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Acute myeloid leukemia (AML) is a neoplasm characterized by infiltration of the blood, bone marrow, and other tissues by proliferative, clonal, poorly differentiated cells of the hematopoietic system. These leukemias comprise a spectrum of malignancies that, untreated, are uniformly fatal. In 2016, the estimated number of new AML cases in the United States was 19,950, comprising ~1.2% of all cancer cases. AML is the most common acute leukemia in older patients, with a median age at diagnosis of 67 years. Long-term survival is infrequent; U.S. registry data report that only 27% of patients survive 5 years.
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Most cases of AML are idiopathic. Genetic predisposition, radiation, chemical/other occupational exposures, and drugs have been implicated in the development of AML, but AML cases with established etiology are relatively rare. No direct evidence suggests a viral etiology. Genome sequencing studies suggest that most cases of AML arise from a limited number of mutations that accumulate with advancing age. Indeed, genome sequencing is providing paradigm-shifting advances in our understanding of leukemogenesis. The Cancer Genome Atlas (TCGA) and other databases demonstrate that blood cells from up to 5–6% of normal individuals aged >70 years contain potentially “premalignant” mutations that are associated with clonal expansion. The additional insults that subsequently direct “premalignant” blood cells to leukemia are quite heterogeneous and still poorly understood.
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Genetic Predisposition
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Myeloid neoplasms typically occur sporadically in adults; inherited predisposition is rare. Yet, it is clear that myeloid neoplasms with germline predisposition represent an important and growing subset of disease. Germline mutations associated with increased risk of developing a myeloid neoplasm include CEBPA, DDX41, RUNX1, ANKRD26, ETV6, and GATA2 (Table 100-1). Likewise, myeloid neoplasms with germline predisposition are a feature of several well-described clinical syndromes, including bone marrow failure disorders (e.g., Fanconi anemia, Shwachman-Diamond syndrome, Diamond-Blackfan anemia), and telomere biology disorders (e.g., dyskeratosis congenita). As new mutations and associations are added to a rapidly growing list, it is increasingly clear that genetic predisposition plays a larger role than has been previously understood.
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Several genetic syndromes with somatic cell chromosome aneuploidy, such as Down syndrome with trisomy 21, are associated with an increased incidence of AML. Down syndrome–associated AML in young children (<4 years) is typically of the acute megakaryocytic subtype and is associated with mutation in the GATA1 gene. Such patients have excellent clinical outcomes but require dose modification of chemotherapy due to high treatment-related toxicities. Inherited diseases with defective DNA repair (e.g., Fanconi anemia, Bloom syndrome, and ataxia-telangiectasia) are also associated with AML. Each syndrome is associated with unique clinical features and atypical toxicities with chemotherapy, requiring expert care. Congenital neutropenia (Kostmann syndrome), due to mutations in the genes encoding the granulocyte colony-stimulating factor receptor and neutrophil elastase, is another disorder that may evolve into AML.
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Chemical, Radiation, and Other Exposures
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Anticancer drugs are the leading cause of therapy-associated AML. Alkylating agent–associated leukemias occur on average 4–6 years after exposure, and affected individuals often have multilineage dysplasia and monosomy/aberrations in chromosomes 5 and 7. Topoisomerase II inhibitor–associated leukemias occur 1–3 years after exposure, and affected individuals often have AML with monocytic features and aberrations involving chromosome 11q23. Exposure to ionizing radiation, benzene, chloramphenicol, phenylbutazone, and other drugs can uncommonly result in bone marrow failure that may evolve into AML.
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The current categorization of AML uses the World Health Organization (WHO) classification (Table 100-2), which defines biologically distinct groups based on cytogenetic and molecular abnormalities in addition to clinical features and light microscope morphology. Myeloid neoplasms with germline predisposition, as introduced above, are included as a new and important feature of this classification (Table 100-1). The WHO classification enables the identification of subsets of disease that may now (or in the future) be treated differently and advances the care of AML patients by enhancing recognition of the molecular basis of the disease from the time of diagnosis. Marrow (or blood) blast count of ≥20% is required to establish the diagnosis of AML, except for AML with the recurrent genetic abnormalities t(15;17), t(8;21), inv(16), or t(16;16).
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Even with advances in molecular biology, recognizing clinical features remains important in understanding AML. For example, therapy-related AML is a distinct entity that develops following prior chemotherapy (e.g., alkylating agents, topoisomerase II inhibitors) or ionizing radiation. AML with myelodysplasia-related changes is recognized based in part on morphology but also on a medical history of an antecedent myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm. These clinical features contribute to AML prognosis and have therefore been included in the WHO classification.
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Subtypes of AML are recognized based on the presence or absence of specific, recurrent cytogenetic, and/or genetic abnormalities. For example, the diagnosis of acute promyelocytic leukemia (APL) is based on the presence of either the t(15;17)(q22;q12) cytogenetic rearrangement or the PML-RARA fusion product of the translocation. Similarly, core binding factor (CBF) AML is designated based on the presence of t(8;21)(q22;q22), inv(16)(p13.1q22), or t(16;16)(p13.1;q22) or the respective fusion products RUNX1-RUNX1T1 and CBFB-MYH11. Each of these groups identifies patients with favorable clinical outcomes when appropriately treated.
