Haematological malignancies

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Chapter 92 Haematological malignancies

The treatment of haematological malignancy has been an evolving success story. In recent years, the prognosis for patients with acute leukaemia has changed from death within 1–3 months without effective therapy to long-term survival and cure in many cases.^1,² In some diseases the potential for regular cure of patients has been realised, including Hodgkin’s disease, childhood acute lymphoblastic leukaemia, some high-grade lymphomas and some adult leukaemias.³ These advances have predominantly resulted from the introduction of a wide range of cytotoxic chemotherapeutic regimens which permit obliteration of the disease in conjunction with comprehensive supportive therapy. In some cases, ‘supralethal’ therapy is necessary, with bone marrow transplantation (autologous or allogeneic) being used as marrow ‘rescue’ therapy. The development of ‘engineered’ highly specific and targeted drugs is offering further promise (e.g. monoclonal antibodies, tyrosine kinase inhibitors for chronic myeloid leukaemia).¹

It is important that clinicians not regularly involved in the care of these patients do not take a nihilistic approach to management of patients with haematological malignancy. If patients can be adequately supported and complications treated during the severe neutropenic stage of chemotherapy, clinical improvement may occur rapidly following marrow recovery. However, in patients requiring prolonged ventilatory support and/or dialysis, the prognosis is poor and intensive supportive therapy can usually only be justified if marrow recovery is imminent and there is a reasonable anticipated life expectancy if the crisis can be survived.

CLASSIFICATION AND PATHOPHYSIOLOGY

The heterogeneous nature of the haemopoietic and lymphoid cells, their individual kinetic characteristics and the disseminated nature of haemopoietic and lymphoid tissue explains the complexity of haematological malignancy. The numerous confusing classification systems advocated to ‘clarify’ understanding have in many cases increased the confusion for the non-expert. In broad terms, the haematological malignancies with origins in the marrow are classified as leukaemia or multiple myeloma, and those arising in the peripheral lymphoid tissues as Hodgkin’s and non-Hodgkin’s lymphomas (nodal and extranodal).

The leukaemias are divided into acute and chronic, generally according to the time span of their clinical course. In general, a leukaemia that is blastic in appearance behaves in an acute and malignant manner with a rapidly fatal outcome without therapy. This is in contrast to the chronic leukaemias in which the cells are more differentiated (‘benign’), with the disease following a more indolent course. Leukaemias are classified on the basis of their cell of origin with broad division into those of myeloid origin (i.e. of haemopoietic marrow origin) and those of lymphoid origin (i.e. arising from the cells of the immune system).

Most patients with acute myeloid leukaemia present with features of bone marrow failure. Acute promyelocytic leukaemia is a unique subtype of acute myeloid leukaemia which may typically present with disseminated intravascular coagulation (DIC) requiring expert haematological management.⁴ Acute lymphoblastic leukaemia is the commonest encountered in children. The lymphomas are a complex and heterogeneous group of malignancies ranging from highly malignant disorders through to low-grade indolent disease not requiring therapy.

The myelodysplastic syndromes are a group of disorders in which the main feature is bone marrow dysplasia. They are a heterogeneous group of potentially malignant haematological disorders which may be the harbingers of more classic leukaemic states or may behave as slowly evolving marrow failure syndromes. They usually occur in the elderly, have an insidious onset and may have a variety of clinical manifestations.

Dysplasia may affect any of the haemopoietic elements, with the patient presenting with a range of peripheral blood abnormalities, most commonly including anaemia, thrombocytopenia and neutropenia. Diagnosis, classification, understanding of pathophysiology and therapy have undergone enormous changes in recent years and the non-specialist can be excused for feeling confused.^5,⁶ There is a rising prevalence and incidence of the myelodysplastic syndromes. Epidemiological data indicate that they are more common than initially thought and probably on the increase, especially due to the ageing population and their occurrence as a late complication of cytotoxic chemotherapy.

Awareness of these relatively common disorders is important as undiagnosed patients with relatively normal blood counts may present de novo with life-threatening infection or haemorrhage in a postoperative or trauma setting.

