It is believed that acute myeloblastic leukaemia arises in a haematopoietic stem cell as a result of mutations which promote growth or inhibit apoptosis arising in association with mutations that inhibit differentiation. In most cases there is no obvious cause, but exposure to chemical and ionizing radiation may be relevant, including previous chemotherapy for solid tumours.
Clinical features and diagnosis
Clinical features—typical manifestations are those of marrow failure, most commonly symptoms and signs of anaemia and of bleeding (petechiae, purpura, from mucous membranes). Acute promyelocytic leukaemia is a medical emergency characterized by bleeding and disseminated intravascular coagulation.
Diagnosis—the key investigations are examination of peripheral blood and bone marrow for blast cell infiltration, with classification and prognosis of disease depending on morphology, immunophenotyping, karyotyping, and definition of particular molecular mutations.
Treatment and prognosis
General approach—aside from providing appropriate supportive care, the first clinical decision to be made in an individual patient is whether to undertake conventional intensive chemotherapy aiming for disease eradication, or to adopt a more palliative approach. Intensive chemotherapy is the norm up to age 60 years, but the biology of the disease tends to be less favourable above this age (e.g. more adverse cytogenetic abnormalities and expression of multidrug resistance genes), and patients develop comorbidities and become less generally fit.
Initial chemotherapy—(1) Intensive chemotherapy—this typically involves the combination of daunorubicin and cytosine arabinoside (cytarabine, ara-C), which achieves complete remission in 40 to 80% of cases, followed by consolidation chemotherapy comprising a second course of induction treatment and then courses of ara-C with or without additional agents (e.g. amsacrine, etoposide, mitoxantone). (2) Less-intensive chemotherapy—most often comprises hydroxycarbamide (hydroxyurea) or low doses of ara-C. (3) Acute promyelocytic leukaemia—this is exquisitely sensitive to all-trans-retinoic acid, which is given concurrently with chemotherapy.
Relapsed disease—more than 50% of patients will ultimately relapse and their overall outcome is generally very poor. The only curative option is allogeneic bone marrow transplantation if a second complete remission can be achieved with reinduction chemotherapy
Prospects for the future
Increasing knowledge of the underlying biology may allow treatment with small molecules that inhibit the effects of the more common molecular mutations. However, unlike chronic myeloid leukaemia (which is characterized by a single molecular abnormality), a single inhibitor is not going to offer corrective therapy.
Epidemiology and causation
The median age at presentation is 68 years. Acute myeloid leukaemia (AML) occurs at all ages, ranging in frequency from 3 per million up to 12 to 15 per million patients in their 70s and 80s. This age range has implications for treatment. In most cases there is no obvious cause; however, it is known that chemical and ionizing radiation exposure can be leukaemogenic. Several diseases of older patients evolve from the related disorder myelodysplastic syndrome, and indeed the boundary between the diseases is sometimes hard to define. The current international consensus defines AML as over 20% blast cells in the bone marrow. At this level, marrow function is usually compromised requiring intervention. An increasing risk of chemotherapy in general is that it may be leukaemogenic, and the development of AML represents a late complication of treatment of solid tumours, which is becoming more often seen as chemotherapy becomes more successful.
At the molecular level it is believed that AML is an example of multi-hit pathogenesis, with mutations which promote growth or inhibit apoptosis, arising in association with mutations that inhibit differentiation. Molecular abnormalities that have such effects are being increasingly recognized.
The heterogeneity of morphology which reflects the ability of the leukaemic blast to achieve some degree of differentiation gave rise to a commonly accepted morphological classification known as the French–American–British (FAB) classification. With the increasing availability of high-quality monoclonal antibodies, immunophenotypic confirmation gave some objectivity to the diagnostic process. Over 30 years ago it was being recognized that various chromosome abnormalities were present in the blast cells. These were nonrandom and comprised balanced translocations, deletions, and trisomies. In about 40% of cases only a normal karyotype could be found. Some of these abnormalities corresponded to the morphological subtype. It took a number of years for the clinical community to feel that this was useful knowledge. However, it is now recognized that the karyotype is the strongest predictor of response to therapy, and is now an essential part of the diagnostic process.
