Leukaemia

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50 Leukaemia

G. Jackson, G. Jones

Key points

• Leukaemias are uncommon malignancies.
• Acute lymphoblastic leukaemia (ALL) is the most common malignancy in childhood.
• With the exception of ALL, leukaemias are more common in the elderly.
• Age is one of the most important prognostic factors in the treatment of leukaemia. With the exception of neonates, older patients are less likely to be cured than younger patients.
• The treatment of leukaemia is continually improving with the introduction of more focused therapy and improvements in supportive care.
• The use of bone marrow transplantation in the treatment of all forms of leukaemia is increasing. Some of the results are exciting, but the short- and long-term problems of this type of intensive treatment need to be considered.

Leukaemias and lymphomas are the commonest forms of haematological malignancy. Although rare, they are of particular interest in that dramatic improvements in the prognosis of patients with these cancers have been achieved through the use of chemotherapy, and cure is now a possibility for many patients.

Many forms of leukaemia exist, but they are all characterised by the production of excessive numbers of abnormal white blood cells. The leukaemias can be broadly divided into four groups:

• acute myeloblastic leukaemia (AML)
• acute lymphoblastic leukaemia (ALL)
• chronic myelocytic leukaemia (CML)
• chronic lymphocytic leukaemia (CLL)

The adjectives ‘myeloid’ and ‘lymphoid’ refer to the predominant cell involved, and the suffix-cytic and -blastic to mature and immature cells, respectively. These characteristics can be determined by a combination of cellular appearances, surface antigen expression and cytogenetic features. The international standard for leukaemia classification is the WHO system (Swerdlow et al., 2008).

Epidemiology

Haematological malignancies account for only 5% of all cancers; of these, CLL is the most common form of leukaemia. UK incidence data are presented in Table 50.1. CLL mainly affects an older age group: 90% of patients are over the age of 50 and nearly two-thirds are over 60 years old at diagnosis. It rarely occurs in young people and is twice as common in men as in women. CML is primarily a disease of middle age with the median onset in the 40–50 year old age group, but it can occur in younger people.

Table 50.1 Incidence of leukaemia in the UK (Leukaemia and Lymphoma Research, 2010)

  New cases/year Incidence per 100,000 of the population
CLL 2750 4.58
CML 750 1.5
ALL 650 1.00
AML 1950 3.25

Acute leukaemia is rare, with a total annual incidence of approximately 4 per 100,000 population. The more common form of the disease is AML, which accounts for 75% of cases. The incidence of AML rises steadily with age, occurring only rarely in young children. In contrast, ALL is predominantly a childhood disease, with the peak incidence in the 3–5 year age group, and is the most common childhood cancer.

Aetiology

In common with other cancers, the aetiology of leukaemia is not fully understood. Leukaemia is thought to result from a combination of factors that induce genetic mutations which allow mutated cells to proliferate faster than normal cells and/or to fail to die in response to normal apoptotic signals. Epidemiological studies have, however, identified a number of specific risk factors for the development of leukaemia, which are described as follows.

Radiation

The association between the ionising radiation and the development of leukaemia is evident from nuclear disasters such as Hiroshima and more recently Chernobyl. Long-term follow-up of survivors of Nagasaki and Hiroshima has shown an increase in all forms of leukaemia other than CLL. The link is also apparent for patients who received radiotherapy for the treatment of malignant and non-malignant conditions such as Hodgkin’s disease or ankylosing spondylitis. The effect of chronic low-level exposure to radiation is less certain.

Exposure to chemicals and cytotoxic drugs

There is a small but definite risk of acute leukaemia occurring in patients successfully treated for other malignancies with cytotoxic and immunosuppressive agents. The combination of chemotherapy, especially alkylating agents such as cyclophosphamide and radiotherapy, presents the highest risk. This has practical implications as an increasing number of patients achieve a ‘cure’ as a result of combination therapy, while occupational exposure of health professionals to these agents is also an area of concern. Occupational exposures to paint, insecticides and solvents, in particular, the aromatic solvent benzene, have all been associated with the development of leukaemia, but it is difficult to be certain whether such exposures genuinely cause the disease.

Viruses

Human T-cell lymphotrophic virus, an RNA retrovirus endemic in Japan and the West Indies, has been linked to a rare T-cell leukaemia/lymphoma.

Genetic factors

Down’s syndrome, constitutional trisomy of chromosome 21, is associated with an increased risk of leukaemia. Disorders that predispose to chromosomal breaks such as Fanconi’s anaemia and ataxia telangectasia are also associated with an increased risk of developing acute leukaemia. These alterations may permit the expression of oncogenes, which promote malignant transformation.

Haematological disorders

Many patients with other haematological disorders have a greatly increased risk of developing leukaemia, particularly AML. These disorders include the myelodysplastic syndromes, the non-leukaemic myeloproliferative disorders, aplastic anaemia and paroxysmal nocturnal haemoglobinuria.

Pathophysiology

In leukaemia, the normal process of haemopoiesis is altered (Fig. 50.1). Transformation to malignancy appears to occur in a single cell, usually at the pluripotential stem cell level, but it may occur in a committed stem cell with capacity for more limited differentiation. Accumulation of malignant cells leads to progressive impairment of the normal bone marrow function.

image

Fig. 50.1 Haemopoiesis.

Acute leukaemias

In acute leukaemia, the normal bone marrow is replaced by a malignant clone of immature blast cells derived from the myeloid (in AML) or lymphoid (in ALL) series. More than 20% of the cellular elements of the bone marrow are replaced with blasts. This is usually associated with the appearance of blasts in the peripheral circulation accompanied by worsening pancytopenia as a result of the marrow’s reduced ability to produce normal blood cells as the proportion of malignant cells increases. In ALL, the blasts may infiltrate lymph nodes and other tissues such as liver, spleen, testis and the meninges, in particular. In AML, blasts tend to infiltrate skin, gums, liver and spleen.

Classification of acute myeloblastic leukaemia

AML has traditionally been classified on the basis of morphological features of the disease. Subtypes displaying granulocytic, monocytic, erythroid and megakaryocytic differentiation can be demonstrated. Recently, the World Health Organization (WHO) has updated this system (Table 50.2). AML is now classified using a combination of morphological, genetic and immunological cell marker features (surface antigen expression) in an attempt to define disease groups of greater prognostic significance (Swerdlow et al., 2008).

Table 50.2 WHO classification of AML

Subgroup Examples
AML with recurrent genetic abnormalities Inversion chromosome 16 (inv 16)
  t(15;17)
  t(8;21)
AML with multilineage dysplasia  
Therapy-related AML  
AML not otherwise classified AML without maturation
  AML with granulocytic maturation
  AML with granulocytic and monocytic differentiation
  AML with monocytic differentiation
  AML with erythroid differentiation
  AML with megakaryocytic differentiation

Classification of acute lymphoblastic leukaemia

As with AML, the WHO classification system takes account of morphological, genetic and immunological features. The disease is, however, mainly classified immunologically, based on the presence or absence of B- or T-cell markers (Table 50.3). Each subtype displays different clinical presentations, response to treatment and, ultimately, prognosis, with pre-B having the best prognosis and B-ALL the worst. It is worth noting that B-ALL (Burkitt’s type), which is associated with translocations of the myc gene normally located on chromosome 8, seems to be a morphologically and biologically distinct form of leukaemia.

Table 50.3 Classification of ALL

Pre-B ALL Possessing the common ALL antigen CD 10
B cell type B-ALL of Burkitt’s type
T cell type T-ALL
Null Non-B, non-T and lacking the common ALL antigen CD 10

Chronic leukaemias

In chronic leukaemia, the normal bone marrow is replaced by a malignant clone of maturing haemopoietic cells.