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Several cytogenetic or genetic AML subtypes often associate with a specific morphologic appearance, such as a complex karyotype and AML with myelodysplasia-related changes. Patients with such changes typically fare poorly with standard treatments. However, only one cytogenetic abnormality is invariably associated with specific morphologic features: t(15;17)(q22;q12) with APL. Other cytogenetic and genetic findings may be commonly but not invariably associated with a morphological description, highlighting the necessity of genetic and cytogenetic testing beyond simple morphology to most accurately diagnose AML. Several chromosomal abnormalities often associate primarily with one morphologic/immunophenotypic group. Examples include inv(16)(p13.1q22) with AML with abnormal bone marrow eosinophils; t(8;21)(q22;q22) with slender Auer rods, expression of CD19, and increased normal eosinophils; and t(9;11)(p22;q23), and other translocations involving 11q23, with monocytic features. Recurring chromosomal abnormalities in AML may also be loosely associated with specific clinical characteristics. More commonly associated with younger age are t(8;21) and t(15;17), and with older age, del(5q) and del(7q). Myeloid sarcomas are associated with t(8;21); disseminated intravascular coagulation (DIC) is associated with t(15;17). 11q23 aberrations and monocytic leukemia are associated with extramedullary sites of involvement at presentation, especially gingival hypertrophy.
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The WHO classification also incorporates molecular abnormalities by recognizing fusion genes or specific genetic mutations with a role in leukemogenesis. As a classic example, t(15;17) results in the fusion gene PML-RARA that encodes a chimeric protein, promyelocytic leukemia (Pml)–retinoic acid receptor α (Rarα), which is formed by the fusion of the retinoic acid receptor α (RARA) gene from chromosome 17 and the promyelocytic leukemia (PML) gene from chromosome 15. The RARA gene encodes a member of the nuclear hormone receptor family of transcription factors. PML is important in many cellular processes, including cell growth control, apoptosis, and senescence; its effects are mediated at least in part by nuclear bodies that store a myriad of proteins/enzymes that are involved in these functions. The PML-RARA fusion protein suppresses gene transcription and blocks differentiation beyond the promyelocyte stage. Pharmacologic concentrations of the Rarα ligand, achieved with the drug all-trans-retinoic acid (tretinoin, ATRA), relieve the block and promote hematopoietic cell differentiation. However, the effects of ATRA are not primarily from direct restoration of gene transactivation via RA signaling. Rather, drug treatment induces degradation of the fusion protein. Mechanistic work has demonstrated that the RARA fusion partner PML is far more important in the pathobiology than was initially understood. PML-RARA disturbs nuclear body assembly. This impairs many PML functions, culminating in enhanced self-renewal of leukemic cells. ATRA and arsenic trioxide (ATO) both induce PML-RARA degradation (by different mechanisms), leading to reformation of PML nuclear bodies (or enhanced nuclear body activity). Restored PML functions include the activation of p53 which triggers senescence in leukemic cells. Clinical therapy with ATRA and ATO has revolutionized the care of APL patients (see “Treatment of Acute Promyelocytic Leukemia” section).
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Similar examples of molecular subtypes included in the category of AML with recurrent genetic abnormalities are those characterized by the leukemogenic fusion genes RUNX1-RUNX1T1, CBFB-MYH11, MLLT3-KMT2A, and DEK-NUP214, resulting, respectively, from t(8;21), inv(16) or t(16;16), t(9;11), and t(6;9)(p23;q34).
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The WHO classification of AML continues to expand as knowledge of specific genetic or cytogenetic aberrations grows. Several AML subtypes are defined by the presence of genetic mutations rather than chromosomal aberrations including, for example, AML with mutated nucleophosmin (nucleolar phosphoprotein B23, numatrin) (NPM1) and AML with biallelic mutated CEBPA, respectively. Both entities are associated with more favorable clinical outcomes, though the NPM1 prognostic impact is affected by coexisting mutation in fms-related tyrosine kinase 3 (FLT3). Activating mutations of FLT3 are present in ~30% of adult AML patients, primarily due to internal tandem duplications (ITD) in the juxtamembrane domain that have negative prognostic impact. In contrast, point mutations of the activating loop of the kinase (called tyrosine kinase domain [TKD] mutations) have uncertain prognostic impact. Aberrant activation of the FLT3-encoded protein provides increased proliferation and antiapoptotic signals to the myeloid progenitor cell. FLT3-ITD, the more common of the FLT3 mutations, occurs preferentially in patients with cytogenetically normal AML (CN-AML). The importance of identifying FLT3-ITD at diagnosis relates to the fact that is it useful not only as a prognosticator but also may predict response to specific treatment such as a tyrosine kinase inhibitor (TKI); several TKI are currently in clinical investigation (e.g., midostaurin, quizartinib, gilteritinib, crenolanib, sorafenib). The FLT3 allelic ratio (of the number of mutated alleles to wild type alleles) provides information beyond the mere presence or absence of the mutation. The ratio is affected by several mutational scenarios such as one mutated gene and one wild type gene, or one mutated gene with no (deleted) wild type gene, and the ratio of malignant to nonmalignant cells in the sample. The allelic ratio affects the prognostic impact of the FLT3-ITD mutation; patients with FLT3-ITD “low” allelic ratio (<0.5) fare better. Accordingly, mutated NPM1 without FLT3-ITD or with FLT3-ITDlow are both viewed as favorable-risk by the European LeukemiaNet (ELN) risk stratification schema (Table 100-3). Conversely, FLT3-ITDhigh is known to have an adverse prognostic impact; patients with mutated NPM1 and FLT3-ITD with an allelic ratio >0.5 are thus intermediate-risk by ELN stratification. Involving a different tyrosine kinase, AML with BCR-ABL1 fusion is a new WHO provisional entity, to recognize rare cases that may benefit from BCR-ABL TKI therapy (Table 100-2).
