What treatments are used?
Treatment can include chemotherapy and radiotherapy, as well as bone marrow and stem cell transplantation or monoclonal antibodies. The choice of treatment depends on the type of leukaemia and the progression of the disease.
How can I manage side effects?
Many side effects can be managed by drugs or simple interventions. An effective prophylaxis strategy to prevent nausea and vomiting is vital, as this can lead to non-compliance. Acute emesis can be managed by domperidone or metoclopramide, or a specific serotonin antagonist given with dexamethasone if high risk. Lorazepam is used in patients who have anticipatory emesis because of its amnesic, sedative and anxiolytic effects.
Treatments for leukaemia range from conventional anticancer chemotherapy and radiotherapy to advanced biological drugs that target the disease’s underlying molecular pathophysiology. Individual management decisions are complex and varied, guided principally by the type of leukaemia and key patient factors such as age and genetic profile.
Main types of treatment for leukaemia include:
– transplantation – bone marrow or stem cell
– tyrosine kinase inhibitors
– monoclonal antibodies.
1. Acute myeloid leukaemia (AML).
Chemotherapy is the main treatment approach for AML, divided into two phases – induction and consolidation. The goal of induction therapy is to achieve “morphological complete remission” – this involves normalisation of neutrophil and platelet counts and reduction in leukaemic blasts to <5 per cent of total white cell count in the bone marrow.1 Patients with a favourable cytogenic profile generally receive two courses of induction, followed by one or two rounds of consolidation. AML sufferers designated ‘intermediate’ or ‘poor risk’ after profiling may be candidates for allogenic stem cell transplantation (SCT) if they respond to induction.1 Consolidation is aimed at preventing the recurrence of leukaemia once remission has been achieved. It can consist of further chemotherapy, a donor transplant or – rarely in AML – an autologous stem cell transplant.2
Common cytotoxics used in AML chemotherapy include daunorubicin, cytarabine, etoposide, fludarabine, idarubicin, doxorubicin, thioguanine, amsacrine and mitoxantrone – at different doses and in various combinations. Most patients will have an induction regimen that starts with cytarabine and an anthracycline (any of the three rubicin drugs), with potentially a third agent added.2
First-line therapy of acute promyelocytic leukaemia (APML), an AML subtype with good prognosis, involves the retinoid all-transretinoic acid (ATRA; tretinoin). In combination with an anthracycline, this produces cure rates in excess of 80 per cent.1 ATRA is not a cytotoxic but promotes maturation of malignant cells. Arsenic trioxide is the second-line treatment for APML and also gives high complete remission rates.
2. Chronic myeloid leukaemia (CML)
CML management has been revolutionised by the advent of the tyrosine kinase inhibitor (TKI) imatinib, which offers overall survival rate of 89 per cent after five years, and has now replaced the previous gold-standard therapy, cytarabine plus interferon alpha.1 Nice recommends imatinib as first choice treatment for Philadelphia (Ph) chromosome carriers in the chronic phase of CML and as an option for patients presenting in the accelerated phase or with blast crisis, the terminal phase of CML, provided imatinib has not been used previously.3
Imatinib is generally preferred over allogenic SCT for the first-line therapy of newly-diagnosed chronic phase CML patients; however, SCT offers the only confirmed potential for a complete cure.1 In patients eligible for SCT, rates of long-term remission or cure are approximately 60 per cent.1
For imatininb-resistant patients, the newer TKIs – dasatinib and nilotinib – are alternatives with greater potency, although nilotinib is not licensed for blast crisis.
3.Chronic lymphocytic leukaemia (CLL)
Currently, CLL is not curable. However, most patients with early-stage disease do not require treatment until the cancer progresses or symptoms become troublesome. Studies have shown immediate treatment offers no significant survival advantages but poses potentially serious side effect problems.4 Instead, a policy of ‘watchful waiting’ is adopted, with regular blood tests and monitoring.
For patients in later disease stages of CLL (known as Binet stage two or three), treatment is recommended. Chemotherapy is the mainstay of CLL management and oral chlorambucil is the first-line agent of choice. Fludarabine, a purine analogue, is recommended by Nice as a second choice option for CLL patients who have failed or are intolerant of chlorambucil and would otherwise have received combination chemotherapy.5 Typical chemotherapy combinations used in CLL include:
¥ CHOP – cyclophosphamide, doxorubicin, vincristine and prednisolone
¥ CAP – cyclophosphamide, doxorubicin and prednisolone
¥ CVP – cyclophosphamide, vincristine and prednisolone.
