Acute myeloid leukemia in younger adults: Post-remission therapy

INTRODUCTION — Sixty to 80 percent of adult patients with newly diagnosed acute myeloid leukemia (AML) will attain a complete remission (CR) with intensive induction chemotherapy. However, without additional cytotoxic therapy, virtually all of these patients will relapse within a median of four to eight months [1]. In contrast, patients who receive post-remission therapy may expect four-year survival rates as high as 40 percent in young and middle-aged adults.

Post-remission therapy aims to destroy leukemia cells that survived induction chemotherapy but are undetectable by conventional studies. There are three basic options for post-remission therapy (in order of increasing intensity): consolidation chemotherapy, autologous hematopoietic cell transplantation (HCT), or allogeneic HCT. The choice among these approaches for an individual patient depends on a number of factors including:

●Expected rate of relapse with consolidation chemotherapy alone (influenced strongly by the tumor karyotype)

●Expected morbidity and mortality associated with treatment options (as determined by patient characteristics such as age and comorbidities)

●Salvage treatments available for the treatment of relapsed disease

This approach minimizes exposure to potentially toxic therapies in patients expected to respond well to conventional chemotherapy while providing maximum antitumor activity for patients with more difficult-to-treat disease.

Post-remission therapy for AML in younger adults will be reviewed here. Induction therapy is presented separately, as are the treatment of relapsed disease and the management of complications related to AML. (See "Acute myeloid leukemia: Induction therapy in medically fit adults" and "Treatment of relapsed or refractory acute myeloid leukemia" and "Acute myeloid leukemia: Overview of complications".)

Among patients with AML, treatment regimens and outcomes may differ between younger and older adults. Although there is no clear dividing line between younger and older adults when dealing with AML, "older adults" was defined as over age 60 in most studies. The treatment of older adults is discussed separately. (See "Acute myeloid leukemia: Management of medically unfit adults".)

RISK STRATIFICATION — It is strongly recommended that every case of newly diagnosed AML undergo cytogenetic and molecular analysis before starting induction therapy, since specific cytogenetic abnormalities in AML have considerable prognostic significance [2-4]. Results from cytogenetic and molecular analyses are essential for World Health Organization (WHO) classification of AML (table 1). Full knowledge of the karyotype determined by metaphase cytogenetics is an essential part of treatment planning and monitoring of the leukemic clone. More recently, information about the genotype based on molecular studies has demonstrated prognostic significance that can be used to guide treatment decisions as well. (See "Acute myeloid leukemia: Induction therapy in medically fit adults" and "Acute myeloid leukemia: Risk factors and prognosis", section on 'Cytogenetics'.)

Stratification by genetic risk — Knowledge of the cytogenetic and molecular abnormalities associated with AML has led to various risk stratification schemata. We prefer the system for risk stratification developed by the European LeukemiaNet (ELN) that describes three risk categories (ie, favorable, intermediate, adverse) (table 2) [4]. Stratification models that incorporate genetic abnormalities (eg, ELN, WHO) are dynamic and evolving as better understanding of the genetic basis of AML emerges and as additional clinical outcome data become available. Such schemata will result in smaller but more homogeneous subsets of patients with AML, and may increasingly inform therapeutic choices that will involve targeted therapies.

Further details of the prognostic value of various karyotypic and molecular features in AML are presented separately. (See "Acute myeloid leukemia: Cytogenetic abnormalities" and "Acute myeloid leukemia: Risk factors and prognosis", section on 'Cytogenetics'.)

FAVORABLE-RISK DISEASE — While the optimal dose, schedule, and number of cycles are unknown, consolidation chemotherapy with high dose cytarabine (HiDAC) appears to provide the best survival for most patients with favorable-risk disease with the least amount of toxicity. This approach results in overall survival rates at four years of 60 to 75 percent. A randomized trial indicated a disease-free survival benefit when gemtuzumab ozogamicin was incorporated into induction and post-remission phases of treatment for patients with core-binding factor AML [5]. (See 'Administration of consolidation HiDAC' below.)

Chemotherapy versus transplantation — Many prospective studies have investigated the use of various post-remission therapies in patients with favorable-risk disease including chemotherapy alone, autologous hematopoietic cell transplantation (HCT), allogeneic HCT, and maintenance therapy. Randomized trials of allogeneic HCT have not been feasible for patients with AML. Instead, investigators have relied on a "genetic randomization" in which patients are assigned to treatment with or without allogeneic HCT based on the presence or absence of an HLA-matched sibling donor. Patients without an HLA-matched sibling are assigned to treatment with either chemotherapy alone or autologous HCT, depending on the trial design. Results are then evaluated by an intention-to-treat analysis for "donor" and "no donor" (available) treatment groups. As with randomized trials, not all patients in the "donor" group ultimately receive an allogeneic HCT, but they would still be included in the "donor" group for the statistical analysis.