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Immunophenotypic Findings
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The immunophenotype of human leukemia cells can be studied by multiparameter flow cytometry after the cells are labeled with monoclonal antibodies to cell-surface antigens. This can be important in quickly distinguishing AML from acute lymphoblastic leukemia and for identifying some subtypes of AML. For example, AML with minimal differentiation, characterized by immature morphology and no lineage-specific cytochemical reactions, may be diagnosed by flow-cytometric demonstration of the myeloid-specific antigens cluster designation (CD) 13 and/or 117. Similarly, acute megakaryoblastic leukemia can often be diagnosed only by expression of the platelet-specific antigens CD41 and/or CD61. Although flow cytometry is widely used, and in some cases essential for the diagnosis of AML, it has only a supportive role in establishing the different subtypes of AML through the WHO classification. Increasingly, multiparameter flow cytometry is used for the measurement of minimal residual disease (MRD) after remission is achieved.
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Several factors predict outcome of AML patients treated with chemotherapy; they should be used for risk stratification and treatment guidance.
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Chromosome findings at diagnosis currently provide the most important independent prognostic information. Several reports have categorized patients as having favorable, intermediate, or adverse cytogenetic risk based on the presence of structural and/or numerical aberrations. Patients with t(15;17) have a very good prognosis (~85% cured), and those with t(8;21) and inv(16) have a good prognosis (~55% cured), whereas those with no cytogenetic abnormality have an intermediate outcome risk (~40% cured). Patients with a complex karyotype, t(6;9), inv(3), or –7 have a very poor prognosis. Another cytogenetic subgroup, the monosomal karyotype, has been suggested to adversely impact the outcome of AML patients other than those with t(15;17), t(8;21), or inv(16) or t(16;16). The monosomal karyotype subgroup is defined by the presence of at least two autosomal monosomies (loss of chromosomes other than Y or X) or a single autosomal monosomy with additional structural abnormalities.
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For patients lacking prognostic cytogenetic abnormalities, such as those with CN-AML, testing for several mutated genes can help to risk-stratify. In addition to the NPM1 mutation and/or FLT3-ITD as described above, biallelic CEBPA mutations have prognostic value. Such mutations predict favorable outcome. Given the proven prognostic importance of NPM1, CEBPA, and FLT3, molecular assessment of these genes at diagnosis has been incorporated into AML management guidelines by the National Comprehensive Cancer Network (NCCN) and the ELN. The same markers help to define genetic groups in the ELN standardized reporting system, which is based on both cytogenetic and molecular abnormalities and is used for comparing clinical features/treatment response among subsets of patients reported across different clinical studies (Table 100-3). These genetic groups should be used for risk stratification and treatment guidance.
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In addition to NPM1 and CEBPA mutations and FLT3-ITD, molecular aberrations in other genes may be routinely used for prognostication in the future (Table 100-4). Among these mutated genes are those encoding receptor tyrosine kinases (e.g., v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog [KIT]), transcription factors (i.e., RUNX1 and Wilms tumor 1 [WT1]), and epigenetic modifiers (i.e., additional sex combs like transcriptional regulator 1 [ASXL1], DNA (cytosine-5-)-methyltransferase 3 alpha [DNMT3A], isocitrate dehydrogenase 1 [NADP+], soluble [IDH1], isocitrate dehydrogenase 2 (NADP+), mitochondrial [IDH2], lysine (K)–specific methyltransferase 2A [KMT2A, also known as MLL], and tet methylcytosine dioxygenase 2 [TET2]). Although KIT mutations are almost exclusively present in CBF AML and impact adversely the outcome, the remaining markers have been reported primarily in CN-AML. These gene mutations have been shown to be associated with outcome in multivariable analyses independent of other prognostic factors. However, for some of them, data remain unclear on the prognostic impact due to conflicting reports (e.g., TET2, IDH1, IDH2). Increasingly, novel drugs that inhibit/modulate aberrant pathways activated by some of these genes (e.g., IDH1, IDH2, KMT2A, among others) are being incorporated into clinical trials to treat AML.
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In addition to gene mutations, deregulation of the expression levels of coding genes and of short noncoding RNAs (microRNAs) also provide prognostic information (Table 100-4). Overexpression of genes such as brain and acute leukemia, cytoplasmic (BAALC), v-ets avian erythroblastosis virus E26 oncogene homologue (avian) (ERG), meningioma (disrupted in balanced translocation) 1 (MN1), and MDS1 and EVI1 complex locus (MECOM, also known as EVI1) predict poor outcome, especially in CN-AML. Similarly, deregulated expression levels of microRNAs, naturally occurring noncoding RNAs that regulate the expression of proteins via degradation or translational inhibition of their target coding RNAs, have also been associated with prognosis in AML. Overexpression of miR-155 and miR-3151 predicts unfavorable outcome in CN-AML, whereas overexpression of miR-181a predicts favorable outcome both in CN-AML and cytogenetically abnormal AML.
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Because prognostic molecular markers in AML are not mutually exclusive and often occur concurrently (>80% patients have at least two or more prognostic gene mutations), the likelihood that distinct marker combinations may be more informative than single markers is increasingly clear.
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Epigenetic changes (e.g., DNA methylation and/or post-translational histone modification) and microRNAs are often involved in deregulation of genes involved in hematopoiesis, contribute to leukemogenesis and may associate with the previously discussed prognostic gene mutations. These changes have been shown to provide biologic insights into leukemogenic mechanisms and also independent prognostic information. Indeed, it is anticipated that with the enormous progress made in DNA and RNA sequencing technology, additional genetic and epigenetic aberrations will soon be discovered, further improving classification and risk-stratification in AML patients.
