Pathophysiology

The pathophysiology of AML can be partially explained by the acquisition of genetic changes in hematopoietic stem cells that both promote self-renewal and impair normal hematopoietic differentiation, resulting in an accumulation of immature cells. The genetic landscape of de novo AML has been recently characterized.⁶ An average of five mutations are found in an individual’s leukemia cells and “only” 30 mutations are recurrent (observed in more than 3% of patients). Of the 30 recurrent mutations, several are relatively common, including gain-of-function mutations, which are targets for therapy in active development. FLT3 is a transmembrane tyrosine kinase, which is mutated in approximately 30% of patients with AML.⁷ Approximately three-quarters of these mutations are length or internal tandem duplication (ITD) mutations, in which the protein is elongated in the juxtamembrane region by three to more than 100 amino acids. This type of mutation is associated with an adverse prognosis because of a high relapse rate. Both the ITD mutation and the less common tyrosine kinase domain point mutation (usually D835Y) cause ligand-independent constitutive activation of the receptor. There are several FLT3 inhibitors in active development, both as single agents and in combination with chemotherapy in mutant FLT3 patients. A second common mutation is a point mutation in the NPM1 shuttle protein.⁸ Such mutations, particularly if occurring in patients with a normal karyotype without an associated FLT3 mutation, confer a favorable prognosis.⁹ Mutations in the Ras guanine nucleotide-binding protein occur in approximately 20% of patients with AML and are associated with increased proliferation.¹⁰ Attempts to inhibit posttranslational modification, a required step for activation of Ras, have been largely unsuccessful in AML.¹¹ Ras pathway interruption, such as with MEK inhibitors (useful in melanoma and other solid tumors), shows promise.¹² Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur in approximately 20% of patients with AML (∼10% for each case).¹³ While the prognostic significance of these mutations is unclear, they cause the neomorphic production of 2-hydroxygluterate (2HG) rather than the usual reaction product, alpha-ketogluterate. 2HG levels may correlate with disease activity.¹⁴ Inhibition of IDH1 or IDH2 with small molecules may prove to be a fertile therapeutic intervention. Mutations in transcriptional machinery and mutations in enzymes, which are epigenetically active (posttranslational modification of the DNA) potentially leading to profound effects on gene expression, are common in AML.⁶ DNMT3, mutations occurring in approximately 20% of patients with AML,¹⁵ confer an adverse prognosis, although may be associated with a response to dose-intensified daunorubicin during induction.¹⁶ The presence of some of these so-called epigenetic modifying enzymes such as ASXL1, EZH2, and TET2 is often associated with AMLs that have arisen from a myelodysplastic syndrome (MDS) prodrome. TP53 mutation confers a bleak prognosis.¹⁷ On the contrary, CEBPα (biallelic) mutations are favorable.¹⁸

Genetic complexity of AML is an important feature of disordered molecular pathophysiology. The epigenetic profiles¹⁹ of AML can differ widely and perhaps suggest a specific therapy. Specific epigenetic profiles are found in distinct cytogenetic subsets of AML. Moreover, because of either mutations or altered patterns of genome regulation, messenger RNA²⁰ and indeed microRNA expression patterns offer both pathophysiological insights and prognostic information. For example, microRNA expression patterns, particularly with moieties that control immunological regulation, have been found to play an important role in AML.²¹ Integration of the vast potential array of data including genomic lesions, epigenomic changes, and RNA and microRNA expression patterns yield an enormous amount of information and will be the subject of intense research in the future. The overexpression of many specific genes such as BAALC²² or WT1²³ has been shown to confer an adverse prognosis, but their independent significance remains to be confirmed.

Genetic changes in AML were first recognized by the identification of genes at cytogenetic break points involved in balanced translocations. Many of these chromosomal abnormalities, for example, t(8;21), t(15;17), and inv(16), are associated with specific AML subtypes and are of prognostic importance. The fusion proteins generated by the translocation generally result in disruption of transcription factors, which is believed to be critical in myeloid differentiation.^24–27 Murine experiments indicate that transfection of mutated genes that primarily alter cell differentiation, such as AML1/ETO resulting from the t(8;21) translocation, produces abnormal hematopoiesis, but is not sufficient to generate frank AML.²⁷ Initial murine experiments suggested a “two-hit” hypothesis, in which mutations affecting both differentiation and proliferative signaling pathways are needed to result in AML.²⁸ The mechanisms that account for poor prognosis in patients with complex cytogenetics remain to be elucidated. Findings in 5q-MDS suggest a mechanism by which haploinsufficiency can lead to a myeloid malignancy.²⁹ Many patients with the so-called monosomal karyotype (two monosomes or one monosomal plus one stromal abnormality) have p53 mutations, and this abnormality likely accounts for the dismal prognosis in this disease subset.¹⁷

Exposure and risk

Although more acquired genetic lesions that lead to leukemia are being defined, DNA damage from a known cause comprises only a small fraction of patients with AML. Leukemia occurs with increased frequency after exposure to nuclear bomb³⁰ or therapeutic radiation,³¹ after certain types of chemotherapy,^{32, 33} and with heavy and continuous occupational exposures to benzene or petrochemicals.^{34, 35} There are two types of chemotherapy-related leukemias: (1) the classic alkylating agent-induced type, in which the leukemia is usually preceded by a myelodysplastic prodrome and is characterized by clonal abnormalities, often with loss of chromosome 5 and/or 7³² and (2) an epipodophyllotoxin/topoisomerase II inhibitor-associated type with a shorter (median 2 years vs 5 years) incubation period, often with myelomonocytic or monocytic differentiation and abnormalities at the 11q23 region.³³ Recent studies have challenged preconceived notions about the origin of therapy-related leukemia: (1) some patients who have been exposed to chemotherapy have genetic⁵ or cytogenetic lesions³⁶ and clinical behavior indistinguishable from de novo AML; (2) preexisting p53 mutant hematopoietic clones due to the “normal” stochastic accumulation of mutations may be selected for survival after genotoxic therapy and thus predispose to the development of AML.³⁷