Chronic lymphocytic leukaemia

CLL is characterised by a clonal expansion of morphologically mature lymphocytes of B-cell origin. These cells accumulate in the peripheral blood and give rise to a lymphocytosis that may be very marked. Lymphocytes accumulate in lymph nodes and spread to the liver and spleen, which become enlarged. The bone marrow is progressively infiltrated. Although the malignant lymphocytes appear morphologically normal, they are functionally deficient.

Chronic myelocytic leukaemia

The characteristic feature of CML is the predominance of maturing myeloid cells in blood, bone marrow, liver, spleen and other organs. CML was the first cancer to be associated with a specific chromosomal abnormality: the Philadelphia chromosome translocation (Ph) seen in over 90% of cases. This is a translocation of genetic material between the long arms of chromosome 22 and chromosome 9. This results in the apposition of the BCR gene (chromosome 22) and the ABL gene (chromosome 9). This novel BCR-ABL gene encodes a fusion protein which has tyrosine kinase activity. This genetic event is believed to be crucial in the pathogenesis, or perhaps even to initiate the development, of CML since overactivity of the tyrosine kinase results in the uncontrolled growth characteristic of leukaemic cells (Cilloni and Saglio, 2009).

Clinical manifestations

Acute leukaemia

Most of the clinical manifestations of acute leukaemia are related to bone marrow failure. The disease commonly presents with a short history, and left untreated, it is rapidly fatal. Symptoms of infection, anaemia and bleeding are common and life-threatening presenting problems. Bleeding may be particularly severe in one subtype of AML, acute promyelocytic leukaemia (APL). This condition is associated with a translocation of genetic material between chromosomes 15 and 17, t(15;17). Disseminated intravascular coagulation (DIC) is commonly the presenting feature of this disease. Some patients with AML develop symptoms and signs due to infiltration of major organs by leukaemic cells.

The involvement of other tissues such as spleen, liver, lymph nodes and meninges is more common in ALL than AML. Involvement of the central nervous system (CNS) may give rise to headaches, vomiting and irritable behaviour. CNS disease is rare at presentation, but develops in up to 75% of children with ALL unless specific prophylactic treatment is given. Less commonly, patients present with features of hypermetabolism, hyperuricaemia or generalised aches and pains.

Chronic leukaemia

Chronic myelocytic leukaemia

Patients with CML commonly present with non-specific symptoms, such as malaise, weight loss and night sweats. The main physical sign is an enlarged spleen that may give rise to abdominal discomfort. Hepatomegaly is also detected in approximately 40% of newly diagnosed patients. Neutropenia and thrombocytopenia are uncommon at presentation. Thus, unlike the acute leukaemias, patients with CML rarely present with symptoms of infection or haemorrhage. In up to 30% of cases, patients are asymptomatic and the disease is detected as a result of a routine blood test performed for other reasons.

CML is a triphasic disease. The initial chronic phase may last from several months to 20 years; the median is around 5 years. During this time, treatment can alleviate symptoms and reduce the white blood count (WBC) and spleen size, allowing patients to lead near normal lives. An accelerated phase eventually occurs where the disease becomes more aggressive with progressively worsening symptoms: unexplained fevers, bone pain, anaemia, thrombocytopenia or thrombocytosis. Finally, after a period of weeks or months, a blast crisis occurs, resembling fulminating acute leukaemia. In a small percentage of patients, this occurs abruptly with no prior accelerated phase.

Chronic lymphocytic leukaemia

An increasing number of patients are diagnosed as having CLL by chance, when a full blood count is performed for an unrelated reason. Symptomatic patients often suffer B symptoms: night sweats, unexplained fever and weight loss. At diagnosis, findings may include generalised lymphadenopathy and some enlargement of the liver and spleen. The course of CLL is variable; in some patients, the disease may remain indolent for many years, while others experience a steady deterioration in their health. Survival typically varies from 2 to 20 years depending on the extent of disease. Patients are immunocompromised with a reduction in serum gammaglobulin and are at increased risk of bacterial and viral infections. There is an increased susceptibility to autoimmune disease, particularly immune haemolytic anaemias and thrombocytopenia. With progressive disease, bone marrow failure becomes apparent, resulting in fatigue, infection and bleeding, and the disease becomes less responsive to treatment. Patients with CLL also have an increased risk of developing a more aggressive malignancy such as high-grade non-Hodgkin’s lymphoma (known as Richter’s transformation) or prolymphocytic leukaemia (PLL).

Investigations

Examinations of peripheral blood and bone marrow are the key laboratory investigations carried out in cases of suspected leukaemia. However, some additional investigations can help in the diagnosis and classification of this group of diseases. Some of the main findings at diagnosis are presented in Table 50.4.

Table 50.4 Findings at diagnosis in leukaemia

image

In acute leukaemia, leukaemic blast cells are usually seen on the peripheral blood film. The blasts of ALL and AML are distinguished using morphology, cytochemical stains, cytogenetics and cell surface antigen analysis. In CML, the principal feature is a leucocytosis with WBC usually ranging from 10 × 109 L−1 to 250 × 109 L−1 and comprising the complete spectrum of myeloid cells. In CLL, it is lymphocytes, in particular, which are increased, with clonal lymphocyte counts exceeding 5 × 109 L−1. Non-random chromosome abnormalities are increasingly being identified in patients with leukaemia. The information obtained from cytogenetic analysis of bone marrow or peripheral blood cells can be used to confirm the diagnosis and classification of leukaemia and may provide a guide to the likely response to treatment and prognosis.

Treatment

Although significant progress has been made in the treatment of leukaemia, work continues to further improve prognosis. As leukaemias are rare malignancies, the most important studies are undertaken on a national or international basis. In addition to the specific anti-leukaemia treatment, general supportive therapy is vital to manage both the disease and the complications of therapy.

Acute leukaemia

At the outset, intensive combination chemotherapy is given in the hope of achieving a complete remission (CR). This initial phase of treatment is termed induction or remission induction chemotherapy. A CR can only be achieved by virtual ablation of the bone marrow, followed by recovery of normal haemopoiesis. If two cycles of therapy fail to induce CR, an alternative drug regimen can be used. If this is unsuccessful, it is unlikely that CR will be achieved. The subsequent duration of the first remission is closely linked to survival.

Remission is defined as the absence of all clinical and microscopic signs of leukaemia, less than 5% blast forms in the bone marrow and return of normal cellularity and haemopoietic elements. Despite achieving CR, occult residual disease (also termed minimal residual disease or MRD) will persist, and further intensive therapy is given in an attempt to sustain the remission. This post-remission consolidation therapy may comprise chemotherapy or a combination of chemotherapy and bone marrow transplantation.

Acute lymphoblastic leukaemia

Treatment of ALL in childhood has been one of the success stories of the past 3 decades. Over 80% of children will achieve a remission lasting more than 5 years, and current studies are often focused on trying to identify the 20% of children with poor risk disease and treating them more aggressively (Vrooman and Silverman, 2009). Unfortunately, the results in adults are not so impressive. The combination of vincristine, prednisolone, anthracyclines and asparaginase induces CR in about 90% of children with ALL and 80% of adults, although sadly relapse is far more common in adults (Table 50.5). Other active drugs in the treatment of ALL include methotrexate, 6-mercaptopurine, cyclophosphamide and mitoxantrone.

Table 50.5 Treatment of ALL (adapted from MRC protocol UKALL 12-2005)

image

Patients with ALL are at a high risk of developing CNS infiltration. Cytotoxic drugs penetrate poorly into the CNS which thus acts as a sanctuary site for leukaemic cells. For this reason, all patients with ALL receive CNS prophylaxis. Cranial irradiation plus intrathecal methotrexate or high-dose systemic methotrexate can be used.

Maintenance treatment is important to sustain a CR. It is usually milder than induction or consolidation chemotherapy, but is carried on for at least 18 months. Treatment usually consists of weekly methotrexate and daily 6-mercaptopurine with intermittent vincristine and prednisolone.

