Acute Myeloid Leukemia (AML) Treatment & Management

Updated: Jul 26, 2023
  • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Treatment

Approach Considerations

Treatment options for acute myeloid leukemia (AML) comprise a variety of chemotherapy regimens, biologic agents, and stem cell transplantation. [41, 42] Treatment recommendations include general recommendations, which take into account patient age and performance status, as well as recommendations for relapsed or refractory disease and acute promyelocytic leukemia (APL). See Acute Myeloid Leukemia Treatment Protocols for details of treatment regimens. Go to Oncology Decision Point for expert commentary on AML treatment decisions and related guidelines.

Current standard chemotherapy regimens cure only a minority of patients with 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. 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. (See Antimicrobial Agents in Neutropenic Cancer Patients and Neutropenic Fever Empiric Therapy .)

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.

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Treatment of Acute Myeloid Leukemia

Induction therapy in younger patients and older "fit" patients

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 100-200 mg/m2 of cytarabine (arabinosylcytosine; ara-C) as a 24-hour infusion daily for 7 days. Traditional dosages have been as follows:

  • Idarubicin: 12 mg/m 2/d for 3 days
  • Daunorubicin: 45-90 mg/m 2/d for 3 days
  • Mitoxantrone: 12 mg/m 2/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.

Improved outcomes have been reported with induction regimens using a higher dose of daunorubicin (90 mg/m2/d for 3 d compared with 45 mg/m2/d). In a study by Fernandez et al in 657 patients younger than 60 years with untreated AML, the complete remission (CR) rate with high-dose daunorubicin was 70.6%, versus 57.3% with conventional-dose daunorubicin, and median overall survival (OS) was 23.7 versus 15.7 months, respectively. [43]

In a similar study in 813 patients 60 years of age or older by Lowenberg et al, the CR rate was 64% in the escalated-dose group compared with 54% in conventional-dose group. In both groups, daunorubicin was administered over 3 hours on days 1-3. Cytarabine was given in a dose of 200 mg/m2/d as a continuous infusion for 7 days, followed by a second cycle at a dose of 1000 mg/m2/12 h for 6 days. [44]

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 between the two groups overall, in patients aged 60-65 years the CR, event-free survival, and OS rates were superior in the escalated-dose group. [44]

A study comparing daunorubicin 90 mg/m2 versus 60 mg/m2 for AML induction found no difference in CR rate (73% versus 75%) or in 2-year OS (59% versus 60%). [45]

A study by Liu et al in 74 patients older than 60 years with newly diagnosed non-M3 AML reported a significantly higher CR rate with reduced-intensity idarubicin plus cytarabine than with daunorubicin plus cytarabine (70.4% vs 40%, P = 0.028). The difference was especially marked in patients with white blood cell (WBC) counts > 10 × 109/L (P = 0.042) and ECOG (Eastern Cooperative Oncology Group) score < 2 (P = 0.021). However, the OS rate of the entire population was poor—a median of 10 months. [46]

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. [47] Thus, high-dose cytarabine results in excessive toxic effects with no therapeutic advantage.

Cladribine

Purine analogs increase intracellular uptake of cytarabine by accumulation of cytarabine triphosphate (ara-CTP) in leukemia blasts. A preliminary trial by the Polish Adult Leukemia Group demonstrated a significantly increased CR rate when cladribine was added to cytarabine and daunorubicin. [49]

In a larger trial, 652 patients with AML, aged 17 to 60 years, were randomized to receive daunorubicin and cytarabine (DA), DA plus cladribine, or DA plus fludarabine. The CR rate was higher with DA plus cladribine than with DA (67.5% versus 56%, respectively, P=0.01). The improvement was due to a reduction in resistant disease. OS was also improved with DA plus cladribine versus DA (45% versus 33% at 3 years, respectively, P=0.02). The addition of fludarabine to DA provided no benefit except in the subset of patients with adverse karyotype. [50]  

Consolidation therapy in younger patients

Most patients younger than 60 years should be evaluated for allogeneic stem cell transplantation (HCT). Exceptions include patients with favorable cytogenetic and molecular markers and those with significant comorbidities. Other options for post-remission therapy include further chemotherapy and, rarely, autologous HCT.

Mayer et al conducted a randomized study of three different doses of cytarabine in patients with AML who achieved remission after standard 3 and 7 induction chemotherapy. [51] Patients received four courses of cytarabine at one of the following dosages:

  • 100 mg/m 2/d by continuous infusion for 5 days
  • 400 mg/m 2/d by continuous infusion for 5 day
  • 3 g/m 2 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 four cycles is a standard option for consolidation therapy in younger patients. [51]

Patients with good-risk AML (ie, t[8;21] or inversion of chromosome 16[inv16]) have a good prognosis after consolidation with standard high-dose cytarabine (see above) for four consolidation cycles.