Familial AML

AML is not usually a familial or inherited disorder, which is a fact worth noting to concerned families. There appears to be an increased incidence of acute leukemia in the first 6 months after diagnosis in the identical twin of an affected child.³⁸ Familial syndromes have been described in which the incidence of leukemia was increased.^39–41 In some of these families, different types of leukemias and other cancers have been found, whereas in other potentially more informative families, such as a large family in which more than or equal to seven cases of erythroleukemia or myelodysplasia developed in three successive generations,⁴¹ the morphologic or clinical characteristics of the leukemia have been similar, suggesting a common, heritable genetic mutation. A family has been described in which three patients with AML had identical inherited mutations in CEBPA,⁴² a gene involved in granulocytic differentiation, while another large kindred with a familial platelet disorder with a predisposition toward AML had been shown to be associated with mutations in the gene encoding CBF-α (formerly AML1).⁴³ Finally, there seems to be a predisposition toward evolution to AML in individuals with inherited polymorphisms in the receptor for granulocyte colony-stimulating factor (G-CSF).⁴⁴ AML is also more common in certain inherited conditions identified by an inability to repair DNA damage (e.g., Fanconi anemia)⁴⁵ or with defective telomerase machinery.⁴⁶

Peripheral blood

Most patients with AML present with anemia (median hemoglobin 8 g%), thrombocytopenia (median platelet count 40,000–50,000/μL), and leukocytosis (median WBC count 10,000–20,000/μL). The red blood cell morphology is usually relatively normal. Large, sometimes hypogranular, platelets can be observed, and functional defects can contribute to hemorrhagic manifestations. Most patients are neutropenic, and morphologic abnormalities (nuclear hyperlobulation, hypogranulation, Pelger–Huet anomaly) are often noted in the remaining neutrophils. Careful examination can detect blasts in most patients, although it can be difficult to distinguish among leukemia subtypes (or occasionally even to be confident of the diagnosis of acute leukemia) in patients with a low number of circulating blasts. In occasional patients, marked leukopenia at presentation (the so-called aleukemic leukemia) may obscure the diagnosis until a marrow examination is performed.

AML with MDS-related changes

Addition of this category shows that a substantial fraction of AML, particularly in older patients, evolves from a prior myelodysplastic disorder. This group includes patients with a prior history of MDS, those with >50% dysplasia in at least two cell lines and patients with the so-called “MDS cytogenetics,” including, -5, -7, i(17)/t(17p), -13, del 11q, del (12p), del 9q and those with complex karyotypes, which may include these changes as well as the presence of marker chromosomes.⁶⁷ These leukemias seem to arise in a very early hematopoietic stem cell and tend to have low response rates with short durations of response. It seems likely that those patients in this category, only based on morphological abnormalities, may exhibit a variety of oncogenic pathways based on mutational profile and thus may not have a uniformly poor prognosis.⁵

Therapy-related AML

This category includes patients whose AML followed treatment with chemotherapy and/or radiation therapy for other disorders. Morphology and karyotypes are often similar to those observed in MDS with the addition of a group of patients with abnormalities of 11q23 associated with prior treatment with topoisomerase II inhibitors and often with a short interval until the development of AML.^{32, 33} Therapy-related AML tends to be more resistant to chemotherapy, and allogeneic transplant should be considered in patients who achieve remission. It is important to note that some patients with therapy-related AML can have inv(16), t(8;21), and t(15;17) (APL) or genetics typical of de novo AML and respond well to standard approaches for these subtypes, although perhaps not as well as those with these karyotypes with de novo disease.^{5, 36}

Extramedullary AML (aka myeloid sarcoma)

Occasionally patients will present for medical attention because of lesions identified to be composed of myeloblasts by histochemical staining, but without apparent bone marrow involvement. Masses can involve the skin, gastrointestinal tract, ovaries, the central nervous system (CNS), and virtually every body organ. There have been only few systematic studies on the management of such patients, although there is a risk of high eventual systemic relapse rate without treatment.⁷¹ Most clinicians consider induction and consolidation in medically fit patients after diagnosis. Despite such “early” treatment, the recurrence rate is high; the role of stem cell transplant is unclear, but it is reasonable to consider transplantation to maintain the remission. Some of these patients have a t(8;21) chromosomal translocation, but in this setting, may not have the same favorable prognostic input as found in more typical t(8;21) AMLs.⁷²

FAB classification

Although the “old” FAB classification is not used currently, clinical–pathological correlates can be discussed. Wright–Giemsa stained peripheral blood or bone marrow aspirate smears can prefer AML to ALL. In general, the blasts from patients with AML are larger, with more abundant cytoplasm and more prominent, often multiple, nucleoli. The definitive diagnosis depends, however, on the presence of Auer rods, which are linear bundles of myeloid-containing granules. Cytochemical stains, such as myeloperoxidase, which is present in 73% of blasts, can diagnose AML.

Other modifications of the 7 and 3 regimen

Most attempts to improve the 7 and 3 induction regimen have not led to increase in OS. Alternative anthracyclines or other agents such as mitoxantrone, rubidazone, aclacinomycin, amsacrine, mitoxantrone, and idarubicin have been used in several trials.^141–145 None of these studies showed a survival or disease-free survival advantage with these different agents, perhaps because most are relatively similar in structure and mechanism of action and hence, become susceptible to the same mechanisms of resistance. The largest reported experience has been with idarubicin, where three initial trials showed that induction results are at least equivalent to results achieved with daunorubicin and ara-C.^{142, 144} An important randomized trial did not show an advantage for idarubicin compared with daunorubicin, in older patients.¹⁴⁶ In addition, the duration of myelosuppression was longer in the idarubicin cohorts, calling into question the equitoxicity of the arms. Therefore, the substitution of these compounds did not have a major impact on the long-term disease-free survival rate of patients with AML.