The treatment of relapsed disease varies with the site of relapse. Isolated CNS or testicular relapse may be successfully treated with radiation and reinduction therapy. Cure can still be achieved for some patients. Bone marrow relapse is much more difficult to cure, especially if it occurs early.

A small proportion of paediatric patients and a larger proportion of adult patients have the Philadelphia chromosome translocation within their ALL blasts. Such patients have a relatively poor prognosis and therefore require more intensive therapy. There is some evidence that drug combinations including imatinib may enhance the response of these leukaemias to therapy.

Acute myeloblastic leukaemia (non-acute promyelocytic leukaemia)

As for ALL, the treatment of AML involves induction and consolidation chemotherapy. In AML therapy, however, the chemotherapy regimens used to achieve remission are much more myelotoxic, and patients require intensive supportive care to survive periods of bone marrow aplasia (Fig. 50.2). The pyrimidine analogue cytarabine has formed the basis of treatment for AML for 20 years. The addition of daunorubicin and oral thioguanine has achieved a CR rate of 75% in patients under the age of 60 years and about 50% in those over 60 years (Dohner et al., 2010). The precise dose and scheduling of these agents is continually being refined in order to improve the response rates. Despite the numbers of patients who achieve CR following induction therapy, the majority relapse, with only about 25% becoming long-term disease-free survivors (Stone et al., 2004). Thus, in common with ALL, additional post-remission therapy is required. Intensive consolidation chemotherapy with high-dose cytarabine and daunorubicin or amsacrine appears to improve survival rates to approximately 50% after 3 years, with even more encouraging results being obtained in patients under 25 years of age (Dohner et al., 2010; Robak and Wierzbowska, 2009). There is generally no role for maintenance therapy in AML. Similarly, CNS prophylaxis is not routinely indicated though patients thought to be at particularly high risk of CNS disease, such as those with testicular or sinus involvement, should receive prophylactic therapy.

image

Fig. 50.2 One example of a possible treatment regimen for AML. The figure demonstrates that patients are treated with initial induction therapy, then remission is consolidated with at least two courses of chemotherapy. This figure provides a summary only and should not be used as a guide to prescribing or dispensing therapy.

An alternative approach to post-remission therapy is stem cell transplantation. In patients under 40 years of age, allogeneic bone marrow transplantation has resulted in disease-free survival of 45–65% at 5 years post-transplant. These patients are considered cured of their disease. Only about 10% of patients are suitable for allogeneic bone marrow transplants, and there is little evidence to suggest that autologous stem cell transplantation improves the outcome for patients with AML in first CR. It is always worth remembering that AML is most common in the elderly, and intensive intravenous chemotherapy regimens are not always appropriate for this population of patients.

Treatment of AML in relapse is difficult and the prognosis is generally poor. Encouraging results have been seen using a combination of fludarabine, cytosine arabinoside and granulocyte colony-stimulating factor (G-CSF). Novel approaches in AML therapy are often piloted in this group of poor-risk patients. A combination of anti-CD33 antibody, which targets myeloid blasts, with calicheamicin, an anthracycline antibiotic, is a promising and effective approach (Stone et al., 2004), but appears most effective when given in combination with conventional chemotherapy. A newly developed purine analogue, clofarabine, has also been shown to have activity against AML. This drug is a promising agent, particularly in the treatment of older patients, as pilot studies suggest that its toxic effects may be less severe than those associated with other chemotherapy regimens (Robak and Wierzbowska, 2009). 5-Azacytidine is also of interest, especially in older patients and those whose disease has evolved from myelodysplastic syndrome MDS. This agent inhibits DNA methyltransferase resulting in DNA hypomethylation. This process is thought to increase activity of some tumour suppressor genes resulting in anti-tumour effects. The agent has been shown to slow the rate of progression to AML in patients with high-risk myelodysplastic syndrome and is currently the subject of clinical trials in AML.

Acute Promyelocytic Leukaemia

This subtype of AML deserves special consideration as the treatment is quite different from that of other AML variants. APL is associated with the t(15;17) translocation which involves a genetic translocation of material between chromosomes 15 and 17. The disease is clinically characterised by the presence of disseminated intravascular coagulopathy (DIC) at presentation. Since these patients are so prone to life-threatening haemorrhage at diagnosis, the management of a new case of APL is considered a medical emergency. The leukaemic cells are exquisitely sensitive to all-trans retinoic acid (ATRA), which induces blast maturation and can induce remission when used as a single agent (Sanz et al., 2009; Soignet and Maslak, 2004). Using a combination of ATRA and anthracycline chemotherapy, it is now possible to achieve long-term cure in >80% patients. There are some data to suggest that the ongoing use of ATRA in consolidation and maintenance treatment improves outcome further. A number of studies have been published demonstrating the efficacy of arsenic trioxide (ATO) in treating relapsed or refractory APL. Comparison of ATRA and anthracyclines against ATO and ATRA is now the subject of a large UK study of newly diagnosed patients (AML 17). The latter regimen has the potential advantage of avoiding significant myelosuppression.

Chronic leukaemia

Chronic myelocytic leukaemia

Until recently, the treatment of CML has been essentially palliative, producing modest increases in survival, but with the main aim of keeping patients asymptomatic by normalising the WBC. Hydroxycarbamide was the most widely used drug in the management of CML in chronic phase. Treatment with hydroxycarbamide is initiated at a dose of 1.5–2 g/day and usually brings the WBC under control within 1–2 weeks. The dose can then be reduced to a maintenance dose of 0.5–2 g/day. Withdrawing or reducing the dose abruptly can cause a rebound increase in WBC. The side effects of hydroxycarbamide are generally mild but include rashes and gut disturbances.

Interferon can control symptoms of CML but was also the first agent shown to modify the disease process. It promotes the expression of suppressed normal haemopoiesis at the expense of the malignant clone. Studies have shown that interferon-α therapy prolongs the chronic phase and improves the median survival of patients with CML, and its effects seem to be enhanced by the addition of low-dose cytarabine (Sawyers, 1999).

Therapeutic options for patients with CML have changed dramatically in the past 10 years due to the development of imatinib mesylate. This drug was specifically designed to target the abnormal tyrosine kinase product of the BCR-ABL fusion gene (Fig. 50.3). In a large randomised controlled trial, patients were randomised to receive imatinib or a combination of interferon-α and cytarabine. Many patients were intolerant of the interferon and cytarabine combination and crossed over to receive imatinib after trial commencement. Despite this problem, progression-free survival at 1 year was 97% in the imatinib arm and 80% in the interferon and cytarabine arm in an intention-to-treat analysis (O’Brien et al., 2003). The Philadelphia chromosome became undetectable in 68% of imatinib recipients compared to 7% of those in the alternative arm (Hughes et al., 2003). However, more sensitive testing methods, such as real-time polymerase chain reaction (PCR), have now shown that many patients who are Philadelphia chromosome negative still possess very low levels of the abnormal BCR-ABL gene produced by the Philadelphia translocation.

image

Fig. 50.3 Inhibition of BCR-ABL protein by imatinib. The protein product of the BCR-ABL fusion gene (BCR-ABL protein) acts as a constitutively active tyrosine kinase and uses ATP, bound within a kinase pocket in the molecule, to phosphorylate tyrosine (o) in a variety of substrates. In doing so, ATP (adenosine triphosphate) is reduced to ADP (adenosine diphosphate) which falls out of the kinase pocket to be replaced by further ATP. Imatinib prevents the action of the BCR-ABL protein by blocking ATP entry into the kinase pocket.

Dasatinib and nilotinib are second-generation tyrosine kinase inhibitors (TKIs) designed to overcome resistance to imatinib caused by mutations in the kinase domain of BCR-ABL. Both agents work well as second-line therapies, producing complete cytogenetic responses in about 50% of patients. The use of dasatinib and nilotinib in newly diagnosed patients is currently being evaluated in ongoing clinical trials. Due to the effectiveness of imatinib therapy and the development of second-generation agents, allogeneic stem cell transplantation is now rarely used to treat CML, but it does represent a potentially curative option for patients with resistant disease.