Three large meta-analyses of these studies performed using data from over 4000 patients with AML in first complete remission (CR) examined the effect of donor availability and cytogenetic risk category on disease-free and overall survival [6-8]. There were 480 patients with favorable-risk disease analyzed. In this group, the availability of an HLA-matched sibling did not result in superior disease-free or overall survival, implying no benefit from allogeneic HCT in this risk group. The estimated risk of relapse after consolidation chemotherapy is approximately 35 percent or less in this population. With such a relatively low risk of relapse, the high rate of treatment-related mortality associated with allogeneic HCT (approximately 20 percent) likely negates the effect of a possible small decrease in relapse rate on disease-free or overall survival. A randomized trial also demonstrated that consolidation chemotherapy results in superior survival rates when compared with lower dose maintenance therapy given over an extended period of time [9].

A decision regarding the use of allogeneic HCT in first remission must also consider the estimated rate of relapse and the efficacy of available treatments at the time of relapse. In one analysis, 494 of 536 younger adults (16 to 49 years) with favorable-risk AML enrolled on prospective trials did not proceed with HCT in their first CR [10]. The 168 (34 percent) patients who relapsed following chemotherapy alone had an estimated five-year survival following relapse of 32 percent. These findings suggest that a significant percentage of patients with favorable-risk disease who defer initial HCT can be effectively treated following relapse. HLA typing should be included in the initial evaluation of these patients to expedite the donor search if the patient relapses.

For young patients with newly diagnosed AML demonstrating favorable cytogenetics, we recommend post-remission therapy with consolidation chemotherapy rather than either autologous HCT or allogeneic HCT. Post-remission chemotherapy is used in this patient population instead of HCT to avoid the unnecessary risks of acute and chronic morbidity and mortality associated with HCT in a considerable number of patients who may be cured with consolidation chemotherapy alone. HCT is then reserved for use at the time of relapse, if necessary. (See "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Hematopoietic cell transplantation'.)

Controversy remains as to whether allogeneic HCT in first CR is of benefit in patients with normal karyotypes that demonstrate certain gene mutations. The European LeukemiaNet classification's favorable risk subgroup includes the following two groups with normal cytogenetics:

●Patients with normal cytogenetics displaying mutations in both alleles of the nucleophosmin 1 (NPM1) gene but lacking coexistent FMS-like tyrosine kinase 3 gene producing internal transmembrane duplications (FLT3-ITD) mutations.

●Patients with normal cytogenetics displaying mutations in the CCAAT/enhancer binding protein alpha (CEBPA) gene.

Support for the use of consolidation chemotherapy in this population comes from the following:

●Subjects with a normal karyotype, NPM1 mutations, wild-type FLT3, and low levels of ERG appear to have an especially favorable prognosis, with an estimated two-year progression-free survival of 60 to 70 percent after induction treatment with cytarabine, daunorubicin, and etoposide followed by high dose cytarabine or autologous HCT [11,12].

●Data from "donor" versus "no donor" analyses demonstrate that a subgroup of cytogenetically normal AML defined by the favorable molecular genotype with NPM1 gene mutations but no FLT3-ITD mutations have outcomes similar to those patients with favorable karyotypes [12,13]. Such patients derive no overall survival benefit from allogeneic HCT in first CR compared with chemotherapy alone.

●In a retrospective analysis of 124 patients with double mutant CEBPA from cooperative group trials, relapse-free survival was higher following allogeneic HCT (hazard ratio 0.23; 95% CI 0.11-0.51) or autologous HCT (0.37; 95% CI 0.17-0.80) rather than consolidation chemotherapy [14]. However, this improved relapse-free survival did not translate into an overall survival benefit, largely due to a high rate of second CR and survival after allogeneic HCT at the time of relapse.

Thus, a subset of patients with normal karyotype may not require an allogeneic HCT. Given the controversy surrounding this group of patients, patients should be encouraged to participate in clinical trials. Outside of a clinical trial, any of the above approaches may be offered.

Choice of agent — High dose cytarabine (HiDAC) has been the consolidation chemotherapy of choice in patients with favorable-risk disease for more than two decades. Attempts to improve survival rates over those attained with HiDAC by altering the dose or schedule of cytarabine, substituting other agents, or other drug combinations have shown similar efficacy [2,15-23].

Trials using alternating courses of other drug combinations have demonstrated similarly favorable outcomes, and offer equally effective alternative options. Examples include:

●In a randomized study of 473 patients <60 years of age, the use of three consolidation courses of HiDAC was equally effective as three courses of sequential multiagent chemotherapy (one course each of HiDAC, etoposide/cyclophosphamide, and diaziquone/mitoxantrone), with less overall toxicity [22].

●A phase 3 trial of 293 patients (<60 years of age; most with intermediate-risk cytogenetics) reported improved leukemia-free survival, but not overall survival, among those who received more intensive idarubicin (9 mg/m² daily for three days versus two days) as a component of two cycles of consolidation therapy that also included five days each of cytarabine 100 mg/m² daily and etoposide 75 mg/m² daily [24].

