Acute Myelogenous Leukemia Treatment & Management

Current standard chemotherapy regimens cure only a minority of patients with acute myelogenous leukemia (AML). As a result, all patients should be evaluated for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy (see below). For consolidation chemotherapy or for the management of toxic effects of chemotherapy, readmission is required.

When receiving chemotherapy, patients should avoid exposure to crowds and people with contagious illnesses, especially children with viral infections. Any patient with neutropenic fever or infection should immediately be treated with broad-spectrum antibiotics.

Appropriate transfusion support must be provided to patients with AML. This includes transfusion of platelets and clotting factors (fresh frozen plasma [FFP], cryoprecipitate) as guided by the patient’s blood test results and bleeding history. Blood products must be irradiated to prevent transfusion-associated graft versus host disease (GVHD).

Patients with AML are best treated at a center whose staff has significant experience in the treatment of leukemia. Patients should be transferred to an appropriate (generally tertiary care) hospital if they are admitted to hospitals without appropriate blood product support, leukapheresis capabilities, or physicians and nurses familiar with the treatment of leukemia patients.

Chemotherapy for AML is discussed separately from therapy for acute promyelocytic leukemia (APL) and therapy for relapsed AML (see below).

Induction therapy

Various acceptable induction regimens are available. The most common approach, "3 and 7," 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 cytarabine (arabinosylcytosine; ara-C) as a 24-hour infusion daily for 7 days. Traditionally, the dosage of idarubicin has been 12 mg/m²/d for 3 days, the dosage of daunorubicin has been 45-60 mg/m²/d for 3 days, and the dosage of mitoxantrone has been 12 mg/m²/d for 3 days.

These regimens require adequate cardiac, hepatic, and renal function. On these regimens, approximately 50% of patients achieve remission with one course. Another 10-15% of patients enter remission after a second course of therapy.

In a study by Fernandez et al, 657 patients younger than 60 years with untreated AML received either conventional-dose daunorubicin (45 mg/m²/d for 3 d) or high-dose daunorubicin (90 mg/m²/d for 3 d).^[24] 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%) as well as an improved overall survival (median, 23.7 mo) compared with the group administered the conventional dose (15.7 mo).^[24]

In a similar study in patients 60 years of age or older by Lowenberg et al, 813 patients received either conventional-dose treatment (daunorubicin 45 mg/m²/d for 3 d) or escalated-dose treatment (daunorubicin 90 mg/m²/d for 3 d), both administered over 3 hours on days 1, 2, and 3.^[25] In both cases, patients received cytarabine 200 mg/m²/d as a continuous infusion for 7 days.

The complete remission rate was 64% in the escalated-dose group compared with 54% in conventional-dose group. No significant difference was seen between the groups in terms of hematologic toxic effects, 30-day mortality, or other significant adverse events. Although survival endpoints did not differ overall, there was an improvement in complete remission rate, event-free survival, and overall survival in patients aged 60-65 years.^[25]

Alternatively, high-dose cytarabine combined with idarubicin, daunorubicin, or mitoxantrone can be used as induction therapy in younger patients. The use of high-dose cytarabine 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 cytarabine during induction.

A study of dosing regimens for cytarabine induction therapy determined that lower doses produce maximal antileukemic effects for all response end points.^[26] Thus, high-dose cytarabine results in excessive toxic effects with no therapeutic advantage.

Consolidation therapy in younger patients

In patients aged 60 years or younger, treatment options for consolidation therapy include high-dose cytarabine, autologous stem cell transplantation, and allogeneic stem cell transplantation.

Mayer et al conducted a randomized study of 3 different doses of cytarabine in patients with AML who achieved remission after standard “3 and 7” induction chemotherapy.^[27] Patients received 4 courses of cytarabine at one of the following dosages: (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. The outcome in older patients did not differ. On the basis of this study, high-dose cytarabine for 4 cycles is a standard option for consolidation therapy in younger patients.^[27]

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, depending on the availability of a human leukocyte antigen (HLA)-matched sibling donor.^[28] There was a decreased rate of relapse at 3 years (34%) and an increased overall survival rate (66%) for patients receiving allogeneic BMT compared with those receiving autologous BMT (60% and 37%, respectively). However, the median patient age in the allogeneic BMT group was 10 years younger than that in the autologous BMT group.

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.^[29]

In this study, the number of relapses was lower for patients receiving autologous BMT (37%) versus no further treatment (58%), and the rate of disease-free survival at 7 years was improved for patients receiving autologous BMT (53%) versus no further treatment (40%).^[29] However, no improvement in the overall survival rate at 7 years was observed for autologous BMT (57%) versus no further treatment (45%).