Transformation of CML into acute leukaemia can be treated in the same manner as de novo acute leukaemia, in an effort to achieve a second chronic phase. Treatment is slightly more successful if transformation is lymphoid rather than myeloid. Imatinib, typically at higher doses than are used in chronic phase disease, can also be used to attempt to return patients to chronic phase disease. In general, remissions are rare and the median survival is less than 6 months.

Chronic lymphocytic leukaemia

Currently, there is no cure for CLL. All treatment is, therefore, considered palliative. There is no evidence that early treatment of asymptomatic patients improves outcome. Indications for treatment are:

• rapidly increasing WBC
• increasing or troublesome lymphadenopathy
• systemic symptoms
• marrow failure
• autoimmune complications.

Formerly, the alkylating agent chlorambucil was the most common agent used in the treatment of CLL. Corticosteroids can reduce the lymphocyte count without contributing to myelosuppression and are used to treat autoimmune phenomena such as haemolytic anaemia and immune thrombocytopenia. The use of purine analogues, particularly fludarabine, marked the beginning of an exciting phase in the treatment of CLL. Although CRs were unusual, good responses were seen even in patients whose leukaemia was resistant to alkylating agents. With regard to initial therapy of CLL, fludarabine-treated patients show a higher response rate than patients treated with chlorambucil. However, no survival advantage for the use of fludarabine has been demonstrated (Rai et al., 2000). More recently, a large randomised study comparing fludarabine and cyclophosphamide with and without the anti-CD20 antibody, rituximab, has been published (Hallek et al., 2009). This study demonstrated an overall response rate of 86% and 73%, respectively. The median progression-free survival with rituximab is the best published in a large randomised controlled trial to date, at 40 months. This combination of fludarabine, cyclophosphamide and rituximab has been adopted, in the UK, as the regimen of choice for first-line treatment of CLL as long as patients are considered fit enough. Chlorambucil remains an excellent choice for patients with significant co-morbidities as the treatment is less immunosuppressive.

Splenic complications may necessitate splenectomy or splenic irradiation. Radiotherapy can also be used to control localised painful lymphadenopathy. Combination chemotherapy, such as CHOP (see Chapter 51) used in lymphoma, may be beneficial in advanced disease. Campath-1H is a humanised monoclonal anti-CD52 antibody. CD52 is present on most lymphocytes including malignant lymphocytes in CLL. Binding of this antibody induces both antibody-mediated and complement-mediated T-cell cytotoxicity against malignant B cells. In relapsed patients, the duration of response to Campath-1H is relatively short. However, the agent is currently being studied, both in combination with other drugs and as a possible means of purging the bone marrow of residual cells prior to autologous stem cell harvest and transplantation.

Patients with CLL are very susceptible to infection. Herpes viruses, in particular herpes zoster, can cause significant problems. This susceptibility is increased because many treatments, such as campath-1H and fludarabine, have generalised anti-lymphocyte action and are not absolutely specific for malignant lymphocytes.

Stem cell transplantation

The potential role of stem cell transplantation is increasingly being explored in the management of all types of leukaemia.

The basic principle

This technique provides a means of rescuing the patient from the potentially lethal effects on the bone marrow of ablative therapy given in an attempt to eradicate all traces of disease (Fig. 50.4). The conditioning regimen most commonly used is a combination of high-dose cyclophosphamide and total body irradiation. Other conditioning regimens include high-dose melphalan, etoposide, busulphan or cytarabine.

image

Fig. 50.4 Stem cell transplantation.

Following administration of conditioning therapy, 2–3 days elapse to allow its elimination from the body, and then previously harvested stem cells are reinfused peripherally. The stem cells will return to and repopulate the marrow, restoring normal haemopoiesis. Peripheral blood counts recover in 2–4 weeks. Throughout this time, patients require intensive supportive care and the procedure, particularly allogeneic stem cell transplantation, causes significant morbidity and has a mortality rate of 5–30%.

The source of stem cells

During allogeneic stem cell transplantation (allograft), stem cells are obtained from a human leucocyte antigen (HLA)-matched donor. These stem cells can be removed directly from the bone marrow, under general anaesthetic, or harvested from the peripheral blood. Under certain circumstances, in the absence of a matched donor, an autologous bone marrow or peripheral blood stem cell transplant (autograft) can be performed. Following conditioning, the patients receive their own cryopreserved marrow or peripheral blood stem cells, previously harvested from them while in CR. There is a potential risk, however, that stem cells obtained in this way may contain undetected, residual disease. Attempts have been made to purge the bone marrow of disease in vitro, but these have generally been unsuccessful.

Peripheral blood stem cell transplantation

This technique for rescuing bone marrow following ablative conditioning therapy is used to restore haemopoiesis (Russell, 1998). Patients receive the haematopoetic growth factor G-CSF, either alone or following an infusion of high-dose chemotherapy such as high-dose cyclophosphamide. Patients receive G-CSF for a period of about 7 days. This stimulates the release of stem cells into the peripheral circulation. Stem cells are then harvested from the peripheral circulation by a process of cell pheresis. The harvested cells can then be reinfused, fresh, into the patient following conditioning therapy or frozen and stored for later use.

Peripheral stem cell transplantation offers some advantages over conventional bone marrow transplant techniques; collection of peripheral stem cells negates the need for general anaesthesia and it has been found that the haemopoietic recovery period following transplantation is shortened by 5–10 days. This technique can also be used to harvest stem cells from allogeneic donors. In this case, G-CSF is used alone to stimulate stem cell release into the peripheral circulation. It is sometimes impossible to harvest enough stem cells from patients to allow an autologous transplant to be performed. The commonest reason for this is that the patient has been heavily pretreated with chemotherapy or radiotherapy. A new CXCR4 chemokine antagonist, plerixafor, is now available. This agent is thought to reduce adhesion of stem cells within the bone marrow milieu. It can be given along with G-CSF and allows a proportion of patients who have failed to mobilise stem cells using G-CSF alone to mobilise cells for an autograft.

Complications

Infection is almost inevitable in patients undergoing bone marrow transplantation. Other significant complications of allografts include interstitial pneumonitis and hepatic veno-occlusive disease, but the major life-threatening complication is acute graft-versus-host disease (GVHD). The likelihood of graft-versus-host disease occurring increases with age, and for this reason, myeloblative allografts are largely restricted to patients under 45 years of age. Graft-versus-host disease is caused by T-lymphocytes in the donated marrow reacting to host tissues. The severity of the reaction ranges from a mild maculopapular rash to multisystem organ failure with a high mortality rate. Acute graft-versus-host disease typically occurs within 100 days of the bone marrow transplantation and typically presents with fever, rash, diarrhoea and liver dysfunction. Prophylactic therapy is routinely given with methotrexate or ciclosporin, alone or in combination, for 6–12 months post-transplant. Should acute graft-versus-host disease develop, high-dose methylprednisolone, ciclosporin, antithymocyte globulin and, more recently, anticytokine monoclonal antibodies, for example, anti-TNF (tumour necrosis factor) antibodies, have been used to treat the condition.

Chronic graft-versus-host disease can occur after 3 months following bone marrow transplantation. It is a multisystem disorder associated with chronic hepatitis, severe skin inflammation and profound immunosuppression. Treatment is successful in approximately 50% of patients and consists of immunosuppression with azathioprine and prednisolone together with prophylactic antibiotics. Ciclosporin and thalidomide have also been used successfully in the treatment of chronic steroid-refractory graft-versus-host disease. The main cause of death amongst patients with chronic graft-versus-host disease is infection.

