eMedicine Specialties > Hematology > Stem Cells and Disorders

Acute Myelogenous Leukemia: Treatment & Medication

Author: Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Contributor Information and Disclosures

Updated: Nov 10, 2009

Treatment

Medical Care

Current standard chemotherapy regimens cure only a minority of patients with acute myelogenous leukemia (AML). 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 (AML) (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 (ara-C) 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% of patients enter remission following a second course of therapy.
  • In a study by Fernandez et al, 657 patients younger than 60 years with untreated acute myeloid leukemia (AML) received either conventional-dose daunorubicin (45 mg/m²/d for 3 d) or high-dose daunorubicin (90 mg/m²/d for 3 d).¹⁰ These induction regimens were administered with cytarabine 100 mg/m²/d for 7 days for the first cycle. A higher rate of complete remission was observed in the high-dose daunorubicin group (70.6%) relative to the conventional dose (57.3%, P <0.001) as well as an improved overall survival (median, 23.7 mo) compared with the group administered the conventional dose (15.7 mo; P = 0.003).¹⁰
  • Alternatively, high-dose ara-C combined with idarubicin, daunorubicin, or mitoxantrone can be used as induction therapy in younger patients. The use of high-dose ara-C 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 ara-C during induction.
• Consolidation therapy in younger patients: In patients aged 60 years or younger, treatment options for consolidation therapy include high-dose ara-C, autologous stem cell transplantation, or allogeneic stem cell transplantation.
  • High-dose ara-C therapy
    • Mayer et al conducted a randomized study of 3 different doses of ara-C in patients with acute myelogenous leukemia (AML) who achieved remission after standard "3 and 7" induction chemotherapy.¹¹ Patients received 4 courses of ara-C 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 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 = 0.002). The outcome in older patients did not differ. Based on this study, high-dose ara-C for 4 cycles is a standard option for consolidation therapy in younger patients.¹¹
  • 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 HLA.¹² This study demonstrated a decreased rate of relapse at 3 years for patients receiving allogeneic BMT (34%) versus autologous BMT (60%) (P = 0.03) and an increased overall survival rate at 3 years for patients receiving allogeneic BMT (66%) versus autologous BMT (37%) (P = 0.05). 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.¹³ In this study, the number of relapses was lower for patients receiving autologous BMT (37%) versus no further treatment (58%) (P <0.001), and the rate of disease-free survival at 7 years was improved for patients receiving autologous BMT (53%) versus no further treatment (40%) (P = 0.04).¹³ However, no improvement in the overall survival rate at 7 years was observed for autologous BMT (57%) no further treatment (45%) (P = 0.2).
      • 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.¹⁴ Other patients randomly received either autologous BMT or a second course of intensive chemotherapy with high-dose ara-C 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 = 0.04). Again, the overall survival rate was similar in all 3 groups, because patients who had a relapse 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.¹⁵ All other patients received a course of consolidation chemotherapy with high-dose ara-C 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.¹⁶ Other patients randomly received either autologous BMT or one additional course of high-dose ara-C. 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 acute myelogenous leukemia (AML) (ie, t[8;21] or inversion of chromosome 16[inv16]) have a good prognosis following consolidation with high-dose ara-C and should be offered such therapy. This is given as ara-C 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 have a 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 a 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 ara-C for 4 courses and reserve transplantation for patients who have a relapse. Studies using newer molecular markers such as FLT3, NPM1, CEBPa, BAALC, and ERG, are helping to define which patients with cytogenetically normal AML should receive standard consolidation therapy versus transplantation.
• Before referral for allogeneic transplantation, a suitable donor must be identified. Ideally, this is a fully HLA-matched sibling; however, many 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 ara-C in select patients, or repeat courses of standard-dose anthracycline and ara-C (2 and 5; ie, 2 d of anthracycline and 5 d of ara-C). 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 acute myelogenous leukemia (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 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 also often have less severe acute graft versus host disease than patients who receive standard transplants. These 2 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 acute myelogenous leukemia (AML).
• Other immune therapies
  • Lintuzumab is a humanized monoclonal antibody that targets CD33, which is present on most AML cells. It induces antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis. Early studies demonstrated activity, although randomized studies of lintuzumab given after chemotherapy did not show a benefit. However, a phase I study of lintuzumab as a single agent in patients with acute myelogenous leukemia (AML) demonstrated a response rate of 28%.
  • PR1 is a nonomeric HLA-A2-restricted peptide derived from the myeloid leukemia-associated antigens proteinase 3 and neutrophil elastase. PR1-specific cytotoxic T lymphocytes (PR1-CTL) selectively kill MDS, acute myelogenous leukemia (AML), and CML and contribute to complete cytogenetic remission. A study demonstrated that PR1 vaccine-induced immune response is associated with better event-free survival in patients with myeloid leukemia who received the vaccine.