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In addition to cytogenetics and molecular aberrations, several other factors are associated with outcome in AML. Age at diagnosis is one of the most important risk factors. Advancing age is associated with a poor prognosis for two reasons: (1) its influence on the ability to survive induction therapy due to coexisting medical comorbidities, and (2) with each successive decade of age, a greater proportion of patients have intrinsically more resistant disease. A prolonged symptomatic interval with cytopenias preceding AML diagnosis, or a history of antecedent hematologic disorders including MDS or myeloproliferative neoplasms, is often found in older patients. Cytopenia is a clinical feature associated with a lower complete remission (CR) rate and shorter survival time. The CR rate is lower in patients who have had anemia, leukopenia, and/or thrombocytopenia for >3 months before the diagnosis of AML, when compared to those without such a history. Responsiveness to chemotherapy declines as the duration of the antecedent disorder increases. Likewise, AML developing after treatment with cytotoxic agents for other malignancies is usually difficult to treat successfully. In addition, older patients less frequently harbor favorable cytogenetic abnormalities (i.e., t[8;21], inv[16], and t[16;16]) and more frequently harbor adverse cytogenetic (e.g., complex and monosomal karyotypes) and/or molecular (e.g., ASXL1, p53) abnormalities.
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Other factors independently associated with worse outcome are a poor performance status that influences ability to survive induction therapy and a high presenting leukocyte count that in some series is an adverse prognostic factor for attaining a CR. Among patients with hyperleukocytosis (>100,000/μL), early central nervous system bleeding and pulmonary leukostasis contribute to poor outcomes.
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Following administration of therapy, achievement of CR is associated with better outcome and longer survival. CR is defined after examination of both blood and bone marrow and essentially represents both eradication of detectable leukemia and restoration of normal hematopoiesis. The blood neutrophil count must be ≥1000/μL and the platelet count ≥100,000/μL. Hemoglobin concentration is not considered in determining CR. Circulating blasts should be absent. Although rare blasts may be detected in the blood during marrow regeneration, they should disappear on successive studies. At CR, the bone marrow should contain <5% blasts, and Auer rods should be absent. Extramedullary leukemia should not be present.
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CLINICAL PRESENTATION
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Patients with AML usually present with nonspecific symptoms that begin gradually, or abruptly, and are the consequence of anemia, leukocytosis, leukopenia/leukocyte dysfunction, or thrombocytopenia. Nearly half have symptoms for ≤3 months before the leukemia is diagnosed.
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Fatigue is a frequent first symptom among AML patients. Anorexia and weight loss are common. Fever with or without an identifiable infection is the initial symptom in ~10% of patients. Signs of abnormal hemostasis (bleeding, easy bruising) are common. Bone pain, lymphadenopathy, nonspecific cough, headache, or diaphoresis may also occur.
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Rarely, patients may present with symptoms from a myeloid sarcoma (a tumor mass consisting of myeloid blasts occurring at anatomic sites other than bone marrow). Sites involved are most commonly the skin, lymph node, gastrointestinal tract, soft tissue, and testis. This rare presentation, often characterized by chromosome aberrations (e.g., monosomy 7, trisomy 8, 11q23 rearrangement, inv[16], trisomy 4, t[8;21]), may precede or coincide with blood and/or marrow involvement by AML. Patients who present with isolated myeloid sarcoma typically develop blood and/or marrow involvement quickly thereafter and cannot be cured with local therapy (radiation or surgery) alone.
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Fever, infection, and hemorrhage are often found at the time of diagnosis; splenomegaly, hepatomegaly, lymphadenopathy, and “bone pain” may also be present less commonly. Hemorrhagic complications are most commonly and, classically, found in APL. APL patients often present with DIC-associated minor hemorrhage but may have significant gastrointestinal bleeding, intrapulmonary hemorrhage, or intracranial hemorrhage. Likewise, thrombosis is another less frequent but well recognized clinical feature of DIC in APL. Bleeding associated with coagulopathy may also occur in monocytic AML and with extreme degrees of leukocytosis or thrombocytopenia in other morphologic subtypes. Retinal hemorrhages are detected in 15% of patients. Infiltration of the gingiva, skin, soft tissues, or meninges with leukemic blasts at diagnosis is characteristic of the monocytic subtypes and those with 11q23 chromosomal abnormalities.
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Anemia is usually present at diagnosis though it is not typically severe. The anemia is usually normocytic normochromic. Decreased erythropoiesis in the setting of AML often results in a reduced reticulocyte count, and red blood cell (RBC) survival is decreased by accelerated destruction. Active blood loss may rarely contribute to the anemia.
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The median presenting leukocyte count is ~15,000/μL. Lower presenting leukocyte counts are more typical of older patients and those with antecedent hematologic disorders. Between 25 and 40% of patients have counts <5000/μL, and 20% have counts >100,000/μL. Fewer than 5% have no detectable leukemic cells in the blood. In AML, the cytoplasm often contains primary (nonspecific) granules, and the nucleus shows fine, lacy chromatin with one or more nucleoli characteristic of immature cells. Abnormal rod-shaped granules called Auer rods are not uniformly present, but when they are, AML is virtually certain (Fig. 100-1).
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Platelet counts <100,000/μL are found at diagnosis in ~75% of patients, and ~25% have counts <25,000/μL. Both morphologic and functional platelet abnormalities can be observed, including large and bizarre shapes with abnormal granulation and inability of platelets to aggregate or adhere normally to one another.