An Australian trial added etoposide to the 7 and 3 regimen.¹⁴⁷ The CR rate was similar in older patients when compared with daunorubicin and ara-C only with a possibly modest prolongation of CR duration in younger patients receiving etoposide. This was a relatively small study and the overall disease-free survival in the group receiving etoposide during both remission induction and postremission therapy was similar to other larger studies using daunorubicin and ara-C only. Large phase I studies from the CALGB, in which etoposide was added to the 7 and 3 regimen, had outcomes similar to the past experience with only the two drugs.¹⁴⁸

Because HIDAC is a beneficial postremission therapy (see below), several groups have tested the use of this approach during induction in younger patients. Studies have compared standard 7 and 3 to daunorubicin plus intermediate- or high-dose ara-C (2–3 g/m² for 8–12 doses).^149–151 These studies failed to show an increased CR rate for the recipients of HIDAC, although one study documented a more prolonged duration of CR (but no change in OS) in the patients randomized to HIDAC.¹⁴⁹ The addition of HIDAC to standard daunorubicin/ara-C during induction has also been studied. Although a small trial showed an 87% remission rate in patients <60 years old,¹⁵² a cooperative group trial failed to confirm those positive results.¹⁵³ Results seem to be equivalent if HIDAC is used either as part of induction or only as postremission therapy.¹⁵⁴

New induction strategies

Although it is evident that 3 + 7-based strategies remain the standard of care, new data suggest that many patients (perhaps all of those up to age 65) should be treated with daunorubicin at a dose exceeding the originally used 45 mg/m². The ECOG 1900 study randomized patients to 45 mg/m² per day of daunorubicin for 3 days versus 90 mg/m² for 3 days and found for most subgroups (and even those with high white counts or FLT3 ITD with longer follow-up)¹⁵⁵ that the higher dose resulted in prolonged survival. A study in older adults in Europe with a similar design also suggested that a dose of 90 mg/m² per day was better than 45 mg/m² at least in those between 60 and 65 years of age.¹⁵⁶ A report from a study conducted in the United Kingdom suggested that 60 mg was equally efficient as 90 mg/m².¹⁵⁷ As noted, most studies that have added drugs to the 3 + 7 backbone or substitute HIDAC for standard continuous infusion ara-C in 3 + 7 have not led to an increased OS. However, the Polish Acute Leukemia Study Group showed that the addition of cladrabine to anthracycline/cytarabine was superior to 3 + 7¹⁵⁸; however, the CR rate in the control group in these younger adults was lower than expected and these results need to be confirmed by additional studies. Continuous infusion of HIDAC and idarubicin has led to favorable results in nonrandomized phase 2 studies at the MD Anderson Cancer Center.¹⁵⁹ Addition of CCNU to the 3 + 7 regimen benefited older adults in a French trial.¹⁶⁰ The FLAG IDA regimen, while quite intensive and toxic, led to a high remission rate and disease-free survival rate.¹⁶¹ Another agent that could potentially be added to a 3 + 7-type backbone is gemtuzumab ozogamicin (GO), an antibody toxin conjugate directed against the CD33 antigen expressed on blasts from most patients with AML and which was initially approved as a single-agent treatment for older adults with relapsed AML¹⁶² and then withdrawn after randomized trials comparing standard initial induction treatment with or without the addition of GO showed marginal benefit and/or equivocal results.¹⁶³ However, trials in France¹⁶⁴ and the United Kingdom¹⁶⁵ have suggested that the addition of relatively small doses of GO to standard chemotherapy may have a benefit in patients up to age 70 with AML. The drug has still not reentered the market until the time of this writing; confirmatory trials in North America will likely be required to show that it is worth using this drug routinely, although results in those with favorable chromosomal abnormalities are encouraging.¹⁶⁶

Approach to the older patient and other poor prognostic subgroups

Is it worth administering cytotoxic chemotherapy with a 3 + 7 induction approach to patients who have little chance for long-term benefit? This is still a subject of major debate and controversy relevant to the care of AML patients older than 60–65 years of age and some selected younger patients whose prognosis is very poor based on monosomal karyotype⁵⁴ or p53 mutations¹⁷ if known at the time of diagnosis. For younger adults with known adverse prognostic features, there seems to be little recourse at the moment to using a 3 + 7 regimen or similar induction approach followed by postremission therapy followed by allogeneic stem cell transplant if possible. If a sibling donor, matched unrelated donor, or “favorable” partially mismatched unrelated donor is not available, then strong consideration should be made for haploidentical or umbilical cord blood stem cell transplantation (SCT) in these cases. The degree of chemotherapeutic resistance is profound in such cases and the results with allogeneic transplant remain relatively poor, but still may offer a slightly better outcome than¹⁷ a chemotherapy-based postremission approach.

It is possible that some older adults will be better served by using a lower-dose chemotherapy approach to initial therapy than a standard 3 + 7 regimen. For a standard chemotherapy, the daunorubicin dose should be ≥60 mg/m² in virtually all patients. On the contrary, particularly when adverse prognostic factors are present, at times it may be reasonable to consider lower-dose chemotherapy with drugs such as the hypomethylating agents, azacitidine or decitabine, or in clinical trials, with the slightly more toxic single agent, clofarabine. Although there are many prognostic algorithms for older adults, features that are generally considered to decrease the likelihood of good outcome with 3 + 7-based chemotherapy are those that were used in the clofarabine phase II¹⁶⁷ trial, including age > 70 years, antecedent hematological abnormality, comorbid diseases, nonfavorable cytogenetics. A phase 2 trial using 30 mg/m² of clofarabine for 5 days produced a 35% CR rate with a 10% rate of toxic death. In part because of difficulties in defining a group of patients “unfit for intensive therapy,” this trial did not result in the Food and Drug Administration (FDA) approval and clofarabine is being evaluated in a large ECOG-led phase III trial comparing clofarabine to 3 + 7 in this age-group.

