Chapter 2: Adult Acute Myeloid Leukemia

Acute myeloid leukemia (AML) consists of a heterogeneous group of hematologic neoplasms characterized by clonal proliferation of myeloid blasts in the peripheral blood, bone marrow, and extramedullary tissues. Despite advances in our understanding of the molecular biology of AML, its treatment remains challenging and outcomes vary greatly depending on the cytogenetic and molecular features as well as age and comorbidities.

Acute myeloid leukemia is thought to be the culmination of genetic mutations and chromosomal aberrations within myeloid precursors resulting in disrupted differentiation, excessive proliferation, and suppressed apoptosis of neoplastic cells referred to as blasts.

Over the last several decades, improvements in chemotherapeutic regimens and supportive care have resulted in significant but modest progress in treating AML. Better understanding of the biology of AML has resulted in the identification of new therapeutic targets. Despite this, currently, the majority of patients with AML die from the complications of their disease. With better definition of molecular abnormalities and elucidation of the pathogenic events in various AML subtypes and with the development of novel targeted agents, a better outcome for patients with AML may be achievable in the future.

Approximately 13,000 individuals are diagnosed annually in the United States with leukemia. The incidence of AML is 4.3 per 100,000 (¹). The median age at presentation is about 65 years. The incidence of AML, as well as myelodysplastic syndrome (MDS), appears to be rising, particularly in individuals over 60 years of age. The incidence of AML is slightly higher in males and in populations of European descent. Acute promyelocytic leukemia (APL), a distinct subtype of AML, has been reported to be more common among populations of Hispanic background (²).

An increased incidence of AML is seen in patients with disorders associated with increased chromatin fragility such as Bloom syndrome, Fanconi anemia, Kostmann syndrome, and Wiskott-Aldrich syndrome or ataxia-telangiectasia. Other syndromes, such as Down (trisomy of chromosome 21), Klinefelter (XXY and variants), and Patau (trisomy of chromosome 13) syndromes, have also been associated with a higher incidence of AML (³).

Therapeutic radiation increases AML risk, particularly if given concomitantly with alkylating agents. Two categories of therapy-related AML have been described. Patients exposed to alkylating agents (eg, cyclophosphamide, melphalan, nitrogen mustard) can develop AML after a latency period of 4 to 8 years, which is often associated with abnormalities of chromosomes 5 and/or 7. Exposure to agents that inhibit the DNA repair enzyme topoisomerase II (eg, etoposide) is also associated with secondary AML with a shorter latency period, usually 1 to 3 years (⁴). Benzene, smoking, dyes, herbicides, and pesticides have been implicated as potential risk factors for development of AML (⁵).

Acute myeloid leukemia may also be secondary to transformation of an antecedent myeloid disorder, such as MDS, myeloproliferative neoplasm (MPN), or MDS/MPN, or other bone marrow disorders, such as aplastic anemia.

Fatigue, bruising or bleeding, fever, and infection, reflecting a state of bone marrow failure, are common in AML. Only 10% of patients present with white blood cell (WBC) count greater than 100 × 10⁹/L (¹). These patients are at higher risk of tumor lysis syndrome, central nervous system involvement, and leukostasis. Leukostasis may manifest as dyspnea, chest pain, headaches, altered mental status, cranial nerve palsies, or priapism. Leukostasis and tumor lysis syndrome are oncologic emergencies and require prompt recognition and management.

Physical findings other than bleeding and infection may include organomegaly, lymphadenopathy, sternal tenderness, retinal hemorrhages, and infiltration of gingivae, skin, soft tissues, or meninges (more common with monocytic variants, M4 or M5). Disseminated intravascular coagulopathy (DIC) with bleeding diathesis is a common presentation in APL.

The diagnosis of AML is typically based on the presence of 20% myeloid blasts in the bone marrow or peripheral blood in accordance with World Health Organization (WHO) classification criteria (Table 2-1) (⁶). Acute myeloid leukemia subtypes in the WHO classification are defined on the basis of morphology, immunophenotype, and molecular/genetic features. In some patients, AML presents as a mass in extramedullary tissues (myeloid sarcoma). Patients who have the cytogenetic abnormalities t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22), and t(15;17)(q22;q12) are diagnosed with AML regardless of the blast percentage.

Bone marrow sampling is essential for the initial workup of a patient with suspected acute leukemia. Sampling should include a core biopsy as well as aspiration material. The core biopsy should be used to perform touch preparations, which are invaluable in case of a dry tap. The aspiration material is used to prepare a clot and aspirate smears, in addition to having portions submitted for flow cytometry, cytogenetics, and molecular diagnostics.

Confirmation of myeloid lineage is commonly accomplished using flow cytometry. In most AML cases, blasts express one or more markers of immature hematopoietic precursors such as CD34 and HLA-DR, in addition to dim CD45 (common leukocyte antigen). Myeloid lineage is predicated on the expression of antigens associated with granulocytic, monocytic, erythroid, and/or megakaryocytic differentiation by blasts (Table 2-2). Expression of myeloperoxidase (MPO) is considered specific for myeloid differentiation, although AML blasts may lack MPO expression. Although aberrant expression of lymphoid antigens is commonly seen in some cases with a bona fide AML phenotype, such expression is generally limited to one or a few lymphoid antigens. Acute leukemia with ambiguous lineage is beyond the scope of this discussion; briefly, it refers to acute leukemia with overlapping expression of myeloid and lymphoid antigens or lack of both.

Molecular diagnostics play a critical role in the laboratory workup of AML. Whereas the scope of known molecular alterations in AML was limited until a few years ago, the advent of next-generation sequencing (NGS) has dramatically increased our understanding of the molecular landscape of AML. As a result, the limited number of polymerase chain reaction (PCR)–based assays that used to be performed during AML workup have been gradually replaced at most large facilities by NGS-based panels that simultaneously assess the mutation status of tens to hundreds of genes. The current NGS mutation panel for new and relapsed myeloid malignancies used at our institution assesses the coding sequences of the 28 genes listed in Table 2-3.

Once a diagnosis of AML has been made, the next step is to risk stratify the patient. Several variables are predictive of outcome, including patient-related variables, such age and performance status, as well as disease-related predictors, such as cytogenetic and molecular characteristics.