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Pretreatment Evaluation
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Once the diagnosis of AML is suspected, thorough evaluation and initiation of appropriate therapy should follow. In addition to clarifying the subtype of leukemia, initial studies should evaluate the overall functional integrity of the major organ systems, including the cardiovascular, pulmonary, hepatic, and renal systems (Table 100-5). Factors that have prognostic significance, either for achieving CR or for predicting CR duration, should also be assessed before initiating treatment, including cytogenetics and molecular markers. Leukemic cells should be obtained from all patients and cryopreserved for future investigational testing as well as potential future use as new diagnostics and therapeutics become available. All patients should be evaluated for infection.
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Most patients are anemic and thrombocytopenic at presentation. Replacement of the appropriate blood components, if necessary, should begin promptly. Because qualitative platelet dysfunction or the presence of an infection may increase the likelihood of bleeding, evidence of hemorrhage justifies the immediate use of platelet transfusion, even if the platelet count is only moderately decreased.
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About 50% of patients have a mild to moderate elevation of serum uric acid at presentation. Only 10% have marked elevations, but renal precipitation of uric acid and the nephropathy that may result is a serious but uncommon complication. The initiation of chemotherapy may aggravate hyperuricemia, and patients are usually started immediately on allopurinol and hydration at diagnosis. Rasburicase (recombinant uric oxidase) is also useful for treating uric acid nephropathy and often can normalize the serum uric acid level within hours with a single dose of treatment, although its expense suggests that limiting its use to patients with severe hyperuricemia and/or kidney injury may be prudent. The presence of high concentrations of lysozyme, a marker for monocytic differentiation, may be etiologic in renal tubular dysfunction for a minority of patients.
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TREATMENT Acute Myeloid Leukemia
Treatment of the newly diagnosed patient with AML is usually divided into two phases, induction and postremission management (consolidation) (Fig. 100-2). The initial goal is to induce CR. Once CR is obtained, further therapy must be given to prolong survival and achieve cure. The initial induction treatment and subsequent postremission therapy are chosen based on the patient’s age, overall fitness, and cytogenetic/molecular risk. Intensive therapy with cytarabine and anthracyclines in younger patients (<60 years) increases the cure rate of AML. In older patients, the benefit of intensive therapy is controversial in all but favorable-risk patients; novel approaches for selecting patients predicted to be responsive to treatment and new therapies are being pursued.
INDUCTION CHEMOTHERAPY The most commonly used induction regimens (for patients other than those with APL) consist of combination chemotherapy with cytarabine and an anthracycline (e.g., daunorubicin, idarubicin). Cytarabine is a cell cycle S-phase–specific antimetabolite that becomes phosphorylated intracellularly to an active triphosphate form that interferes with DNA synthesis. Anthracyclines are DNA intercalators. Their primary mode of action is thought to be inhibition of topoisomerase II, leading to DNA breaks.
In adults, cytarabine used at standard dose (100–200 mg/m2) is administered as a continuous intravenous infusion for 7 days. With cytarabine, anthracycline therapy generally consists of daunorubicin (60–90 mg/m2) or idarubicin (12 mg/m2) intravenously on days 1, 2, and 3 (the 7 and 3 regimen). Other agents can be added (e.g., cladribine) when 60 mg/m2 of daunorubicin is used. With the 7 and 3 regimen, it is now clearly established that 45 mg/m2 dosing of daunorubicin results in inferior outcomes; patients should receive higher doses as described. Patients failing remission after one induction are offered reinduction with the same (or slightly modified) therapy.
In older patients (age ≥60–65 years), the outcome is generally poor due to a higher frequency of resistant disease and increased rate of treatment-related mortality. This is especially true in patients with prior hematologic disorders (MDS or myeloproliferative neoplasms), therapy-related AML, or cytogenetic and genetic abnormalities that adversely impact on clinical outcome. All older patients should be considered for clinical trials, but in particular older patients in the adverse-risk groups delineated above should be offered investigational approaches when possible. Conventional therapy for older patients is similar to that for younger: the 7 and 3 regimen with standard-dose cytarabine and idarubicin (12 mg/m2), or daunorubicin (60 mg/m2, or 90 mg/m2 for those <65 years). For patients aged >65 years, high-dose daunorubicin (90 mg/m2) has increased toxicity and is not recommended. Older patients and those with adverse-risk genetics may receive lower intensity therapy with a hypomethylating agent (decitabine or azacitidine), clofarabine, or preferably investigational therapy (Table 100-6).
With the 7 and 3 regimen, 60–80% of younger and 33–60% of older patients (among those who are candidates for intensive therapy) with primary AML achieve CR. Of patients who do not achieve CR, most have drug-resistant leukemia, although induction death is more frequent with advancing age and medical comorbidity. Patients with refractory disease after induction should be considered for salvage treatments, preferentially on clinical trials, before receiving allogeneic hematopoietic stem cell transplantation (HCT) that is usually reserved for patients in or near CR. However, fit younger patients with primary refractory disease have ~15–20% cure rates with allogeneic HCT (after myeloablative conditioning); for this reason early consideration of future allogeneic HCT feasibility (including HLA typing, donor search, etc.) should be part of the initial induction approach for most AML patients.
POSTREMISSION THERAPY Induction of a durable first CR (CR1) is critical to long-term survival in AML. However, without further therapy virtually all patients relapse. Thus, postremission therapy is designed to eradicate residual (typically undetectable) leukemic cells to prevent relapse and prolong survival. As for induction, the type of postremission therapy in AML is selected for each individual patient based on age, fitness, and cytogenetic/molecular risk.