Reduced intensity allografting

Myeloablative allogeneic transplantation, as described earlier, is a very intensive procedure associated with significant morbidity and mortality, hence its restriction to younger patients. Attempts have been made to reduce the intensity of transplant conditioning regimens whilst using increased immunosuppression to facilitate marrow engraftment. Although such an approach reduces the intensity of therapy delivered to any residual tumour, the possible downside of this reduction is offset by an immunological graft-versus-tumour effect and by reduced early post-transplant mortality. This form of transplant is often offered to older patients who are considered unfit to receive a standard allograft. However, the long-term outcomes of this approach are under continual review. Several trials now suggest that the overall survival after myeloablative and reduced intensity transplants may be similar though the causes of death in the two groups are different. More patients die of disease relapse after reduced intensity transplants, and more die of transplant-related complications in the myeloablative group (Pollack et al., 2009).

The place of stem cell transplantation

The place of stem cell transplantation in the management of a particular form of leukaemia depends very much on the prognosis of patients treated with conventional chemotherapy (Table 50.6). For example, the results of intensive chemotherapy in children with ALL are good, and bone marrow transplantation is generally only considered for children who have relapsed and in whom a second remission can be achieved. However, conventional treatment of adults is less successful, and allogeneic bone marrow transplantation may be offered to adults in first remission.

Table 50.6 Indications for allogeneic stem cell transplantation in leukaemia

AML First remission with the exception of patients with good risk genetic abnormalities: t(15;17), t(8;21) and inversion of chromosome 16
CML Chronic phase but only if patient fails to respond to first- and second-line tyrosine kinase inhibitors
ALL First remission in adults
  Second remission in children
CLL Not generally appropriate as part of standard therapy but under investigation within several clinical studies

Patient care

Supportive care

The treatment of CLL and CML is largely carried out on a hospital outpatient basis, with patients taking oral medication at home or attending outpatient clinics on a weekly or monthly basis for injections of chemotherapy. Patients are routinely monitored to follow the progress of disease and to observe treatment-related side effects. Supportive therapy such as blood transfusions can also be given on an outpatient basis. In contrast, the intensity of induction and consolidation regimens used in the management of patients with acute leukaemia renders them severely pancytopenic. Therapy is usually given as a hospital inpatient with patients often remaining in hospital following treatment for 3–4 weeks until their bone marrow recovers sufficiently. This is in contrast to therapy for most solid tumours where, following administration of treatment, patients are often well enough to remain at home until their next cycle of chemotherapy is due.

Advanced leukaemia, bone marrow transplantation and aggressive chemotherapy for acute leukaemia all result in pancytopenia. Red cell transfusions are given to patients to maintain their haemoglobin above 9–10 g/dL. Evidence of bleeding includes petechial haemorrhages in skin and mucous membranes, and patients receiving aggressive treatment must be examined daily for any of the above signs. Platelet concentrates are given to thrombocytopenic patients who have signs of bleeding and are given prophylactically should platelets fall below 10 × 109 L−1. The probability of infection developing rises as the WBC, specifically the neutrophil count, falls. With an absolute neutrophil count of below 0.5 × 109 L−1, patients are at high risk of infection, with the risks being even greater if the period of neutropenia is prolonged.

Chapters 51 and 52 examine many of the non-haematological toxicities which result from the use of cytotoxic drugs, and these are clearly pertinent to haematology patients. The major contributors to morbidity and mortality in patients with leukaemia are relapsed disease and infection.

Infection in the immunocompromised patient

A number of intrinsic and extrinsic factors all contribute to the risk of infection in this vulnerable group of patients (Fig. 50.5).

image

Fig. 50.5 Infection risk in immunocompromised patients.

While cross-infection can occur via staff, other patients or contaminated objects, the main sources of infection in this group of patients are endogenous, arising from commensal gut and skin organisms. The normal host defences to infection are broken down; damage to mucous membranes, particularly in the gastro-intestinal tract, occurs with chemotherapy and radiotherapy, allowing infecting organisms to enter the bloodstream. Most infections in neutropenic patients arise from three main sites: the gastro-intestinal and respiratory tracts, and the skin. Table 50.7 lists the main pathogens responsible for infection in this group of patients.

Table 50.7 Pathogens commonly causing infection in neutropenic patients

Gram-negative bacteria Pseudomonas spp.
Escherichia coli
Klebsiella spp.
Enterobacter spp.
Proteus spp.
Serratia spp.
Legionella pneumophilia
Gram-positive bacteria Streptococcus spp.
Staphylococcus epidermidis
Staphylococcus aureus
Anaerobes Clostridium difficile
Clostridium perfringens
Bacteroides spp.
Fungi Candida spp.
Aspergillus spp.
Viruses Herpes simplex
Herpes zoster
Cytomegalovirus
Hepatitis
Protozoa Pneumocystis carinii

Preventive measures

Oral hygiene

Mouth care is important in all patients receiving chemotherapy but particularly neutropenic patients. Patients are generally asked to use mouthwashes regularly, and prophylactic antifungal therapy may also be given. Although it is important to avoid any sort of trauma to the oral mucosa, teeth should be cleaned regularly using a soft toothbrush. Attention must also be paid to the care of dentures. Patients require careful counselling on mouth care, stressing the importance of oral hygiene.

Prophylactic anti-infectives

In general, prophylactic antibiotics are avoided because of the possible development of resistant organisms, but they may have a place in the management of periods of prolonged myelosuppression following chemotherapy and bone marrow transplantation. Prophylactic antifungal agents are often given and patients undergoing bone marrow transplantation and therapy for ALL require prophylaxis against herpes virus and Pneumocystis carinii (Table 50.8).

Table 50.8 Prophylactic anti-infectives

Gram-negative bacteria Ciprofloxacin
Candidiasis Nystatin
Fluconazole
Itraconazole
Herpes simplex Aciclovir
Pneumocystis carinii Co-trimoxazole

Gut decontamination

Gut decontamination using a combination of non-absorbable oral antibiotics and antifungal agents reduces the burden of potentially pathogenic organisms in the intestine. One such combination includes neomycin sulphate, colistin sulphate, nystatin and amphotericin. However, opinions are divided over this practice, as gut decontamination can lead to the overgrowth of resistant organisms.

Growth factors

An exciting development in the care of patients with leukaemia has been the production of haemopoietic growth factors using recombinant DNA technology. The first of these, G-CSF, given daily by subcutaneous injection or intravenous infusion after completion of chemotherapy, stimulates neutrophil production and may reduce the duration of neutropenia by up to 7 days. The cost of these compounds is a major issue and results of studies investigating the effects of G-CSF on morbidity and mortality, following chemotherapy, have been disappointing (Smith et al., 2006). Newer pegylated growth factors have been introduced. These have a longer half-life than standard agents, and thus fewer injections are required. The impact of these agents on morbidity and mortality post-chemotherapy, however, remains controversial.

Aseptic technique

Careful attention should be paid to the care of intravenous cannulae, particularly central venous catheters. The increased incidence of staphylococcal infection in immunocompromised patients can largely be attributed to their use. Invasive procedures, such as venepuncture, must be carried out using strict aseptic technique. Similarly, urinary catheters are a major source of infection and their use should be avoided if at all possible.

Protective isolation

Reverse barrier isolation during periods of neutropenia, nursing in strict sterile environments and high-efficiency particulate air (HEPA) filtration have been used in an attempt to reduce infection rates. This is extremely demanding for staff and patients alike and is generally only appropriate following bone marrow transplantation.