The karyotype remains one of the best predictors of outcome in patients with AML. The European LeukemiaNet (ELN) guidelines have proposed a risk stratification system based on cytogenetics and molecular analysis (⁷). As listed in Table 2-4, the patients are classified as having favorable-, intermediate-, and unfavorable-risk disease. The drawback of this classification system is that it takes into account few mutations for prognostication. More recent data suggest that the favorable prognosis attributed to mutant CEBPA is true in cases of bilallelic CEBPA mutation rather than the monoallelic mutation (⁸). Of note, in patients with FLT3-negative/NPM1-positive AML, DNMT3A assessment is of importance. Loghavi et al showed that in patients with karyotypically normal AML with NPM1 mutations, presence of concurrent DNMT3A mutation has an adverse effect on outcomes, with the effect being more detrimental than either FLT3-ITD or FLT3-TKD mutations (⁹). This analysis showed that of patients with de novo karyotypically normal AML, particularly those <60 years old, AML^{DNMT3A/FLT3/NPM1} patients seem to have the worst clinical outcomes, followed by those with AML^FLT3/DNMT3A and then those with AML^NPM1/DNMT3A (⁹). Currently, normal karyotype AML patients with NPM1-positive/FLT3-negative disease are considered favorable risk according to the ELN guidelines.

The presence of TP53 mutations is associated with a poor outcome. A recent report by German/Austrian investigators indicated that the outcome of patients with TP53 mutations is worse than that of patients with the monosomal karyotype known to be an adverse prognostic indicator (¹⁰). In this study, the analysis showed that the TP53 mutation was commonly associated with older patients and a monosomal karyotype and correlated with a low complete remission (CR) rate and shorter relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS). On multivariate analysis, TP53 mutations were associated with the worst prognosis (¹⁰).

Several novel molecular aberrations, including mutations of the IDH, ASXL1, DNMT3A, TET2, MLL, and PHF6 genes, have been described, particularly in patients with a normal karyotype (¹¹). However, their utility in clinical practice remains limited, and they have limited value in determining best treatment strategies for patients.

In the 1960s, Freireich et al demonstrated the significance of achieving a CR to improve survival (¹²). Since then, the objective of therapy has been to produce and maintain CR, the only currently accepted approach to AML cure. Criteria for CR have been defined by the International Working Group and are followed in the clinic and in clinical trials for response assessment (¹³). After 3 years in CR, the probability of AML recurrence sharply declines to less than 10% (¹⁴), and patients in continuous CR for 3 or more years can be considered “potentially cured.” However, clearly the definition of CR is an arbitrary one, and with improved technology, the precision for detection of residual disease after the initial therapy has increased. Whether this improved detection and application of novel strategies to eradicate the residual leukemia will translate to improved cure rates will be the subject of future trials.

Once AML is diagnosed, the need for emergency therapy must be assessed. Emergency treatment is required (1) in cases of APL, (2) if the circulating blast count is >50 to 100 × 10⁹/L, and (3) in the presence of DIC or organ dysfunction (especially pulmonary) attributed to leukemic infiltration (mostly seen in patients with >10 × 10⁹/L circulating blasts and/or M4 or M5 French-American-British [FAB] morphology). In the latter situation, it is important to initiate immediate chemotherapy. Leukapheresis for severe leukocytosis and/or leukostasis should also be considered (¹⁵). In patients with low presenting WBC count, several studies have demonstrated that initiation of therapy can delayed for several days until all the necessary diagnostic information is available (¹⁶).

At University of Texas MD Anderson Cancer Center (MDACC), most patients are enrolled on clinical trials, if eligible. The therapy is tailored to the individual patient characteristics including their cytogenetic and molecular profile. We discuss here the therapies for the various patient groups with AML.

Conventional treatment for AML, divided into remission induction and postremission therapy, has been with combinations of anthracyclines and cytarabine (ara-C).

Anthracyclines and Cytarabine

At MDACC, young patients with AML (<60 years old) are treated with idarubicin (IDA) plus cytarabine-based regimens. The dose of IDA is 12 mg/m² for 3 days, and ara-C is given as a continuous infusion at a dose of 1.5 g/m² for 4 days. An alternative used by many cooperative groups is the “3+7 regimen,” where the anthracycline (ie, IDA or daunorubicin [DNR]) is usually given daily for 3 days and ara-C is given at 100 to 200 mg/m² daily for 7 days by continuous infusion.

In clinical practice, a bone marrow aspirate is usually obtained 2 to 3 weeks after beginning therapy. A biopsy is needed only if the quality of the aspirate does not permit determination of cellularity. If the day 21 marrow is hypoplastic, therapy is usually delayed until it is clear that leukemia has reappeared, at which time the second course begins. A second repeated course of therapy can produce remissions, but these are usually of shorter duration than remissions produced after one course of therapy. The timing of a second course with persistent AML is controversial. Several cooperative groups advocate starting a second course if there is persistent AML on days 10 to 15 of chemotherapy. With high-dose ara-C (HDAC), a delay of a second course with persistent disease on days 21 to 28 may be indicated if the blasts are decreasing because most (90%) CRs are obtained after the first course and response to a second course is poor. It is important to recognize that the initial marrow obtained after a period of hypoplasia may demonstrate up to 30% to 50% blasts as a reflection of the regeneration of normal, not “leukemic,” marrow recovery. In this circumstance, follow-up (eg, at 1- to 2-week intervals) marrows may show reduction in blast percentages concomitant with a rise in neutrophils and platelets.

Typically, once in remission after treatment with the induction course, patients receive postremission therapy, with the same drugs administered at approximately monthly intervals for 4 to 12 months.

Choice of Anthracyclines

Randomized trials have attempted to identify which anthracycline (eg, IDA, DNR, mitoxantrone [MTZ], aclarubicin) is better (¹⁷). In a three-arm randomized study comparing DNR, IDA, and MTZ as part of the induction regimen for older patients, there was no advantage for any one arm (¹⁸). In contrast, in a three-arm randomized trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) and Italian Group for Hematological Diseases in Adults (GIMEMA) comparing the same three agents, the 5-year disease-free survival (DFS) and OS were significantly better for patients receiving IDA and MTZ (P = .03 and .02, respectively). The recovery time was longer with IDA and MTZ (P < .0001) (¹⁹). Gardin et al analyzed pooled data from trials conducted in AML patients age ≥50 years (²⁰). These trials compared the efficacy of IDA versus DNR in induction and consolidation. They assessed the outcomes of these patients and showed that IDA resulted in a higher CR rate of 69% (vs 61% with DNR, P = .02) but did not lead to superior OS (median OS, 14.2 months; P = .13) (²⁰).