The choice between consolidation with chemotherapy or transplantation is complex and based on age, risk, and practical considerations. In younger patients receiving chemotherapy, postremission therapy with intermediate/high-dose cytarabine for two to four cycles is standard practice. Higher doses of cytarabine during post remission therapy appear more effective than standard doses (as are used in induction), at least for those who do not have adverse-risk genetics. Recent studies suggest that the long-standing practice of high-dose cytarabine (3 g/m2, every 12 h on days 1, 3, and 5) may not improve survival over intermediate-dose cytarabine (IDAC, 1-1.5 g/m2) for such patients. Thus, the ELN has recommended IDAC at 1–1.5 g/m2, every 12 h, on days 1–3, as the optimal postremission chemotherapy approach for favorable and intermediate-risk younger patients, for two to four cycles. While high-dose cytarabine may not be necessary, it is important to note that younger favorable-risk patients have worse outcomes when doses below 1g/m2 are used. In contrast to favorable-risk, intermediate- and adverse-risk patients should be considered for allogeneic HCT CR1 when feasible (see transplant discussion below). As older patients have increased toxicities with higher doses of cytarabine, ELN recommends relatively attenuated cytarabine doses (0.5–1g/m2, every 12 h, on days 1–3) in favorable-risk older patients. There is no clear value for intensive postremission therapy in non–favorable-risk older patients; allogeneic HCT in CR1 (up to age 75 years) or investigational therapy is recommended. Indeed, postremission therapy is an appropriate setting for introduction of new agents in both older and younger patients (Table 100-6).
Allogeneic HCT is the best relapse-prevention strategy currently available for AML. Allogeneic HCT is probably best understood as an opportunity for immunotherapy; residual leukemia cells potentially elicit an immunologic response from donor immune cells, the so-called graft-versus-leukemia (GVL) effect. The benefit of GVL in relapse risk reduction, unfortunately, is offset somewhat by increased morbidity and mortality from complications of allogeneic HCT including graft-versus-host disease (GVHD). Given that relapsed AML is typically resistant to chemotherapy, allogeneic HCT in CR1 is a favored strategy. It is recommended in patients age <75 years who do not have favorable-risk disease and who have a human leukocyte antigen (HLA)–matched donor (related or unrelated). We recommend allogeneic HCT in CR1 for patients with intermediate-risk disease (Table 100-3). However, considerable debate exists regarding whether allogeneic HCT in CR1 is a requirement for younger patients with intermediate-risk AML, as one large series from the Medical Research Council reported that such patients have similar outcomes if transplanted only after relapse (and achievement of CR2), sparing some the long-term morbidity of transplantation. That said, allogeneic HCT is generally recommended as soon as possible after CR1 is achieved unless the patient is in a favorable-risk group. Selected adverse-risk patients without HLA-matched donors are considered for alternative donor transplants (e.g., HLA-mismatched unrelated, haploidentical related, and umbilical cord blood) even in CR1. Notably, more effective methods of in vivo T cell depletion (i.e., posttransplant cyclophosphamide following haploidentical transplantation) have broadened the availability of potential allogeneic HCT donors. Now, virtually any patient with a healthy parent or child (i.e., haploidentical) has an available donor suitable for allogeneic HCT if desired. Long-term outcomes with conventional chemotherapy for older patients are dismal; transplantation for such patients is expanding. For older patients, nonrandomized data demonstrate benefit for older patients in CR1 treated with reduced-intensity conditioning regimens and allogeneic HCT. Prospective data suggest that 40% of older patients in CR1 who are candidates for allogeneic HCT may be cured.
Trials comparing allogeneic HCT with intensive chemotherapy or autologous HCT have shown improved duration of remission with allogeneic HCT. However, the relapse risk reduction that is observed with allogeneic HCT is partially offset by the increase in fatal treatment-related toxicity (GVHD, organ toxicity). Despite this, there is no debate that patients with adverse-risk AML have improved long-term survival with early allogeneic HCT. Alternatively, high-dose chemotherapy with autologous HCT rescue is another postremission approach in non-adverse risk subsets. Autologous HCT patients receive their own stem cells (collected during remission and cryopreserved), following administration of myeloablative chemotherapy. The toxicity is relatively low with autologous HCT (5% mortality rate), but the relapse rate is higher than with allogeneic HCT, due to the absence of the GVL effect. Favorable and intermediate-risk patients may benefit from autologous HCT more so than adverse-risk patients. Practically speaking, however, autologous HCT in AML patients is less frequently employed currently due to enhanced relapse risk reduction seen with allogeneic HCT and the growing use of HLA mismatched donors (in novel transplantation approaches).
Prognostic factors help to select the appropriate postremission therapy in patients in CR1. Our approach includes allogeneic HCT in first CR for patients without favorable cytogenetics or genotype (e.g., patients who do not have CEBPA biallelic mutations or NPM1 mutations without FLT3-ITD/with FLT3-ITDlow). Patients with adverse-risk disease should proceed to allogeneic HCT at CR1 if possible. The decision for allogeneic HCT for younger intermediate-risk patients is complex and individualized as described above; we recommend it when an HLA-matched donor is available. Subsets of patients may benefit from targeted therapy given during remission; emerging data demonstrate survival benefit from incorporation of the FLT3 inhibitor midostaurin, for example, into induction and postremission therapies for patients with FLT3 mutated AML. On April 28, 2017, the U.S. Food and Drug Administration (FDA) approved midostaurin (RYDAPT, Novartis Pharmaceuticals Corp.) for the treatment of adult patients with newly diagnosed AML who are FLT3 mutation-positive (either ITD or TKD+), in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. Allogeneic transplantation in CR1 is still recommended for these patients.