COMPLICATIONS OF HAEMATOLOGICAL MALIGNANCY AND ITS THERAPY

METABOLIC DISTURBANCES

At presentation, haematological malignancy may be associated with a range of metabolic derangements.⁷ Hyperuricaemia and hypercalcaemia are well-recognised complications which may be associated with renal failure.⁸ The tumour lysis syndrome is a rarer complication which may occur spontaneously or shortly after the initiation of therapy.^9,¹⁰ There is sudden liberation of intracellular contents in quantities that overwhelm the excretory capacity of the kidneys, resulting in hyperkalaemia, hyperphosphataemia, hypocalcaemia and occasionally lactic acidosis. Pre-empting the development of this syndrome usually allows control of the metabolic effects, especially with the maintenance of high intravenous fluid intake, alkalinising the urine and administration of allopurinol. More recently, intravenous rasburicase – a recombinant uricolytic agent which, in contrast to allopurinol, acts on existing uric acid concentrations – is being used for the management of anticancer therapy-induced hyperuricaemia.¹¹ Rasburicase is contraindicated in patients with methaemoglobinaemia and glucose-6-phosphate dehydrogenase deficiency.

Multiple myeloma may be complicated by renal insufficiency, hypercalcaemia, hyperviscosity and hyperuricaemia. Most of these can be managed conventionally; however, with large amounts of monoclonal protein, fluid management can be difficult due to the hypervolaemia with or without hyperviscosity and plasma exchange may be indicated (see Chapter 90).

Figure 92.1 illustrates the numerous interacting factors to be considered when managing patients with neutropenia in association with haematological malignancy and its therapy. Table 92.1 lists the organisms which may be associated with various defects in the host defence system.

Figure 92.1 The neutropenic patient. GIT, gastrointestinal tract; MRSA, meticillin-resistant Staphylococcus aureus.

Table 92.1 Organisms associated with immune deficiency states

Neutropenia

Bacteria

Gram-negative bacilli

Escherichia coli

Pseudomonas aeruginosa

Klebsiella pneumoniae

Acinetobacter

Gram-positive cocci

Staphylococcus epidermidis

Staphylococcus aureus

Streptococci viridans group

Fungal

Candida

Aspergillus

Mucormycosis

Cellular immune dysfunction Bacteria

Listeria monocytogenes

Salmonella

Mycobacterium

Nocardia asteroides

Legionella

Fungi

Cryptococcus neoformans

Histoplasma capsulatum

Coccidioides immitis

Viruses

Varicella zoster

Cytomegalovirus

Herpes simplex

Protozoa

Pneumocystis jiroveci

Toxoplasma gondii

Cryptosporidium

Humoral immune dysfunction Bacteria

Streptococcus pneumoniae

Haemophilus influenzae

PRINCIPLES OF MANAGEMENT OF HAEMATOLOGICAL MALIGNANCIES

ICU ADMISSION

Patients with haematological malignancy may be critically ill from their disease or therapy, for brief or long periods. At times during therapy they may require intensive supportive therapy and can develop a range of life-threatening complications. Rarely, it is necessary to admit critically ill patients with haematological disorders to the ICU. Under normal circumstances, admission of such patients is to be avoided as they have severely impaired host defences and poor tolerance for invasive procedures. However, mechanical ventilation may be required for severe respiratory infections or pneumonitis. Such patients may present specific problems for the ICU staff. Most patients have severe marrow failure requiring intensive transfusion support. Severe neutropenia is the main, and most life-threatening, defect in the host defence system. Nutrition can be a challenge in these patients due to a multitude of factors. The anorexia, nausea and vomiting with chemotherapy, oral mucositis, hypermetabolism, malabsorption and diarrhoea are only some of the factors mitigating against maintaining an adequate nutritional state, and parenteral nutrition may be needed if the period of therapy is prolonged.

There must be good communication between the ICU staff and clear policies on admission and treatment. If the patient’s ultimate prognosis is poor, extraordinary invasive measures cannot be justified. A palliative approach will be instituted if the patient does not respond to treatment within a specific period of time. However, if the haematological malignancy has a high likelihood of cure or long-term good-quality survival, more strenuous and extended intensive care support can be justified.

INFECTION PREVENTION

Prevention of infection is extremely important and meticulous attention to sterility with invasive procedures (e.g. i.v. line insertions) is essential. Infection may be endogenously or exogenously acquired. Most patients when they are admitted to hospital become colonised with the hospital flora. The major sources of infecting organisms, however, are the patients themselves (e.g. from the oropharynx, the gastrointestinal tract, i.v. line sites, lung and local lesions).

All ICUs must demand strict adherence to infection control guidelines. The most effective procedure is hand-washing by all health care workers involved in the care of the immunocompromised patient.