Treatment of infection

Commonly, neutropenic patients show no signs of focal infection; they are unable to form pus. The only clinical manifestations of septicaemia might be general malaise, fever or hypotension. A patient’s condition can deteriorate very rapidly, with collapse occurring within hours of the first signs of infection. Treatment should be instigated as soon as infection is suspected. Following a clinically serious febrile episode (temperature: 37.5 °C for more than 1 h or 38 °C or more on a single reading), samples are taken for culture; these may include blood, urine, sputum and stool cultures along with line and throat swabs. Intravenous antibiotics must be started empirically without delay (Sipsas et al., 2005). Standard empirical therapy varies from unit to unit but may involve the combination of an aminoglycoside with an antipseudomonal penicillin such as piperacillin to provide broad-spectrum bactericidal cover. In penicillin-allergic patients, ceftazidime or cefotaxime may be substituted, but local resistance patterns are of paramount importance. Antibiotics with a broad spectrum of activity, such as ciprofloxacin, have been used as single agents.

Vancomycin or teicoplanin are often prescribed if an infected central venous catheter is suspected, to provide additional cover against Gram-positive organisms. Microbiological advice should be sought in cases of methicillin-resistant Staphylococcus aureus (MRSA) infection. Metronidazole may be added to the antibiotic regimen to cover anaerobes if the clinical presentation suggests that the source of the infection may be oral, perineal or gut. Anti-infective therapy should subsequently be modified on the basis of cultures, but in the majority of neutropenic patients, a causative organism is never identified.

If the pyrexia persists for more than 4 days in spite of broad-spectrum antibiotics, or if the patient’s condition is deteriorating, systemic fungal infection should be suspected. Empirical antifungal therapy for neutropenic patients with antibiotic-resistant fever reduces mortality and is considered a standard of care. A number of broad-spectrum agents are now available for use in this setting, including standard amphotericin, lipid formulation of amphotericin, caspofungin and voriconazole. Intravenous amphotericin is often the first choice to ensure that Aspergillus and Candida are covered. The main limitation of amphotericin is its toxicity, in particular, nephrotoxicity. Lipid formulation of amphotericin may be appropriate in patients with pre-existing renal impairment or in cases where conventional amphotericin has induced nephrotoxicity. Voriconazole is a useful agent with a similarly broad spectrum of activity. Hepatotoxicity, visual disturbances and prolonged QT interval are the most common side effects of voriconazole. This agent has the advantage of being available as both intravenous and oral preparations, so the conversion from parenteral to oral therapy is straightforward.

Although the antifungal activity of the echinocandin, caspofungin, is more limited than that of amphoteracin or voriconazole, it has been shown to be effective for empirical therapy as it has good efficacy against Candida and Aspergillus spp. It has the advantage of reduced toxicity in comparison with other available agents. The most common side effect is hepatotoxicity. Since this agent has a relatively limited spectrum of activity, it is probably best avoided in the setting of presumed fungal sinus or CNS infection, which are often caused by fungi other than Aspergillus or Candida spp. Table 50.9 lists some of the common problems encountered in the treatment of the leukaemias.

Table 50.9 Common therapeutic problems in the leukaemias

Problem Cause Solutions
Mucositis and oral ulceration Chemotherapeutic agents directly toxic to mucosal epithelium Regular mouth toilet including the use of antibacterial mouthwash
Prophylactic use of antiviral and antifungal agents for patients in whom myelosuppression is likely to be prolonged
Radiotherapy is directly toxic to the mucosa and also reduces saliva production by salivary glands
Vulnerable mucosa is likely to be attacked by infective agents, for example, herpes simplex, candida  
Fever in neutropenic patients Infection predominantly caused by bacteria and/or fungi Broad-spectrum antibiotics must be commenced as soon as blood cultures have been taken
A strategy of planned progressive therapy including use of an antifungal agent in non-responsive fever is appropriate
Graft-versus-host disease (GVHD) T lymphocytes from the donor react against host tissues Use a sibling donor if possible
  Use the donor most closely HLA matched to the patient
  Consider T-cell depletion of graft (though this may increase the risk of disease relapse)
  Prophylactic therapy with methotrexate and ciclosporin
  Treat GVHD with corticosteroids, ciclosporin, anti-thymocyte, globulin, FK 506, anticytokine monoclonal antibodies
  Irradiate all blood products
Late complications of treatment Risks of haemopoietic malignancy and non-haemopoietic malignancy are increased post-chemotherapy Aim to tailor therapy to the underlying disease, that is, do not overtreat and do not undertreat
  Late cardiotoxicity secondary to anthracyclines Do not exceed maximum cumulative doses of anthracyclines
    Liposomal anthracyclines may be useful in the future

The following practice points should be used to control infection in immunocompromised patients.

• Measures to prevent infection are important.
• Particular attention should be paid to scrupulous hand washing, mouth care and the use of antifungal, antiviral and antipneumocystis prophylaxis for patients at high risk.
• Preventive measures do not eliminate the risk of infection.
• Treatment of fever in a neutropenic patient is a medical emergency.
• Empirical antifungal therapy should be used to treat neutropenic patients with antibiotic resistant fever, at high risk of fungal infection.

Case studies

Case 50.1

A 30-year-old woman recently diagnosed with CML attends the haematology clinic to discuss the options for treatment.

Questions

1. Which treatment options are available?
2. Which treatment is likely to be the best choice for this patient?

Answers

1. There are clearly a number of potential treatment options which need to be explored with the patient.

The various treatment options are:

• palliative therapy with hydroxycarbamide to control cell counts
• interferon-α
• interferon-α and cytosine
• imatinib
• allogeneic matched sibling transplant
• matched unrelated donor (MUD) transplantation if a matched sibling is not available
• treatment as part of a clinical trial which is likely to involve imatinib in varying doses or in combination with other effective agent.

2. A purely palliative approach is unlikely to be acceptable to a young patient, but hydroxycarbamide can still be used acutely to control high cell counts. There is no doubt that use of interferon-α alone results in cytogenetic remission in a small percentage of patients, and this effect is enhanced by the addition of cytosine. The side effects of interferon-α include flu-like and affective symptoms. The addition of cytosine increases myelosuppression and risk of mucositis. Although these treatments can induce cytogenetic remission, the duration of such responses is unclear and only a minority of patients respond completely. The high risk of side effects and the low chance of complete cytogenetic response to interferon-α, with or without cytosine, are likely to make these therapeutic modalities unattractive to this patient.

It remains true that allogeneic stem cell transplantation is the only proven curative therapy for patients with CML. The difficulty with this approach is that the mortality rate for transplant recipients remains high. The 1-year mortality rate for a 30-year-old patient transplanted using a sibling donor is approximately 15–20%, and this may rise to 25–30% if a MUD has to be used. The major causes of death in this group are GVHD and infection. In addition to this high risk of mortality in the short-term, there is also a risk of long-term morbidity post-allograft. Chronic graft-versus-host disease can have a significant impact on quality of life for many patients and requires long-term medical follow-up. Ironically, patients with a degree of chronic graft-versus-host disease are at reduced risk of disease relapse since a graft-versus-host response is also associated with a graft-versus-leukaemia effect; some disparity between the immune systems of the transplant donor and recipient is helpful. In addition to these problems, all transplanted patients are at increased risk of a second malignancy developing later in life as a consequence of the conditioning therapy received as part of the transplant and probably also as a consequence of deficiencies within the transplanted immune system.

Given the problems associated with the various therapeutic strategies discussed earlier, it is not surprising that there was great excitement surrounding the development of a targeted tyrosine kinase inhibitor, imatinib. Results with this agent, particularly for patients with newly diagnosed chronic phase disease, are excellent. Complete cytogenetic responses have been seen, although very sensitive quantitative PCR techniques can still detect the abnormal BCR-ABL gene in the vast majority of CML patients in whom the Philadelphia chromosome itself is undetectable. In addition, the drug has been shown to delay progression to accelerated phase disease or blast crisis. It is still not possible, however, to say that imatinib cures patients with CML.

Although no randomised study has been undertaken, it is clear from historical data that, in the short-term, the mortality associated with allogeneic stem cell transplantation far exceeds that associated with imatinib. In addition to these very encouraging data which pertain to the effect of the drug on the disease, the side effects of imatinib are generally mild and patients report this agent far easier to tolerate than interferon-α. The main side effects are rash, cytopenias, fluid retention and abnormalities of liver function tests.