In a European Organization for Research and Treatment of Cancer (EORTC)/Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) study, patients with an HLA-identical sibling underwent allogeneic BMT.^[30] Other patients randomly received either autologous BMT or a second course of intensive chemotherapy with high-dose cytarabine 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. 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, however, 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.^[31] All other patients received a course of consolidation chemotherapy with high-dose cytarabine and an anthracycline and then randomly received either a second course of consolidation chemotherapy or autologous BMT. The type of postremission therapy had no effect on outcome.

In a North American Intergroup study, patients in remission with a matched donor received allogeneic BMT.^[32] Other patients randomly received either autologous BMT or one additional course of high-dose cytarabine. In this study, the survival rate was better for patients receiving chemotherapy without BMT than for patients in the other groups.

In view of these conflicting results, the following recommendations can be made:

• Patients with good-risk AML (ie, t[8;21] or inversion of chromosome 16[inv16]) have a good prognosis after consolidation with high-dose cytarabine and should be offered such therapy. This is given as cytarabine 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. Alternatively, autologous transplantation can be given after (typically) 1-2 cycles of consolidation therapy. Allogeneic stem cell transplantation should be reserved for patients who relapse.
• Patients with high-risk cytogenetics findings are rarely cured with chemotherapy and should be offered transplantation in first remission. However, these patients also are at high risk for 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 cytarabine for 4 courses and reserve transplantation for patients who 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.

Therapy in older patients

Overall, the results of treatment of AML in elderly patients (particularly those older than 75 years) remain unsatisfactory. In a Cancer and Leukemia Group B (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; accordingly, these results overestimate the benefit of chemotherapy in elderly patients.

Many patients are never referred for treatment, because of 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 AML.^[33] 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, novel treatments need to be developed for this patient population.^[33]

There is evidence that patients who are treated have improved survival over those who are not treated. In the study by Menzin et al, the median survival was 6.1 months for patients who received chemotherapy versus 1.7 months for those who did not.^[33]

Similarly, Lowenberg et al reported a median survival of 21 weeks for elderly patients randomized to therapy compared with 11 weeks for patients randomized to a “watch and wait” approach.^[34] 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 greater than 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.^[35]

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%.^[35] Thus, some low-risk elderly patients can benefit from standard intensive chemotherapy.

A recent study in elderly patients with newly diagnosed AML compared conventional-dose daunorubicin (45 mg/m²/d for 3 d) with high-dose daunorubicin (90 mg/m²/d for 3 d).^[25] 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^[25] ; remission after the first cycle was 52% in the high-dose daunorubicin group compared with 35% in the conventional-dose group.

Other therapies are being studied in older patients who are not candidates for intensive chemotherapy.^[36] As part of National Cancer Research Institute Acute Myeloid Leukemia 14 Trial, 217 patients who were deemed unfit for intensive chemotherapy were randomized to receive low-dose cytarabine (Ara-C) (20 mg twice daily for 10 d) or hydroxyurea with or without all-trans retinoic acid (ATRA). Low-dose ara-C produced a better remission rate (18% vs 1%; P =.00006) and better overall survival (OR, 0.60; P =.0009) .  Overall survival was 80 weeks for patients achieving a complete remission verus 10 weeks for patients with no remission.^[37]

The hypomethylators azacytidine and decitabine are also options for the treatment of AML in elderly patients. Itzykson et al recently reported prolonged survival for patients with AML treated with azacytidine in 2 different trials. The AZA-001 study included 55 patients with WHO-defined AML randomized to azacytidine treatment, and the French AZA compassionate program (ATU) included 148 patients with WHO-defined AML treated with azacytidine as frontline therapy. Patients received azacytidine, 75 mg/m²/d X 7d/28d for a minimum of 6 cycles in the AZA -001 trial, as did 48% of patients in the ATU for a minimum of 4 cycles.

For the 55 patients in the AZA-001 cohort, with a median follow-up of 20.1 months, 11 (20%) of 55 were alive greater that 2 years after beginning azacytidine. None of the 11 patients had achieved complete or prolonged with azacytidine. In the ATU cohort, median follow-up was 15.6 months. Of 148 AML patients, 68 (46%) had entered the study 2 or more years before the reference date of analysis (January, 2010). Of patients with 20-30% bone marrow blasts, 7 (24%) of 29 were alive at 2 years.^[38]

Decitabine is another hypomethylator with activity in AML. Ansstas et al reported a single institution, retrospective study of patients older than 60 years with either de novo AML or AML arising out of myelodysplastic syndrome who were treated with decitabine at 20 mg/m² for 5 consecutive days of a 4-week cycle. Patients continued to receive decitabine until disease progression or an unacceptable adverse event occurred. The best response to therapy was complete remission (CR)/CR with incomplete blood count recovery (CRi) 29%, stable disease/partial remission 49%, and progressive disease 22%. The median duration of CR/CRi was 393 days (range, 184-748 d). Median overall survival for patients presenting with WBC less than 10,000 cells/µL was 11 months (range, 0.5-59.8 mo) and WBC greater than 10,000 cells/µL was 7.1 months (range, 1.9-32.7 mo).^[39]