Currently a similar awakening is underway with the recognition that molecular abnormalities are often found. The most common are mutations of the FMS receptor FLT3, NPM1, CEBPα, RAS, and c-KIT. These represent in some cases additional strong independent prognostic factors, but may become the target of a new generation of molecular-based therapies.
Bullet list 1 Prognostic factors
- ◆ Age
- ◆ Cytogenetics
- ◆ Presenting white cell count
- ◆ Secondary disease
- ◆ Performance score
- ◆ FLT3/NPM1 mutation status
- ◆ Expression of resistance phenotype
- ◆ Marrow response to first chemotherapy course
The following are among the main characteristics that independently predict how a patient will respond to treatment. Most apply to the prospect of initial treatment achieving complete disease remission, and to overall survival. Performance score is only useful for predicting response to induction treatment. It should be mentioned here that these factors have been defined in the setting of large clinical trials, into which poor performance patients may not be entered.
These factors are shown in Box 126.96.36.199. Cytogenetics has been most widely adopted, and can guide treatment decisions such as who should be subjected to allogeneic transplant. Grouping the more favourable abnormalities (t(8;21), inv(16), and t(15;17)) and the poorer group abnormalities (of chromosomes 5 or 7, 3q–, complex) leaves about 60% of patients as at standard risk. As can be seen in Fig. 188.8.131.52, this subdivision has a major impact on survival. One of the reasons that older patients respond less well to the same chemotherapy is that older patients tend to have a high proportion of adverse features, in contrast to younger patients.
Treatment of AML
Because of the variation of disease and patient biology, treatment and the assessment of treatment is complex. Treatment outcomes have improved over the years in children and adults under 60 years, but there is little sign of such progress in older patients. Chemotherapy has continued with similar chemotherapeutic agents over the years, and it is easy to attribute the better outcomes to improved supportive care, which in turn has allowed treatment to be given in a more intensive way.
Definition of remission
The standard definition of ‘remission’ is that the bone marrow should show evidence of trilineage activity with less than 5% blasts, and peripheral blood counts should have returned to at least 100 × 109/litre for platelets and 1.0 × 109/litre for neutrophils. Molecular and other markers of disease still indicate the presence of the leukaemic clone, and it is well established that failure to deliver further courses of treatment to consolidate the response will result in rapid regrowth of disease.
The first clinical decision to be made in an individual patient is whether to undertake conventional intensive chemotherapy aiming for disease eradication, or to adopt a more palliative approach. The aim of intensive chemotherapy is to kill off the leukaemic population, which then enables normal haemopoiesis to re-establish itself.
The combination of the anthracycline daunorubicin and the antimetabolite cytosine arabinoside (cytarabine, ara-C) has been the mainstay of treatment of AML for nearly 40 years with the intention of inducing complete remission (CR) and curing the disease. Such a combination is extremely myelosuppressive and is associated with a significant risk of infection and severe systemic toxicity. Among younger patients there is a risk of death during induction therapy of almost 10%, usually due to infection or bleeding. Such toxicity may limit the applicability of such a regimen to the treatment of older adults who constitute the majority of patients with AML. Patients who achieve CR will continue with further courses of chemotherapy, at approximately monthly intervals, to consolidate the remission and reduce the risk of relapse.
In the United Kingdom, initial induction therapy for younger people (<60 years of age) comprises 3 days of daunorubicin at doses of 45 to 50 mg/m2 (usually given on days 1, 3, and 5) with 10 days of ara-C 200 mg/m2 daily. In the United States of America this is usually shortened to a 7-day continuous infusion of ara-C, the so-called 3+7 approach. There are other apparent differences between the United States and the United Kingdom. Comparison of large national trials has not shown convincing evidence that the addition of a third drug, usually etoposide or thioguanine, improves the outcome of induction treatment in younger adults since the additional leukaemia cell kill is potentially offset by increased toxicity. Equally, attempts to improve outcomes with alternative anthracyclines (idarubicin or mitoxantrone) have shown no advantage. The United Kingdom Medical Research Council (MRC) AML12 trial compared mitoxantrone with daunorubicin, in combination with either etoposide or thioguanine, and found no overall difference in long-term outcome. In general, daunorubicin remains the anthracycline of choice.