Dose of cytarabine — Cytarabine is one of the most effective agents available for the treatment of AML and is a key component of induction therapy. HiDAC produces high intracellular drug concentrations, which saturate the deaminating metabolic enzyme pathway, leading to increased levels of the active agent ara-cytidine triphosphate. In this way, HiDAC can often effectively eliminate measurable residual disease (MRD; also referred to as minimal residual disease) that survived induction with cytarabine containing regimens.

A variety of HiDAC doses and schedules have been used in clinical trials [25]. Higher doses of cytarabine are preferable to lower doses (as described below), but the ideal dose remains unknown and there is likely a dose above which additional cytarabine is not of benefit. A cytarabine dose of 3 g/m² given over three hours is frequently used, but cytarabine 1 to 1.5 g/m² twice daily for five days has demonstrated similar rates of disease-free and overall survival; these regimens have not been compared directly in a prospective trial [17]. There was no difference in five-year overall survival when young patients (age 15 to 60) were randomly assigned to consolidation therapy with cytarabine 3 g/m² twice daily for six days versus cytarabine 1 g/m² twice daily for six days (both cytarabine doses combined with mitoxantrone for a first consolidation course, followed in some cases by an autologous or allogeneic transplant) [20].

Consolidation chemotherapy with HiDAC produces superior survival rates than those seen with lower doses of cytarabine. This was principally demonstrated in a randomized trial of consolidation therapy in 596 patients using 4 courses of cytarabine at low (100 mg/m² per day) or intermediate doses (400 mg/m² per day) as continuous IV infusions for 5 days or at high doses (HiDAC: 3 g/m² every 12 hours on days 1, 3, and 5) [26]. Patients <60 years old who received HiDAC had the following significant outcomes when compared with patients who received intermediate or low dose cytarabine:

●Higher rates of four-year disease-free survival (44 versus 29 and 24 percent, respectively)

●Improved four-year overall survival rates (52 versus 40 and 35 percent, respectively)

●Fewer relapses more than two years after attaining complete remission (44 versus 29 and 24 percent, respectively)

●Greater toxicity (see 'Toxicities' below)

Number of cycles — The ideal number of post-remission chemotherapy cycles is not known, but patients who receive at least three cycles appear to do better than those who receive fewer.

As an example, a total of 50 patients with AML and t(8;21)(q22;q22) from four successive CALGB studies were assigned (but not randomized) to receive either one (29 patients) or ≥3 cycles (21 patients) of HiDAC as post-induction therapy [27]. When compared with those receiving a single cycle of HiDAC, patients treated with ≥3 cycles of HiDAC demonstrated:

●A lower rate of relapse – 19 versus 62 percent

●Longer median relapse-free survival – >35 versus 10.5 months

●A higher estimated rate of five-year overall survival – 76 versus 44 percent

A similar report using data from AML patients with inv(16) or t(16;16) found that repetitive HiDAC therapy decreases the likelihood of relapse compared with consolidation regimens including less HiDAC [28]. However, there was no significant difference in overall survival, likely due to a high success rate using salvage treatment with hematopoietic cell transplantation in relapsing patients.

Administration of consolidation HiDAC — We typically give three courses of cytarabine 3 g/m² administered over three hours twice per day on days 1, 3, and 5 for a total of six doses per course [26]. Patients older than 60 years typically receive 2 g/m² and those older than 70 years 1.5 g/m². The initial course is begun after confirmation of a complete remission and resolution of all toxicities from induction therapy. Sequential courses are administered no sooner than every 28 days or 1 week after marrow recovery as documented by an absolute neutrophil count ≥1000 and platelets ≥100,000 without transfusion.

Saline or steroid eye drops should be administered to both eyes four times daily until 24 hours after completion of the HiDAC infusion to prevent chemical conjunctivitis due to cytarabine in the tears. Cerebellar evaluations for dysdiadochokinesis or past-pointing should be performed at least every 12 hours during therapy.

Toxicities — This regimen is usually administered as an inpatient and requires close monitoring for toxicities. Even within the context of a clinical trial, only approximately 56 percent of patients under age 60 were able to complete four courses of this regimen. Treatment related mortality, mostly due to infection, is approximately 5 percent. Common major side effects of HiDAC include pancytopenia, infection (62 percent), central nervous system toxicity (13 percent), hyperbilirubinemia (11 percent), and fatigue (10 percent) [22,26].

Of particular importance, serious central nervous system toxicities (eg, somnolence and confusion, and rarely seizures, cerebral dysfunction, and acute cerebellar syndrome) can be seen in approximately 12 percent of patients overall. This percentage rises to approximately 30 percent in patients over the age of 60, 40 percent of whom may be left with permanent disability. If cerebellar toxicity occurs, cytarabine should be discontinued. The clinical situation can be confusing if patients are also receiving anti-emetics or other drugs that can have CNS effects. It is unclear whether patients should be rechallenged with HiDAC in the future.