Given the efficacy of imatinib and the fact that the drug is generally very well tolerated, imatinib is regarded as the initial treatment of choice for the vast majority of patients with CML. Ongoing management involves haematological and molecular monitoring of the patient to determine whether they have a good response to imatinib. In the event of a good response, the patient continues to take the drug. If at a later stage the molecular response to the agent begins to diminish, then transplantation is reconsidered. Amongst patients who fail to respond or respond poorly to imatinib, transplantation options are likely to be considered at an earlier stage.

Case 50.2

A patient with AML is currently in first CR and has a fully HLA-matched brother who is medically fit. You have been asked to counsel the potential transplant donor about stem cell collection.

Questions

1. What methods are available for the collection of stem cells for haemopoietic stem cell transplantation?
2. What are the advantages and disadvantages of each of these stem cell collection methods for the transplant donor?
3. What are the advantages and disadvantages of each of these stem cell collection methods for the transplant recipient?

Answers

1. There are two main methods of collection of haemopoietic stem cells from a sibling donor. These are:

• direct harvesting of cells from the bone marrow in the pelvis;
• collection of circulating peripheral blood stem cells using an apheresis technique after stimulation of the stem cell compartment using (G-CSF).

2. Direct harvesting of marrow stem cell from the bone marrow is an operative procedure and is performed under general anaesthetic. Clearly, there are risks associated with the use of general anaesthesia, but the risk of death associated with this approach is less than 1 in 10,000 procedures. Marrow harvesting involves a hospital stay, usually for one night post-operatively, but some units also require donors to be admitted the night before surgery. Donors are likely to experience pain around the pelvis, and there is a risk of mechanical back pain in the short to medium term due to pressure applied to the pelvis during repeated needle insertions. This risk is increased in those with a history of back problems prior to the procedure. Indeed, such potential donors may prefer a peripheral blood stem cell harvesting approach. Donors must be warned about bruising and potential infection at the site of their wounds.

One of the other potential problems associated with marrow harvesting is that it is impossible to select the type of blood cell harvested and a large component of the volume of fluid collected comprises red blood cells. This can lead to a degree of anaemia in the donor who may take several weeks to normalise their haemoglobin. It is usually possible to avoid blood transfusion in this situation as it is unusual for donors to be significantly symptomatic. Nonetheless, donors must be warned that the need for allogeneic blood transfusion is a possibility with this procedure.

Peripheral blood stem cell harvesting has several advantages over direct marrow harvesting from the iliac crests. The procedure can be undertaken during hospital outpatient visits and does not require the use of a general anaesthetic. As the stem cell-harvesting procedure allows selective collection of mononuclear cells, significant anaemia is very unlikely after this procedure. Clearly, red cells do circulate within the apheresis circuit, and if the circuit clots off and has to be disconnected from the donor, then red cells will be lost. This is unlikely to be of clinical significance unless the donor is a child and hence has a relatively low blood volume.

Disadvantages of this approach include the need for stimulation of donor haemopoiesis by the G-CSF.

Marrow stimulation can result in significant pain especially around the shoulders, back and pelvic girdle. Most donors can manage this pain at home with simple analgesia, but very occasionally hospital admission is required for pain control. Very occasionally patients develop splenic pain, and there have been a couple of reports of splenic rupture in normal donors after G-CSF stimulation, but this is very rare. One difficulty with the use of G-CSF is that it has only been in routine use for the past 15 years. This makes it impossible to categorically reassure potential stem cell donors that use of G-CSF in this way is absolutely safe in the long-term. There is, however, currently no evidence that acting as a peripheral blood stem cell donor increases one’s risk of leukaemia development later in life. Some potential donors find this element of uncertainty difficult and prefer to undertake a marrow harvest in which the risks, although present, are better quantified.

The apheresis procedure itself involves the donor lying relatively still with a needle in one or both arms (depending upon the type of apheresis kit used) for approximately 4–5 h. Some collections can be done in one procedure, but some donors will need to be harvested in two procedures, over 2 days.One prerequisite for peripheral blood stem cell donation is that the potential donor has good enough peripheral veins to allow reliable venous access. If this is not the case and the donor prefers to donate using this method, a temporary central venous line has to be inserted.

Most donors tolerate the apheresis procedure with few problems. One of the most common complications of the procedure is hypocalcaemia which results from calcium binding by the citrate anticoagulant used to prevent clotting within the apheresis circuit. Donors may notice perioral tingling or paraesthesia in other areas and are asked to report this immediately. The problem is easily treated by reducing the concentration of anticoagulant in the circuit and by asking the donor to drink a small amount of milk. If this problem is not picked up early, the consequences can be more severe, with the development of tetany which would require intravenous calcium replacement.

In summary, peripheral blood stem cell donation is generally a less invasive and better-tolerated procedure than direct stem cell harvest from the marrow space. However, the associated procedural risks are more easily quantifiable for the latter procedure.

3. There are some potential advantages, to the transplant recipient, in the use of peripheral blood stem cells as opposed to bone marrow stem cells. Engraftment is quicker, so the recipient spends less time in the neutropenic phase, and hence the risk of infection is reduced. Similarly, there is evidence that duration of hospital stay is reduced when peripheral blood stem cells are used. One potential disadvantage of this approach is that the graft includes a larger dose of T-lymphocytes than a graft of stem cells derived directly from the marrow (approximately a 10-fold increase). There is some evidence that rates of chronic graft-versus-host disease are increased amongst recipients of peripheral blood stem cells, but this observation has not been borne out in all studies. This potential disadvantage of peripheral blood stem cells is negated if a T-cell-depleted approach is used, as is the case for most matched unrelated procedures.

Case 50.3

A 25-year-old woman is admitted with newly diagnosed AML. Once her condition is stabilised, the consultant seeks her consent to start intensive chemotherapy.

Questions

1. How should the consultant ensure the consent process is performed as well as possible?
2. What side effects should the consultant discuss?

Answers

1. It is vital that consent is taken only after very careful discussions. Consent for such intensive chemotherapy usually requires several conversations. The final consent conversation should be done in a quiet private room if possible, and interruptions should be kept to a minimum. The patient should be allowed to have a friend, partner or relative present if they wish, and ideally a clinical nurse specialist should be present too. If possible, the patient should be given some written material on chemotherapy before consent even if it is important the treatment is started promptly. The patient should be given a clear explanation of their potential treatment options and should be informed of any clinical trials that may be available to them. It is vitally important to fully inform patients regarding their condition and its prognosis, and about treatment options and their potential advantages and disadvantages. Only if the patient has all the necessary information can they decide on the treatment option that is most appropriate/acceptable to their individual circumstances.
2. The consent discussion should include a discussion of all common side effects and less common but severe side effects of treatment. Common side effects of AML chemotherapy would include nausea, vomiting, mucositis, tiredness, malaise, infections, hair loss, bleeding and anaemia. Patients should be warned that they will require transfusions of blood and platelets. They will always need good venous access and usually a Hickman or other long-term in-dwelling central line. They will need to be warned they will have to spend at least 3–4 weeks in hospital. Severe side effects may include infertility and a premature menopause in young women. Options for the prevention and treatment of infertility must be discussed before treatments commences. Anthracyclines can be associated with cardiac problems, infections and bleeding can be life threatening and patients must be warned that they may not respond to therapy or may relapse after treatment. They should also be warned that a cure cannot be guaranteed. There is a risk of treatment-related mortality of around 1–2%. Longer-term risks include a greater lifetime risk of cancers including skin cancer and lung cancer, particularly in smokers.