Cytarabine remains one of the most active drugs in the treatment of AML. Several groups have increased the dose up to 3 g/m2 in induction with mixed results. At these high doses there is significant skin, renal, and central nervous system toxicity. However, certain subsets of AML, particularly the core binding factor leukaemia associated with t(8;21) and inv(16), are particularly sensitive to ara-C and may benefit from this approach. Newer analogues of cytarabine such as clofarabine are now entering randomized trials.
Outcomes of treatment
Between 40 and 80% of patients will achieve CR with this approach. Factors influencing the chance of CR include age at diagnosis, cytogenetic abnormalities, and expression of multidrug resistance genes (p-glycoprotein). For example, 75 to 80% of patients under 60 will achieve a CR, compared with 45 to 55% of older patients given the same treatment schedule.
Indications for further chemotherapy
At least 70% of those attaining CR will do so after a single course of chemotherapy. The usefulness of adding a third drug to this conventional induction is disputed. However, in recent years, it has become feasible to conjugate chemotherapeutics with antibodies as a means of targeting the antileukaemic potential without increasing toxicity. The archetypal agent in AML is gemtuzumab ozogamicin, which is a CD33-targeted immunoconjugate of the anthracycline-like drug, calicheamicin. CD33 is a transmembrane protein expressed on the cells of 95% of patients with AML. On binding antibody, it is rapidly internalized, and free calicheamicin is released causing genotoxic damage. Early studies with the combination of gemtuzumab ozogamicin with conventional chemotherapy are reporting an improved level of disease control—i.e. reduced relapse risk in younger patients.
Consolidation of chemotherapy
Patients who achieve CR will require further consolidation chemotherapy. A second course of the initial induction treatment is followed by two or three further courses of alternative drugs. High doses of ara-C (1.5 g/m2) are common in the United States of America, whereas the combination of ara-C with amsacrine, etoposide, or mitoxantrone is favoured in the United Kingdom. There is no clear difference in outcome rates with the two approaches, which have been compared directly in the United Kingdom MRC AML15 trial. It also remains unclear as to whether a total of four or five courses of treatment is ideal.
Treatment of older patients
Age is a major factor determining CR rates and long-term outcome. Older age is associated with the onset of significant comorbidities such as hypertension, lung disease, and renal impairment, which limit chemotherapy delivery. Similarly, the biology of leukaemia appears to change as people age, with a higher incidence of adverse genetic changes and multidrug resistance in older patients. Consequently, older people tend to do less well than younger patients with AML.
The age of 60 years is frequently taken as an arbitrary threshold for the use of the term ‘older’. Up to this age there is little doubt that intensive chemotherapy should be the norm; however, with increasing age, patients develop comorbidities and become less generally fit. This makes intensive treatment more risky. In addition the biology of the disease is less favourable, with a higher proportion of patients with secondary AML, more with leukaemia that has associated resistance proteins within the leukaemic population, and a higher proportion with an adverse risk karyotype. A number of epidemiological studies indicate that as many as 40% of older patients are not treated with intensive chemotherapy and receive supportive care only with hydroxycarbamide (hydroxyurea). Older or less fit patients may do better with a more palliative approach to their disease. There has been much recent interest in the development of treatments for this patient group. A major national trial in the United Kingdom attempted to analyse which patients would benefit from these two approaches, but was unable to recruit adequate numbers of patients to the randomization. Nonetheless, the same trial was able to demonstrate that low doses of ara-C given subcutaneously (20 mg twice daily for 10 days) repeated at 4- to 6-week intervals is superior to the orally active ribonucleotide reductase inhibitor hydroxyurea. Indeed, one in six patients will gain CR with this approach, although these remissions tend to be less durable than those seen in younger patients treated with conventional doses of chemotherapy. However, overall the outlook for older patients with AML remains very poor.
Treatment of relapsed AML
Despite 60 to 80% of patients with AML attaining CR with induction chemotherapy, more than 50% of these will ultimately relapse with their disease. Induction with intensive chemotherapy remains an option for these patients, but the overall outcome is generally very poor. Remission rates with reinduction are less than in first presentation, and remissions are generally of shorter duration. The only curative option is to proceed to an allogeneic bone marrow transplantation when in CR2. No randomized trial has shown a superiority of one reinduction regimen over another, but the combination of fludarabine (a purine analogue) with ara-C and idarubicin with granulocyte-colony stimulating factor (G-CSF) support is one favoured regimen.