In Europe, low-dose ara-C is another frequently used option for patients who are deemed not fit or at least “inappropriate” for standard induction chemotherapy. Low-dose ara-C seems to be slightly better than hydrea,¹⁶⁸ but is used little in the United States. Two important trials have compared hypomethylating agent to other therapies for older adults with AML. One such trial compared decitabine to low-dose ara-C or supportive care and yielded a 25% CR rate.¹⁶⁹ Although decitabine is approved for an initial therapy for older AML patients in Europe, it is not approved in the United States, primarily because the pivotal trial did not meet its primary end point of extending OS. A trial reported in preliminary form comparing 5-azacitidine to conventional care regimens for AML patients whose white count was less than 15,000/μL again did not meet its primary end point, but certainly suggested that 5-azacitidine was a viable alternative to low-dose ara-C or supportive care.¹⁷⁰ It should be emphasized, however, that the CR rates are much lower with hypomethylating agents and low-dose ara-C than with standard chemotherapy, and that the less-intensive treatments have largely been evaluated only in patients with less-proliferative forms of AML with the likelihood that results would be even poorer than summarized, should these treatments be used in patients with high circulating blast counts or a high marrow blast infiltration; as such induction with a 3 + 7-based regimen ideally in the context of a clinical trial should be the default therapy for the relatively fit older adult under approximately 75 years of age.

Patients to be treated with a hypomethylating agent should probably be managed in the same manner as those with MDS receiving such agents. The patient should continue to receive the hypomethylating agent every 4–6 weeks until toxicity or obvious progression occurs. It certainly seems that prolonged exposure to these agents is an important factor in achieving relatively good long-term results. If a patient does achieve a very good outcome such as a CR rate in response to a hypomethylating agent, then the older adult in question, if under approximately 75 years of age, could yet be considered for a nonmyeloablative allogeneic transplant.¹⁷¹ This usually occurs only in people who elect or are given aggressive chemotherapy, but this is nonetheless a consideration even in those who receive a less-intensive chemotherapy.¹⁷²

Postremission therapy

Morphologic assessments of CR are subjective and relatively insensitive. A better quantitation of malignant cells present at the time of CR (MRD) could segregate patients into prognostic subgroups. It is estimated that as many as 10⁹ leukemia cells may still be present in patients with apparent morphologic CR. Only few patients can remain in CR for 1–2 years without further treatment, but it is generally accepted that some form of therapy after CR is required to achieve long-term disease-free survival. In a trial conducted by the German Cooperative Leukemia Group, a subset of 37 patients did not receive postremission therapy for a variety of protocol and medical reasons; all of these individuals relapsed.¹⁷³ The ECOG reported a randomized study in which patients achieving CR were randomized to either no therapy, lower-dose maintenance therapy, or an intensive postremission program.¹⁷⁴ All of the patients in the no-treatment arm relapsed rapidly, with a median CR duration of 4 months, resulting in early termination of this arm of the trial. Similar results were noted in a smaller randomized study reported by Embury and colleagues.¹⁷⁵ Although timed sequential therapy, in which patients receive additional chemotherapy during the early postinduction recovery phase, has been associated with prolonged remissions in the absence of postremission chemotherapy,^{176, 177} this treatment regimen is more analogous to consolidation therapy. Thus, it remains a standard practice to administer chemotherapy with or without subsequent SCT after remission is achieved with conventional regimens.

Younger adults are generally treated with curative intent and should receive postremission chemotherapy that includes intensive (or myelosuppressive) “consolidation” chemotherapy and/or SCT. The term “maintenance” is generally referred to lower-dose outpatient therapy administered on an intermittent basis for months to years, patterned on the model successfully used in childhood ALL, but this approach has not been clearly found to be useful in patients with AML.

A variety of agents have been used for postremission therapy, including the agents successfully administered in initial induction, with a particular focus on HIDAC as consolidation, as well as different classes of compounds, some of which have proved activity in AML, and others of which may have had only limited activity. Because a variety of prognostic factors significantly affect ultimate outcome, independent of the type of therapy administered, good results in small nonrandomized studies may reflect inadvertent patient selection and must ultimately be confirmed by multi-institutional applicability.

Overall, in adults, it can be expected that the administration of some sort of intensive postremission chemotherapy will result in a median CR duration of 12–18 months with approximately 20–25% of complete responders remaining as long-term disease-free survivors (Figure 10). A large review of CALGB patients who achieved CR showed a relatively constant relapse rate of 4.7% per month during the first 6 months following CR. The failure rate decreased in subsequent 6-month intervals (3.5% per month in months 7–12 and 2.4% per month in months 13–18), with a flattening of the curves after 3+ years of CR.¹⁷⁸ In general, patients relapsing earlier have leukemia that is more drug resistant than those who relapse late.¹⁷⁹ Older randomized trials of postremission therapy conducted by the CALGB failed to demonstrate long-term benefits from: (1) an alternate month compared with a monthly schedule of maintenance therapy; (2) 3 years of relatively low-dose maintenance therapy compared with 8 months of a similar program (indeed, there was a modest survival advantage for patients randomized to stop therapy after 8 months); (3) doubling of the dose of ara-C from 100 to 200 mg/m² during maintenance therapy; and (4) addition of nonspecific immunotherapy in the form of methanol-extractable residue of Bacille Calinette Grain (MER) to maintenance therapy. With regard to the role of maintenance chemotherapy, an older ECOG study demonstrated no benefit from the addition of 2 years of maintenance therapy following two courses of postremission treatment with DAT (daunorubicin, ara-C, thioguanine).¹⁸⁰ Studies from Germany reported by Buchner et al.^{181, 182} suggested a modest prolongation of CR duration when long-term maintenance therapy was administered after a single course of postremission DAT, although with a questionable effect on long-term survival. There was less effect of maintenance in later studies when more intensive postremission consolidation was used before the maintenance.^{181, 182}