INTERMEDIATE-RISK DISEASE — Post-remission therapy options for patients with intermediate-risk disease include consolidation chemotherapy with high dose cytarabine (HiDAC) as given for favorable-risk disease, HiDAC followed by autologous hematopoietic cell transplantation (HCT), or allogeneic HCT alone:

●Consolidation chemotherapy with HiDAC is nonmyeloablative and has a low treatment-related mortality rate (approximately 5 percent). Rates of four-year disease-free survival among patients with intermediate-risk disease are approximately 30 percent [29]. Common major side effects include pancytopenia, infection, central nervous system toxicity, and hyperbilirubinemia [22,26]. (See 'Toxicities' above.)

●Autologous HCT allows the use of myeloablative chemotherapy and is not associated with graft-versus-host disease, but does not provide the graft-versus-leukemia effect seen with allogeneic HCT [30-37]. Treatment-related morbidity and mortality are relatively low (≤6 percent) but relapse rates are high (30 to 50 percent) [38-42]. Rates of four-year disease-free survival are approximately 45 percent and are in the same range as those in patients who receive intensive but nonablative consolidation chemotherapy (eg, HiDAC) [43,44].

●Allogeneic HCT targets cancer cells both by administering myeloablative chemotherapy and by harnessing a graft-versus-leukemia effect. Treatment-related mortality is high (approximately 20 percent) as is morbidity associated with graft-versus-host disease [7]. Rates of four-year disease-free survival are approximately 48 percent overall; patients younger than 35 or 40 years have superior results [7,43,45].

Three large meta-analyses of prospective studies comparing these post-remission therapies for patients with AML, subdivided by karyotypes, have been performed using data from over 4000 patients with AML in first complete remission (CR) [6-8]. There were 603 patients with intermediate-risk disease analyzed. In an intention-to-treat analysis, patients "genetically assigned" to matched related donor HCT (ie, those who had an HLA-matched sibling) had superior rates of four-year disease-free survival. While overall survival did not reach statistical significance in the first meta-analysis, combination of the data from these three meta-analyses demonstrated a benefit in overall survival implying that allogeneic HCT was beneficial for patients in this risk group overall. Such results were particularly noticeable for patients younger than age 35 years who tolerate the morbidity from HCT better.

A decision regarding the use of allogeneic HCT in first CR must also consider the estimated rate of relapse and the efficacy of available treatments at the time of relapse. In one analysis, 1337 of 2029 younger adults (16 to 49 years) with intermediate-risk AML enrolled on prospective trials did not proceed with HCT in first CR [10]. Of these, 780 (58 percent) relapsed with an estimated five-year survival following relapse of 17 percent. Among patients with relapsed disease, survival was superior for the 326 patients who underwent allogeneic HCT after relapse (47 versus 15 percent). In this particular (time-dependent) analysis, there was a similar difference in survival outcome for patients who had allogeneic HCT in first CR and for those who did not undergo HCT in first CR but underwent a late HCT for salvage after relapse of leukemia.

The choice of post-remission therapy for an individual with intermediate-risk disease depends on the patient's age and comorbidities. Advances in conditioning regimens (eg, non-myeloablative or reduced intensity conditioning) and alternative donor sources (eg, umbilical cord blood, haploidentical donors) have increased the number of patients with intermediate-risk disease who are candidates for allogeneic HCT [46]. Age and comorbidities are host factors that define the mortality risk of the transplant and which can be taken into account in relation to the risk of relapse of the disease. As an example, young patients (eg, <40 years old) with few comorbidities may choose allogeneic HCT rather than autologous HCT or HiDAC. This preference places a strong emphasis on the survival benefit seen on meta-analysis and a lesser emphasis on the high rate of treatment related mortality and morbidity. A post-remission treatment calculator has been proposed that incorporates age, percentage of CD34 positive blasts, FLT3-ITD mutant-to-wild-type ratio, cytogenetic risk, and disease status to predict probability of survival with these therapies [47]. However, FLT3-ITD mutant-to-wild-type ratio is not widely available and measures of CD34-positive blasts may have variability among institutions [48]. As such, we await validation of this calculator in other cohorts prior to its widespread application.

UNFAVORABLE-RISK DISEASE — For most patients with unfavorable-risk cytogenetics or molecular genetics (especially those age <40 years), we recommend allogeneic hematopoietic cell transplantation (HCT) rather than autologous HCT or consolidation chemotherapy alone. Furthermore, we suggest myeloablative conditioning rather than reduced intensity or nonmyeloablative conditioning. Enrollment in a clinical trial is advised if a related or unrelated donor is not available or if the patient is not a candidate for transplantation.

Patients with unfavorable karyotypes, as defined above, do poorly when treated with consolidation chemotherapy alone after attainment of a complete remission; rates of five-year overall survival with this approach are 15 to 30 percent [2,3,7,10,29]. In contrast, treatment with allogeneic HCT provides an additional graft-versus-leukemia (GVL) effect together with myeloablative chemotherapy, resulting in superior survival rates of approximately 40 percent at four years [7].