In recent years the molecular-genetic heterogeneity of AML has become better understood. This is now introducing the era of targeted therapy, the prime example of which is the modern management of the APL subtype. Recently several genetic mutations have been described which influence prognosis and relapse risk. Fms-like tyrosine kinase 3 (FLT-3) is a type 3 tyrosine kinase receptor expressed in bone marrow, brain, and gonadal tissue. An activating tandem duplication resulting in the insertion of a variable number of in-frame base pairs has been described leading to a constitutively active protein resulting in increased cell survival pathways. This mutant, or an activating point mutation (D835Y), is present in approximately one-third of patients with AML and is associated with an adverse prognosis from an increased relapse risk. CEP-701 is an orally active inhibitor of FLT-3 and may decrease the relapse risk in early-phase clinical trials. Other potentially useful agents include tipifarnib (an inhibitor of farnesyl transferase which is required for RAS activation) and arsenic trioxide (which is active in APL, including relapsed disease, in combination with low doses of ara-C).
Maintenance chemotherapy and DNA methylation
In many human cancers, including leukaemia, genomic DNA is frequently hypermethylated. This methylation, occurring on CpG tandem repeats, results in gene silencing. The cytotoxic purine analogue 2-deoxyazacytidine is incorporated into DNA, but the nitrogen atom in the 5-position of the purine ring cannot be methylated. At low doses, this agent and its RNA dependent counterpart, azacytidine, result in demethylation of DNA allowing increased gene expression.
Traditionally, maintenance therapy has not been shown to be of benefit in AML, unlike in acute lymphoblastic leukaemia (ALL), where prolonged maintenance chemotherapy substantially reduces the risk of relapse, and, more recently, in APL as discussed above. However, the potential of these hypomethylating agents to induce epigenetic changes is now being explored as a maintenance treatment for older patients in remission after receiving intensive induction chemotherapy.
Bone marrow transplantation
Having entered remission, the main challenge is to prevent relapse. There is no doubt that the most effective approach is to administer myeloablative chemoradiotherapy followed by infusion of haematopoietic stem cells. These have been obtained from an HLA-matched sibling donor as bone marrow cells. This approach reduces the risk of disease relapse from 40 to 50%, to 10 to 15%. This powerful antileukaemic effect is partly due to the myeloablation and partly due to the associated ‘graft versus leukaemia’ mediated by donor T lymphocytes in the graft. Unfortunately, it has not been possible to fully realize the antileukaemic potential of allogeneic transplantation because to the associated risks of graft-versus-host disease and immunosuppression which usually involve a life-threatening risk of 30%. The risks increase with age and in the United Kingdom experience, there is no overall survival benefit seen in patients older than 35 years. The development of large donor banks has made the finding of a matched unrelated donor a practical possibility, and the results of this approach are now equivalent to those using a matched sibling. Allografting involving reduced intensity conditioning has become well developed. Here the mechanism is primarily immunological. It was initially thought that this approach would be more suitable for chronic lymphoproliferative diseases, but data now emerging suggest that this is also a feasible approach in AML in older patients up to the age of 70 years. There are, however, no controlled studies to provide information about how much better, if at all, this is than chemotherapy.
As discussed above, once patients enter remission, they are at differing risks of relapse, based on their cytogenetic group. It is unlikely that patients with favourable cytogenetics will benefit, because the additional reduction in relapse risk is more than outweighed by the treatment risks. For patients at intermediate risk, there are mixed opinions, but no convincing evidence of overall survival benefit in United Kingdom prospective trials. Most would accept that patients with bad risk disease should undergo a transplant as soon as the risk is known. Such patients will have a higher risk of relapse after the transplant, but they have a very poor outcome with chemotherapy alone.
For patients who relapse from chemotherapy and enter a second remission, the prospects for cure are poor and are largely dictated by the length of CR1. It is axiomatic that second remissions will be shorter that first remissions. Transplantation is the only treatment that can change this and is indicated for all patients who relapse, where it offers a 30 to 40% chance of salvage.
Supportive care in AML
The steady but significant improvements seen in disease survival rates over the last 30 to 40 years have been facilitated by the development of better supportive care strategies which have allowed the safer intensification of chemotherapy regimens.