A study by Li et al of consolidation therapy in 45 patients with t(8;21) AML found that relapse-free survival (RFS) and overall survival (OS) were significantly higher with four courses of fludarabine plus cytarabine, compared with four courses of high-dose cytarabine, especially in patients without c-kit mutations. At 36 months, RFS for patients without c-kit mutations was 100% in those who received fludarabine plus cytarabine, compared with 57.8% in those who received high-dose cytarabine (P = 0.005); OS was 100% and 51.4%, respectively (P = 0.004). [52]

Alternatively, autologous HCT can be given after (typically) one or two cycles of consolidation therapy. Allogeneic HCT should be reserved for patients who experience relapse. Other patients who are considered at low risk for relapse and in whom a non-transplant approach could be considered include those with isolated NPM1 or biallelic CEBPA mutations.

Most other patients have less than a 50% chance of cure with consolidation chemotherapy and should thus be considered for allogeneic HCT. Newer techniques for patients without sibling or unrelated donors (cord blood and haploidentical transplants) have increased the percentage of patients who have an appropriate donor and are thus eligible for such an approach.

In 2020, the FDA approved an oral formulation of azacitidine (Onureg) for the continued treatment of adult patients with AML who have achieved first CR or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy but are not able to complete intensive curative therapy. Approval was based on results of the phase III QUAZAR AML-001 study, which included patients age 55 or older who were within 4 months of achieving first CR or CRi following intensive induction chemotherapy with or without consolidation treatment and were not candidates for HCT. In patients (n = 238) who received azacitine tablets, 300 mg once daily on days 1 to 14 of each 28-day cycle, median OS was 24.7 months, versus 14.8 months in the placebo arm (n= 234)(P=0.0009). [53]

Hematopoietic stem cell transplantation in younger patients

The American Society for Blood and Marrow Transplantation (ASBMT) considers that in patients with AML who are under age 55, allogeneic HCT offers no survival advantage for those with low-risk cytogenetics who are in first clinical remission, but does offer a survival advantage versus chemotherapy for those with high-risk cytogenetics. [54]

In patients younger than 60 years, National Comprehensive Cancer Network (NCCN) guidelines recommend matched sibling or alternate donor HCT as an option in the following situations [25] :

  • After induction failure with standard-dose or high-dose cytarabine
  • In patients with significant residual disease without a hypocellular marrow, after high-dose cytarabine induction therapy
  • As post-remission therapy in patients with intermediate-risk or poor-risk cytogenetics and/or molecular abnormalities, or those with treatment-related disease

Before referral for allogeneic HCT, a suitable donor must be identified. Ideally, this is a fully HLA-matched sibling; however, many patients do not have such a donor. In those 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.

Targeted therapy

Targeted therapy is available for the following forms of AML:

  • CD33-positive AML
  • FLT3-mutated AML
  • FLT3 internal tandem duplication–positive AML
  • IDH-mutated AML

CD33-positive AML

In 2017, the FDA approved gemtuzumab ozogamicin (Mylotarg) for the treatment of adults with newly diagnosed AML whose tumors express the CD33 antigen (CD33-positive AML). The FDA also approved gemtuzumab ozogamicin for the treatment of relapsed or refractory CD33-positive AML in patients aged 2 years and older. [55]

Gemtuzumab ozogamicin originally received accelerated approval in 2000 as a stand-alone treatment for relapsed CD33-positive AML in older patients, but was voluntarily withdrawn from the market after subsequent confirmatory trials failed to verify clinical benefit. The 2017 approval includes a lower recommended dose, a different treatment schedule, and a different patient population. [55]

The approval was based on data from several trials, including the ALFA-0701 and AML-19 trials. The multicenter, open-label phase III ALFA-0701 trial randomized 271 patients with newly-diagnosed AML to daunorubicin and cytarabine alone or combined with gemtuzumab ozogamicin. Gemtuzumab at 3 mg/m2 was administered on days 1, 4, and 7 during induction and day 1 of each of the 2 consolidation chemotherapy courses. The primary endpoint was event-free survival (EFS) with a secondary endpoint of OS. Gemtuzumab ozogamicin was associated with a statistically significant improvement in EFS of 7.8 months. However, the drug was not associated with a significant improvement in OS. [56]