Different doses of DNR have been evaluated in several trials, in addition to standard-dose ara-C (100 or 200 mg/m² daily for 7 days). Two studies showed that using DNR 90 mg/m² had better outcomes than DNR 45 mg/m², regardless of age. Both studies showed higher CR rates and OS in patients receiving a higher dose of DNR, without any additional toxicity. The beneficial effect was mostly seen in patients less than 50 years old and with more favorable cytogenetics (^21,22). More recently, a French group also showed that DNR 60 mg/m² had similar relapse rate, RFS, and OS compared to DNR 90 mg/m² (²³).

Even though the studies do not show survival advantage with IDA over DNR, the CR rates are definitely higher with IDA. Hence, at MDACC, IDA is the preferred anthracycline of choice.

CPX-351

CPX-351 is a novel formulation for delivery of ara-C and DNR synergistically to the leukemic cells. In this formulation, ara-C and DNR are encapsulated in a 5:1 fixed molar ratio that was found to be consistently synergistic in vitro. A multicenter, open-label, phase II study was conducted across 18 centers in the United States in the first-line setting. Patients >60 years old with de novo AML were randomized to receive the CPX-351 versus the 7+3 regimen. Higher response rates were noted with CPX-351, with an overall response rate (ORR) of 66.7% (vs 57.6%, P = .06). Patients with adverse cytogenetics had an improved response with CPX-351 (77% vs 38%). Improvements in the median OS (14.7 months vs 12.9 months) and EFS (6.5 months vs 2 months) were noted in the CPX-351 cohort (²⁴). A phase III trial is currently ongoing.

High-Dose Cytarabine

Several randomized trials have assessed the efficacy of HDAC (1-3 g/m²) versus standard-dose ara-C (SDAC) (100-200 mg/m²) for induction therapy. The Cancer and Leukemia Group B (CALGB) and the Eastern Cooperative Oncology Group (ECOG) restricted their analysis to patients in CR, whereas the Southwestern Oncology Group (SWOG) compared HDAC with SDAC during induction and randomized SDAC patients to SDAC or HDAC once the patients were in CR (²⁵). Finally, the Australian Leukemia Study Group (ALSG) randomized patients to HDAC or SDAC during induction only (Table 2-5) (²⁶). These trials concluded that (1) the toxicity of HDAC (eg, cerebellar) outweighs the anti-AML effect in patients >65 years; (2) patients >60 years benefit from HDAC given during induction (SWOG, ALSG), in CR (CALGB, ECOG), and perhaps both (SWOG); and (3) HDAC potentially increases the cure rates to 70% to 80% in patients with inversion 16 or t(8;21) and to 30% to 40% in patients with normal karyotype, but little, if at all, in patients with adverse karyotypes. In a meta-analysis of three trials in 1,691 patients, induction with HDAC was compared to SDAC. Although there was no difference in CR rates, the 4-year RFS (P = .03), 4-year OS (P = .0005), and 5-year EFS (P < .0001) were better with HDAC (²⁷).

Gemtuzumab Ozogamicin

Gemtuzumab ozogamicin (GO) is a CD33-targeted immunoconjugate linking an anti-CD33 antibody to calicheamicin. It received an accelerated approval by the US Food and Drug Administration for use in relapsed/refractory elderly AML patients but was withdrawn voluntarily by the manufacturer from the market in 2010 due to toxicity concerns. However, in a recent trial by the French Leukemia Association, patients age 50 to 70 years with previously untreated de novo AML were randomized to receive standard chemotherapy with 7+3 (DNR, ara-C) with or without GO. Gemtuzumab was administered in fractionated doses. The ORR was 78%, with 73% achieving CR and 5% achieving CR with incomplete platelet recovery (CRp). The OS (34 months vs 19 months, P = .036), EFS (15.6 months vs 9.7 months, P = .0003), and RFS (28 months vs 11 months, P = .0003) were significantly better in the GO group. Another study by the Medical Research Council (MRC) in the United Kingdom showed a benefit for the addition of GO to ara-C and anthracycline-based induction regimens (²⁸). A recent meta-analysis examined five randomized trials in untreated patients with AML and demonstrated a benefit of GO in the frontline therapy of some subsets of patients with AML. The available data suggest utility of GO in patients with AML allowing the argument for the reconsideration of its approval in the United States.

Clofarabine, Idarubicin, and Cytarabine

Clofarabine is a second-generation nucleoside analogue that has activity in adult patients with AML. A phase I trial of clofarabine, conducted at MDACC, in combination with IDA alone versus IDA and ara-C (CIA) in patients with relapsed, refractory AML showed a CR rate of 13% versus 48%, respectively. The median duration of remission was also longer with the CIA combination (15 months) as compared to clofarabine and IDA (4.5 months) (²⁹). This was followed by a phase II trial that investigated the CIA regimen in patients ≤60 years old with newly diagnosed AML. Patients who achieved a response (CR or CRp) went on to receive up to six cycles of consolidation therapy. The cycles were administered every 4 to 6 weeks. All patients received prophylactic antibiotics, antifungals, and antivirals. The median age of the patients was 48 years (range, 19-60 years), 66% had intermediate-risk cytogenetics, and 36% had diploid and 34% adverse karyotype. The ORR was 79%, with 74% CR and 3% CRp. Eighteen percent of patients received two induction cycles to achieve a CR/CRp, and 42% went on to receive an allogeneic stem cell transplantation (SCT) in first CR. The median OS and RFS were not reached, whereas the median EFS was 13.5 months. A subset analysis showed better OS (P = .04) and EFS (P = .04) in patients ≤40 years old as compared to >40 years old (³⁰).

Purine Analogues

The addition of purine analogues, cladribine and fludarabine, to anthracyclines and ara-C has been associated with improved outcomes in a number of studies.

Cladribine/Fludarabine

Holowiecki et al conducted a randomized phase III trial evaluating the addition of cladribine or fludarabine to DNR/ara-C in younger patients with untreated AML. Six hundred fifty-two patients, with a median age of 47 years (range, 17-60 years), were randomized to receive DNR plus ara-C (DA), DA plus cladribine (DAC), and DA plus fludarabine (DAF). The consolidation regimen was the same for all arms and included two consecutive courses of ara-C (1.5 g/m² intravenously [IV] days 1-3) plus MTZ (10 mg/m² IV days 3-5) and HDAC (2 g/m² IV twice a day on days 1, 3, and5). Overall CR rate was 61%, with 56% achieving a CR after one cycle of induction and 5% after two cycles. The CR rate was higher in the DAC arm compared to the DA arm (62% vs 51%, P = .02). The CR rates were similar in the DA and DAF arms. The median OS was significantly higher in the DAC arm (24 months) compared to the DA arm (14 months, P = .02). There was no significant difference in the median OS between the DAF and DA arms (³¹).