The strong GVL response in AML is illustrated by the following:

●Rates of AML relapse are much higher in patients who have received identical twin (syngeneic) transplants compared with HLA-identical sibling transplants administered with identical cytotoxic treatment (eg, 52 versus 16 percent in one series) [49]; this difference relates to the allogeneic GVL effect.

●Patients who relapse after an allogeneic HCT may benefit from donor lymphocyte infusion (DLI). As an example, remission was achieved with DLI in 29 percent in one study of 23 patients [50].

Unfortunately, the beneficial GVL response is closely associated with acute and chronic graft-versus-host disease (GVHD), while intensive myeloablative chemotherapy is associated with life-threatening cytopenias. Both are major causes of morbidity and mortality following allogeneic HCT. GVHD can be reduced by T cell depletion from the donor marrow, generally at the risk of increased rates of graft failure and leukemia relapse. (See "Prevention of graft-versus-host disease".)

In order to offer these patients the best chance of a successful HCT before relapse, planning for HCT should begin as early as possible with HLA typing and a donor search. (See "Donor selection for hematopoietic cell transplantation".)

Myeloablative allogeneic transplantation — Several prospective studies have evaluated different post-remission strategies in patients with unfavorable-risk disease [30,51-56]. Investigators have generally relied on a "genetic randomization" in which patients are assigned to treatment with or without allogeneic HCT based on the presence or absence of an HLA-matched sibling donor. The strength of evidence provided by these observational studies is limited by a lack of true randomization. (See 'Chemotherapy versus transplantation' above.)

Three large meta-analyses of these observational studies performed using data from patients with AML in first complete remission examined the effect of patient age, donor availability and cytogenetic risk category on disease-free and overall survival [6-8]. Patients with unfavorable-risk disease who had an HLA-matched sibling donor had the following significant outcomes when compared with patients assigned to treatment with chemotherapy with or without autologous HCT, when analyzed in an intention-to-treat fashion:

●Superior rates of four-year overall survival (40 versus 30 percent)

●Improved rates of disease-free survival at four years (33 versus 17 percent)

●Fewer relapses at four years (39 versus 77 percent)

●Higher treatment-related mortality (28 versus 6 percent)

Further analysis using age cutoffs of either 35 or 40 years found that younger patients have a lower treatment-related mortality and, as a result, the benefits of allogeneic HCT become more pronounced.

Conditioning regimen — Allogeneic HCT should be delivered shortly after attainment of an initial complete remission. Post-remission consolidation therapy with standard or high-dose cytarabine is not associated with improved outcome, compared with proceeding directly to allogeneic transplantation following successful induction therapy [57,58]. (See "Preparative regimens for hematopoietic cell transplantation".)

The ideal conditioning (preparative) regimen is unknown and clinical practice differs by institution according to experience. Conditioning regimens have variable intensity, toxicity, and dependence on a graft-versus-tumor effect (figure 1). The terms myeloablative conditioning (MAC), nonmyeloablative (NMA) conditioning, and reduced intensity conditioning (RIC) have been used with variable definitions and the dividing lines between these categories are not clear. In addition, the ability of individuals to tolerate the toxicities associated with these regimens has improved with advances in supportive care (eg, antifungal agents, CMV prophylaxis, GVHD prophylaxis).

For most younger adults (<40 years) undergoing allogeneic HCT, we suggest MAC rather than RIC or NMA conditioning. Randomized trials suggest that, when compared with MAC, the less intensive regimens (NMA/RIC) are associated with a modest decrease in transplant-related mortality, but higher relapse rates and comparable overall survival, as described in greater detail below. (See 'NMA/RIC versus MAC regimens' below.)

For patients who are not candidates for MAC, these less intensive regimens may offer higher rates of leukemia-free survival when compared with consolidation chemotherapy alone. RIC and NMA are discussed in more detail separately. (See 'Nonmyeloablative/reduced intensity HCT' below.)

MAC regimens include:

●Busulfan and cyclophosphamide (Bu/Cy) [59]

●Busulfan and fludarabine (Bu/Flu) [60]

●Fludarabine plus melphalan 140 mg/m² (Flu/Mel) [61,62]

●Melphalan, busulfan, and total body irradiation (TBI) [63]

●Cyclophosphamide plus TBI (Cy/TBI) [59,64]

Retrospective and observational studies suggest that myeloablative conditioning with intravenous Bu/Cy results in superior survival rates when compared with Cy/TBI. Many centers prefer intravenous busulfan to oral busulfan because of the better and more predictable pharmacokinetics.