In the open-label phase III study AML-19, elderly patients who could not tolerate other AML treatments were randomized to gemtuzumab ozogamicin (n=118) or best supportive care (n=119). Gemtuzumab ozogamicin was initially administered at 6 mg/m2 on day 1 and 3 mg/m2 on day 8. Patients without evidence of disease progression then received up to eight infusions of the drug at 2 mg/m2 on day 1 every 4 weeks. Median OS was 4.9 months with gemtuzumab ozogamicin versus 3.6 months with best supportive care (hazard raio [HR], 0.69; 95% CI, 0.53 to 0.90; P = 0.005); the 1-year OS rates were 24.3% versus 9.7%, respectively. Following treatment with gemtuzumab ozogamicin, 26% of patients achieved a complete remission that lasted a median 11.6 months. [57]

FLT3-mutated AML

Midostaurin (Rydapt), an orally administered multitargeted kinase inhibitor, was approved by the US Food and Drug Administration (FDA) in 2017 for adults with newly diagnosed AML that is FLT3 mutation positive. The FLT3 mutation is observed in approximately 30-35% of patients with AML.

Midostaurin is used in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy. Midostaurin and its major active metabolites inhibit the activity of wild-type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFR-alpha/beta, VEGFR2, and members of the serine/threonine kinase protein kinase C (PKC) family.

Approval of midostaurin was based on the CALGB 10603 (RATIFY) study, conducted in 717 adults younger than 60 years with newly-diagnosed FLT3-mutated AML. Patients who received midostaurin plus standard induction and consolidation chemotherapy had significantly longer OS than patients who received standard treatment plus placebo (HR for death, 0.78; one-sided P=0.009), as well as longer EFS (HR for event or death, 0.78; one-sided P=0.002). [48]

FLT3 internal tandem duplication–positive AML

In July 2023, the FDA approved quizartinib (Vanflyta) for induction and consolidation therapy (in combination with the standard 3+7 induction regimen and cytarabine consolidation), and as maintenance monotherapy following consolidation chemotherapy, in adults with newly diagnosed AML that is FLT3 internal tandem duplication (ITD)–positive.

Approval was based on QuANTUM-First, a randomized, double-blind, placebo-controlled trial of 539 patients with newly diagnosed FLT3-ITD positive AML. Patients were randomized (1:1) to receive quizartinib (n=268) or placebo (n=271) with induction and consolidation therapy and as maintenance monotherapy. Patients who proceeded to hematopoietic stem cell transplantation (HSCT) initiated maintenance therapy after HSCT recovery. OS was significantly better in the quizartinib arm: 31.9 months, versus 15.1 months in the placebo arm (hazard ratio [HR]= 0.78; 2‑sided P=0.0324). Adverse event rates were similar in the two arms. [119]

IDH-mutated AML

NCCN guidelines recommend the following targeted therapies for patients who are not candidates for intensive remission induction therapy or who decline intensive therapy [25] :

  • IDH1-mutated AML - Ivosidenib
  • IDH2-mutated AML -  Enasidenib

Therapy in older patients and patients with comorbidities

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, an analysis by Menzin et al of Medicare claims for treatment of AML found that 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). [58]

Despite the low rate of chemotherapy use in these patients, approximately 90% of them 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. [58]

There is evidence that patients who are treated have longer survival than 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. [58]

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. [59] In a Medical Research Council study, the median survival was significantly improved for patients who received low-dose cytarabine 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, the following factors were associated with an adverse outcome: [60]

  • Age greater than 75 years
  • Poor performance status
  • Previous antecedent hematologic disorder
  • Unfavorable karyotype
  • Kidney insufficiency
  • Treatment outside of a laminar flow room

Patients with none of those 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%. [60] Thus, some low-risk elderly patients can benefit from standard intensive chemotherapy.

A 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). [44] 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 [44] ; remission after the first cycle was 52% in the high-dose daunorubicin group compared with 35% in the conventional-dose group.

Older patients with AML with myelodysplasia-related changes are eligible for liposomal cytarabine and daunorubicin (Vyxeos). In the registration study, which also included patients with therapy-related AML, 309 patients aged 60-75 years received the liposomal combination product or cytarabine and daunorubicin given separately, in the 3+7 regimen. The CR or CRi rate was 47.7% for the combination, compared with 33.3% for 3+7. OS at 12 and 24 months for the fixed-dose combination was 41.5% and 31.1%, respectively, compared with OS of 27.6% and 12.3% with 3+7. [61]

Glasdegib

In 2018, the FDA approved glasdegib, a hedgehog pathway inhibitor, for newly diagnosed AML. It is indicated in adults aged 75 years or older, or adults who have comorbidities that preclude use of intensive induction chemotherapy, in combination with low-dose cytarabine. Approval was based on interim results of the phase 2 BRIGHT 1003 study that evaluated glasdegib combined with low-dose cytarabine (LDAC) or LDAC alone. Median OS was 8.8 months for patients treated with glasdegib plus LDAC compared with 4.9 months for LDAC. This difference represented a nearly 50% reduction in the risk of death for patients treated with glasdegib plus cytarabine. [62]  