Vorinostat

Vorinostat is an oral histone deacetylase inhibitor that has been shown to have single-agent activity in AML (³²). It was studied in combination with the IDA plus ara-C regimen at MDACC in a phase II trial in the frontline setting in patients with AML or intermediate-2/high-risk MDS. Induction was given as vorinostat 500 mg orally three times a day (days 1-3) along with IDA (12 mg/m² days 4-6) and ara-C (1.5 mg/m² continuous infusion days 4-7). Subsequently, patients achieving a remission could be treated with five cycles of consolidation and up to 12 months of single-agent vorinostat for maintenance. At a median follow-up of 82 weeks, the median OS was 82 weeks (range, 3-134 weeks) and median EFS was 47 weeks (range, 3-134 weeks). There was trend for a longer survival in the FLT3-ITD–mutated patients (91 weeks; range 6-134 weeks). The overall remission rate was 85%, with 76% achieving a CR and 9% achieving a CRp; 25% of the patients went on to undergo an allogeneic SCT in first CR.

Acute myeloid leukemia in older adults (≥60 years) is considered a biologically and clinically distinct entity. The outcomes of older AML patients are poor with the standard anti-AML therapies. The analysis of the Swedish Acute Leukemia Registry (1976-2005) showed that the early death rates in all AML patients, regardless of age, were lower with intensive therapy compared to palliative therapy (³³).

Acute myeloid leukemia in the elderly has adverse biologic features such as higher frequency of stem-cell–like phenotype of leukemic blasts, higher frequency of multilineage involvement with dysplastic features, higher frequency of antecedent hematologic disorders, and higher frequency of MDR-1 gene expression, which leads to higher potential for cytotoxic drug extrusion by the leukemic blasts, causing resistance to chemotherapeutic agents (³⁴). Acute myeloid leukemia in older patients is more frequently associated with poor-risk cytogenetics (up to 50% vs 10%-15% in younger patients) (³⁵). Hence, the majority of elderly AML patients should be considered for investigational clinical trials. Other factors contributing to worse outcome in elderly patients include poor performance status, organ dysfunction, and a higher incidence of an antecedent hematologic disorders. In general, patients with three or more of these factors have expected CR rates of less than 20%, 8-week mortality rates greater than 50%, and 1-year survival rates of less than 10% using conventional regimens. These patients constitute 25% to 30% of elderly patients with AML. Approximately 20% of elderly patients have none or one of these adverse factors and have a reasonable outcome with expected CR rates above 60%, 8-week mortality rates of 10%, and 1-year survival rates of ≥50% (³⁶).

Low-Dose Cytarabine

Low-dose ara-C (LDAC) was superior to hydroxyurea in a randomized trial enrolling 204 elderly patients with AML considered unfit for chemotherapy (³⁷). The CR rates were 15% with LDAC and 1% with hydroxyurea (P = .0003); the 1-year survival rates were 27% versus 3% (P = .0004).

Clofarabine

A randomized phase II study compared clofarabine (30 mg/m² IV × 5 days) versus clofarabine and ara-C (20 mg/m² subcutaneously daily × 14 days) in 70 elderly patients with AML (³⁸). Combination therapy achieved a better CR (63% vs 31%; P = .025) and better EFS (7.1 months vs 1.7 months; P = .04) but did not improve OS (11.4 months vs 5.8 months; P = .1).

Hypomethylating Agents

Kantarjian et al conducted a randomized phase III trial comparing decitabine 20 mg/m² for 10 days with physician's choice in 485 patients (³⁹). This study showed that decitabine improved CR/CRp rates compared with physician's choice (18% vs 8%; P = .001). Decitabine was well tolerated with a good safety profile. The primary analysis showed a nonsignificant improvement in the OS, but an unplanned analysis 2 years later demonstrated an improvement in the OS in the decitabine arm (P = .03) (³⁹). Quintas-Cardama et al showed that patients with newly diagnosed AML who are >65 years old have an ORR of 47% (CR rate, 42%) with intensive chemotherapy and an ORR of 29% (CR rate, 28%) with epigenetic therapy (azacitidine, decitabine) (P ≤ .001) (⁴⁰). The median OS was similar in both the groups (6.5 months; P = .413) (⁴⁰). These studies show that hypomethylating agents have similar survival outcomes in elderly AML patients when compared to intensive chemotherapy.

Recently, the results of the AML-AZA001 trial were presented. Four hundred forty-eight patients ≥65 years old with newly diagnosed de novo or secondary AML who were deemed ineligible for transplant and with intermediate- or poor-risk cytogenetics were enrolled. Patients were randomized to receive either azacitidine or a conventional care regimen. Azacitidine was administered at 75 mg/m²/d for 7 days subcutaneously. A prolongation in the median OS was observed in the azacitidine arm (6.4 months vs 3.2 months; P = .0185). The conventional care regimen included best supportive care in 18%, LDAC in 64%, and intensive chemotherapy in 18% (⁴¹). Several groups have consistently shown a CR rate of 31% to 47% with decitabine 20 mg/m² administered daily for 10 days, with a median OS of 9 to 12 months. However, the associated increased myelosuppression leads to increased rates of hospitalization for infections (⁴²).

Vosaroxin

Vosaroxin is an anticancer quinolone that was shown to have activity in older patients with poor-risk AML in the REVEAL-1 study (⁴³). In this study, patients ≥60 years old with unfavorable-risk AML were treated with single-agent vosaroxin. An ORR of 32% was observed including 29% CR and 32% CR/CRp. The median OS was about 7 months, and the 1-year OS rate was 38% (⁴³). Overall, vosaroxin resulted in low early mortality and an encouraging response rate. Subsequently, a combination of vosaroxin and decitabine was evaluated in older patients with newly diagnosed AML and high-risk MDS. The ORR was 76% (including 59% CR, 14% CRp, and 3% CR with incomplete blood count recovery [CRi]). Interestingly, the response rate in the patients with adverse cytogenetics was 69%. The median OS was 8.3 months, and the median remission duration had not been reached (⁴⁴).