●A retrospective analysis from the Center for International Blood and Marrow Transplantation Research (CIBMTR) included 1230 patients with AML in first complete remission who underwent sibling or matched unrelated donor HCT following conditioning with Cy/TBI (586 patients), oral Bu/Cy (408 patients), or intravenous Bu/Cy (236 patients) from 2000 to 2006 [65]. When compared with Cy/TBI, intravenous Bu/Cy (but not oral Bu/Cy) resulted in less nonrelapse mortality (relative risk [RR] 0.58; 95% CI 0.39-0.86), better leukemia-free survival (RR 0.70; 95% CI 0.55-0.88), and better overall survival (RR 0.68; 95% CI 0.52-0.88).

●A multicenter nonrandomized cohort study reported outcomes following different conditioning regimens for patients with myeloid malignancies (40 percent AML in first complete remission) undergoing sibling or unrelated donor HCT [66]. When compared with the 458 patients who received Cy/TBI, the 1025 patients who received intravenous Bu/Cy demonstrated superior survival (RR 0.82; 95% CI 0.68-0.98). Rates of relapse and treatment-related mortality were similar between the two groups.

●In an unblinded multicenter phase III trial, 252 adults (age 40 to 65 years) with AML in first remission were randomly assigned to receive Bu/Cy or the same myeloablative dose of busulfan plus fludarabine [60]. After a median follow-up of 28 months, Bu/Cy resulted in greater estimated two-year nonrelapse mortality (18 versus 10 percent), but the estimated rates of relapse (30 versus 32 percent) and overall survival (64 versus 62 percent) at two years were similar.

Additional issues related to the choice of conditioning regimen are discussed in more detail separately. (See "Preparative regimens for hematopoietic cell transplantation".)

Choice of donor — All of the prospective trials evaluating allogeneic HCT in first complete remission included in the meta-analyses mentioned above used HLA-matched related donors since this criterion was used as the method for treatment stratification. However, only 25 to 30 percent of potential recipients have HLA-matched siblings who can serve as donors. With the advent of molecular typing techniques, morbidity and mortality associated with the use of HLA-matched unrelated donors has declined. (See "Donor selection for hematopoietic cell transplantation", section on 'Unrelated donors'.)

For patients without an HLA-matched sibling, the following donors may be considered since they are expected to result in similar outcomes [67-79]:

●Matched unrelated donor

●Single antigen mismatched related donor

●Umbilical cord blood transplantation

Allogeneic HCT using a matched unrelated donor (MUD) is an option for younger adults who lack a sibling donor. The likelihood of finding a MUD in the National Bone Marrow Donor Registry is related in part to the ethnic background of the patient compared with the volunteer donor pool. It also depends on the number of allelic mismatches between donor and recipient that one wishes to allow (eg, a full 10/10 match or 9/10 or 8/10 with mismatches). The overall match rate is approximately 50 percent for White Americans but only 10 percent for racial/ethnic underrepresented groups who are both underrepresented in the donor pool and more polymorphic with respect to HLA [80].

Due to the relative immaturity of the immune system in umbilical cord samples, stem cells from this source allow the crossing of immunologic barriers that would otherwise be prohibitive. As a result, the degree of HLA-disparity that is tolerable is much greater, making this approach more feasible for members of underrepresented groups. In addition, cord blood has already been collected and cryopreserved before the time a match is identified, thereby greatly reducing the time required for accessing the donor and completing the transplant procedure; however, there is less clinical follow-up with cord blood transplantations and long term follow-up will be necessary to determine whether they truly provide equivalent results [73,81].

Another option which would significantly increase donor availability is to use T cell depleted stem cells from related donors with one fully mismatched HLA haplotype, sometimes called partially-matched family member transplants or haploidentical transplants [82-85]. This method should be considered as investigational as only limited data in selected patients are available and this procedure is associated with severe and prolonged immunodeficiency after transplantation. (See "HLA-haploidentical hematopoietic cell transplantation".)

Nonmyeloablative/reduced intensity HCT — We recommend myeloablative conditioning (MAC) regimens rather than nonmyeloablative (NMA) or reduced intensity conditioning (RIC) preparative regimens for patients with unfavorable risk AML who are candidates for HCT. (See 'Conditioning regimen' above.)

We generally offer NMA/RIC conditioning regimens rather than autologous HCT or consolidation chemotherapy alone for patients with unfavorable risk AML who are not considered eligible for MAC regimens (eg, based on advanced age or co-morbid conditions). For such patients, NMA/RIC allogeneic HCT may offer higher rates of leukemia-free survival when compared with consolidation chemotherapy alone [86].

NMA and RIC preparative regimens were developed as an alternative strategy for allogeneic HCT because MAC may lead to significant early morbidity and mortality in older patients and those with comorbid medical conditions. These procedures rely less on the dose intensity of the pretransplant cytotoxic regimen and depend heavily upon the graft-versus-leukemia response [67,87-92]. For this approach to achieve long-term disease-free survival, it seems likely that a durable complete remission must first be achieved before HCT.

Preparative regimens for HCT have variable intensity, toxicity, and dependence upon a graft-versus-tumor effect (figure 1). Eligibility criteria for NMA/RIC allogeneic HCT and choice of preparative regimen are generally determined by the transplant center. General eligibility criteria, definitions, and examples of MAC, NMA, and RIC preparative regimens are presented separately. (See "Preparative regimens for hematopoietic cell transplantation", section on 'Definitions' and "Determining eligibility for allogeneic hematopoietic cell transplantation".)