Other preventive measures include sterile techniques for invasive procedures by experienced staff, maintaining a clean environment, cooked patient meals, and limited use of prophylactic antibiotics. Needless to say, excessive use of antibiotics is a major factor in the emergence of resistant strains and the susceptibility to colonisation with hospital-acquired organisms. Many would argue that the efficacy of empirical therapy in the neutropenic patient is such that prophylaxis may be unnecessary. Reverse barrier nursing is instituted in order to minimise exposure to exogenous infection. This can be difficult in a critical care setting and will not prevent infections of endogenous origin.

INVASIVE PROCEDURES

Invasive procedures should be kept to a minimum and, when performed, appropriate steps should be taken to minimise bleeding and the risk of infection. Endotracheal intubation should be avoided or minimised if at all possible. Biopsy procedures, arterial access, and other invasive procedures should be well planned and discussed with the haematologists.

BLOOD COMPONENT THERAPY

During the period of marrow suppression red cell concentrates may need to be administered to maintain oxygen-carrying capacity at a satisfactory level. There is much debate as to the appropriate trigger for red cell transfusion. The decision is essentially a clinical one that takes into account the numerous comorbidities that may occur in these patients, such as cardiorespiratory compromise, thrombocytopenia and physical activity. In general, a fixed haemoglobin level trigger is no longer appropriate. In some patients a higher oxygen delivery may be necessary (i.e. acute respiratory failure) and a higher haemoglobin level may be required (> 120 g/l). Maintenance of a higher haemoglobin may avoid the requirement for intubation and assisted ventilation.

Regular platelet concentrates are required. In the presence of sepsis platelets are consumed rapidly and transfusions may be necessary on a daily basis, otherwise every second day is usually adequate. The patient should be examined daily for evidence of haemostatic failure (e.g. purpura, ecchymoses, mouth, fundoscopy). Granulocyte transfusion may have a role in patients with proven unresponsive bacterial sepsis.¹³

ANTIMICROBIAL THERAPY

The febrile neutropenic patient

After resistance of the malignant cell to therapy, infection is the commonest cause of death in patients with haematological malignancy. Patients usually tolerate neutropenia without developing infection until the count is < l.0 × 10⁹/l and it is not until the neutrophil count falls to < 0.2 × 10⁹/l that spontaneous overwhelming sepsis becomes a major potentially life-threatening problem. These patients must be watched closely for infection and treated early if necessary. When the neutrophil count is < 0.5 × 10⁹/l any temperature above 38°C should be regarded as representing serious sepsis until proven otherwise. High-risk patients include those with pneumonitis, severe mucositis, an infected i.v. catheter and evidence of local sepsis. In patients with haematological malignancy and in allogeneic marrow transplant patients there may be pre-existing immunodeficiency.

The role of prophylactic antibiotic therapy has been controversial due to concerns related to the development of antibiotic resistant micro-organisms, but there is evidence to support their use.^14,¹⁵ Early empirical antibiotic therapy, without microbiological proof of cause, may be life-saving.¹⁶ With most patients fever resolves, especially if marrow function returns in the short term. Ultimate proof of infection is frequently not established. Patients with agranulocytosis will not show the typical features of inflammation. For example, lung consolidation may not occur, cellulitis or sputum may not be clinically obvious, and urinary tract symptoms may be minimal. The role of steroids in suppressing temperature and clinical features of inflammation must also be considered. Non-infectious fever should be borne in mind (e.g. malignancy or drugs).

The presence of rigors, hypotension and shock may point more towards Gram-negative sepsis. The value of combination therapy with a β-lactam antibiotic in combination with an aminoglycoside has been demonstrated in patients with prolonged and severe neutropenia with Gram-negative septicaemia. Gram-negative sepsis is potentially rapidly fatal in the neutropenic patient, but is less common than in the past as the less virulent Gram-positive organisms now predominate. This may be related to several factors including the increased use of permanent indwelling intravenous devices, mucositis, H₂ antagonists and the use of quinolones as antibiotic prophylaxis. However, both streptococcal and staphylococcal sepsis can be severe and empiric use of vancomycin in high-risk patients is justified. Staphylococcus epidermidis is an indolent form of sepsis and time is usually available for adjustment of therapy, with most patients recovering.

THE choice of empirical antibiotic therapy

Empirical antibiotic therapy should be aggressive with cover against Gram-negative sepsis as this is potentially lethal for the neutropenic patient.¹⁷ Anaerobic cover may need to be included when there is any problem with the gastrointestinal tract (e.g. intra-abdominal or perianal problems). This is not usually necessary when problems are confined to the mouth.