For patients in morphologic CR, measurement of MRD remains a very important and challenging research area. Cytogenetics are a mainstay of disease assessment, and persistence of abnormal karyotype (in spite of morphologic CR) is clearly associated with poor clinical outcomes. Immunophenotyping to detect minute populations of blasts or sensitive molecular assays (e.g., reverse transcriptase polymerase chain reaction [RT-PCR]) to detect AML-associated molecular abnormalities (e.g., NPM1 mutation, the CBF AML RUNX1/RUNX1T1 and CBFB/MYH11 transcripts, the APL PML/RARA transcript) can be performed to assess whether MRD is present at sequential time points during or after treatment. Whether emerging next-generation sequencing or serial quantitative assessment using flow or RT-PCR, performed during remission, can effectively direct successful subsequent therapy and improve clinical outcome remains to be determined. Currently, no consensus exists for the optimal MRD measurement technique, or its application. Data suggest that MRD measurement can in some settings be a reliable discriminator between patients who will continue in CR or relapse, but whether subsequent therapy (i.e., allogeneic HCT or additional chemotherapy) can effectively eradicate disease in such patients is not yet clear. In the subset of patients with APL, serial RT-PCR (for the PML/RARA transcript) is a very useful and reliable tool to detect early relapse and direct initiation of reinduction therapy prior to onset of overt relapse.
SUPPORTIVE CARE Measures geared to supporting patients through several weeks of neutropenia and thrombocytopenia are critical to successful AML therapy. Patients with AML should be treated in centers expert in providing supportive care. Multilumen central venous catheters should be inserted as soon as newly diagnosed AML patients have been stabilized. They should be used thereafter for administration of intravenous medications/chemotherapy and transfusions, as well as for blood drawing instead of venipuncture.
Adequate and prompt blood bank support is critical to therapy of AML. Platelet transfusions should be given as needed to maintain a platelet count ≥10,000/μL. The platelet count should be kept at higher levels in febrile patients and during episodes of active bleeding or DIC. Patients with poor posttransfusion platelet count increments may benefit from administration of platelets from HLA-matched donors. RBC transfusions should be administered to keep the hemoglobin level >70–80 g/L (7–8 g/dL) in the absence of active bleeding, DIC, or congestive heart failure, which require higher hemoglobin levels. Blood products leukodepleted by filtration should be used to avert or delay alloimmunization as well as febrile reactions. Blood products may also be irradiated to prevent transfusion-associated GVHD. Cytomegalovirus (CMV)–negative blood products should be used for CMV-seronegative patients who are potential candidates for allogeneic HCT; fortunately white blood cell filtration is quite effective at reducing CMV exposure as well.
Neutropenia (neutrophils <500/μL or <1000/μL and predicted to decline to <500/μL over the next 48 h) can be part of the initial presentation and/or a side effect of the chemotherapy treatment in AML patients. Thus, infectious complications remain the major cause of morbidity and death during induction and postremission chemotherapy for AML. Antibacterial (i.e., quinolones) and antifungal (i.e., posaconazole) prophylaxis, especially in conjunction with regimens that cause mucositis, is beneficial. For patients who are herpes simplex virus or varicella-zoster seropositive, antiviral prophylaxis should be initiated (e.g., acyclovir, valacyclovir).
Fever develops in most patients with AML, but infections are documented in only half of febrile patients. Early initiation of empirical broad-spectrum antibacterial and antifungal antibiotics has significantly reduced the number of patients dying of infectious complications (Chap. 70). An antibiotic regimen adequate to treat gram-negative organisms should be instituted at the onset of fever in a neutropenic patient after clinical evaluation, including a detailed physical examination with inspection of the indwelling catheter exit site and a perirectal examination (for perirectal abscess), as well as procurement of cultures and radiographs aimed at documenting the source of fever. Specific antibiotic regimens should be based on institutional antibiotic sensitivity data obtained from where the patient is being treated. Acceptable regimens for empiric antibiotic therapy include monotherapy with imipenem-cilastatin, meropenem, piperacillin/tazobactam, or an extended-spectrum antipseudomonal cephalosporin (cefepime or ceftazidime). The combination of an aminoglycoside with an antipseudomonal penicillin (e.g., piperacillin) or an aminoglycoside in combination with an extended-spectrum antipseudomonal cephalosporin should be considered in complicated or resistant cases. Aminoglycosides should be avoided, if possible, in patients with renal insufficiency. Empirical vancomycin should be added in neutropenic patients with catheter-related infections, blood cultures positive for gram-positive bacteria before final identification and susceptibility testing, hypotension or shock, or known colonization with penicillin/cephalosporin-resistant pneumococci or methicillin-resistant Staphylococcus aureus. In special situations where decreased susceptibility to vancomycin, vancomycin-resistant organisms, or vancomycin toxicity is documented, other options including linezolid, daptomycin, and quinupristin/dalfopristin need to be considered.