Following diagnosis of AML, early mortality can result either directly from presenting complications of the disease, from the direct consequences of treatment initiation, or from problems arising during the 3 to 4 weeks of profound pancytopenia that inevitably follow remission induction chemotherapy. Effective supportive care during this period requires close coordination between specialists from a number of disciplines including haemato-oncologists, microbiologists, radiologists, intensivists, specialist nurses, pharmacists, and dieticians working in facilities dedicated to the care of this type of patient. Clear written standards should be adhered to, including local policies for infection prophylaxis and treatment, national guideline documents, and, where appropriate, clinical trial protocols.
Supportive care at the initiation of therapy
The presenting clinical features of AML vary according to both the depth of bone marrow failure and the rate of turnover of the leukaemic clone. Prompt chemotherapeutic intervention is required in cases with high rates of blast proliferation but, paradoxically, rapid cell kill may lead to life-threatening metabolic disturbances.
Although a feature of only a minority of cases, a high presenting white cell count (WCC) is a well-established poor prognostic factor in AML. Patients with hyperleucocytosis (WCC > 100 × 109/litre) are at a threefold greater risk of early mortality (15%) than those with lower counts. Hyperleucocytosis predisposes to hyperviscosity and leucostasis. ‘Sludging’ in the microvasculature, particularly of the lungs and brain, clinically manifests most frequently as hypoxia and central nervous system dysfunction and carries significant risks of both thrombotic and haemorrhagic sequelae. The effects of hyperviscosity may be partially offset at presentation by the presence of concurrent anaemia: red cell transfusion should thus be delayed, unless absolutely unavoidable, until the WCC has been reduced. Oral hydroxycarbamide (hydroxyurea) may be of practical value in reducing the WCC prior to the commencement of formal induction chemotherapy. Leucapheresis is generally safe and, although evidence is lacking, may be considered in patients presenting with symptomatic hyperleucocytosis. However, leucapheresis may fatally exacerbate the presenting coagulopathy of APL and should be avoided in this setting.
Tumour lysis syndrome and metabolic complications
Acute tumour lysis syndrome (ATLS) describes a collection of metabolic abnormalities including hyperuricaemia, hyperphosphataemia, hypocalcaemia, and hyperkalaemia that result from the release of nuclear and cytoplasmic degradation products from malignant cells and may precipitate acute renal failure. It is vital that treating physicians are aware of the risks of ATLS, particularly when instituting cytoreductive therapy in AML patients with hyperleucocytosis or bulky extramedullary disease. Emergency haemodialysis may be required in the event of acute renal failure, rising potassium levels, or recalcitrant hyperphosphataemia.
Standard measures to prevent ATLS prior to the commencement of chemotherapy include use of the xanthine oxidase inhibitor allopurinol (300 mg daily) coupled with vigorous intravenous hydration and with meticulous monitoring of fluid balance and electrolyte levels as induction therapy commences. Alkalinization of the urine using intravenous bicarbonate has been used historically to reduce tubular uric acid crystal deposition, but it remains controversial as it carries the potential for both reducing tubular xanthine solubility and exacerbating calcium pyrophosphate deposition in organs including the heart. The recombinant urate oxidase enzyme rasburicase is able to rapidly reverse hyperuricaemia by promoting the breakdown of uric acid into allantoin. It is now the treatment of choice in patients with hyperleucocytosis at presentation, renal failure, or early evidence of evolving ATLS. Rasburicase also avoids any need for urinary alkalinization.
Hypokalaemia is also frequently encountered in AML patients, both at presentation (due to high serum lysozyme levels particularly in monocytic subtypes M4 and M5) or later as a consequence of prolonged diarrhoea or the renal tubular effects of amphotericin. Vigorous intravenous electrolyte supplementation is frequently required.
Other supportive measures prior to starting cytotoxic therapy
Secure central venous access is usually established through insertion of a tunnelled Hickman line or temporary central line, allowing safe administration of vesicant drugs, blood products, and intravenous antibiotics, as well as facilitating frequent blood-sampling procedures. Young men should be counselled regarding potential loss of fertility and, whenever possible, offered the opportunity to store sperm. Loss of fertility due to chemotherapy is less common in women: in vitro preservation of unfertilized ova is not yet undertaken routinely. There is a high risk of severe emesis with intensive chemotherapy, and strenuous efforts should be made to prevent this distressing complication. Serotonin antagonists (ondansetron or granisetron) are a standard first choice, although combination therapy is often necessary.