Clofarabine is a purine analogue that is approved by the US Federal Drug Administration (FDA) for the treatment of relapsed pediatric acute lymphocytic leukemia (ALL). A study of clofarabine and cytarabine in newly diagnosed patients with AML who were 50 years or older yielded a complete response rate of 52% and a CRp rate of 8%. Induction deaths occurred in 7% of patients.^[40]

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 cytarabine (2 and 5; ie, 2 d of anthracycline and 5 d of cytarabine). Select patients can be considered for autologous stem cell transplantation or nonmyeloablative allogeneic transplantation.

Although allogeneic stem cell transplantation is a potentially curative treatment option for patients with AML, all age groups have a significant risk of death from the procedure. The risk of death increases with age, particularly in patients older than 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, veno-occlusive disease [VOD]), and GVHD. In an attempt to reduce these toxicities, several investigators have developed new, less toxic conditioning regimens known as nonmyeloablative transplants or mini transplants.^{[41, 42, 43]}

Nonmyeloablative 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 GVHD 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 GVHD, which can be fatal. In addition, relapse rates following nonmyeloablative transplants appear to be higher than those following standard transplants. Further studies are ongoing to determine the best role for these transplants in patients with AML.

APL is a special subtype of AML. It 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 white blood cell (WBC) counts. In fact, WBC counts higher than 5000 cells/µL at presentation are associated with a poor prognosis.

APL is the subtype of AML that is most commonly associated with coagulopathy due to disseminated intravascular coagulation (DIC) and fibrinolysis. Therefore, aggressive supportive care is an important component of the treatment of APL. Platelets should be transfused to maintain a platelet count of at least 30,000/µL (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 on the basis of 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 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.^{[44, 45, 46]}

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.^[47] 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 cytarabine) 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 commonly employed 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 cytarabine and daunorubicin to 2 cycles of cytarabine and daunorubicin chemotherapy without arsenic trioxide.^[32] 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 mo).

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). Maintenance therapy with ATRA, 6-mercaptopurine (6-MP), and methotrexate is effective in preventing relapses compared with no maintenance therapy; however, the optimal schedule of this therapy is not yet determined.

Patients who 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 cytarabine from the induction therapy for newly diagnosed patients.^[48] For example, the GIMEMA AIDA regimen (ie, ATRA 45 mg/m² daily combined with idarubicin 12 mg/m² on days 2, 4, 6, and 8 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/µL were randomly assigned to receive either ATRA combined with and followed by 3 daunorubicin plus cytarabine courses and a 2-year maintenance regimen (cytarabine group) or the same treatment but without cytarabine (no-cytarabine 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 cytarabine 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 cytarabine and the no-cytarabine groups, the complete remission rates were 99% for the ara-C arm and 94% for the no-cytarabine arm, the 2-year cumulative incidence of relapse (CIR) rates were 4.7% in those who received cytarabine and 15.9% in those who did not receive cytarabine, the event-free survival rates were 93.3% in the cytarabine group and 77.2% in the no-cytarabine group, and survival rates were 97.9% in patients who received cytarabine and 89.6% in those who received no cytarabine.

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).^[49]

Other areas of investigation include the use of arsenic in front-line therapy (with or without chemotherapy) and the use of lintuzumab as consolidation therapy. Gemtuzumab ozogamicin was initially intended for use as consolidation therapy, but this agent was withdrawn from the US market in June 2010.

Patients with relapsed AML have an extremely poor prognosis. Most patients should be referred for investigational therapies. Young patients who have not previously undergone transplantation should be referred for such therapy.

Estey et al reported that the chances of obtaining a second remission with chemotherapy correlate strongly with the duration of the first remission.^[50] 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 underscore the need to develop new treatment options for these patients.

Response to third-line therapy is even worse. Giles et al studied 594 patients with AML undergoing second salvage therapy from 1980 to 2004. The patient median age was 50 years. Salvage therapy included allogeneic stem cell transplantation (SCT), standard-dose cytosine arabinoside (ara-C) combinations, high-dose ara-C combinations, non–ara-C combinations, and phase I-II single agents. Overall, 76 patients (13%) achieved CR. The median CR duration was 7 months. The median survival was 1.5 months, and the 1-year survival rate was 8%. A multivariate analysis of prognostic factors for CR identified the following 6 independent adverse factors: first CR duration less than 6 months, second CR duration less than 6 months, salvage therapy not including allogeneic SCT, noninversion 16 AML, platelet counts less than 50 X 10⁹/L, and leukocytosis greater than 50 X 10⁹/L.^[51]

Owing to the poor outcome with salvage therapy, it is important to refer patients for well-designed clinical trials whenever possible. Agents in late-stage clinical trials include clofarabine, vosaroxin, and elacytarabine. For patients who are unable to participate in a clinical trial, options include high-dose cytarabine-based regimens, hypomethylators, and supportive care. Two standard regimens with high response rates include CLAG-M (cladribine combined with high doses of ara-C, mitoxantrone, and G-CSF) and MEC (mitoxantrone, etoposide, and intermediate dose cytarabine).