The nature and site of infection is determined by a range of factors including:

• the host defence defect

• time course of neutropenia

• local microbiological ecology

• antibiotic usage (e.g. prophylaxis)

• haemostasis

• presence of indwelling lines (i.v., endotracheal, urinary)

• type of chemotherapy

• nature of disease

• patient factors (e.g. hepatic, renal, respiratory or other factors)

Antibiotic regimens

Empirical antimicrobial regimens for neutropenic patients remain a constant changing and controversial issue.^17,¹⁸ Initial empirical antibiotic therapy should cover Pseudomonas aeruginosa, Escherichia coli, Klebsiella species, Streptococcus viridans, Staphylococci (coagulase negative and coagulase positive) depending on clinical circumstances. Other organisms should be covered after the results of cultures have been assessed or it is known that a specific organism is present in the ward (e.g. Streptococcus viridans) or on surveillance cultures. Coverage against Staphylococcus epidermidis is not necessary until bacteraemia is demonstrated.

Single-drug therapy

Single-agent therapy with a third-generation cephalosporin (e.g. cefotaxime, ceftriaxone, ceftazidime, cefepime) may be adequate therapy in low-risk patients, i.e. neutrophil count > 0.5 × 10⁹/l and expected to stay above 0.5 × 10⁹/l or neutropenia expected to last less than 7 days. The carbapenems (e.g. imipenem and meropenem) are alternative choices to third-generation cephalosporins, having good Pseudomonas cover, and can also be used as monotherapy in low-risk individuals.

Two-drug therapy

Two-drug therapy with an added aminoglycoside (gentamicin, tobramycin, amikacin, netilmicin) is recommended as standard initial empirical regimen in patients with prolonged and profound neutropenia and no additional risk factors.

Three-drug therapy

Three-drug therapy with a glycopeptide (vancomycin, teicoplanin) added to the aminoglycoside and cephalosporin is indicated for patients who are particularly likely to be infected with coagulase-negative staphylococci, meticillin-resistant Staphylococcus aureus, Corynebacterium species and penicillin-resistant Streptococcus viridans (e.g. infected indwelling central venous catheter, pneumonitis, rash and severe mucositis).

Daily clinical assessment and review of microbiological results is essential. Antibiotic therapy is modified according to microbiological results. If no helpful microbiological information is forthcoming in the case of single- or two-drug therapy, the antibiotic regimen should be re-evaluated at 48 hours and if there has been no response, a glycopeptide added. If the fever has resolved and the cultures are negative, the aminoglycoside may be ceased.

Multiresistant Gram-negative organisms occasionally cause problems (e.g. some species of Acinetobacter) and need treatment with amikacin. Vancomycin-resistant Enterococcus is also occasionally seen although it may only be a ‘commensal’ rather than actual cause of infection. Therapy with a new antibiotic of the oxazolidinone class, such as linezolid, may be necessary.

With patients on three-drug therapy, antibiotic reassessment at 72 hours is appropriate. If there is no response, further investigation such as a CT chest and bronchoalveolar lavage may be indicated. Depending on the clinical state of the patient the introduction of antifungal therapy should be considered. Fungal infections are an increasing problem in patients with profound prolonged neutropenia.¹⁹ There is an increasing range of antifungals available, including voriconazole and the echinocandins (caspofungin, micafungin). Standard amphotericin is now rarely used. Prophylaxis with new azoles such as posaconazole may reduce the incidence of Aspergillus as fluconazole has with Candida infection. The use of potent anti-Aspergillus agents seems to be resulting in the emergence of breakthrough fungal infections with Mucormycosis, Scedosporium and Fusarium. These are uncommon fungal infections which were only rarely seen previously.

Haemopoietic growth factors, immunotherapy and granulocyte transfusions

Genetically engineered haemopoietic growth factors are now widely used to minimise the degree and time of neutropenia. Granulocyte and granulocyte-macrophage colony-stimulating factors are glycoproteins which stimulate the proliferation and maturation of bone marrow progenitor cells, and increase the number and function of these committed cell populations. Treatment reduces the duration and severity of neutropenia in patients receiving chemotherapy and after haemopoietic stem cell transplantation.²⁰ Growth factors do not prevent neutropenia, but do shorten its duration, and their use has been associated with fewer infectious febrile episodes. Intravenous immunoglobulin should be infused in patients with hypogammaglobulinaemia. Granulocyte transfusion may have a role if bacterial-proven sepsis is not resolving or there is evidence of spreading local bacterial infection.