Volasertib

Polo-like kinases (Plks) are serine/threonine protein kinases that play a role in mitotic checkpoint regulation and cell division. The Plk-1 is expressed in dividing cells, and its expression peaks during the G₂/M phase of cell cycle. It has been shown to be overexpressed in AML cells (⁴⁵). Volasertib is a Plk inhibitor that was evaluated in a phase II trial in older patients with AML considered not to be candidates for intensive induction therapy (⁴⁶). Patients were randomized to LDAC 20 mg subcutaneously twice a day for 10 days with or without volasertib 350 mg IV on days 1 to 15 every 4 weeks. Eighty-seven patients with a median age of 76 years (range, 57-86 years) were enrolled. The ORR (CR+CRi) was 13.3% for the LDAC alone arm versus 31% for the LDAC plus volasertib arm (P = .052). The time to response was a median of 63.5 days (range, 30-120 days). Patients received a median of 8 cycles of therapy (range, 2-22 cycles) in the combination arm compared with 7 in the LDAC alone arm (range, 5-11 cycles). At a median follow-up of 28.2 months, the median EFS was 5.6 months in the LDAC plus volasertib arm compared with 2.3 months in the LDAC alone arm (P = .021). The addition of volasertib led to a longer RFS of 18.5 months (vs 10 months) and a longer median OS of 8 months (vs 5.2 months; P = .047). A higher incidence of grade 3 gastrointestinal toxicity, febrile neutropenia, and infections was noted in the combination arm, but there was no difference in early mortality noted between the two arms.

Nonchemotherapy Options

Nonchemotherapy options are also being explored for this subset of patients with AML. Pollyea et al reported the results of upfront combination of azacitidine (75 mg/m² × 7 days) and lenalidomide (escalating doses, starting at day 8 of each cycle, every 6 weeks) in patients ≥60 years old (⁴⁷). They reported an ORR of 40%, with a median time to response of 3 months and median duration of response of 7 months. The median OS was 5 months for all patients (⁴⁷). Wetzler et al evaluated octogenarian patients with AML who had been enrolled in cooperative group trials and concluded that intensive induction (7+3 or similar) is effective therapy, with a 30% CR rate (⁴⁸). In these patients, FLT3-ITD did not impact median OS (10 months; P = .31) in contrast to NPM1 mutations, which were associated with a prolonged median OS (91 months; P = .002) (⁴⁸).

Several groups have proposed predictive models for geriatrics assessment prior to determining what therapy to assign older patients (^49,50). These models look at several prognostic factors, including functional status, cytogenetics, age, and molecular status, to predict mortality and survival with therapy. This suggests that a careful assessment of the patient and disease characteristics is needed before assigning therapy to older patients.

Investigational treatment and palliative care options are more plausible in poorer-prognosis elderly patients, and the patients and their families should be involved in discussions of treatment decisions.

Consolidation Therapy

There is debate as to the best therapy for consolidation following achievement of CR after initial induction therapy. The number of cycles of therapy is also not agreed upon. However, for patients treated with hypomethylating agents, it is recommended that the treatment is continued indefinitely until disease progression, as is the practice for patients with MDS.

FMS-like tyrosine kinase 3 (FLT3) is a member of the class III receptor tyrosine kinase family that plays an important role in the survival, proliferation, and differentiation of hematopoietic progenitor cells. FLT3 is overexpressed in most patients with AML, and activating mutations of FLT3 are among the most prevalent molecular abnormalities in AML, with internal tandem duplication (ITD) occurring in 25% to 35% of patients with normal karyotype (⁵¹). In addition, 5% to 7% of patients may have point mutations within the activation loop of the kinase domain or in the juxtamembrane domain. Patients with FLT3 activating mutations have an inferior outcome with a shorter RFS and OS. In addition, after exposure to FLT3 inhibitors, nearly a quarter of patients with FLT3-ITD develop mutations in the kinase domain as a mechanism of resistance. The major FLT3 inhibitors are summarized in Table 2-6. Table 2-7 lists the FLT3 inhibitors currently under development.

Core-binding factor (CBF) AML is a distinct entity. It is considered a favorable karyotype. It includes patients with a pericentric inversion of chromosome 16 (inversion 16; associated with FAB subtype M4EO) and translocation (16;16) or a translocation between chromosomes 8 and 21 (t[8;21]; associated with FAB subtype M2). Each of these abnormalities disrupts the function of a transcription factor (CBF), regulating the expression of genes important in hematopoietic differentiation. inv(16) and t(16;16) lead to the formation of the CBF-MYH11 fusion gene. t(8;21) leads to the formation of the RUNX1-RUNXT1 fusion gene. The CBF-MYH11– and RUNX1-RUNXT1–related leukemias represent CBF-AML. These leukemias are very sensitive to induction and consolidation and have high response rates. About 10% of unselected patients (typically younger patients) have CBF-AML. At MDACC, all newly diagnosed patients with CBF-AML are treated with fludarabine (30 mg/m²/d on days 1-5) and HDAC (2 g/m²/d on days 1-5) regimens with or without the addition of granulocyte colony-stimulating factor (G-CSF). This is followed by up to six courses of an HDAC-containing regimen. A CR rate of 93% and an EFS of 20 months in 114 newly diagnosed CBF-AML patients were previously reported (⁵²). A frontline regimen of fludarabine, ara-C, and G-CSF (FLAG)-GO was evaluated at MDACC and showed a remission rate of 95% and a 3-year OS and RFS of 78% and 85%, respectively (⁵³). In the UK MRC-AML15 trial, 1,113 patients with AML were randomized to receive or not receive a small dose of GO (3 mg/m²) with their induction therapy. A benefit for adding GO to the induction regimen was seen in patients with CBF-AML (²⁸). In a meta-analysis of five clinical trials wherein addition of GO to induction chemotherapy was evaluated, a significant improvement in OS was noted in patients with favorable- and intermediate-risk cytogenetics (P = .01). The improvement in survival was attributed to reduced relapse (P = .00006) (⁵⁴). All of these studies strongly support the use of FLAG-based regimens for CBF-AML and advocate the addition of GO to the induction to improve survival and RFS in these patients.

Approximately 25% of CBF-AML patients carry a gain-of-function mutation in the KIT gene, which results in a constitutively activated tyrosine kinase. Hence, the CALGB 10801 alliance and a group in Germany are evaluating the addition of a KIT inhibitor, dasatinib, to the standard induction therapy. The initial results showed a 92% CR rate and 1-year DFS and OS rates of 90% and 87%, respectively. Long-term outcomes of this study are awaited (⁵⁵).

