incidence serious systemic streptococcal sepsis in patients with severe mucositis. Acyclovir has been useful in preventing herpes simplex infections, particularly in patients who have undergone bone marrow transplantation. Reports have suggested that prophylactic levofloxacin decreases the incidence of sepsis and other life-threatening infections. Patients who develop GVHD that requires significant immunosuppressive therapy require more intense and more broadened infection prophylaxis.
  • Vigilance is most important in the patient with acute myeloid leukemia and persistent fever. Frequent cultures of possible sites of infection should be performed.
  • To facilitate proper diagnosis, bronchoscopy, lung biopsy, and imaging studies are often necessary.
• Treatment with biologic-response modifiers
  • Granulocyte colony-stimulating factor (G-CSF) and granulocyte monocyte colony-stimulating factor (GM-CSF) shorten the period of chemotherapy-induced neutropenia. However, their role in the treatment of leukemia has not been definitively established because no improvement in survival has been demonstrated. Their use is not recommended in patients with acute myeloid leukemia.
  • The role of synthetic erythropoietin is yet to be elucidated, and its use is not recommended.

Surgical Care

• The role of surgery is limited.
• Insertion of a central venous catheter is necessary to begin treatment and to manage all aspects of chemotherapy and transfusion support.
• Biopsy or aspiration of tissue for culture is often necessary for febrile patients with a possible abscess.
• Acute abdomen often results in serious complications (eg, typhlitis) that require expeditious surgical intervention.

Consultations

• Urologist: Consider consulting a urologist when male teenagers are undergoing intense chemotherapy that may cause oligospermia and fertility problems in the future. These conditions are usually temporary. However, they are particularly problematic for patients who undergo high-dose chemotherapy in preparation for blood or marrow transplantation, and they are major problems for patients who may be receiving total-body irradiation. Encourage sperm banking, preferably before these patients begin any treatment that may affect the quality of their sperm.
• Psychologists, psychiatrists, or other mental health professional: Patients and their families may experience majors stresses as a result of intense treatment and frequent, prolonged hospitalizations for chemotherapy and its resulting complications (especially fin patients undergoing stem cell transplant). Another stressor is the real possibility of life-threatening complications. Psychologic support, with educational information and numerous meetings and updates, are important for the family's psychological well-being.

Diet

• Careful attention must be directed toward adequate nutrition. Because of prolonged neutropenia with infections that blunt a patient's appetite and recurrent episodes of chemotherapy-induced mucositis, high-calorie oral supplements are often helpful for maintaining weight. They allow help the patient in tolerating therapy. Most patients require intravenous total parenteral nutrition or, preferably, nasogastric alimental nutrition.
• Low-bacteria diets are often prescribed to patients receiving a blood or marrow transplant to decrease the incidence of infections because of the profound immunosuppression after transplantation. This would include avoiding uncooked fresh vegetables and fruits. These recommendations are probably not necessary for patients with acute myeloid leukemia who are not undergoing transplant.

Activity

• Minimal limits on activity are necessary. Patients should avoid crowds and exposure to potentially contagious disorders when they have neutropenia or immunosuppression after transplantation.
• During episodes of thrombocytopenia, patients should curtail their participation in potentially traumatic physical sports activities to avoid serious hemorrhage. Medications that can potentiate bleeding, such as antiplatelet agents (eg, aspirin, nonsteroidal anti-inflammatory drugs) should be avoided.

Medication

Treatment is directed toward 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 must also be included in treatment. Such classes include broad-spectrum antibacterial, antiviral, and antifungal antibiotics; biologic-response modifiers; and other classes of supportive medications.

Chemotherapeutic agents

Although many chemotherapeutic agents are active, most current regimens include combinations of an anthracycline and cytosine arabinoside. Chemotherapeutic agents destroy myeloblasts in various mechanisms.

Cytarabine, cytosine arabinoside, ARA-C (Cytosar-U)

Purine antimetabolite; inhibits DNA polymerase. Used in both induction and intensification phases of treatment.

Daunorubicin, daunomycin (Cerubidine)

Anthracycline that binds to nucleic acids by intercalating between pairs of DNA, interfering with DNA synthesis. Used in induction phase of treatment.

Etoposide, VP-16 (VePesid)

Podophyllotoxin derivative. Used in induction and consolidation phases of treatment.

Mitoxantrone (Novantrone)

Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II. Used in consolidation phase of treatment.

Tretinoin, all-trans -retinoic acid, ATRA (Vesanoid)

Used in induction and maintenance phases in patients with APL.

Arsenic trioxide (Trisenox)

May cause DNA fragmentation and damage or degrade fusion protein promyelocytic leukemia protein–retinoic acid receptor alpha (PML-RAR alpha). Use only in patients who have relapse or whose disease is refractory to retinoid or anthracycline chemotherapy.

L-asparaginase (Elspar)

Used in consolidation phase of therapy.

Gemtuzumab ozogamicin (Mylotarg)

Monoclonal antibody against CD33 antigen, which is expressed on leukemic blasts in >80% of patients with acute myeloid leukemia and normal myeloid cells. Antibody-antigen complex is then internalized and the calicheamicin derivative is released inside the myeloid cell where binds to DNA resulting in double strand breaks and cell death. Nonhematopoietic and pluripotent cells are not affected.
For administration to patients >60 years (CD33 positive) in first relapse who are not considered candidates for cytotoxic chemotherapy.

Antiemetic agents

Antineoplastic-induced vomiting is stimulated by actions on the chemoreceptor trigger zone. This zone then stimulates the vomiting center in the brain. Increased activity of central neurotransmitters, dopamine in the chemoreceptor trigger zone or acetylcholine in the vomiting center, appears to be a major mediator in inducing vomiting. After antineoplastic agents are given, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With this release and with the subsequent of 5-HT binding to 5-HT3-receptors, vagal neurons are stimulated and transmit signals to the vomiting center, resulting in nausea and vomiting.

Emesis is a notable 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.

Ondansetron (Zofran)

Selective 5-HT3 receptor antagonist that blocks serotonin peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and whole-body radiotherapy.

Granisetron (Kytril)

At chemoreceptor trigger zone, blocks serotonin centrally and peripherally on vagal nerve terminals.

Antimicrobials, prophylactic

Infections remain the biggest problem. Use of prophylactic drugs can help prevent several of these often life-threatening infections.

Sulfamethoxazole and trimethoprim (Bactrim, Septra)

Sulfa drugs can effectively prevent P carinii pneumonia in this immunocompromised group of patients.

Fluconazole (Diflucan)

Effective in treating and decreasing host colonization of candidiasis.

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