Alternative options for elderly patients include the following:

• Results of treatment of acute myelogenous leukemia (AML) in the elderly patient (particularly above the age of 75) remain unsatisfactory. In a CALGB study, patients older than 60 years had a complete remission rate of 47% after standard therapy. There were 31% aplastic deaths, and only 9% of patients were alive at 4 years.
  • It should be noted that patients with antecedent hematologic disorders were excluded so that these results overestimate the benefit of chemotherapy in elderly patients. Many patients are never referred for treatment due to serious comorbid medical conditions and the knowledge that the treatment results are poor in this group of patients.
  • For example, Menzin et al analyzed Medicare claims for treatment of acute myelogenous leukemia (AML).¹⁷ In this study, only 30% of patients received chemotherapy (44% of patients aged 65-74 y, 24% of patients aged 75-84 y, and only 6% of patients 85 y or older). Despite this, approximately 90% of patients were hospitalized and the patients spent approximately one third of their remaining days in the hospital. Therefore, there is a need to develop novel treatments in this patient population.¹⁷
• There is evidence that patients who are treated have improved survival over those who are not treated. In the study of Menzin, the median survival was 6.1 months for patients who received chemotherapy versus 1.7 months for those who did not.¹⁷ Similarly, Lowenberg et al reported a median survival of 21 weeks for elderly patients randomized to therapy versus 11 weeks for patients randomized to a "watch and wait" approach.¹⁸ In a Medical Research Council study, the median survival was significantly improved for patients who received low dose ara-C as opposed to hydroxyurea.
• Some older patients do reasonably well with standard therapy. In an analysis of 998 older patients treated at MD Anderson Cancer Center, age >75 years, poor performance status, previous antecedent hematologic disorder, unfavorable karyotype, renal insufficiency, and/or treatment outside of a laminar flow room were associated with an adverse outcome.¹⁹ Patients with none of these risk factors had a complete remission rate of 72%, 8-week mortality of 10%, and median 2-year survival of 35%, whereas patients with 3 or more risk factors had a complete remission rate of 24%, an 8-week mortality of 57%, and a median 2-year survival of only 3%.¹⁹ Thus, some low risk elderly patients can benefit from standard intensive chemotherapy.
• A recent study in elderly patients with newly diagnosed acute myeloid leukemia (AML) compared conventional-dose daunorubicin (45 mg/m²/d for d) (n = 411) with high-dose daunorubicin (90 mg/m²/d for 3 d) (n = 402).²⁰ These regimens were administered with cytarabine 200 mg/m²/d for 7 days for the first cycle. A second cycle of cytarabine alone (1000 mg/m²/d for 6 d) was also administered. Complete remission occurred in 64% in the high-dose daunorubicin group compared with 54% in the conventional-dose group (P = 0.002)²⁰ ; remission after the first cycle was 52% in the high-dose daunorubicin group compared with 35% in the conventional-dose group (P <0.001).
• Novel agents are being studied in older patients who are not candidates for intensive chemotherapy.²¹
  • Tipifarnib (a farnesyl transferase inhibitor) initially showed promise. However a larger study demonstrated a response rate of only 8%, and a randomized trial comparing tipifarnib with best supportive care showed no benefit to the use of this drug.
  • Cloretazine is a novel alkylating agent with activity against acute myelogenous leukemia (AML), independent of cytogenetics. In a phase II study in elderly patients, a single dose of 600 mg/m² resulted in a response rate (CR + complete responses with incomplete platelet recovery [CRp]) of 35%.²²
  • Clofarabine is a purine analogue that is US Federal Drug Administration (FDA) approved for the treatment of relapsed pediatric ALL. A study of clofarabine and ara-C in newly-diagnosed patients with AML who were 50 years or older yielded a complete response rate of 52% and CRp rate of 8%. Induction deaths occurred in 7% of patients.²³
  • The hypomethylating agents, azacytidine and decitabine, are approved for use in patients with MDS. However both of these agents have activity in acute myelogenous leukemia (AML) (complete response rates 15-20%). Both drugs are well tolerated and are therefore being used in elderly patients.^24,25
  • Other agents being studied include CP-4055, a cytarabine 5'-elaidic acid ester that is independent of nucleoside transporters, sapacitabine, a 2'-deoxycytidine nucleoside analogue, and SNS-595, a replication-dependent DNA damaging agent.

