Lymphomas

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51 Lymphomas

L. Cameron, C. Loughran

Key points

• Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL) are aggressive diseases that are fatal if untreated.
• Early-stage HL patients are treated with combined modality treatment usually consisting of two to four cycles of ABVD (Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine) and involved field radiotherapy (IFRT) (20–30 Gy); a relapse-free survival rate of 85–90% at 5–10 years is achieved.
• ABVD chemotherapy is the current gold standard regimen for advanced HL, and overall survival at 5 years is 75–80%.
• Low-grade NHL may be treated using R-CVP (rituximab, cyclophosphamide, vincristine, prednisolone) or chlorambucil chemotherapy or by adopting a ‘watch and wait’ policy.
• R-CHOP (cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), prednisolone, rituximab) chemotherapy is the standard for the treatment of aggressive (intermediate and high grade) NHL, curing 60% of patients.
• Relapsed HL and NHL may be treated with further chemotherapy followed by high-dose chemotherapy with bone marrow or peripheral stem cell transplantation.
• Patients receiving chemotherapy for HL and NHL should have full blood count (FBC) and blood biochemistry monitored at frequent intervals.
• Complications such as nausea and vomiting, tumour lysis syndrome (TLS), mucositis and bone marrow suppression may occur as a result of chemotherapy and are significant factors in morbidity.
• Supportive care of the patient undergoing chemotherapy includes appropriate drug therapy to minimise the adverse effects of the treatment.

Lymphoma is cancer of the lymphatic system and accounts for approximately 3% of new cases of cancer reported in the UK each year. The primary cancerous cell of origin is the lymphocyte; as a result, there is often considerable overlap between lymphomas and lymphoid leukaemias. Lymphomas are subdivided into two main categories: Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). Both HL and NHL can be further classified based on histology.

The site of malignancy is usually a lymph node. Extranodal disease, most frequently of the stomach, skin, oral cavity and pharynx, small intestine and CNS, can occur and is more common in NHL than HL.

Hodgkin’s lymphoma

Hodgkin’s disease, now known as HL, was first described by Thomas Hodgkin in 1832. HL accounts for 30% of all lymphomas and has an incidence in the UK of 2.2 per 100,000 for women and 3.3 per 100,000 for men. It is predominantly a disease of young adults, having a peak incidence between the ages of 15 and 35 years.

Aetiology

The cause of HL is unknown, but a number of risk factors have been identified. Epstein–Barr (glandular fever) virus has been identified in 50% of HL cases and is likely to be associated with an increase in risk of developing HL. Certain associations have been identified which suggest a genetic link with HL; for example, same-sex siblings of patients with HL have a 10 times higher risk of developing the disease. Patients with reduced immunity, for example, AIDS or those taking immunosuppressants, may have an increased risk of developing HL.

Pathology

The diagnosis is made by histological examination of an excised lymph node biopsy. The characteristic pathological finding in HL is the identification of a large, abnormal binucleate lymphocyte called a Reed-Sternberg cell. HL as classified by the World Health Organization (WHO) has two distinct entities: classic HL and nodular lymphocyte-predominant Hodgkin’s lymphoma (NLPHL). Classic Hodgkin’s is further subdivided into four histological types:

• nodular sclerosis: this is the most common type in the UK, predominant in young adults and females, and has an excellent prognosis
• mixed cellularity: this is second most common type of classic HL and more common in males (70% male)
• lymphocyte depleted: this carries a poor prognosis and is more common in HIV-positive individuals
• lymphocyte rich: this is a rare type of classic HL

NLPHL accounts for 5% of HL cases and is more common in men.

Signs and symptoms

HL usually presents with painless enlargement of lymph nodes, often in the neck. About 40% of patients will present with fever, night sweats and/or weight loss. These have prognostic significance and are designated B symptoms; others include malaise, itching (25%) or pain at the site of enlarged nodes after drinking alcohol. Bone pain may result from skeletal involvement. Primary involvement of the gut, central nervous system or bone marrow is rare.

If lymph nodes in the chest are involved, patients may present with breathlessness. There is often a disturbance of immune function due to a progressive loss of immunologically competent T-lymphocytes, with patients becoming particularly prone to viral and fungal infections.

Laboratory findings

Laboratory findings include normochromic, normocytic anaemia, a raised erythrocyte sedimentation rate and eosinophilia. One-third of patients have a leucocytosis due to an increase in neutrophils. Advanced disease is associated with lymphopenia (lymphocytes <0.6 × 109 L−1). Plasma lactate dehydrogenase (LDH) is raised in 30–40% of patients at diagnosis and has been associated with a poor prognosis.