The treatment for newly diagnosed AML is summarized in Figs. 2-1 and 2-2.

Although the outcome of patients with AML has improved, relapse remains frequent and constitutes the leading cause of mortality. Breems et al defined a prognostic score for patients with AML in first relapse based on the following variables: (1) relapse-free interval from first CR; (2) cytogenetics at diagnosis; (3) age at first relapse; and (4) SCT before first relapse (⁵⁶). In an analysis of 594 patients who underwent second salvage therapy for relapsed AML at MDACC, 13% achieved CR (median CR duration, 7 months), and 1-year survival was 8% (⁵⁷) (Fig. 2-3).

Allogeneic transplant appears superior to HDAC- or intermediate-dose ara-C–containing regimens in patients with duration of first CR less than 1 year; the great majority of these transplants were from a human leukocyte antigen (HLA)–matched sibling donor (^58,59). However, because few patients are cured with conventional therapy, all patients with relapsed or refractory AML should be treated in clinical trials. Gemtuzumab, a conjugate composed of a humanized anti-CD33 antibody linked to the antitumor antibiotic calicheamicin, was the only approved treatment for relapsed AML in patients older than 60 years of age with the CR1 duration (CRD1) of 3 months or longer. Complete response rates of 30% were reported with this agent. Veno-occlusive disease was observed in 5% to 10% of patients. Gemtuzumab is no longer commercially available.

For relapsed/refractory AML patients, enrollment in a clinic trial remains the first consideration. Recently, results of VALOR, a phase III trial of vosaroxin or placebo with ara-C in patients with refractory AML or in first relapse, were reported (⁶⁰). The vosaroxin and ara-C arm had a higher complete CR rate of 30% (vs 16%; P < 0.0001). The median OS was statistically prolonged in the patients ≥60 years old who received vosaroxin and ara-C (7.1 months vs 5 months; P = 0.003). The 30- and 60-day mortality rates were similar in both arms. These results suggest that the combination of vosaroxin and ara-C could become a new standard for treatment of older patients with refractory or relapsed AML.

High-dose chemotherapy with or without radiation followed by SCT is increasingly used as therapy for AML patients in first CR. In prospective, nonrandomized trials in Europe and the United States, patients younger than age 55 years in first CR with an HLA-matched sibling were assigned to allogeneic transplantation or, if no donor, to autologous transplantation or one further course of HDAC (with DNR in the European study) (Table 2-8) (^61,62,63,64).

In a meta-analysis of 24 prospective clinical trials involving more than 6,000 patients with AML in first CR, Koreth et al showed that allogeneic SCT has significant survival benefit in patients with intermediate- and poor-risk AML but not with good-risk AML (⁶⁵). This finding contrasts with the retrospective review of 999 patients by Ferrant et al that observed similar benefit with allogeneic and autologous transplantation for patients with poor-risk karyotype and a benefit with allogeneic SCT only in patients with good- and intermediate-risk cytogenetics (⁶⁶). However, further stratification of risk groups based on molecular markers within individual karyotypes suggests that only specific subsets of patients may benefit from allogeneic SCT. Schlenk et al demonstrated superior OS with allogeneic SCT compared to intensive chemotherapy in only the following groups of normal karyotype de novo AML patients: (1) FLT3-ITD positive and (2) NPM1/CEBPA/FLT3-ITD negative (⁶⁷). Patients with inversion 16 or t(8;21) do better with chemotherapy (⁶⁸). Patients with AML who are younger than 20 years old have relatively low transplant-related mortality and may do better with allogeneic SCT.

New concepts in both transplantation and chemotherapy have emerged. These include the use of peripheral blood rather than marrow as the source of SCT (⁶⁹), the use of nonmyeloablative regimens to allow engraftment and take advantage of the graft-versus-leukemia effect, and the use of IV busulfan to overcome the erratic pharmacology of the oral form (⁷⁰). In particular, nonmyeloablative regimens (reduced-intensity conditioning or “mini-transplant”) have gained particular traction in elderly patients who have traditionally experienced high treatment-related mortality with conventional myeloablative regimens. The principles of this approach include reduction of regimen-related toxicities and shifting the burden of tumor cell kill from high-dose cytotoxic therapy to graft-versus-leukemia effects. A number of recent studies have reported 2- to 5-year survival rates of 25% to 64% after nonmyeloablative allogeneic SCT for older patients with high-risk MDS and AML. Survival was similar for recipients of related and unrelated HLA-matched grafts. The nonrelapse mortality was 16% to 39%, resulting mainly from complications of graft-versus-host disease and comorbidities preceding SCT. Relapse rates ranged from 16% to 53% and were influenced both by disease burden and cytogenetics at the time of SCT (⁷¹). Further details on this subject are beyond the scope of this chapter.

Adequate and close supportive care is extremely important in the care of acute leukemia. Both G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF) have reduced the median time to neutrophil recovery by an average of 5 to 7 days (⁷²). Antileukemic therapeutic efficacy is not compromised by these agents. Therapy of acute leukemia often results in rapid reduction of elevated WBC counts. This is often associated with the development of tumor lysis, characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, acidosis, and renal failure. Prevention of tumor lysis syndrome requires administration of IV fluids and allopurinol (or rasburicase) if the blast count is above 10 × 10⁹/L. Saline or steroid eye drops daily should be given to patients undergoing HDAC therapy until 24 hours after completion of chemotherapy. In these patients, neurologic assessments for cerebellar neurotoxicity should be performed before each dose of HDAC.

Acute pulmonary failure during induction therapy for AML is a serious complication. Predictive factors identified at diagnosis include male sex, diagnosis of APL, poor ECOG performance status, lung infiltrates at diagnosis, and an increased serum creatinine. Fluid restriction, high-dose steroids, and continuous veno-venous hemofiltration have been shown to be effective strategies in treating acute pulmonary failure.

Infectious complications are a major cause of morbidity and death. Prophylactic administration of antibiotics in the absence of fever is usually offered. The development of fever (>101°F), unrelated to administration of chemotherapy, calls for administration of broad-spectrum antibiotics, such as imipenem or a third- (eg, ceftazidime) or fourth-generation cephalosporin (eg, cefepime). Antibiotic selection should be prompt, individualized, and in accordance with the updated antibiotic susceptibility profile of each institution. If infection persists, G-CSF should be started, and if indicated, granulocyte transfusions, using G-CSF to increase the donors’ granulocyte counts, should be given. Close fluid balance is critical because fluid retention is common, can radiologically mimic pneumonia, and may increase the risk of diffuse alveolar hemorrhage during induction.