Patient subgroups

Indwelling intravenous catheters

Indwelling intravenous silastic catheters provide a nidus for both infectious and non-infectious complications. The incidence of catheter-associated infections varies. Indwelling i.v. catheters present an increased risk of infection for both neutropenic and non-neutropenic patients. Coagulase-negative staphylococci are the most common cause of catheter-associated bacteraemia, but Staphylococcus aureus, Bacillus species, Corynebacteria and Gram-negative organisms (especially species of Acinetobacter and Pseudomonas) can also cause catheter infections and Candida infection can be catheter related. Exit-site infections and infections along the subcutaneous tunnel of the catheter can be caused by aerobic bacteria, Mycobacteria and fungi.

If bacteraemia is thought to be catheter related, it may be possible to avoid removal of the catheter, particularly if the infection is caused by coagulase-negative staphylococci. Even patients with Gram-negative infections can often be successfully treated with antibiotics infused through the catheter. In patients with multiple-lumen catheters, the administration of antibiotics should be rotated through all the lumens, as infection may be restricted to only one. However, removal of the catheter is usually necessary for bacteria (e.g. species of bacillus) that may not be eradicated even though sensitive to antibiotics and with candidaemia in which there is a high incidence of dissemination. Patients with tunnel infections usually require catheter removal.

Lung infiltrates

Lung infiltrates in febrile patients with neutropenia represent a high risk of treatment failure. Prolonged neutropenia has a significantly adverse effect on the outcome of infection. Incorporation of systemic antifungal agents into first-line therapy, particularly in selected high-risk subgroups, may improve the outcome. Involvement of a respiratory physician with experience in managing immunocompromised patients is important. Pulmonary investigations such as fine-cut chest CT, bronchoscopy, bronchoalveolar lavage ± transbronchial biopsy may be required. Pulmonary haemorrhage can be a sudden and life-threatening cause of pulmonary infiltration and respiratory insufficiency. This usually occurs in severe thrombocytopenia associated with infection, and in patients who have become resistant to platelet transfusions.

HAEMOPOIETIC STEM CELL TRANSPLANTATION

Haemopoietic stem cell transplantation therapy is increasingly establishing a role in the treatment of a wide range of malignant and non-malignant disorders.²¹ Allogeneic haemopoietic stem cell transplantation has been used as an adjunct to the treatment of acute leukaemia with an impressive success rate, which is translating into long-term survival and cure. This success is now being extended to the management of a wider range of haematological malignancies and some solid tumours. Haemopoietic stem cells can be obtained from either marrow aspiration or from the peripheral blood by apheresis using a blood cell separator following stimulation of the marrow with haemopoietic growth factors ± cytotoxic chemotherapy. Allogeneic transplantation brings with it a range of potentially serious and potentially fatal complications related to graft-versus-host disease (GVHD).²² It does, however, have the advantage of using normal stem cells which need not be stored and a limited degree of GVHD may have a beneficial anti-tumour effect. Autologous stem cell transplantation is of particular advantage when relatively normal bone marrow can be obtained, in which case GVHD is not a problem.

The principles for the use of bone marrow transplantation in the management of malignancy include the following:

• The tumour must be responsive to chemotherapy and/or radiotherapy.

• The dose limitation of the chemotherapeutic agents used relate to marrow toxicity and not other end-organs.

• There should be a source of uncontaminated, or minimally contaminated, haemopoietic stem cells.

• Appropriate haemopoietic supportive therapy must be available during the marrow aplastic period.

• High-quality clinical and laboratory facilities must be available for the collection and preservation of haemopoietic stem cells.

• An integrated team of medical and nursing and scientific staff is essential.

• The preparation of a well-documented clinical protocol and effective implementation, with appropriate monitoring, is essential for success. The general management of the patient during the procedure is similar to the management of other patients receiving high-dose chemotherapy who will have prolonged neutropenic periods.