In a study by the Polish Adult Leukemia Group, the CLAG-M regimen yielded complete remissions in 58% of patients. White blood count cell greater than 10 g/L and age older than 34 years were factors associated with increased risk of treatment failure. Hematological toxicity was the most prominent toxicity of this regimen. The probability of overall survival at 4 years was 14%, and the probability of 4-year disease-free survival was 30% for all 66 patients in complete remission.^[52]

In an initial study of MEC, 32 patients with refractory acute myeloid leukemia received salvage therapy with mitoxantrone at 6 mg/m² intravenous (IV) bolus, etoposide at 80 mg/ m² IV for a period of 1 hour, and cytarabine (Ara-C) at 1 g/ m² IV for a period of 6 hours daily for 6 days. Eighteen patients were primarily resistant to conventional daunorubicin and Ara-C induction treatment, 8 patients had relapsed within 6 months from initial remission, and 6 patients had relapsed after a bone marrow transplantation (BMT) procedure. Overall, 21 patients (66%) achieved a CR. The median remission duration was 16 weeks; the overall median survival was 36 weeks. Severe myelosuppression was observed in all patients, resulting in fever or documented infections in 91% of patients. Nonhematologic toxicity was minimal.^[53]

In a study by Levis et al, lestaurtinib was administered twice daily to patients with FLT3 mutant AML in first relapse.^[54] Because such a small proportion of patients in the trial achieved sustained FLT3 inhibition in vivo, conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not prolong survival or increase response rates in first relapse.

Replacement of blood products

Patients with AML have a deficiency in the ability to produce normal blood cells and, therefore, need replacement therapy. The addition of chemotherapy temporarily worsens this deficiency. All blood products should be irradiated to prevent transfusion-related GVHD, which is almost invariably fatal.

Packed red blood cells are given when the hemoglobin concentration is lower 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 platelet count is lower than 10,000-20,000/µL. Patients with pulmonary or GI hemorrhage should receive platelet transfusions to maintain a value greater than 50,000/µL. Patients with CNS hemorrhage should be transfused until they achieve a platelet count of 100,000/µL. Patients with APL should have their platelet count maintained above 50,000/µL, at least until evidence of DIC has resolved.

FFP 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.

Antibiotic therapy

Intravenous (IV) 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. Both the National Comprehensive Cancer Network (NCCN) and Infectious Diseases Society of America (IDSA) guidelines strongly recommend antifungal prophylaxis in this group of patients.

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 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.

Once patients receiving these antibiotics become febrile, the regimen is changed to IV 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, IV drugs such as rasburicase are an option. Rasburicase should also be considered in patients at high risk of severe tumor lysis (very high lactate dehydrogenase [LDH] level, baseline renal insufficiency).

Growth factors

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), a smaller number of febrile days (3 d vs 7 d, respectively), and fewer documented infections.^[55] 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%) than in those who received placebo (47%); however, the overall survival rate was unaffected.^[56]

In a Southwestern Oncology Group (SWOG) 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.^[57]

Other groups have studied the effect of granulocyte macrophage colony-stimulating factor (GM-CSF) on induction therapy.

In an Eastern Cooperative Oncology Group (ECOG) study of yeast-derived GM-CSF in elderly patients with AML, no significant increase in response rate was observed; however, a significant decrease in the death rate from pneumonia and fungal infection was observed.^[58] 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).^[58]

In a CALGB study of GM-CSF derived from E coli, no difference was observed in response rates between the GM-CSF group and the placebo group.^[59] The risk of severe infection and resistant leukemia was similar in the 2 groups. However, in an EORTC study using GM-CSF derived from E coli, patients who randomly received GM-CSF after induction had a significantly lower complete rate (48%) than those who did not receive GM-CSF (77%).^[60]

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.^[60] For this reason, most clinicians use either of these growth factors in patients who are at high risk for complications from infection.

Venous catheter placement

Placement of a central venous catheter (eg, triple lumen, Broviac, Hickman) is necessary.

Patients with 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).

Patients should limit their activity to what is tolerable. They should refrain from strenuous activities (eg, lifting, exercise).

Patients should come to the office for monitoring of disease status and chemotherapy effects.