Another controversial area is whether adherence to a neutropenic diet (avoidance of fresh fruits and vegetables) during induction chemotherapy decreases the risk of infection. One hundred fifty-three patients with AML diagnosed at MDACC were admitted to a high-efficiency particulate air-filtered room for induction chemotherapy (⁷³). They were randomized to receive a diet containing no raw fruits or vegetables (cooked diet) or to a diet containing fresh fruits and vegetables (raw diet). Twenty-nine percent of patients in the cooked group and 35% of patients in the raw group developed a major infection (P = .60). Time to major infection and survival time were similar in the two groups, thereby suggesting that a neutropenic diet did not prevent major infection or death.

In the new era of molecular prognostication, targeted therapies and immunotherapies are the new kids on the block. FLT3 inhibitors have been discussed earlier in the section on FLT3 AML.

IDH Inhibitors

IDH mutations occur in approximately 20% of AML. The reported frequency is 6% to 16% for IDH1 and 8% to 18% for IDH2 mutations. The majority (85%) occur in patients with diploid or trisomy 8 cytogenetics. The prevalence increases with increasing age, and these mutations are strongly associated with NPM1-positive and MPN-derived AML (21%-31%) (⁷⁴). AG221 is an oral IDH2 inhibitor that has been shown to have the ability to trigger differentiation of leukemic blast cells, leading to objective durable responses, including CRs. At the American Society of Hematology 2014 annual meeting, Stein et al reported response rates of 62% (CR, CRp, CRi, and partial response) in AML patients treated with AG221 in a phase I trial (⁷⁵). The median duration of response was 3 months, noted in 90% of the patients.

Venetoclax (ABT199)

ABT199 (venetoclax) is a selective, oral, BCL-2 inhibitor that was evaluated in a phase II trial at MDACC in relapsed/refractory AML patients unfit for intensive chemotherapy. Thirty-two patients were enrolled, of whom 11 had IDH mutations. An ORR of 19% (CR and marrow CR) was noted, with a suggestion that patients with IDH mutations might benefit more than other patients (⁷⁶).

Immunotherapy with monoclonal antibodies in AML is also an area of interest in the treatment of AML. Newer agents are being developed in this area, and we should have more agents in the arsenal to treat AML in the near future.

Acute promyelocytic leukemia is a distinct subtype of AML accounting for 5% to 15% of cases, with unique clinical, morphologic, and cytogenetic features. It results from a translocation between the retinoic acid receptor α (RARα) locus on chromosome 17 and the promyelocytic leukemia protein (PML) locus located on chromosome 15 (⁷⁷). This PML-RARα fusion is demonstrable in 95% to 100% of cases. Independent risk factors for a diagnosis of APL in a patient with AML are younger age, Hispanic ethnicity, and obesity (²). The main clinical presentation is bleeding diathesis resulting both from plasmin-dependent primary fibrinolysis and DIC (⁷⁸). Cytogenetic analysis detects the distinctive t(15;17). In the rare case where such analysis does not show the t(15;17) but the clinical or morphologic picture is suggestive, molecular test for PML-RARα can be confirmatory. The POD test, an immunohistochemical test that can be performed in few hours, can detect the characteristic disruption of PML in virtually all cases and is a rapid and reliable quick test for APL. Recognition of APL is crucial because appropriate treatment with all-trans-retinoic acid (ATRA) and arsenic trioxide is different than for other types of AML and is curative in most patients (⁷⁹). A stratification system has been developed that distinguishes newly diagnosed patients with APL as low, intermediate, or high risk. Low-risk patients present with WBC count less than 10 × 10⁹/L and platelet count above 40 × 10⁹/L; a WBC count above 10 × 10⁹/L identifies high-risk patients. Others are at intermediate risk. Anticipated cure rates are close to 100%, 90%, and 70% in low-, intermediate-, and high-risk patients, respectively (⁸⁰) (Table 2-9).

Several findings have contributed recently to the increased cure rates in APL. Anthracyclines were historically the first effective treatment, inducing a cure rate of 30% to 40% in APL. The role of ara-C is questionable and probably beneficial only in the setting of suboptimal anthracycline therapy. Addition of ATRA 45 mg/m² twice daily to chemotherapy (eg, IDA 12 mg/m² on days 2, 4, 6, and 8) increases CR rate and, more dramatically, increases the cure rate from 40% to 70%. The major toxicity of ATRA is a potentially fatal APL differentiation syndrome characterized by fever and leakage of fluid into the extravascular space producing fluid retention, effusions, dyspnea, and hypotension; it is effectively treated with dexamethasone (10 mg IV twice a day for 3-5 days, with a rapid taper) (⁸¹). A molecular test (PML-RARAα fusion transcript by PCR) that detects molecular evidence of the t(15;17) provides a relatively sensitive and highly specific means to document minimal residual disease negativity and detect impending relapse (⁸²).

Once a diagnosis of APL is suspected, it is imperative that the patient be given ATRA, even before the diagnosis is confirmed. All-trans-retinoic acid is given at a dose of 45 mg/m²/d in divided doses. It serves to prevent coagulopathy and start induction therapy (⁸³).

Arsenic trioxide (ATO) was shown to be at least noninferior, and possibly superior, to ATRA and chemotherapy in low-/intermediate-risk APL. In the Italian-German APL 0406 trial, Lo-Coco et al showed that the CR rate was 100% in the ATRA+ATO arm versus 95% in the ATRA plus chemotherapy (IDA) arm, with a superior OS of 98.7% versus 91.1% (P = .02) (⁸⁴).

The regimens generally used for treatment of APL, according to risk category, are summarized in Tables 2-10, 2-11, and 2-12.

Ravandi et al evaluated outcomes of newly diagnosed APL patients treated with ATRA and ATO with or without GO without traditional cytotoxic chemotherapy (⁸⁵). The regimen is summarized in Table 2-13. They reported CR rates of 95% and 81%, respectively, for low-risk and high-risk patients. The estimated 3-year survival rate was 85%.

Hence, in the modern era of APL treatment, it is possible to have long-term cure for APL without the use of conventional chemotherapy, which is a tremendous achievement for modern-day oncology.