Treatment of APL

APL is a special subtype of acute myelogenous leukemia (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 acute myelogenous leukemia (AML) that is most commonly associated with coagulopathy due to 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 (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 of APL 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 of APL, cytogenetic 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 all-trans-retinoic acid (ATRA). Older studies using standard chemotherapy regimens without ATRA showed that approximately 70% of patients achieved complete response 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.^26,27,28

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.²⁹ 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 ara-C) 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 a complete response. 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 followed by maintenance therapy.

A North American Intergroup study evaluated the addition of 2 cycles of consolidation therapy with arsenic trioxide followed by 2 cycles of chemotherapy with ara-C and daunorubicin to 2 cycles of ara-C and daunorubicin chemotherapy without arsenic trioxide.¹⁶ Event-free survival, the primary endpoint, was 77% at 3 years in the arsenic trioxide arm (median, not reached) compared with 59% at 3 years in the standard arm (median, 63 mos; P = 0.0013).

Overall, 84% of adults were alive at last follow up. Overall survival was 86% at 3 years in the arsenic trioxide arm compared with 77% at 3 years in the standard arm (medians not reached; P = 0.029). Maintenance therapy with ATRA, 6-mercaptopurine (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 have a relapse are usually treated with arsenic trioxide. Arsenic trioxide induces complete remission in 85% of patients. Toxicities include the APL differentiation syndrome (similar to that seen with ATRA), leukocytosis, and abnormalities found on electrocardiographs (ECGs). Patients can also be retreated with chemotherapy plus ATRA, depending on the duration of their first remission and cardiac status. Evaluate patients in second remission for allogeneic or autologous stem cell transplantation.

Many newer studies have eliminated ara-C from the induction therapy for 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. However a randomized study from France questioned this approach. Newly diagnosed APL patients younger than 60 years with a WBC count of less than 10,000/CL were randomly assigned to receive either ATRA combined with and followed by 3 daunorubicin (DNR) plus ara-C courses and a 2-year maintenance regimen (ara-C group) or the same treatment but without ara-C (no ara-C group).

Patients older than 60 years and patients with an initial WBC count of greater than 10,000/μL were not randomly assigned but received risk-adapted treatment, with higher dose of ara-C and central nervous system (CNS) prophylaxis in patients with WBC counts greater than 10,000/μL. Overall, 328 (96.5%) of 340 patients achieved complete remission.

In the ara-C and the no ara-C groups, the complete remission rates were 99% for the ara-C arm and 94% for the no ara-C arm (P = 0.12), the 2-year cumulative incidence of relapse (CIR) rates were 4.7% in those who received ara-C and 15.9% in those who did not receive ara-C (P = 0.011), the event-free survival rates were 93.3% in the ara-C group and 77.2% in the no ara-C group (P = 0.0021), and survival rates were 97.9% in patients who receive ara-C and 89.6% in those who received no ara-C (P = 0.0066). In patients younger than 60 years with WBC counts more than 10,000/μL, the complete response rate was 97.3%, 2-year CIR was 2.9%, event-free survival was 89%, and survival rate was 91.9%.

Another trend is the development of risk-adapted approaches to consolidation therapy. In the Programa de Estudio y Traitmiento de las Hemopatias Malignas (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).³⁰

Other areas of investigation include the use of arsenic in front-line therapy (with or without chemotherapy) and the use of gemtuzumab ozogamicin or lintuzumab as consolidation therapy.

Treatment of relapsed AML

Patients with relapsed acute myelogenous leukemia (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.³¹ Patients with an initial complete response duration of longer than 2 years had a 73% complete response rate with initial salvage therapy. Patients with an initial complete response duration of 1-2 years had a complete response rate of 47% with initial salvage therapy.

Patients with an initial complete response duration of less than 1 year or with no initial complete response had a 14% complete response rate with initial salvage therapy. Patients with an initial complete response duration of less than 1 year (or no initial complete response) 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.

Many of the agents listed under treatment of elderly acute myelogenous leukemia (AML) are also being studied in patients with relapsed AML.