COMPLICATIONS OF HAEMOPOIETIC CELL TRANSPLANTATION

Respiratory failure in haemopoietic cell transplant patients

Respiratory failure is the commonest cause of death in patients undergoing bone marrow transplantation. Both CMV-induced interstitial pneumonia and the idiopathic pneumonia syndrome rarely occur in the early cytopenic phase post transplantation. Haematological reconstitution with donor-type cells seems to be a prerequisite to the development of these pulmonary complications, suggesting a key role of immunological reactions. While CMV pneumonia can be effectively treated or prevented by ganciclovir, the idiopathic syndrome is usually fatal. Due to improved prophylaxis and therapy, lethal interstitial pneumonia due to Pneumocystis jiroveci (formerly P. carinii), herpes simplex, varicella zoster or Toxoplasma gondii, as well as lethal pneumonia caused by bacteria or Candida species, is generally less common. However, Aspergillus species have emerged as frequent causative pathogens. Prolonged granulocytopenia and prolonged medication with corticosteroids are major risk factors for pulmonary aspergillosis, which is commonly fatal, but prophylaxis may be achieved by sterile air supply during the hospital stay and by prophylactic inhalation of amphotericin B. Pulmonary haemorrhage, diagnosed by bronchoalveolar lavage, may develop due to the toxicity of the conditioning regimen, or may be secondary to infectious pneumonia of various kinds. Congestive heart failure might give rise to the development of pulmonary oedema. Patients with hepatic veno-occlusive disease have a high risk of subsequent pulmonary complications.

Graft-versus-host disease (GVHD)

GVHD is a major complication of allogeneic haemopoietic stem cell transplantation, especially with the increasing use of unrelated and mismatched donors.²² The target of the immune response in GVHD has long been regarded to be histocompatibility antigens possessed by the host, but not the donor. However, it is now recognised that self-antigens have been documented in GVHD, confirming that it is more complex than simple alloreactivity. Cytokines play a central role in mediating many of the manifestations of GVHD.

Nearly all patients with GVHD have a rash. Other features include liver and gastrointestinal dysfunction. Initial therapy for low-grade disease is systemic corticosteroids. Treatment for more severe disease may include a range of therapies, including ciclosporin, antithymocyte globulin, tacrolimus, methotrexate, PUVA and thalidomide.

Veno-occlusive disease of the liver

Veno-occlusive disease can be a major complication of haemopoietic stem cell transplantation, predominantly seen in allogeneic transplants, and is a major contributor to mortality.²³ The disorder is due to thrombotic occlusion in the small hepatic vessels, probably as a result of endothelial damage associated with high-dose chemotherapy. The problem manifests as weight gain, oedema, ascites, tender hepatomegaly, jaundice and may proceed to liver failure. Prophylaxis with low-dose heparin or prostaglandins may be useful. Treatment is predominantly supportive with fluid management a critical aspect. Treatment with tissue plasminogen activator and antithrombin III concentrates has been successful.

REFERENCES

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2 Bassan R, Gatta G, Tondini C, et al. Adult acute lymphoblastic leukaemia. Crit Rev Oncol Hematol. 2004;50:223-261.

3 Kuppers R, Yahalom J, Josting A. Advances in biology, diagnostics, and treatment of Hodgkin’s disease. Biol Blood Marrow Transplant. 2006;12(1 Suppl 1):66-76.

4 Arbuthnot C, Wilde JT. Haemostatic problems in acute promyelocytic leukaemia. Blood Rev. 20, 2006. 289–297

5 Vardiman JW. Hematopathological concepts and controversies in the diagnosis and classification of myelodysplastic syndromes. In: Hematology/the Education Program of the American Society of Hematology. Washington, DC: American Society of Hematology; 2006:199-204.

6 Schiffer CA. Clinical issues in the management of patients with myelodysplasia. In: Hematology/the Education Program of the American Society of Hematology. Washington, DC: American Society of Hematology; 2006:205-210.

7 Filippatos TD, Milionis HJ, Elisaf MS. Alterations in electrolyte equilibrium in patients with acute leukemia. Eur J Haematol. 2005;75:449-460.

8 Jibrin IM, Lawrence GD, Miller CB. Hypercalcemia of malignancy in hospitalized patients. Hosp Physician. 2006;42:29-35.. http://www.turner-white.com/memberfile.php?PubCode=hp_nov06_malig.pdf.

9 Rampello E, Fricia T, Malaguarnera M. The management of tumor lysis syndrome. Nature Clin Pract. 2006;3:438-447.

10 Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127:3-11.

11 Oldfield V, Perry CM. Spotlight on rasburicase in anticancer therapy-induced hyperuricemia. BioDrugs. 2006;20:197-199.