Case 50.4

A 24-year-old patient with ALL is undergoing chemotherapy and needs intrathecal chemotherapy to prevent relapse in the meninges. Giving drugs by this route is EXTREMELY DANGEROUS. Several patients have died as a result of the inadvertent administration of vinca alkaloids into the CSF.

Question

What steps have been taken nationally to try to prevent the inadvertent intrathecal injection of vincristine and other agents not suitable for intrathecal use?

Answer

In the UK, there are now strict guidelines for administration of intrathecal chemotherapy. It can only be performed in hospital units which have passed a rigorous peer review process. The procedure must be undertaken in a specially designated area. Intravenous drugs must not be given in this area. The intrathecal drugs must only be prescribed by a consultant or specialist registrar who has been trained to prescribe or give intrathecal chemotherapy and whose name appears on a locally held register. Drugs for intrathecal administration must only be prescribed on a specially designated prescription sheet. Once the prescription has arrived in pharmacy, the drugs must be manufactured and checked by pharmacists trained in the manufacture and checking of intrathecal prescriptions. The drugs must be positively labelled ‘for intrathecal use only’ and must be dispensed by a trained pharmacist. They can only be dispensed once the patient has been given any intravenous drugs that are due that day. The doctor collecting the drugs must sign to confirm that the i.v. drugs, if due, have been given before the drugs are dispensed. The drugs must only be dispensed to a doctor trained and on the register for giving intrathecal drugs. The intrathecal drugs must be transported in a specially designated container, and if they need to be stored, then it must be in a separate, specially designated fridge, that is separate from any intravenous chemotherapy. Once the procedure is under way, the intrathecal drugs must be checked by the registered doctor and by a nurse who has been trained and appears on a register of nurses trained to check intrathecal drugs. The drugs should also be checked by the patient or a patient’s representative. Intrathecal drugs must not be given in hospitals not approved for the procedure, in non-designated areas, outside office hours or at the weekend unless there are exceptional circumstances. All staff working on oncology or haematology units should be taught about the rules for giving intrathecal therapy.

In addition, in order to prevent inadvertent vincristine administration into the intrathecal space, hospitals giving intrathecal chemotherapy should follow special rules for labelling vinca alkaloid prescriptions and vinca alkaloids should be made up in a minimum volume of 20 mL in order to prevent intrathecal administration.

Case 50.5

A 37-year-old dental technician presented with acute promyelocytic leukaemia (APL). He had a number of bleeding problems at presentation. He was randomised on an APL trial to be commenced on oral all-trans retinoic acid (ATRA) and arsenic trioxide (ATO).

Questions

1. Why is ATRA used in this circumstance and what are its side effects?
2. Why is ATO used in this circumstance and what are its side effects?

Answers

1. APL is a variant of AML which presents with coagulation defects, low platelet counts and severe bleeding. Patients are at risk of severe haemorrhage at presentation but have a relatively good prognosis with chemotherapy. ATRA can rapidly correct the coagulopathy found at presentation. This agent also increases the likelihood of the patient entering remission, when combined with standard high-dose chemotherapy. It is also used as a maintenance agent and when used with 6-mercaptopurine and methotrexate, it increases the number of patients who remain in long-term remission. The side effects of ATRA include dry eyes and a dry mouth. In addition, ATRA can cause a severe and life-threatening sterile pneumonitis. It is important to recognise this syndrome quickly as it often responds to high-dose dexamethasone and if left untreated leads to respiratory failure and death.
2. ATO has been shown to bring about remission in patients who have APL in association with the 15;17 chromosomal translocation and the PML:RARA genetic abnormality. It is not considered a conventional chemotherapeutic agent and seems to work in a synergistic fashion with ATRA. There is a lot of interest in combining these agents in an attempt to reduce the exposure of these patients to chemotherapy. Side effects include the APL differentiation syndrome, similar to the ATRA differentiation syndrome.

ATO can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging drugs, a history of torsade de pointes, pre-existing QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics or other conditions that result in hypokalemia or hypomagnesemia. Prior to initiating therapy with ATO, a 12-lead ECG should be performed and serum electrolytes (potassium, calcium and magnesium) and creatinine should be assessed; pre-existing electrolyte abnormalities should be corrected and, if possible, drugs that are known to prolong the QT interval should be discontinued. For QTc greater than 500 ms, corrective measures should be completed and the QTc reassessed with serial ECGs prior to considering using ATO.

Case 50.6

A 57-year-old man with a 6-year history of CLL presented with a rising white cell count, worsening lymphadenopathy and hepatosplenomegaly. Treatment was commenced with oral fludarabine 40 mg/m2 and oral cyclophosphamide 250 mg/m2 daily for 3 days with rituximab given on day 1 (FC-R).

Question

What additional precautions would you advise the physician to take and why?

Answer

Fludarabine, cyclophosphamide and rituximab are a very powerful combination available for the initial treatment of CLL. It has been used as a second-line therapy, although recent data support its use as a first-line therapy. It has been associated with more frequent and deeper remissions which are longer than single-agent therapy. It is a very immunosuppressive combination with activity against both T- and B-cells, and patients treated with this regime are at high risk of developing Pneumocystis pneumonia. It is important that patients are given prophylaxis against this severe infection. Herpes virus infections including herpes simplex and herpes zoster are also common, and most patients are given acyclovir prophylaxis.

As patients are immunosuppressed, they are also at risk of developing transfusion related graft-versus-host disease. This is a complication of blood product transfusion, caused by engraftment of lymphocytes from the transfused product, which is frequently fatal. This complication can be prevented by irradiation of blood products prior to transfusion. Rituximab is an antibody-based therapy and can be associated with significant reactions which can occasionally be severe and life threatening (see Chapter 51).

References

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Dohner H., Estey E.H., Amadori S., et al. Diagnosis and management of acute myeloid leukaemia in adults: recommendations from an international expert panel, on behalf of the European LeukaemiaNet. Blood. 2010;115:453-474.

Hallek M., Fingerle-Rowson G., Fink A.M., et al. First-line treatment with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) improves overall survival (OS) in previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a randomized phase III trial on behalf of an international group of investigators and the German CLL Study Group. Blood. 2009;114:535.

Hughes T.P., Kaed J., Branford S., et al. Frequency of major molecular responses to imatinib or interferon-alpha plus cytarabine in newly diagnosed chronic myeloid leukaemia. N. Engl. J. Med.. 2003;349:1423-1432.

Leukaemia and Lymphoma Research. Disease Facts. Available at www.beatbloodcancers.org/leukaemia, 2010.

O’Brien S., Guilhot F., Larson R.A., et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukaemia. N. Engl. J. Med.. 2003;348:994-1004.

Pollack S.M., O’Connor Jr T.P., Hashash J., et al. Non-ablative and reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation: a clinical review. Am. J. Clin. Oncol.. 2009;32:618-628.

Rai K.R., Peterson B.L., Appelbaum F.R., et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukaemia. N. Engl. J. Med.. 2000;343:1750-1757.

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Sanz M.A., Grimwade D., Tallman M.S., et al. Management of acute promyelocytic leukaemia: recommendations from an expert panel on behalf of European LeukaemiaNet. Blood. 2009;113:1875-1891.

Sawyers C.L. Medical progress: chronic myeloid leukaemia. N. Engl. J. Med.. 1999;340:1330-1340.

Sipsas N.V., Bodey G.P., Kontoyiannis D.P. Perspective for the management of febrile neutropenic patients with cancer in the 21st century. Cancer. 2005;103:1103-1113.

Smith T.J., Khatcheressian J., Lyman G.H., et al. Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J. Clin. Oncol.. 2006;24:3187-3205.

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Further reading

Hoffbrand A.V., Pettit J.E., Moss P.A.H. Essential Haematology, fifth ed. Oxford: Blackwell Publishing; 2006.

Howard M.R., Hamilton P.J. Haematology: An Illustrated Colour Text, third ed. Edinburgh: Churchill Livingstone; 2007.

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