• Other therapies
  • 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 FDA for the treatment of patients with CD33-positive acute myelogenous leukemia (AML) in first relapse who are aged 60 years or older and who are not considered candidates for other cytotoxic chemotherapy.
  • Sievers et al reported the results of gemtuzumab ozogamicin administration in 142 patients with acute myelogenous leukemia (AML) who were in their first relapse and who had no history of an antecedent hematologic disorder.³² 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.³²
  • Later studies have shown that use of gemtuzumab ozogamicin either before or following stem cell transplantation is associated with an increased risk of VOD.³³ 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 acute myelogenous leukemia (AML). Although gemtuzumab ozogamicin is an active drug, the response rate is less than that obtained with standard "3 and 7" chemotherapy.

Elements of supportive care include the following:

• Replacement of blood products
  • Patients with acute myelogenous leukemia (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, however, a number of other antifungal agents have become available. These include the lipid-preparation amphotericins (Abelcet and AmBisome), newer azoles (voriconazole and posaconazole), and the echinocandins (caspofungin, anidulafungin, and micafungin). These drugs have varying roles in the treatment of neutropenic patients with either suspected or proven fungal infections.
  • Prophylactic antibiotics are usually used in nonfebrile patients undergoing intensive chemotherapy. A commonly used regimen is ciprofloxacin, fluconazole, or itraconazole, and acyclovir or valacyclovir.
    • A randomized trial of posaconazole versus either fluconazole or itraconazole (center choice) in patients with acute myelogenous leukemia (AML) and MDS undergoing intensive chemotherapy demonstrated a significant reduction in all cause mortality at day 100, as well as a decrease in invasive fungal infections and a decrease in aspergillosis in patients randomized to posaconazole.
    • Both the National Comprehensive Cancer Network (NCCN) and Infectious Diseases Society of America (IDSA) guidelines strongly recommend antifungal prophylaxis in this group of patients.
  • 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 the clearance of blasts and resolution of hyperuricemia. For patients who cannot tolerate oral medications, intravenous drugs such as rasburicase are an option. Rasburicase should also be considered in patients at high risk of severe tumor lysis (very high LDH, baseline renal insufficiency).
• 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 (20 d) than those receiving no drug (28 d), decreased febrile days (3 d vs 7 d, respectively), and fewer documented infections.³⁴ 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 in the G-CSF arm (21 d) compared with those in the placebo arm (27 d), and the complete response rate was higher in those who received G-CSF (70%) compared with those who received placebo (47%); however, the overall survival rate was unaffected.³⁵
  • In a Southwestern Oncology Group study, a decrease was observed in the time to neutrophil recovery and days with fever in those who received G-CSF; however, no difference in complete remission rate and overall survival rate was observed for patients receiving G-CSF versus no drug.³⁶
  • 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 acute myelogenous leukemia (AML), no significant increase in response rate was observed; however, a significant decrease in the death rate from pneumonia and fungal infection was observed.³⁷ 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 = 0.048).³⁷
  • 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 between the groups that received GM-CSF and placebo.³⁸ 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 complete rate (48%) compared with patients who did not receive GM-CSF (77%).³⁹
  • These data suggest that G-CSF and yeast-derived GM-CSF accelerate neutrophil recovery and decrease the risk of infection in patients who are undergoing induction therapy.³⁹ 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 with acute myelogenous leukemia (AML) 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).

Medication

Medications used for the treatment of acute myelogenous leukemia (AML) cause severe bone marrow depression. Only physicians specifically trained in their use should use these agents. In addition, access to appropriate supportive care (ie, blood banking) is required.

Antineoplastics

Antineoplastic agents are used for induction or consolidation therapy.

Cytosine arabinoside, cytarabine (Cytosar-U)

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.

Daunorubicin (Cerubidine)

Topoisomerase-II inhibitor. Inhibits DNA and RNA synthesis by intercalating between DNA base pairs.

Idarubicin (Idamycin)

Topoisomerase-II inhibitor. Inhibits cell proliferation by inhibiting DNA and RNA polymerase.

Mitoxantrone (Novantrone)

Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II.

Gemtuzumab ozogamicin (Mylotarg)

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.

Arsenic trioxide (Trisenox)

Used in patients with relapsed APL. The mechanism of action of Trisenox is not completely understood. Arsenic trioxide causes morphologic changes and DNA fragmentation that are 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.

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• Novel Targeted Drug Therapies for the Treatment of Childhood Acute Leukemia
• Treatment of Acute Myeloid Leukemia With Hematopoietic Stem Cell Transplantation

• Acute Leukemia Resource Center