Newer monoclonal antibody therapies for CLL include alemtuzumab and rituximab. Rituximab is a chimeric antibody that binds selectively to the CD20 antigen expressed on the surface of mature B-lymphocytes and tumour cells. It is recommended by Nice – in combination with fludarabine and cyclophosphamide – as a first-line option for CLL in patients suitable for fludarabine and cyclophosphamide combination therapy.6
Like rituximab, alemtuzumab also causes lysis of B lymphocytes and is licensed for CLL where fludarabine treatment is not appropriate.7 Nice has not yet reviewed alemtuzumab but the Scottish Medicines Consortium has accepted it for restricted use in previously untreated B-cell CLL patients with the cytogenetic abnormality 17p-deletion.7
4. Acute lymphoblastic leukaemia (ALL)
Chemotherapy is the main treatment for ALL and 80 per cent of patients will achieve remission. Treatment for ALL follows three phases:7
¥ Induction – an initial intensive phase of treatment to destroy leukaemic cells. Common chemotherapy drugs used are vincristine, daunorubicin or doxorubicin, methotrexate, crisantaspase (asparaginase), mercaptopurine and cyclophosphamide.
¥ Intensification (consolidation) – further chemotherapy to destroy residual leukemic cells
in the blood or bone marrow. Drugs include cytarabine, etoposide and tioguanine (thioguanine).
¥ Maintenance – to reduce the risk of recurrence. Usually oral mercaptopurine or methotrexate, or intravenous vincristine.
Some ALL patients will be suitable for high-dose treatment (including total body irradiation and high doses of etoposide or busulfan) followed by stem cell transplant. Carriers of the Ph chromosome may receive imatinib.
Side effects common to most cytotoxic drugs include: oral mucositis, tumour lysis syndrome (a particular risk in ALL and AML if white counts are high or there is bulky disease), hyperuricaemia, nausea and vomiting, bone marrow suppression, alopecia, reproductive toxicity and thromboembolism.7 All cytotoxics are contraindicated during pregnancy. Drug interactions are common and widespread – see BNF for details.
The anthracyclines doxorubicin, daunorubicin and idarubicin are cardiotoxic, with high cumulative doses potentially causing cardiomyopathy and heart failure. Doxorubicin and idarubicin are contraindicated in patients with severe myocardial insufficiency, recent myocardial infarction and severe arrhythmias. Side effects include cardiac disorders, extravasation, elevated bilirubin, diarrhoea and red coloration of the urine.
Key problems with the prolonged use of alkylating agents are impaired gametogenesis and increased risk of acute non-lymphocytic leukaemia (especially when combined with excessive irradiation).
Rarely, chlorambucil can cause widespread rashes that may progress to Stevens-Johnson syndrome or toxic epidermal necrolysis. If a rash occurs, it should be substituted for cyclophosphamide. Chlorambucil should be used cautiously in patients with a history of epilepsy and children with nephrotic syndrome, and avoided in acute porphyria.
Side effects of cyclophosphamide include anorexia, cardiotoxicity at high doses, interstitial pulmonary fibrosis, inappropriate secretion of diuretic hormone, disturbances of carbohydrate metabolism, urothelial toxicity, and pigmentation of palms, nails and soles. A urinary metabolite of cyclophosphamide can cause haemorrhagic cystitis – increased fluid intake for 24-48 hours after intravenous injection is recommended.
Cyclophosphamide is contraindicated in haemorrhagic cystitis and caution is required in acute porphyria and renal or hepatic impairment.
Cytarabine is a potent myelosuppressive and requires haematological monitoring.
Fludarabine has a powerful and prolonged immunosuppressive effect. Co-trimoxazole is used to prevent pneumocystis infection and only irradiated blood products can be given (to avoid graft-versus-host reaction). Immune-mediated haemolytic anaemia, thrombocytopenia and neutropenia are less common side effects. Monitoring is required for signs of haemolysis, neurological toxicity and skin cancer. Fludarabine is contraindicated in haemolytic anaemia.
Methotrexate causes myelosuppression, mucositis and rarely pneumonitis. It is contraindicated in severe renal or hepatic impairment and pleural effusion or ascites. Concomitant folic acid can reduce side effects.
Neurotoxicity – typified by peripheral paresthesia, loss of deep tendon reflexes, abdominal pain, constipation or ototoxicity – is a limiting side effect of vincristine.
Vincristine can cause severe local irritation, extravasation and bronchospasm.
Tyrosine kinase inhibitors (TKIs)
Side effects of TKIs include diarrhoea, elevated transaminases, hypophosphataemia, muscle cramps, nausea and vomiting, periorbital or peripheral oedema, pleural effusion, QTc prolongation and skin rash. Imatinib should be used cautiously in cardiac disease, with monitoring of fluid retention and liver function.
Dasatinib may cause severe neutropenia and thrombocytopenia in up to 50 per cent of patients.1 Nilotinib is less myelosuppressive but associated with biochemical abnormalities such as elevated bilirubin, transaminases and lipases. Caution should be exercised in patients susceptible to QT-interval prolongation.
Metabolism of TKIs is primarily via the cytochrome P450 CYP3A4 so enzyme inducers
(eg rifampicin and phenytoin) and inhibitors (eg itraconazole, clarithromycin, grapefruit juice) should not be given concurrently.1
ATRA is generally well tolerated but can cause retinoic acid syndrome – a serious adverse event characterised by fever, fluid retention, low blood pressure and dyspnoea.