Final outcome of the BRIGHT 1003 study confirmed that glasdegib LDAC significantly improved OS vs LDAC alone (hazard ratio, 0.495 [95% CI, 0.325-0.752]; P=0.0004). Furthermore, the addition of glasdegib to LDAC did not result in a substantial increase in adverse events. [63]

Venetoclax

Similarly, venetoclax gained accelerated approval for AML in 2018 for treatment of newly diagnosed AML in adults aged 75 years or older, or adults who have comorbidities that preclude use of intensive induction chemotherapy. It is used in combination with azacytidine or decitabine or low-dose LDAC. Venetoclax is a selective inhibitor of the B-cell lymphoma 2 (Bcl-2) regulator protein. BCL-2 overexpression has been demonstrated in AML cells, where it mediates tumor cell survival and has been associated with resistance to chemotherapeutics.

The accelerated approval of venetoclax was based on data from the phase 1b M14-358 and phase 1-2 M14-387 dose escalation and expansion studies. In the M14-358 study, complete remission was 37% (N=25/67) in the venetoclax plus azacitidine group and 54% (N=7/13) in the venetoclax plus decitabine group. [64] In the M14-387 study, the complete remission rate was 21% (N=13/61) for patients receiving venetoclax plus low-dose cytarabine. [65]  

The FDA granted full approval for venetoclax in combination with azacitidine, decitabine, or LDAC in 2020, based on results from the phase 3 VIALE-A (M15-656) and VIALE-C (M16-043) trials. In VIALE-A, OS for patients who were receiving venetoclax plus azacitidine versus placebo was 14.7 versus 9.6 months, respectively. In VAILE-C, venetoclax did not produce statistically significant OS improvement in patients with AML who were ineligible for intensive chemotherapy. However, the complete remission (CR) rate was higher with venetoclax plus LDAC: the median CR rate in the venetoclax arm was 27%, with a median duration of 11.1 months, compared with 7.4% and a median duration of 8.3 months in the placebo group. [66]  

Hypomethylating agents

The hypomethylating agents azacytidine and decitabine are the therapies most commonly prescribed for elderly patients with AML. Although response rates are low, these drugs are well tolerated and can result in prolonged remissions in some patients. Additionally, hypomethylators are active in AML subtypes that typically respond poorly to standard chemotherapy, including those with complex cytogenetics and TP53 mutations. [67] In a study of azacytidine treatment in 149 previously untreated AML patients (median age, 74 years) who were considered ineligible for intensive chemotherapy, 2-year OS was 51% in responders to azacytidine and 10% in non-responders (P < 0.0001). [68]

A randomized, open-label, phase III trial in 488 patients age ≥65 years with newly diagnosed AML with > 30% bone marrow blasts reported a 1-year survival rate of 46.5% with azacitidine versus 34.2% with conventional care regimens. [69] In a study of azacitidine treatment in 130 AML patients older than 50 years (median age, 67 years) who had experienced relapse or induction failure with intensive chemotherapy, the overall response rate was 17% (complete response [CR], 10%, CR with incomplete platelet or neutrophil count recovery [CRi], 7%). [70]

A systematic review and meta-analysis by He at al of nine published studies that enrolled 718 elderly AML patients concluded that decitabine is an effective and well-tolerated therapeutic alternative with acceptable side effects in this patient population. [71] Pooled estimates (and 95% confidence index) were as follows:

  • Complete remission (CR): 27% (19%-36%)
  • Overall response (OR): 37% (28%-47%)
  • Overall survival: 8.09 months (5.77-10.41 mos)
  • Early death: 7% (2%-11%) within 30 days, 17% (11%-22%) within 60 days

A meta-analysis by Bian et al of 38 studies (3298 AML patients) in elderly patients with AML compared decitabine with several traditional chemotherapy regimens, including intensiv therapy and low-dose cytarabine and found that the response rate to decitabine was better than those observed with other treatments, albeit with similar rates of infection and early death. Decitabine combined with other regimens achieved a CR rate of 46% and an OR rate of  75%. [72]

A retrospective single-institution study by Talati et al of survival outcomes in 980 elderly (≥70 years) AML concluded that hypomethylating agents (ie, azacytidine, decitabine) provided a significant survival benefit, compared with high-intensity, low-intensity, or supportive care. [73] Median OS rates were as follows:

  • Hypomethylating agent: 14.4 months
  • High-intensity therapy (daunorubicin/cytarabine or equivalent): 10.8 months
  • Low-intensity therapy (low-dose cytarabine or similar without hypomethylating agents): 5.9 months
  • Supportive care (including hydroxyurea): 2.1 months