Two important randomized trials have shown that HIDAC in the postremission setting is better than lower doses of the drug in younger patients. In an ECOG study, patients randomized to receive one course of very intensive postremission consolidation with a HIDAC-type regimen had a longer median duration of remission than patients receiving 2 years of lower-dose maintenance therapy.¹⁸³ The CALGB randomized 596 AML patients in CR to receive four courses of ara-C administered at three different dose levels [100 mg/m² by continuous intravenous infusion (CIV) for 5 days, 400 mg/m² CIV for 5 days, and 3 g/m² IV for 3 h q12h on days 1, 3, and 5 (total six doses/course)]. There was no benefit from the higher-dose arms in patients >60 years of age with a median duration of CR of approximately 13 months and with only 10–12% long-term disease-free survival.¹⁸⁴ In addition, there was a substantial incidence of CNS neurotoxicity in older patients, manifested primarily as cerebellar dysfunction. Other studies have also failed to show a benefit for higher doses of ara-C in older patients.¹⁸⁵ By contrast, patients <60 years of age benefited substantially from the HIDAC regimen in terms of both relapse-free and OS. The long-term results in patients <40 years of age were similar to those reported with autologous or allogeneic bone marrow transplant (BMT).

These studies strongly support the use of HIDAC-based consolidation programs in younger patients with AML. It is not known how many courses of such therapy are needed, the optimal dose and schedule of HIDAC, and whether the addition of other active agents will improve on these results. It is likely that ara-C incorporated into DNA is maximal at 1–1.5 g/m² per dose and a recently completed randomized study from the United Kingdom has shown identical OS when doses of 1.5 g/m² were compared with the original CALGB doses of 3 g/m².¹⁸⁶ In another randomized study, the use of other potentially noncross-resistant regimens substituted for HIDAC was not superior to three cycles of HIDAC¹⁸⁷ and studies from the Medical Research Council (MRC) in Britain, which used multiple postremission courses using a variety of different drugs, produced similar overall outcomes.^{188, 189} The CALGB data suggest that the benefit from HIDAC was most pronounced in patients with favorable cytogenetic findings [t(8;21) and inv (16)] with much less effect in patients with unfavorable karyotypes typically associated with drug resistance.⁷⁷ If a chemotherapy-based approach is medically feasible, most clinicians attempt to administer at least three courses of reasonably intensive HIDAC-based therapy postremission regimens. As allogeneic SCT is currently becoming more commonly used, HIDAC-based postremission therapy has been reserved most appropriately for younger patients with inv16, t(8;21) or those with normal cytogenetics with an NPM1 mutation but no FLT3 ITD mutations.⁹

The decision about the type of postremission therapy must consider the patient’s medical condition and the possible persistence of infection (particularly with fungal organisms) acquired during induction, as well as the ability to provide adequate platelet transfusion therapy, in an attempt to balance the risk of intensive postremission approaches with the potential benefit. Depending on the intensity of the consolidation program, a 5% mortality rate in CR is to be expected and must be carefully explained to the patient, although the use of myeloid growth factors after consolidation can appreciably shorten the duration of severe neutropenia and potentially make the administration of this therapy safer.^{190, 191}

An alternative way to administer high-dose chemotherapy in AML is autologous SCT. Cryopreserved autologous bone marrow can rapidly reconstitute recipients of ablative regimens, although marrow recovery may be delayed compared with allogeneic BMT.¹⁹² Experience using cytokine-mobilized peripheral blood stem cells (PBSCs) indicates that the durations of neutropenia and particularly thrombocytopenia are shortened compared with the use of bone marrow.¹⁹³ The autologous procedure is well tolerated and can be readily used in patients up to 65 years of age and perhaps older. The major disadvantages include the absence of a graft-versus-leukemia effect, as well as concern that viable leukemic progenitors will be administered with the autologous stem cells. A number of purging techniques have been used including monoclonal antibodies directed against myeloid blasts, as well as incubation with high concentrations of cytotoxic agents¹⁹² that rather remarkably spare hematopoietic progenitors, although delayed marrow reconstitution is not uncommon.¹⁹³ It is unknown whether these in vitro manipulations are beneficial. When unpurged autologous BMT was harvested after high-dose consolidation therapy, retrospective comparisons did not suggest an increased rate of relapse. A number of centers and groups have reported relapse-free survival rates >40% following autologous SCT in first CR.^194–196 Historically, syngeneic transplant experience in this situation showed relapse rates of approximately 50%, which is probably the best that can be expected with the autologous approach. Other evidence of the potential of this approach derive from reports of apparent cure rates of 20% in patients transplanted in the second and third remissions of AML.¹⁹²

Allogeneic SCT represents an alternative major therapeutic option for postremission therapy for younger patients, and increasingly, nonmyeloablative SCT is being considered in selected older patients. Syngeneic SCT, using identical twins as donors,¹⁹⁷ and allogeneic SCT using HLA-identical siblings,¹⁹⁸ were first evaluated in patients with advanced, refractory AML. After demonstrating an approximately 10% rate of long-term disease-free survival in this refractory group of patients and a 40–50% disease-free survival in patients in first remission receiving syngeneic transplants, studies of allogeneic transplantation in first remission AML were conducted.¹⁹⁹ Early small series were promising, demonstrating a low rate of relapse with most of the mortality related to complications of acute and chronic graft-versus-host disease (GVHD). With the current advances in supportive care, particularly the use of novel GVHD prophylactic and active therapies, allogeneic SCT is safer and more commonly used.^{200, 201}

In the 1990s several large prospective trials “genetically” assigned patients with histocompatible siblings to allogeneic BMT (usually only in those ≤45 years of age) while randomizing the others to either autologous BMT or chemotherapy.^{188, 202} In the first of these trials which included 422 patients <45 years of age (median 33 years), disease-free survival was similar in patients undergoing allogeneic BMT (55% projected at 4 years) and autologous BMT (48%) and superior to the chemotherapy group (30%), which received a second course of consolidation chemotherapy with intermediate-dose ara-C and m-amsacrine.²⁰² OS was similar, however, because many patients relapsing after chemotherapy could be successfully re-induced and then undergo SCT in second CR. Many patients did not undergo treatment as randomized, and no information was provided about responses to the three treatments in different cytogenetic risk groups.