Supportive care during chemotherapy-induced pancytopenia
Clearance of leukaemic blasts by induction chemotherapy is achieved at the expense of 3 to 4 weeks of severe pancytopenia, and similar cytopenic episodes will follow subsequent courses of consolidation therapy. During these periods, patients remain at high risk: prompt access to blood product support and robust procedures to prevent and manage neutropenic infections are vital.
Blood product support
By the time of initial disease presentation, the ability of most patients to produce red cells and platelets is severely impaired. Due to the often rapid onset of anaemia, there may be little time for haemodynamic compensation making many patients symptomatic due to acute impairment of oxygen-carrying capacity. In the absence of hyperleucocytosis, red cells should be transfused promptly.
Following intensive chemotherapy, patients will inevitably be dependent on regular transfusional support until bone marrow recovery. Although there is no firm evidence to support a particular red cell transfusion threshold, many units operate a policy of transfusing as required to maintain haemoglobin levels in excess of 8 g/dl. All patients in whom allogeneic stem cell transplantation is a possibility should be transfused cytomegalovirus (CMV)–negative cellular products until their CMV status is known, while those treated with cytotoxic regimes containing purine analogues (fludarabine or clofarabine) should receive irradiated blood products to minimize the risk of transfusion-associated graft-versus-host disease.
In general, one adult therapeutic dose of platelets should be transfused whenever the platelet count falls to below 10 × 109/litre. Platelet survival may be further compromised by sepsis or the use of concurrent intravenous antibiotics, and in these situations or in the presence of additional haemostatic abnormalities a higher transfusion threshold of 20 × 109/litre is usually observed. Antifibrinolytic agents such as tranexamic acid may be useful for local mucosal bleeding but are contraindicated in the presence of haematuria due to the potential for ureteric clot formation.
The risk of infection in AML is influenced by both the degree and duration of neutropenia and increases markedly during episodes of chemotherapy-induced bone marrow aplasia. Changes to the bacterial flora as a consequence of broad-spectrum antibiotic use, and poor nutritional status following prolonged periods of hospitalization also contribute significantly. The vast majority of AML patients will become febrile at some point, although only a minority of these episodes will be accompanied by symptoms or signs of localizing infection. Sepsis should be suspected in the presence of any sudden nonspecific clinical deterioration; inflammatory responses may be muted in the neutropenic setting and may be associated with hypothermia, declining mental status, myalgia, or increasing lethargy. Potential portals of bacterial entry include indwelling lines and chemotherapy-induced breaches in the integrity of the bowel mucosa.
Neutropenic patients should be advised to pay particular attention to personal hygiene and dental care. Careful hand-washing and decontamination before patient contact is mandatory for health care workers. The role of prophylactic antibiotic therapy remains contentious. Prophylactic quinolone (ciprofloxacin or ofloxacin) use is widespread, and while there is a lack of evidence for any reduction in mortality or incidence of febrile episodes, there may be a reduction in the incidence and morbidity of Gram-negative infections.
Patients should be made aware of their susceptibility to infection and provided with emergency contact details to allow rapid clinical assessment. In the presence of neutropenic sepsis, the prompt institution of broad-spectrum antibacterial therapy is potentially life-saving. Patterns of infection and pathogen isolation will vary between hospitals, and clear written guidelines for the emergency management of patients with febrile neutropenia should be decided in discussion with local microbiologists. Examples of empirical antibiotic regimes include monotherapy with a third-generation cephalosporin or carbopenem, or combination therapy with a broad-spectrum antipseudomonal penicillin and aminoglycoside. Vancomycin or teicoplanin may be added to broaden Gram-positive coverage if there are particular clinical concerns regarding indwelling line infection. Mandatory investigations include central and peripheral blood cultures, cultures of urine and stool, and a chest radiograph. Further modifications to the initial antibiotic regime should be based on culture results and regular clinical examination, although surveys demonstrate that the rate of proven bacteraemia during episodes of febrile neutropenia has remained between 20 and 25% for many years. Persistent infection or blood culture isolation of Gram-negative organisms or candida should prompt indwelling central line removal.