Ivosidenib

In 2019, the FDA expanded use of the IDH1 inhibitor ivosidenib (Tibsovo) for AML to include newly-diagnosed IDH1-mutated AML in adults aged 75 years or older, or adults who have comorbidities that preclude use of intensive induction chemotherapy. Ivosidenib had previously been approved for use in relapsed or refractory IDH1-mutated AML. Approval for the expanded indication was based on an open-label, single-arm, multicenter clinical trial (AG120-C-001, NCT02074839) that included 28 adult patients with newly-diagnosed AML with an IDH1 mutation. Twelve (42.9%) of the 28 achieved complete remission or complete remission with partial hematologic recovery, and 7 (41.2%) of the 17 transfusion-dependent patients achieved transfusion independence lasting at least 8 weeks. [74]

In May 2022 the FDA approved ivosidenib in combination with azacitidine for the treatment of patients with newly diagnosed, IDH1-mutated AML who are aged 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Approval was based on a randomized, multicenter, double-blind, placebo-controlled study (AG120-C-009, NCT03173248) that included 146 patients with newly-diagnosed AML with an IDH1 mutation. Compared with patients in the azacitidine plus placebo arm, patients in the ivosidenib plus azacitidine arm had longer median overall survival (24.0 vs 7.9 months; P=0.0010) and a higher complete response rate (47% vs 15%). [75]

Other agents

Other therapies are being studied in older patients who are not candidates for intensive chemotherapy. [76] As part of the 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 (20 mg twice daily for 10 d) or hydroxyurea with or without all-trans retinoic acid (ATRA). Low-dose cytarabine produced a better remission rate (18% vs 1%; P = 0.00006) and better OS (odds ratio, 0.60; P = 0.0009) OS was 80 weeks for patients achieving CR verus 10 weeks for patients with no remission. [77]

Clofarabine is a purine analogue that is approved by the 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 CRi rate of 8%. Induction deaths occurred in 7% of patients. [78]

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.

Hematopoietic stem cell transplantation

Although allogeneic HCT is a potentially curative treatment option for patients with AML, the risk of death increases with age. Fit elderly patients are candidates for reduced-intensity conditioning and nonmyeloablative transplants. [79, 80, 81, 82] Reduced-intensity and nonmyeloablative regimens feature the use of the purine analog fludarabine and lower doses of alkylating agents or total body irradiation (TBI). Nonmyeloablative regimens may cause only minimal cytopenias that do not require stem cell support, whereas reduced-intensity regimens do require stem cell support. [83]

A study in 190 patients age 60-70 years with AML in first remission reported lower risk of relapse and longer leukemia-free survival with reduced-intensity allogeneic HCT than with induction and postremission chemotherapy using CALGB protocols. At 3 years, risk of relapse was 32% vs 81%, respectively (P < 0.001) and leukemia-free survival was 32% vs 15% (P = 0.001); however, nonrelapse mortality was higher with transplantation (36% vs 4% at 3 years; P < 0.001). [84]

For patients 60 years of age or older who have residual disease after standard-dose cytarabine, the National Comprehensive Cancer Network (NCCN) recommends reduced-intensity HCT as an option. Allogeneic HCT is an option for post-remission therapy in patients with a complete response to intensive therapy, preferably in the first remission. Allogeneic HCT, preferably in a clinical trial, can also be considered in patients with induction failure after previous intensive therapy. [25]

Treatment of therapy-related AML

Patients who develop AML as a complication of conventional chemoradiotherapy for a primary malignancy have traditionally had a poor prognosis, with a median survival of only 6 months. Allogeneic HCT has generally been recommended because these cases respond poorly to traditional chemotherapy. [85]

In August 2017, the FDA approved a fixed-dose combination of cytarabine and daunorubicin liposomal (CPX-351; Vyxeos) for newly diagnosed therapy-related AML and AML with myelodysplasia-related changes. Approval was based on a phase III trial in 309 patients aged 60-75 years that evaluated the efficacy and safety of the combination product with cytarabine and daunorubicin given separately in the 3+7 regimen (daunorubicin, 60 mg/m2 on days 1, 2, and 3; cytarabine, 100 mg/m2/day x 7 days;). [61]

The CR or CRi rate was 47.7% for the combination compared with 33.3% for 3+7. For CR alone, the rates were 37.3% for the combination and 25.6% percent for 3+7. OS at 12 and 24 months for the fixed-dose combination was 41.5% and 31.1%, respectively, compared with 3+7 OS of 27.6% and 12.3%. [61]

In an exploratory analysis of the phase III study for those with secondary untreated AML, 34 of the 52 patients (65%) in the fixed-dose combination arm who proceeded to transplant remained alive after a median follow-up of 521 days. In the 3+7 arm, after 442 days of follow-up, 13 of 39 patients remained alive (33%). [61]

The principal role for CPX-351 appears to be in patients with a history of myelodysplastic syndrome who were never treated with a hypomethylating agent (eg, azacitidine, decitabine). In these patients, the combination may not only improve outcome but increase eligibility for transplantation. Adverse effects of CPX-351 are the same as with the standard 3+7 regimen, so for unfit/elderly patients, hypomethylating agents remain the preferred therapy. [86]

 

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Treatment of Acute Promyelocytic Leukemia

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 also 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 mg/dL.