Another similarly designed trial performed in France failed to show a benefit for either type of BMT compared with patients receiving intensive postremission chemotherapy.²⁰³ A large study conducted in Germany failed to show a benefit from autologous transplantation given as a component of consolidation therapy. The MRC 10 trial conducted in Great Britain¹⁸⁸ showed that autologous BMT was beneficial. Patients who were not assigned to allogeneic BMT received three cycles of post-CR chemotherapy and were then randomized to nonpurged autologous BMT or observation. The addition of the autologous transplant prolonged CR duration, but there was no significant difference in OS between the two groups. Allogeneic BMT was not significantly better than autologous BMT; no modality was clearly better than another in different cytogenetic risk groups. The MRC trials were updated with an intent to treat analysis of results in patients with and without matched sibling donors.¹⁸⁹ Again, there was no apparent survival benefit compared with chemotherapy for patients who had available donors in whom a transplant could have been performed, and no advantage when patients with donors who were and were not transplanted were compared.

The trial conducted by the North American Intergroup²⁰⁴ found that chemotherapy was at least as good as autologous or allogeneic BMT in leading to cure, based on the intent to treat analysis. As in all the other studies, many patients assigned to either modality of BMT did not receive this therapy for a variety of reasons. Some general conclusions can be drawn concerning the role of allogeneic BMT in the management of patients with AML in first CR:

1. 1. Applicability of the technique is somewhat limited by patient age. Mortality from GVHD increases every decade. Improvements in supportive care and the increased use of reduced intensity transplants using nonmyeloablative conditioning regimens and PBSCs allow increased use of transplantation to older individuals. Early side effects are markedly decreased by the nonablative approach, which is medically feasible in most older patients.²⁰⁵ A systematic prospective study showed that because of clinical, administrative, and donor availability issues, only a small fraction of older patients in first CR can in fact proceed to transplantation.²⁰⁶ Nonetheless, because the results are poor with chemotherapy in older adults and are better (at least with those who make it to transplant (35% disease-free survival) with reduced-intensity alloSCT, it is generally accepted as feasible for adults up to age 75.
   
2. 2. Less than one-third of potential recipients have suitable HLA-matched family donors. Alternatives include the use of matched unrelated donors, partially mismatched family donors, haploidentical donors, or cord blood preparations. Administrative delays in identifying suitable donors remain problematic despite the availability of millions of HLA-type donors worldwide.²⁰⁷ This is particularly true for patients from ethnic minority groups with less common HLA types and also indicates that there is considerable selection bias in reports of unrelated donor transplants, because some higher-risk patients relapse while awaiting for a donor to be identified. Nonetheless, with the use of molecular histocompatibility typing, the results following unrelated allogeneic transplant are equivalent to those with matching sibling transplant extending the use of allogeneic transplant for a much larger group of patients with AML in first remission.^{208, 209} Umbilical cord blood may offer an alternative source of stem cells for those without matched siblings or unrelated donors. The incidence of GVHD is much lower following cord blood transplants despite the fact that many of these transplants use mismatched donors. Engraftment can be delayed, however, and dosage considerations represent an issue for many adult recipients, although the use of double cord transplants has helped to address this problem.^{210, 211} At present, haploidentical transplantation from partially matched siblings, parents, or children is also available, and hence donors are available for almost all recipients, although the relapse rate may be higher than that with matched donor.²¹²
   
3. 3. Although allogeneic SCT can cure some patients with chemotherapy-resistant disease, there remains an appreciable relapse rate and at least some of the factors predictive of drug resistance and relapse after chemotherapy also apply to SCT recipients.^{213, 214}
   
4. 4. The antileukemic effect following BMT correlates with the occurrence and severity of GVHD, presumably as a result of a graft-versus-leukemia effect. Attempts to attenuate GVHD with a variety of immunosuppressive approaches are associated with a decrease in GVHD, but also an increase in the relapse rate.²¹⁵ Selective T-cell depletion approaches and other immunologic manipulations of the graft are being evaluated in an attempt to make allogeneic SCT safer without an increased relapse risk.^{216, 217}
   
5. 5. As many as 10–20% of surviving patients may have significant symptoms and impairment of performance status because of chronic GVHD. There is also a small increase in the frequency of secondary tumors in long-term survivors.²¹⁸

There seems little controversy about the advisability of using a HIDAC-based postremission approach for those with CBF cytogenetic abnormalities and in using an allogeneic transplantation-based approach for those with adverse prognosis based on molecular or karyotypic findings at diagnosis. However, there still remains controversy about handling intermediate-risk patients, particularly those with normal chromosomes. Meta-analysis have suggested that in general, all patients with nonfavorable cytogenetics should fare slightly better with an SCT approach.^219–221 The only subgroup in the intermediate prognosis group for whom this is not clear-cut is those with normal cytogenetics and an NPM1 mutation but without a FLT3 ITD mutation. Survival rats of patients treated by a chemotherapy-based approach are higher, and it would be reasonable to reserve SCT for second remission for such patients as well as for those with favorable translocations.