NMA/RIC versus MAC regimens — Trials that randomly assigned patients to NMA/RIC versus MAC preparative regimens have reported that the less intensive regimens are associated with higher rates of relapse, but a modest decrease in transplant-related mortality (TRM); these offsetting effects have generally resulted in comparable overall survival (OS). The following phase 3 trials have compared MAC versus NMA/RIC regimens for AML:

●A multicenter trial that randomly assigned 272 adults with AML or MDS (18 to 65 years old) in morphologic CR was closed early after review by the Data and Safety Monitoring Board suggested a benefit for MAC over RIC [93]. Compared with RIC, MAC was associated with superior relapse-free survival (RFS; 68 versus 47 percent, respectively), but a higher rate of TRM (16 versus 4 percent); as a result, there was no difference in OS at 18 months. A subsequent analysis of this trial reported that the benefits of MAC were confined to the approximately two-thirds of patients who had measurable residual disease (MRD) prior to transplantation. A next-generation sequencing (NGS)-based assay was used to detect mutations with a minimum allele frequency of 0.001 in 13 genes associated with AML [94]. No mutations were detected in 32 percent of MAC and 37 percent of RIC recipients; for these MRD-negative patients, there was no difference in outcomes between conditioning regimens (ie, 56 versus 63 percent three-year OS, respectively). For MRD-positive patients, compared with RIC, those who underwent MAC had a more favorable three-year cumulative incidence of relapse (19 percent versus 67 percent, respectively) and superior three-year OS (61 versus 43 percent). In multivariate analysis of NGS-positive patients, after adjusting for disease risk and donor group, RIC was associated with an increased risk for relapse (hazard ratio [HR], 6.4; 95% CI 3.4 to 12.1), decreased RFS (HR, 2.9; 95% CI 1.8-4.7), and decreased OS (HR, 2.0; 95% CI 1.2 to 3.3).

●A multicenter trial randomly assigned 195 younger adults (age ≤60 years) with intermediate-risk or high-risk AML in first complete remission who had an available HLA-matched sibling or matched unrelated donor to MAC or RIC, each followed by allogeneic HCT [95]. The trial closed early due to poor accrual and thus has limited statistical power. When compared with RIC, MAC was associated with similar estimated rates at three years of OS (58 versus 61 percent, respectively), nonrelapse mortality (NRM; 18 versus 13 percent), and rates of relapse (26 versus 28 percent).

●Another phase 3 trial reported that among 129 patients, RIC and MAC were associated with comparable two-year RFS and OS [96].

NMA/RIC versus chemotherapy consolidation — RIC or NMA conditioning is feasible in a subset of patients who are not candidates for MAC HCT. For such patients with intermediate- or unfavorable-risk disease in first complete remission, we suggest RIC or NMA conditioning followed by related or unrelated donor HCT rather than consolidation chemotherapy alone.

The following studies illustrate the efficacy of RIC and NMA in patients who are not candidates for MAC:

●A single center prospective trial compared outcomes with a RIC allogeneic HCT versus consolidation chemotherapy in 95 patients with intermediate-risk (80 percent) or unfavorable-risk AML in first complete remission [86]. All patients were considered to be candidates for RIC, and "genetic randomization" was used to assign treatment with or without allogeneic HCT based on the presence or absence of an HLA-matched sibling donor. At a median follow-up of 4.8 years, patients with an HLA-matched sibling donor had significantly higher estimated rates of leukemia-free survival at seven years (60 versus 23 percent). Treatment-related mortality for those who underwent RIC was 12 percent [97].

●A prospective study employed NMA conditioning using 2 Gy total body radiation with or without fludarabine in 122 patients with AML, most of whom were considered ineligible for conventional allogeneic HCT because of older age or comorbidities [91]. The median age was 58 years (range: 17 to 74). At a median follow-up of 44 months, rates of OS were 51 and 61 percent for patients transplanted in first or second complete remission, respectively, and 28 percent for those beyond second complete remission at the time of HCT. Two-year incidences of NRM were 10 and 22 percent for those with related or unrelated donors, respectively.

●RIC with a fludarabine/melphalan regimen incorporating alemtuzumab was utilized in 76 patients with high-risk AML or MDS, 42 of whom were in first, second, or third complete remission [90]. Median age was 52 years (range: 18 to 71 years). Estimated three-year disease-free survival was 42 percent for those in complete remission at the time of HCT. One-year transplant-related mortality was 19 percent.

If feasible, we suggest the use of a reduced intensity or nonmyeloablative conditioning followed by related or unrelated donor HCT rather than consolidation chemotherapy for older patients with intermediate- or unfavorable-risk AML who are not candidates for myeloablative allogeneic HCT. Ideally this treatment should be performed within the context of a clinical trial to allow for the collection of additional data regarding its safety and efficacy.