There are two histologic subtypes of APL: hypergranular and hypogranular. In both cases the bone marrow contains atypical promyelocytes that have bilobed nuclei. In the hypergranular variant the cells contain large dense cytoplasmic granules, sheets of fine granules, and/or varying numbers of Auer rods. In the hypogranular variant granules are nearly absent and the cytoplasm has a pale appearance.

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. [87, 88, 89]

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. [90] 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 (idarubicin and cytarabine) resulted in a reduction of deaths caused by retinoic acid syndrome.

In a US Intergroup study, 346 patients with previously untreated APL received either ATRA or daunorubicin plus cytarabine as induction therapy [91] . Patients in remission then received a second cycle of the same therapy as their induction, followed by one cycle of high-dose cytarabine plus daunorubicin. Patients then underwent a second randomization to either ATRA maintenance or observation. In this study ATRA as either induction or maintenance improved disease-free and overall survival compared with chemotherapy (3 year overall survival 67% for ATRA versus 55% for chemotherapy (P=0.003). Using this approach, as many as 70% of these patients are long-term survivors. [92]

European groups proposed that cytarabine was not necessary in induction therapy for newly diagnosed patients. [93] 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) yielded remissions in 95% of patients.

However, a randomized study from France questioned this approach. [93] 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 three courses of daunorubicin plus cytarabine  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, witha  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 cumulative incidence of relapse (CIR) was 2.9%, event-free survival was 89%, and the survival rate was 91.9%.

After studies from China demonstrated that arsenic trioxide was highly active against APL cells in vitro, [94] clinical trials demonstrated that arsenic trioxide resulted in high response rates in patients with relapsed disease. [95, 96] Arsenic trioxide was then moved into the frontline setting, first in combination with standard chemotherapy and then without chemotherapy.

A North American Intergroup study compared the addition of two cycles of consolidation therapy with arsenic trioxide followed by two cycles of chemotherapy with cytarabine and daunorubicin to consolidation with two cycles of cytarabine and daunorubicin chemotherapy without arsenic trioxide. [97] 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 was effective in preventing relapses compared with no maintenance therapy; however, the optimal schedule of this therapy is not yet determined.

More recent trials have studied regimens utilizing ATRA plus arsenic trioxide without chemotherapy. Lo-Coco et al conducted a phase III randomized trial of ATRA plus chemotherapy verus ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (WBC ≤10 x 109/L). Complete remission was achieved in 100% of patients in the ATRA-arsenic group and 95% of the ATRA-chemotherapy group. Two-year event-free survival rates were 97% for ATRA-arsenic and 86% for ATRA-chemotherapy group. Overall survival was better with ATRA-arsenic trioxide, largely due to a reduction in cytopenic deaths. Longer follow-up is needed to determine if long term cure rates will be the same. [98]

Current guidelines for treatment are as follows [25] :

  • Patients with suspected APL should begin therapy with at least ATRA immediately. Do not delay therapy pending confirmatory tests because this disease is rapidly fatal. Most deaths occur due to early hemorrhage, often before treatment is initiated.
  • Patients are then stratified according to risk: Patients with a WBC less than 10 x 10 9/L are considered low risk. All others are considered high risk.
  • Low-risk patients receive ATRA 45 mg/m 2/d (in two divided doses) plus arsenic trioxide 0.15 mg/kg daily until bone marrow remission. If arsenic is contraindicated, ATRA plus idarubicin is the recommended alternative. Consolidation therapy is most often ATRA plus arsenic trioxide for 4 weeks out of 8 weeks for 4 cycles, followed by ATRA 2 weeks on, 2 weeks off for 7 cycles. Other regimens using various combinations of ATRA, arsenic trioxide, and chemotherapy are available.
  • High-risk patients receive induction therapy with ATRA plus chemotherapy (daunorubicin and cytarabine or idarubicin) with or without arsenic trioxide. Consolidation therapy consists of combinations of ATRA, arsenic trioxide, and chemotherapy.