Hematopoietic growth factors

Because of the higher myelosuppression-associated toxicity and mortality, particularly in older adults with AML, the development of hematopoietic growth factors (HGFs) ameliorated such side effects. Granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and interleukin (IL)-3 as well as the thrombopoietic factors, megakaryocyte growth and development factor (MGDF), IL-11, and the newer thrombopoietic agents (romiplostim and eltrombopag) were evaluated. The use of these agents in AML lagged behind that in solid tumors, because of the concern that pharmacologic doses would lead to blast proliferation and a poor clinical outcome. Although adverse effects of this clinical problem have not been proved, the HGFs have not lived up to their promise for other reasons.

Multiple randomized studies have been completed in which older patients received an HGF or placebo following the completion of initial induction therapy, with the goal of increasing CR rate by reducing infectious complications as a consequence of shortened durations of severe myelosuppression.^254–259 All trials noted a decrease in the order of 2–5 days in the number of days of neutropenia <500/μL, sometimes in association with a smaller 1- to 2-day reduction in the duration of hospital stay, but with the exception of a smaller trial reported by the ECOG,²⁵⁴ there was no significant difference in the incidence of severe infection, deaths from infections, CR rate, or survival. One randomized trial using G-CSF after induction therapy for older patients with AML showed an increased CR rate for the G-CSF recipients.²⁵⁸ Unexpectedly, the infectious mortality was similar in the two groups of patients, and the reason for the increased CR rate is unclear. There was no difference in OS.

In conclusion, the benefits of growth factors administered after the completion of induction therapy are modest at best.²⁶⁰ By contrast, G-CSF following intensive consolidation therapy has appreciably shortened the duration of neutropenia, albeit without improvement in CR duration or survival.¹⁹⁰ Because of the potential for eliminating the need for hospitalization, the use of HGF can be recommended following consolidation therapy. Smaller studies with pegylated thrombopoietin failed to show reduced needs for platelet transfusions during the induction or consolidation treatment of AML.²⁶¹ The thrombopoietin agonists romiplostim and eltrombopag, each approved in steroid-refractory ITP, have been used in clinical trials in MDS,^{262, 263} but evidence suggesting leukemia cell stimulation has precluded use in AML and MDS.

Although in vitro evidence suggests that HGFs can increase the cytotoxic effects of ara-C, at least in part by increasing the fraction of cells in S-phase,^{264, 265} clinical results with the priming strategy have been disappointing. An early study from the MD Anderson Group suggested that GM-CSF administered before and during chemotherapy produced lower response rates and survival than those observed in a historical control group treated with chemotherapy only.²⁶⁶ Most subsequent studies that randomized patients to receive GM-CSF/G-CSF or no marrow stimulants, before, during, and/or after induction chemotherapy^267–269 also failed to show an advantage for patients primed with growth factor. Some of these studies used HIDAC, whereas others evaluated more conventional continuous infusion schedules. One of the studies purporting to show an advantage²⁷⁰ could not be confirmed in a follow-up investigation.

Hyperleukocytosis

Leukemic blasts are considerably less deformable than mature myeloid cells³¹⁷ and are “stickier” than lymphoblasts because of the expression of cell surface adhesion molecules. With increasing blast counts, usually at levels >100,000/μL in the myeloid leukemias, blood flow in the microcirculation can be impeded by plugs of these more rigid cells. Local hypoxemia may be exacerbated by the high metabolic activity of the dividing blasts, with endothelial damage and hemorrhage. Red blood cell transfusions can potentially further increase the blood viscosity and make the situation worse and should be either withheld or administered slowly, until the WBC decreases. Coagulation abnormalities, including DIC, further increase the risk of local hemorrhage. Liberal use of platelet transfusions is recommended, particularly because the platelet count is frequently overestimated because of the presence of fragments of blasts on blood smears, which can be mistakenly counted as platelets by automated blood cell counters.³¹⁸

Although pathologic evidence of leukostasis can be found in most organs in patients with extremely high blast cell counts, clinical symptomatology is usually related to CNS and pulmonary involvement.^{319, 320} Occasionally, dyspnea with worsening hypoxemia can occur following therapy and lysis of trapped leukemic cells. Spurious elevation of serum potassium can occur because of the release from WBCs during clotting, and it is sometimes necessary to measure potassium levels on heparinized plasma. Similarly, pO₂ can appear falsely decreased because of the enhanced metabolic activity of the WBCs, even when the specimen is appropriately placed on ice during transport to the laboratory. Pulse oximetry provides an accurate assessment of O₂ saturation in such circumstances. Hyperleukocytosis is more common in patients with myelomonocytic or monocytic leukemia, and it is possible that the clinical manifestations are exacerbated by the migration of leukemic promonocytes into tissue where further proliferation occurs.

The initial mortality rate for patients with AML and symptomatic hyperleukocytosis is high.³²⁰ If patients survive the initial period, they tend to have somewhat lower remission rates and shorter CR durations. Symptomatic hyperleukocytosis in AML (and rarely in ALL) constitutes a medical emergency, and effort should be made to lower the WBC count rapidly. In most patients, rapid cytoreduction can be achieved by chemotherapy, with either standard induction agents or high doses of hydroxyurea (3 g/m²/day). Some centers also advocate low-dose cranial irradiation, including the retina, to prevent further proliferation of leukemic cells in CNS sites, where drug delivery may theoretically be compromised. This treatment is well tolerated, although there are no comparative studies to determine whether the results are superior to chemotherapy only.