Minimal residual disease (MRD) is defined as any measurable disease detectable above a certain level of detection, depending on the methodology applied. Minimal residual disease predicts a failure to maintain CR, and its detection is critical to assess the quality of response after induction therapy and to outline postremission therapy based on the individual risk of relapse. As mentioned in the section on APL, the detection of PML-RARAα fusion transcript after achieving CR and its subsequent monitoring to detect early relapse has become the standard of care for patients with APL. Detection of MRD in non-APL AML is an upcoming field where guidelines and standard of care need to be defined. Several methods are being assessed to determine the best method for detection of MRD in patients with AML. There are several issues with the detection of MRD, including lack of a standardized methodology to measure MRD, inconsistency in MRD thresholds, and uncertainty of the ideal time for evaluation of MRD.

Konopleva et al reported that in patients with newly diagnosed AML who have abnormal cytogenetics at presentation, determination of cytogenetics in the marrow at day 21 of induction chemotherapy predicts RFS independent of the number of blasts (⁸⁶). Chen et al from MDACC demonstrated that persistence of cytogenetic abnormalities at the time of morphologic CR portends a worse outcome (⁸⁷). They looked at patients with abnormal cytogenetics at time of diagnosis who achieved a morphologic CR after induction. Twenty-eight percent of patients in CR had abnormal karyotype (ACCR) and the remaining 72% had normal cytogenetic CR (NCCR). Patients with ACCR had a shorted RFS and OS compared to patients with NCCR (6 months vs 21 months; P < .001; and 11 months vs 46 months; P < .001, respectively). The RFS and OS for patients with unfavorable cytogenetics at diagnosis who were NCCR were similar to those in patients with favorable/intermediate risk at diagnosis who were ACCR. The ACCR patients who underwent an allogeneic SCT had a significantly longer 3-year RFS (33% vs 9%; P = .04) and a 3-year OS (33% vs 8%; P = .06) than the patients who did not undergo an SCT. Interestingly, the RFS and OS achieved by patients with ACCR, who underwent an allogeneic SCT, was similar to the NCCR patients who did not undergo an SCT. This suggests a role for individualizing AML therapy based on cytogenetic MRD status.

Another method of quantitative detection of MRD in AML is real-time PCR (RT-PCR) (Table 2-14). Real-time PCR rapidly quantifies PCR products by reverse transcriptase fluorescent signals during exponential amplification. The sensitivity of molecular detection of fusion transcripts ranges from 1 leukemic cell in 1,000 to 100,000 normal cells, that is, 0.1% to 0.001% The fusion transcripts most extensively used to monitor MRD in AML (in addition to PML-RARα for APL) are AML1-ETO, CBFβ-MYH11, and MLL-AF9, which are present in approximately one-third of non-APL AML cases (⁸⁸). Various mutations, such as FLT3, NPM1, and c-KIT, can also be assessed by RT-PCR to determine the residual disease status. Polymerase chain reaction analysis of NPM1 mutations after therapy is prognostic and can be used to predict relapse. NPM1 mutations are present in 30% of all AML patients and in 50% of patients with normal-karyotype AML. Chou et al looked at the role of MRD analysis of NPM1 mutations by PCR and the impact on outcomes (⁸⁹). One hundred ninety-four samples from 38 patients with de novo AML and NPM1 mutations were analyzed over 10 years. The samples were taken 1 month after induction and 3 months after consolidation. Any rise in the mutant signals during follow-up was associated with a 3.2 times increased risk of relapse. Of the relapsed patients, the rise in the mutation levels predicted a relapse at a median of 4.9 months (range, 1-12.3 months) prior to a clinical relapse being seen. This analysis also showed that the degree of reduction in mutation levels affects outcomes and that there is a co-relation between MRD after consolidation and OS and RFS (but not after induction). The Wilms tumor 1 gene (WT1) is highly expressed in most acute leukemias, and its detection in bone marrow has been associated with the presence, persistence, or relapse of leukemia. Recently, investigators from Turin, Italy, systematically applied their best-performing WT1 RT-PCR assay on 620 patient samples and demonstrated that application of a standardized WT1 assay can indeed provide independent prognostic information in AML (⁹⁰). Studies are ongoing to further elucidate the role of the WT1 gene assay to risk stratify patients who might benefit from intensification of therapy to improve outcomes.

Leukemic cells express abnormal patterns of cellular markers, and these aberrant immunophenotypes can be identified by multiparameter flow cytometry. To yield a sensitivity of 0.01% (10⁻⁴), at least 200,000 cells are needed per tube (at least 200,000 events are required to detect 20 aberrant blasts), and three to four tubes are run per patient; 0.1% is the commonly used threshold in most studies in the literature. An advantage of flow cytometry–based studies of MRD is that they can accurately quantify residual leukemic cells and can also distinguish aberrant blasts from normal myeloid precursors. An immunophenotypic fingerprint of the AML can be established for MRD analysis for follow-up. However, there are several advantages and disadvantages with this technique (Table 2-15).

Rubnitz et al reported outcomes with MRD-directed therapy in childhood AML (⁹¹). In this study, patients were randomized to receive HDAC-based induction versus LDAC-based induction. Minimal residual disease levels, on day 22 after induction, were used to allocate GO to determine the timing of the second induction. Minimal residual disease was determined, and GO was given to patients with poor early response, and high-risk patients were allocated to allogeneic SCT. This study showed that MRD was no different with high-dose chemotherapy versus low-dose chemotherapy at day 22 of induction 1. Minimal residual disease >1% on day 22 was a significant prognostic factor influencing OS and EFS in the high-risk patients but not in the standard-/favorable-risk patients. Patients with low-level MRD (0.1% to <1%) did as well as the MRD-negative cohort. An Italian group analyzed the outcomes of adult AML patients based on MRD levels after induction and consolidation and reported that the MRD status at the end of consolidation was the most important predictor of prognosis. In the MRD-positive group, patients who underwent an allogeneic SCT had improved outcomes (⁹²).

In general, a lack of standardization among different laboratories, identification of thresholds, and time points during follow-up represent the major subjects of controversy for the routine implementation of MRD detection in non-APL AML at this time.

After a period of paucity in discoveries, new strategies are finally evolving that may help patients with AML. The biology of the disease is now better understood. Patients with CBF-AML have a high cure rate with HDAC. Patients with APL have benefited from newer treatment with ATRA and arsenical derivatives. Better definition of the complex process initiating and sustaining the leukemic process will lead to a better definition of targets for therapeutic intervention that may translate into improved cure rates. Specific attention must be given to prognostic factors that identify subsets of AML in which specific tailored therapies will be helpful.