 

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Treatment of Relapsed Acute Myeloid Leukemia

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

Estey et al reported that the chances of obtaining a second remission with chemotherapy correlate strongly with the duration of the first remission. [99] Patients with an initial complete response (CR) 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. [100] 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 identified the following 6 independent adverse prognostic factors:

  • First CR duration < 6 months
  • Second CR duration < 6 months
  • Salvage therapy not including allogeneic SCT
  • Noninversion 16 AML
  • Platelet counts < 50 × 10 9/L
  • Leukocytosis > 50 × 10 9/L.

Owing to the poor outcome with salvage therapy, it is important to refer patients for well-designed clinical trials whenever possible. For patients who are unable to participate in a clinical trial, but are able to tolerate aggressive therapy, options include the following [25] :

  • Cladribine + cytarabine + granulocyte colony-stimulating factor (G-CSF), with or without mitoxantrone or idarubicin [49]
  • High-dose cytarabine (if not received previously in treatment) with or without idarubicin, daunorubicin, or mitoxantrone
  • Fludarabine + cytarabine + G-CSF with or without idarubicin
  • Etoposide + cytarabine with or without mitoxantrone [101]
  • Clofarabine with or without cytarabine + G-CSF, with or without idarubicin

For patients who require less aggressive therapy, possible regimens include the following [25] :

  • Hypomethylating agents (azacitidine or decitabine)
  • Venetoclax with hypomethylating agents or low-dose cytarabine 
  • Low-dose cytarabine

Targeted therapy

Targeted therapeutic options for AML include the following [25] :

  • FLT3-TKD mutation – Gilteritinib
  • FLT3- ITD mutation – Gilteritinib, or a hypomethylating agent (azacitidine or decitabine) + sorafenib
  • IDH1 mutation - Ivosidenib, olutasidenib
  • IDH2 mutation - Enasidenib
  • CD33-positive AML - Gemtuzumab ozogamicin

In 2018, the FDA approved gilteritinib (Xospata), an orally administered multiple tyrosine kinase inhibitor, for treatment of adults with relapsed or refractory AML that has an FLT3 mutation. Gilteritinib inhibits multiple receptor tyrosine kinases, including FMS-like tyrosine kinase 3 (FLT3). It inhibits FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3. Gilteritinib also induces apoptosis in leukemic cells expressing FLT3-ITD.

Approval of gilteritinib was based on interim analysis of the ADMIRAL clinical trial, a phase 3 open-label, multicenter, randomized study comparing gilteritinib with salvage chemotherapy in 371 adults with relapsed or refractory FLT3-mutated AML. Salvage chemotherapy consisted of low-dose cytarabine or azacitidine, MEC (mitoxantrone, etoposide, and intermediate-dose cytarabine), or FLAG-IDA (fludarabine, cytarabine, G-CSF, and idarubicin). Final results of ADMIRAL demonstrated significant superiority of gilteritinib over salvage chemotherapy. Patients randomized to gilteritinib had significantly longer overall survival (9.3 months, versus 5.6 months with salvage chemotherapy; hazard ratio [HR] for death = 0.637; P=0.0007), as well as 1-year survival (37.1% versus 16.7%, respectively). [102]  

Ivosidenib (Tibsovo), an oral isocitrate dehydrogenase-1 (IDH1) inhibitor, received FDA approval in 2018 for relapsed and/or refractory AML with a confirmed IDH1 mutation. [103] Approval was based on a single-arm trial in 174 adult patients, in which 32.8% of patients experienced a complete remission (CR) or CR with partial hematologic recovery (CRh). that lasted a median 8.2 months. [104]

A second IDH inhibitor, olutasidenib (Rezlidhia), was approved in 2022 for relapsed and/or refractory AML with a confirmed IDH1 mutation. [103] FDA approval was supported by data from Study 2102-HEM-101, an open-label, single-arm, multicenter clinical trial that included 147 adult patients. Efficacy was established on the rate of CR or CRh, the duration of CR+CRh, and the rate of conversion from transfusion dependence to independence. Results from the trial demonstrated a 35% (51/147) CR+CRh rate, with a median duration of response of 25.9 months. The median time to CR or CRh was 1.9 months. Of the patients who achieved the primary endpoint of CR+CRh, 92% (47/51) were CR with a median duration of response of 28.1 months. [105]

Enasidenib (Idhifa)—an oral, selective inhibitor of mutant IDH2 enzymes—was approved by the FDA in 2017 for treatment of relapsed/refractory IDH2-mutated AML. The approval was based on data from a phase I/II dose-escalation and expansion study (AG221-C-001) in which enasidenib proved safe and well tolerated, and induced hematologic responses. Median overall survival (OS) with enasidenib was 9.3 months. In those achieving a CR, the median OS was 19.7 months and in the non-CR responders the median OS was 13.8 months. In those without a response, the median OS was 7 months.