In some patients, it is impossible to initiate chemotherapy immediately because of renal insufficiency, metabolic problems, delays in initiating allopurinol therapy to prevent hyperuricemia, or similar considerations. In such patients, emergency leukapheresis has been used to lower or stabilize the white count.^{321, 322} Although intensive leukapheresis, with procedure times often lasting many hours, can improve pulmonary and CNS symptomatology, there are theoretic and practical limitations to its benefits. It is difficult, for example, for leukapheresis to affect already established vascular plugs, particularly if vascular invasion has taken place. In such cases, chemotherapy is the primary modality, although theoretically, leukapheresis could decrease further accumulation of leukocytes at these sites. Furthermore, it is precisely the patient in whom leukostasis is most likely to occur, that is, the patient with high and rapidly rising blasts counts, in whom the technical limitations of leukapheresis are apparent, in that it is often difficult, even with highly efficient cell separators, to reduce the rising count. In such patients with a high proliferative thrust, cycle-specific chemotherapeutic agents are more likely to be most immediately effective. Leukapheresis is also of modest benefit to patients who develop pulmonary problems during cytotoxic treatment, because in some such patients, the symptoms are related at least in part to a local inflammatory response following leukocyte lysis.³²³

Ophthalmic complications

Essentially every ocular structure can be involved in the leukemias, sometimes dominating the clinical picture in the prechemotherapy era.³³⁰ Leukemia cells can infiltrate the conjunctiva and lacrimal glands, producing obvious masses that may require treatment with radiation therapy. Involvement of the choroid and retina is most common, however. A prospective study of 53 newly diagnosed adults with AML documented retinal or optic nerve abnormalities in 64% of patients.³³¹ Hemorrhage and cotton wool spots (a consequence of nerve fiber ischemia) were most frequent, and the occurrence of these findings was unrelated to patient age, FAB type, WBC count, or hematocrit. Initial platelet counts were lower in patients with retinopathy. A total of 10 patients had decreased visual acuity, including five with macular hemorrhages. It was felt that many of the cotton wool spots were either a consequence of or exacerbated by ischemia due to anemia. Definite leukemic infiltrate of the retina could not be confirmed. All patients received aggressive chemotherapy and platelet transfusion support; no patient received cranial or ocular irradiation. All ocular findings resolved in patients achieving CR and there was no residual visual deficit in any patient. Infectious ocular problems were not noted and seem to be uncommon, perhaps because the prompt empiric use of antibacterial and antifungal antibiotics has decreased the possibility of hematogenous spread of infections to the eye.

Pregnancy

AML is occasionally diagnosed in pregnancy, either because of clinical manifestations or as an incidental finding during blood count checks. If detected during the first trimester, termination of pregnancy followed by treatment of the leukemia is advisable. The management of patients diagnosed later in pregnancy, such as late in the second trimester or during the third trimester, is more problematic. If the leukemia is relatively indolent, it is sometimes possible to manage patients conservatively with leukapheresis and/or transfusion with induction of labor and delivery of the fetus as soon as possible.³³² There have also been many reports of patients treated with chemotherapy later in their pregnancy.^{333, 334} The majority of these women have not aborted, and there has been no report of leukemia occurring in children or an increased incidence of abnormalities in infants.

Metabolic abnormalities

Patients receiving therapy for AML can experience a wide range of metabolic problems such as vomiting, diarrhea, impaired nutrition, or renal dysfunction, usually because of side effects from antibiotics, particularly amphotericin B. Some metabolic disorders are related to the leukemic process itself. Hyperuricemia, occasionally accompanied by urate nephropathy with renal insufficiency, is the most frequent metabolic accompaniment of AML. All patients should receive allopurinol (≥300 mg/day) as soon as the acute leukemia is diagnosed, so that chemotherapy can be administered once it is medically appropriate. In most patients, urate nephropathy can be avoided or ameliorated with vigorous hydration and urinary alkalization with systemic or oral administration of sodium bicarbonate. Allopurinol can usually be discontinued within 1 or 2 days after chemotherapy is completed. In occasional patients with markedly elevated levels of uric acid, the use of recombinant urate oxidase, which can rapidly lower levels within a few hours, may be advisable.³³⁵ A single dose is almost always sufficient, and the decision about subsequent doses depends on serial monitoring of uric acid.³³⁶

Tumor lysis syndrome occurs more frequently in patients with ALL, although some AML patients experience hyperphosphatemia, hypocalcemia, hyperkalemia, and renal insufficiency because of massive leukemic cell death. The inciting cause seems to be the release of large amounts of phosphate from lysed blasts, which coprecipitates with calcium in the kidneys, leading to hypocalcemia and sometimes to oliguric renal failure. Hyperuricemia further contributes to this problem, which is usually self-limited and responds to judicious hydration.

Despite markedly hypercellular marrows, hypercalcemia is extremely unusual in patients with AML. Severe, occasionally symptomatic, hypokalemia is frequent, particularly in patients with monocytic leukemias. The mechanism appears to be renal potassium loss because of tubular damage induced by the high levels of lysozyme often noted in these patients. Aggressive replacement with parenteral potassium is required; the syndrome usually abates after cytoreduction by chemotherapy. Finally, rare patients have been described in whom lactic acidosis has been a constant metabolic accompaniment of the leukemia both at the time of presentation and relapse.³³⁷ The mechanism is unclear, although anaerobic metabolism by the leukemia cells at sites of leukostasis has been postulated.

Summary

Largely because of improvements in supportive care and the anticipatory management of complications of the treatment and underlying disease, the overall outlook for adults <60 years of age with AML has improved worldwide. It is equally clear, however, that results have leveled off and that new approaches are needed to increase the fraction of patients cured. Dramatic advances in molecular genetics offer promise both because of increased understanding of leukemia biology and the production of small molecules, monoclonal antibodies, cytokines, and HGF with potential clinical utility. Further clarification of mechanisms of drug resistance with the possibility of enhancement of the effectiveness of currently available drugs is also an exciting and achievable prospect. These strategies, as well as clinical trials designed to assess the appropriate use of SCT and newer more specifically targeted drugs, determine that therapy for AML will be both more successful and less empiric in the future.

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