POST-CONSOLIDATION MANAGEMENT — Following the completion of post-remission therapy, patients are seen at periodic intervals to monitor for treatment complications and assess for possible relapse. The frequency and extent of these visits depends on the comfort of both the patient and physician. There have been no prospective, randomized trials comparing various schedules of follow-up.

Maintenance therapy alone, using relatively nonmyelosuppressive doses of cytotoxic drugs following remission induction, has no proven benefit in the cure of AML. For patients under 60 years of age, consolidation therapy results in significantly longer survival than maintenance therapy alone. Clinical trials are investigating the use of agents such as interleukin 2, decitabine, or midostaurin as a maintenance therapy [98,99].

Monitoring for relapse — Our approach to patient surveillance is to schedule patient visits every one to two months for the first two years when the disease is most likely to relapse, and then every three to six months for up to five years post-consolidation. At these visits we perform a complete blood count including platelets, white blood cell differential, and review of the peripheral blood smear. Bone marrow biopsy and aspirate is not routinely performed, but is indicated if the peripheral smear demonstrates abnormalities or if cytopenias develop.

The use of measurable residual disease (MRD; also referred to as minimal residual disease) monitoring in patients with AML is discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Monitoring'.)

Treatment of the patient with AML who has relapsed after attainment of a complete remission is presented separately. (See "Treatment of relapsed or refractory acute myeloid leukemia".)

Monitoring for treatment complications — Long-term treatment complications differ based on the post-remission treatment strategy used. Immunizations and general health maintenance guidelines are recommended.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute myeloid leukemia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Autologous bone marrow transplant (The Basics)" and "Patient education: Allogeneic bone marrow transplant (The Basics)")

●Beyond the Basics topics (see "Patient education: Acute myeloid leukemia (AML) treatment in adults (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Description – Most adults with acute myeloid leukemia (AML) achieve a complete remission (CR) with intensive induction chemotherapy, but virtually all will relapse within months without post-remission therapy. Post-remission management is informed by the risk of relapse, medical fitness, and the patient's values and preferences.

●Risk stratification – We stratify risk of relapse according to the European LeukemiaNet (ELN) model (table 2), which considers cytogenetic/molecular features and measurable residual disease (MRD) (see 'Risk stratification' above):

•Favorable features – Examples include t(8;21), inv(16), or t(16;16), and MRD-negative patients.

•Intermediate features – Cytogenetic features that are neither favorable nor adverse or MRD-positive patients

•Adverse features – Examples include: complex karyotype; monosomal karyotype (eg, -5, del(5q), -7, –17/abn(17p)); t(9;22)/BCR::ABL1; t(6;9)/DEK::NUP214; t(v;11q23.3)/KMT2A rearranged; inv(3) or t(3;3)/GATA2,MECOM; FLT3-ITD-high with wild-type NPM1; mutated RUNX1, ASXL1, or TP53.

●Favorable risk – For patients with favorable cytogenetics, we recommend consolidation chemotherapy, rather than allogeneic hematopoietic cell transplantation (HCT) (Grade 1B). (See 'Favorable-risk disease' above.)

●Intermediate risk – For patients with intermediate risk, we consider either consolidation chemotherapy or allogeneic HCT acceptable; the choice of approach is guided by medical fitness, age, availability of a suitable graft donor, and patient preference. (See 'Intermediate-risk disease' above.)

●Adverse risk – For patients with adverse risk, we suggest allogeneic HCT for patients with adequate medical fitness and a suitable graft donor. Management is individualized for others. (See 'Unfavorable-risk disease' above.)

●Consolidation chemotherapy – Stratified according to age (see 'Choice of agent' above):

•<60 years – We favor three or four cycles of high-dose cytarabine (HiDAC; eg, 3 g/m² over 3 hours every 12 hours on days 1, 3, 5 of each cycle).

Gemtuzumab ozogamicin (for CD33-positive) or midostaurin (for FLT3-mutated) may be added in selected cases, as discussed above.

•≥60 years – We favor standard-dose cytarabine (eg, 200 mg/m² by continuous infusion 1 g/m² every 12 hours on days 1, 3, and 5) for four cycles.

●Allogeneic HCT – For most younger adults (<40 years) undergoing allogeneic HCT, we suggest myeloablative conditioning rather than reduced intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning (Grade 2B). In contrast, RIC or NMA conditioning followed by allogeneic HCT is preferred over consolidation chemotherapy for eligible patients with unfavorable-risk cytogenetics who are not candidates for myeloablative conditioning. (See 'Nonmyeloablative/reduced intensity HCT' above.)

●Maintenance therapy – Maintenance therapy can be given after either consolidation chemotherapy or HCT if a targetable mutation is present, as discussed above. (See 'Post-consolidation management' above.)

●Monitoring – Surveillance for relapse and treatment-related adverse effects is described above. (See 'Post-consolidation management' above.)