Gemtuzumab ozogamicin (Mylotarg)—a CD33-directed antibody-drug conjugate—was approved by the FDA in 2017 for the treatment of patients aged 2 years and older with relapsed or refractory AML whose tumors express the CD33 antigen (CD33-positive AML). [55] This agent is The dosage for these patients is 3 mg/m2 on days 1, 4 and 7. Differences in CD33 expression (with lower levels seen in cases with adverse karyotype and core-binding factor AML, and higher expression seen in AML with mutations in FLT3, MLL or NPM1) and CD33 splicing polymorphisms are factors influencing response rates [106]

Investigational therapies

Chimeric antigen receptor (CAR) T-cell therapy is being studied for use in AML that relapses after allogeneic HCT.  More than 20 clinical trials of CAR T-cell therapy in patients with AML are currently in progress. In most of those trials, the target antigens are CLL-1, CD33, or CD123. [107]

Mutation in the nucleophosmin 1 gene (NPM1) is the most common genetic alteration in adult AML, occurring in up to 30% of patients, and rearrangements of the gene KMT2A occur in up to 15% of children and adults with AML. With both of these mutations, the protein menin is a critical oncogenic cofactor. In AUGMENT-101, a phase I trial in patients with relapsed or refractory NPM1-mutant or KMT2A-rearranged AML, therapy with the menin inhibitor revumenib was associated with a 30% rate of CR or CRh, along with a low frequency of grade 3 or higher treatment-related adverse events. [108]

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Supportive Care

Replacement of blood products

Patients with AML have a deficiency in the ability to produce normal blood cells and, therefore, need replacement therapy. The addition of chemotherapy temporarily worsens this deficiency. All blood products should be irradiated to prevent transfusion-related graft versus host disease, 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.

Fresh frozen plasma (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.

Infection treatment and prophylaxis

Intravenous (IV) antibiotics should be given to all febrile patients. At a 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 should be evaluated for an alternate source of infection. Persistent fever can be due to fungal infections, viral infections (including cytomegalovirus [CMV]), Clostridium difficile, and resistant bacteria such as vancomycin-resistant enterococcus, bacteria with extended spectrum beta-lactamases, and carbapenem-resistant Enterobacteriaceae. Evaluation of persistent fever should include CT scans of the chest, abdomen, pelvis and sinuses, fungal markers (aspergillus antigen and Fungitell), and other tests depending on the symptoms of the patient. Empiric antifungal therapies include the following:

  • Lipid-preparation amphotericins (Abelcet, AmBisome)
  • Azoles (voriconazole, isavuconazole, posaconazole)
  • Echinocandins (caspofungin, anidulafungin, micafungin).

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. The following combination regimen is commonly used for prophylaxis:

  • Ciprofloxacin
  • Fluconazole
  • Voriconazole or posaconazole
  • Acyclovir or valacyclovir

In a randomized trial of posaconazole versus either fluconazole or itraconazole (selected on the basis of local practice) in patients with AML and myelodysplastic syndrome undergoing intensive chemotherapy, posaconazole proved more effective at preventing invasive fungal infections, including invasive asperglilosis. In addition, all-cause mortality at day 100 was significantly lower in patients who received posaconazole. However, serious adverse events possibly or probably related to treatment occurred more frequently in the posaconazole group. [109]

Once patients receiving oral antibiotic prophylaxis become febrile, the regimen is changed to IV agents, as indicated above.

Treatment of hyperuricemia

Allopurinol 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  be administered to patients at high risk of severe tumor lysis, including those with very high white blood counts, very high lactate dehydrogenase [LDH] levels, and/or 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 olony-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), fewer febrile days (3 vs 7 d, respectively), and fewer documented infections. [110] 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) than 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. [111]

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. [112]

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 induction chemotherapy response rate was observed; however, a significant decrease in the death rate from pneumonia and fungal infection was observed. [113] 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). [113]

In a CALGB study of GM-CSF derived from E coli, no difference was observed in induction chemotherapy response rates between the GM-CSF group and the placebo group. [114] 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%). [115]

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. [115] 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. Caution should be used in patients with severe DIC (APL); nevertheless, proper access is needed to administer the needed blood products in a timely fashion.  

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Diet and Activity

Patients with AML should follow 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).

 

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Long-Term Monitoring

Patients should come to the office for monitoring of disease status and chemotherapy effects. Guidelines from the National Comprehensive Cancer Network (NCCN) recommend that after completion of consolidation therapy for AML, patients should undergo surveillance with a complete blood cell count every 1–3 months for 2 years, then every 3–6 months up to 5 years. The NCCN recommends a bone marrow aspirate and biopsy only if a peripheral smear is abnormal or cytopenias develop. [25]

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