The main adverse effects with rituximab and alemtuzumab are infusion-related reactions, usually occurring during the first intravenous administration. Symptoms include fever and chills, nausea and vomiting, allergic reactions, flushing and tumour pain. Premedication with analgesic, antihistamine and corticosteroid is recommended.
Other rare but serious side effects of rituximab include neutropenia, leucopenia, infection and cardiovascular events.6 Progressive multifocal leucoencephalopathy (a rare and often fatal viral disease causing damage to the white matter of the brain) has also been reported and warrants close cognitive, neurological and psychiatric monitoring.
Rituximab should be used with caution in patients on cardiotoxic chemotherapy or with a history of cardiovascular disease due to the risk of exacerbating angina, arrhythmia or heart failure.
Leukaemia treatment involves powerful drugs that bombard and batter the body, eliciting a whole host of unwanted effects. Maintaining compliance with the treatment plan can therefore prove extremely challenging. Pharmacists have an important role to play minimising and managing these medication side effects, offering lifestyle advice and self-help measures to help patients obtain maximum benefit from treatment. See table 1.
Nausea and vomiting are among the most infamous of chemotherapy side effects and can cause considerable distress, sometimes leading to refusal of further treatment. Effective prophylaxis strategies are therefore vital. Certain patients will show increased susceptibility to emesis including women, patients under 50 years of age, anxious patients and sufferers of motion sickness. Pharmacotherapy choices will depend on whether the symptoms are acute (occurring within 24 hours of treatment), delayed (onsetting after 24 hours) or anticipatory (experienced prior to subsequent doses):7
¥ Acute: patients at low emesis risk – domperidone or metoclopramide, with dexamethasone or lorazepam as additional options; high-risk patients – a specific serotonin antagonist (given orally) in combination with dexamethasone.
¥ Delayed: oral dexamethasone, alone or in combination with metoclopramide or prochlorperazine.
¥ Anticipatory: lorazepam is good for its amnesic, sedative and anxiolytic effects.
Table 1, further information and references are available online in the full version of this article at www.chemistanddruggist.co.uk/update
Helen Boreham is a freelance medical writer with an MSci in medicinal chemistry.
What does Nice recommend for the treatment of CML? What are the side effects of anthracyclines? How are the side effects of chemotherapy such as sickness and nausea managed?
This article describes the treatment of the different types of leukaemia and includes information about cautions, contraindications and side effects of the drugs that are used. The management of side effects such as nausea and vomiting and sore mouth are also discussed.
¥ Find out more about the side effects and contraindications of cytotoxic drugs from section 8.1 in the BNF.
¥ Read more about stem cell transplant on the Patient UK website at http://tinyurl.com/leukaemia04.
¥ Read the information about sore mouth and taste changes on the Cancer Research website at http://tinyurl.com/leukaemia05.
¥ The Cancer Research website also has some useful advice for patients suffering from nausea and vomiting at http://tinyurl.com/leukaemia06.
Are you now confident in your knowledge of the drugs used to treat leukaemia? Could you advise patients about how to cope with sore mouth and nausea and vomiting due to chemotherapy?
Useful further information
¥ Cancer Research UK www.cancerresearchuk.org
¥ Leukaemia and Lymphoma Research www.beatbloodcancers.org
¥ Leukaemia Care www.leukaemiacare.org.uk
¥ Children with Leukaemia www.leukaemia.org
¥ Children’s Cancer and Leukaemia Group (CCLG) www.cclg.org.uk
1. Duncan N. Adult myeloid leukaemias: current and future treatments. Clinical Pharmacist 2010; 2: 122-127.
2. Cancer Research UK www.cancerresearchuk.org
3. Nice Technology Appraisal: TA70 Leukaemia (Chronic Myeloid) – Imatinib: Guidance. Guidance on the use of imatinib for chronic myeloid leukaemia. October 2003. http://www.nice.org.uk/nicemedia/live/11516/32754/32754.pdf
4. Smith V. Chronic leukaemia – characteristics and treatment. Hospital Pharmacist 2003; 10: 110-116
5. Nice Technology Appraisal: TA29 Leukaemia (Lymphocytic) – Fludarabine: Guidance. Guidance on the use of fludarabine for B-cell chronic lymphocytic leukaemia. September 2001. http://www.nice.org.uk/nicemedia/live/11437/32238/32238.pdf
6. Nice Technology Appraisal: TA174 Leukaemia (Chronic Lymphocytic, First Line) – Rituximab: Guidance. Rituximab for the first-line treatment of chronic lymphocytic leukaemia. July 2009. http://www.nice.org.uk/nicemedia/live/11907/44906/44906.pdf
7. British National Formulary (BNF) 57
8. Macmillian Cancer Support http://www.macmillan.org.uk/Home.aspx