Caspofungin (or a similar echinocandin), voriconazole, isavuconazonium, or liposomal amphotericin B should be considered for antifungal treatment if fever persists for 4–7 days following initiation of empiric antibiotic therapy. Amphotericin B has long been used for antifungal therapy. Although liposomal formulations have improved the toxicity profile of this agent, its use has been limited to situations with high risk of or documented mold infections. Caspofungin has been approved for empiric antifungal treatment. Voriconazole has also been shown to be equivalent in efficacy and less toxic than amphotericin B; isavuconazonium may also be effective with fewer drug-drug interactions. Antibacterial and antifungal antibiotics should be continued until patients are no longer neutropenic, regardless of whether a specific source has been found for the fever. Unfortunately, this practice likely contributes to development of resistance and increased incidence of nosocomial infections such as Clostridium difficile colitis, so great care should be taken preferably in hospital-wide antibiotic surveillance and isolation strategies to reduce these complications. Recombinant hematopoietic growth factors have a limited role in AML; myeloid growth factors may be useful in the postremission setting but are not recommended in induction or for “palliative” care for patients not in remission.
TREATMENT FOR REFRACTORY OR RELAPSED AML In patients who relapse after achieving CR, the length of first CR is predictive of response to salvage chemotherapy treatment; patients with longer first CR (>12 months) generally relapse with drug-sensitive disease and have a higher chance of attaining a CR, even with the same chemotherapeutic agents used for first remission induction. Whether initial CR was achieved with one or two courses of chemotherapy and the type of postremission therapy may also predict achievement of second CR. Similar to patients with refractory disease, patients with relapsed disease are rarely cured by salvage chemotherapy treatments. Therefore, patients who eventually achieve a second CR and are eligible for allogeneic HCT should be transplanted. However, there is no consensus on optimal treatment for patients who relapse after allogeneic HCT; outcomes in this setting are very poor.
Because achievement of a second CR with routine salvage therapies is relatively uncommon, especially in patients who relapse rapidly after achievement of first CR (<12 months), these patients and those lacking HLA-compatible donors or who are not candidates for allogeneic HCT should be considered for innovative approaches on clinical trials. Many new agents are in current testing (Table 100-6). The discovery of novel gene mutations and mechanisms of leukemogenesis that might represent actionable therapeutic targets has prompted the development of many new targeting agents. In addition to kinase inhibitors for FLT3-mutated AML, other compounds targeting the aberrant activity of mutant proteins (e.g., IDH1/2 inhibitors) and numerous other biologic mechanisms are being tested in clinical trials. Furthermore, approaches with antibodies targeting markers commonly expressed on leukemia blasts (e.g., CD33) or leukemia-initiating cells (e.g., CD123) are also under investigation. Once these compounds have demonstrated safety and activity as single agents, investigation of combinations with other molecular targeting compounds and/or chemotherapy should be pursued.
TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA APL is a highly curable AML subtype, and ~85% of these patients achieve long-term survival with current approaches. APL has long been shown to be responsive to cytarabine and daunorubicin, but in the past patients who were treated with these drugs alone frequently died from DIC induced by the release of granule components by the chemotherapy-treated leukemia cells. However, the prognosis of APL patients has changed dramatically with the introduction of tretinoin (ATRA), an oral drug that induces the differentiation of leukemic cells bearing the t(15;17), where disruption of the RARA gene encoding a retinoid acid receptor occurs. ATRA decreases the frequency of DIC but often produces another complication called the APL (differentiation) syndrome. Occurring within the first 3 weeks of treatment, it is characterized by fever, fluid retention, dyspnea, chest pain, pulmonary infiltrates, pleural and pericardial effusions, and hypoxemia. The syndrome is related to adhesion of differentiated neoplastic cells to the pulmonary vasculature endothelium. Glucocorticoids, chemotherapy, and/or supportive measures can be effective for management of the APL syndrome. Temporary discontinuation of ATRA is necessary in cases of severe APL syndrome (i.e., patients developing renal failure or requiring admission to the intensive care unit due to respiratory distress). The mortality rate of this syndrome is ~10%. APL syndrome may also occur, less commonly, with ATO in APL.
In low-risk APL (low leukocyte count at presentation), ATRA (45 mg/m2/d) plus ATO (0.15 mg/kg/d) was recently compared to ATRA plus concurrent idarubicin chemotherapy. ATRA/ATO was superior and is the new standard of care for such patients. CR rates in low-risk disease approach 100%, with excellent long-term survival. Notably, patients with high-risk APL (high leukocyte count) must be uniquely treated, as they require immediate cytoreduction with chemotherapy due to life-threatening APL syndrome often with rapidly rising leukocyte count after initiation of ATRA. High-risk patients are at increased risk for induction death due to this syndrome as well as increased frequency of hemorrhagic complications (related to DIC).
Assessment of residual disease by RT-PCR amplification of the t(15;17) chimeric gene product PML-RARA following the final cycle of treatment is important. Disappearance of the signal is associated with long-term disease-free survival; its persistence or reemergence invariably predicts relapse. Sequential monitoring of RT-PCR for PML-RARA is now considered standard for postremission monitoring of APL, at least in high-risk patients.
Patients in molecular, cytogenetic, or clinical relapse should be salvaged with ATO with or without ATRA; in patients who were treated with ATRA plus chemotherapy in the frontline setting, ATO-based therapy at relapse produces meaningful responses in up to 85% of patients. Though experience with relapsed APL in patients who received ATO during initial induction is limited (given that few relapses occur in low-risk patients, and widespread use of ATO during first-line therapy is relatively new), ATO remains the preferred reinduction therapy for patients who relapse. Achievement of CR2 should be followed by consolidation with autologous HCT (for patients who achieve RT-PCR negative status). In the minority who do not achieve negative RT-PCR or who relapse again, allogeneic HCT may still be potentially curative.
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