The risk of invasive fungal infection is high in AML patients receiving intensive chemotherapy, and its incidence increases with the severity and duration of neutropenia, often occurring in the aftermath of bacterial sepsis. Established fungal infections carry a high mortality. The diagnosis of invasive fungal infection should be confirmed wherever possible, and there is an increasing move away from the empirical use of antifungal agents as treatment of fever of unknown origin. High resolution CT scanning of the chest in patients with persistent pyrexia refractory to antibiotic therapy, and screening of patients using the sandwich enzyme-linked immunosorbent assay (ELISA) for Aspergillus galactomannan aid the early detection of invasive pulmonary aspergillosis, allowing the targeted implementation of antifungal therapy with agents including liposomal amphotericin B and caspofungin. Azole antifungal agents are widely prescribed prophylactically during neutropenia in AML. Itraconazole is the drug of choice in this setting and has activity against a broader spectrum of fungal organisms than fluconazole which is inactive against moulds including aspergillus species.
A modest reduction in duration (but not depth) of neutropenia may be achieved with the use of recombinant growth factors (G-CSF or granulocyte-macrophage colony stimulating factor) following induction and consolidation chemotherapy. Large controlled trials show variable effects on the incidence of severe infection and no clear overall survival benefit. Routine growth factor use is not recommended, although there may be cost–benefit advantages in terms of reduction in both antibiotic usage and the duration of hospital admissions.
Acute promyelocytic leukaemia
Acute promyelocytic leukaemia (APL) is a medical emergency characterized by bleeding and disseminated intravascular coagulation (DIC). It usually presents with pancytopenia rather than a raised white cell count. The diagnosis is made on morphology with a typical hypercellular marrow with characteristic heavily granulated promyelocytes, and confirmed on immunophenotyping which shows a characteristic perinuclear speckled pattern on staining for PML and cytogenetic or molecular studies for the PML-RARa rearrangement of the t(15;17) translocation.
Treatment of APL
This disease is exquisitely sensitive to treatment with all-trans-retinoic acid (ATRA), a vitamin A analogue normally present in blood. The translocation renders cells resistant to physiological concentrations of ATRA, but sensitive to pharmacological doses. ATRA is given concurrently with chemotherapy, inducing higher rates of CRs and an excellent long-term prognosis with 5-year disease-free survival of around 80%. However, treatment is associated with an increased risk of bleeding in these patients, and intense support of the coagulation system is required with blood products. Very few patients with APL who attain CR subsequently relapse, and this risk is further reduced by maintenance chemotherapy for up to 2 years following the intensive induction and consolidation chemotherapy. Further, due to the specific nature of the molecular lesion in APL, monitoring of minimal residual disease by polymerase chain reaction (PCR) allows very sensitive detection of any impending relapse. Restarting chemotherapy at the time of molecular detection of disease recurrence improves overall outcome.
Supportive care issues specific to treatment initiation in APL
Although abnormalities of coagulation may contribute to a bleeding tendency at presentation in any subtype of AML, APL and more especially its hypogranular variant (M3v) are particularly associated with a high risk of early haemorrhagic death due to a combination of DIC and increased fibrinolysis. Eighty per cent of APL patients have clinically significant coagulopathy: this condition constitutes a genuine haematological emergency that requires rapid diagnosis and prompt initiation of therapy. There is now considerable evidence that the early introduction of ‘differentiation therapy’ with ATRA alongside anthracycline-based chemotherapy improves the coagulopathy associated with APL. The platelet count and coagulation profile should be checked at least twice daily during the early stages of treatment. By employing an aggressive transfusion policy, the platelet count should be maintained above 50 × 109/litre, and coagulation times kept within the normal range using fresh frozen plasma replacement. Cryoprecipitate or fibrinogen concentrates should be used to maintain a fibrinogen level close to 2 g/litre. The use of heparin is no longer recommended.
Complications of treatment in APL
Retinoic acid syndrome (RAS; also known as differentiation syndrome) is a potentially life-threatening complication of the use of ATRA or arsenic trioxide (ATO) therapy in APL. It is caused by cytokine release from differentiating APL cells and characterized by a rising WCC with accompanying features of fluid retention and capillary leak including pulmonary infiltrates, pleural and pericardial effusions, peripheral oedema, hypoxia, and progressive respiratory failure. Standard treatment on first suspicion of RAS is dexamethasone 10 mg intravenously twice daily, with interruption of ATRA therapy and provision of respiratory support until all symptoms and signs have resolved.