Investigations and staging

Once the diagnosis has been made on biopsy, further investigations are needed to assess disease activity and the extent of its spread through the lymphoid system or other body sites. This is called staging and is essential for assessing prognosis, with cure rates for localised tumours (stage I or II) being much higher than those for widespread disease (stage IV). The staging of HL is assessed by the Cotswolds modification of the Ann Arbor classification system (Box 51.1). Information about prognostic factors such as mediastinal mass and bulky disease is included in the classification system. The tests required to establish the stage include a complete history, physical examination, FBC, urea and electrolytes (U and Es), chest X-ray and computed tomography (CT). Other useful tests include erythrocyte sedimentation rate (ESR), serum LDH and liver function tests (LFTs). Positron emission tomography (PET) can be used to detect active residual disease.

Box 51.1 Cotswolds modification of the Ann Arbor classification system for Hodgkin’s lymphoma

Clinical stage Defining features
I Involvement of a single lymph node region or lymphoid structure
II Involvement of two or more lymph node regions on the same side of the diaphragm
III Involvement of lymph node regions or structures on both sides of the diaphragm:

III1 – with or without involvement of splenic, hilar, coeliac or portal nodes
III2 – with involvement of para-aortic, iliac or mesenteric nodes

IV Involvement of extranodal site(s) beyond that designated E Modifying characteristics   A: no symptoms
B: fever, drenching sweats, weight loss
X: bulky disease
>one-third width of the mediastinum
>10 cm maximal dimension of nodal mass
E: involvement of a single extranodal site, contiguous or proximal to known nodal site
CS: clinical stage
PS: pathological stage

Management

HL is potentially curable and, in general, sensitive to both chemotherapy and radiotherapy; therefore, the two main goals of treatment are to maximise the likelihood of cure whilst minimising the risk of late toxicity such as infertility. Stage of disease is the biggest factor in treatment choice and outcome. The management of classic HL is determined by the stage of the disease, and this is summarised in Fig. 51.1. Localised NLPHL frequently involves one isolated lymph node and tends to be indolent (slow growing). If there are no risk factors, it can be treated with IFRT alone (30 Gy); all other types are treated as advanced (stage III or IV) classic HL.

image

Fig. 51.1 Treatment algorithm for classic Hodgkin’s lymphoma.

In Europe, the treatment of classic HL is determined by whether the disease is staged as early favourable disease, early unfavourable disease, advanced disease or relapsed (see Box 51.2).

Box 51.2 Disease staging for Hodgkin’s lymphoma (West of Scotland Blood Cancer Network, 2009)

Early stage

European Organisation for Research and Treatment of Cancer (EORTC) risk factors in localised disease

A. Favourable (patients must have all features)

1. Clinical stage 1 or 2
2. Maximum of three nodal areas involved
3. Age less than 50 years of age
4. ESR< 50 mm/h
5. Mediastinal/thoracic mass ratio < 0.33 at D5/6

B. Unfavourable

1. Clinical stage 2 with 4 or more nodal areas involved
2. Age >50 years of age
3. ESR >50 mm/h without B symptoms or >30 mm/h with B symptoms (fever, night sweats, weight loss)
4. Mediastinal/thoracic ratio >0.33 at D5/6a

Advanced stage

Hasenclever score

1. Age >45 years of age
2. Male gender
3. Serum albumin <40 g/L
4. Hb <10.5 g/dL
5. Stage 4 disease
6. Leucocytosis, that is, WCC >15 × 109 L−1
7. Lymphopenia, that is, <0.6 × 109 L−1 or <8% of total WCC

a Mediastinal/thoracic ratio >0.33 at D5/6 – thoracic ratio of maximum transverse mass diameter greater than or equal to one-third (0.33) of the internal transverse thoracic diameter measured at the T5/6 intervertebral disc level.

Early-stage (favourable) disease

The cure rate for patients with stages I and IIA disease is greater than 90%. Patients with stages I and IIA disease may be cured with radiotherapy alone (wide or extended field irradiation). However, due to radiation-related late effects, cardiac toxicity and secondary malignancy and the incidence of relapse (25–30%), most receive combined modality treatment (chemotherapy and radiotherapy). This usually consists of two to four cycles of ABVD (Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine) chemotherapy followed by IFRT of 20–30 Gy (Diehl et al., 2004). The aim of chemotherapy is to destroy subclinical disease outside the field of radiotherapy.

Where disease is confined to above the diaphragm, the mantle field is used (Fig. 51.2). The inverted Y is employed when the disease is confined below the diaphragm. This group of patients have a relapse-free survival rate of 80% at 5–10 years. Patients should be considered for entry into the National Cancer Research Institute (NCRI) 18–30 study or NCRI Lymphoma Groups PET in Hodgkin’s Disease Study.

image

Fig. 51.2 The mantle and inverted Y fields commonly employed in the treatment of Hodgkin’s lymphoma with radiotherapy

(from Souhami and Tobias, 1998, p. 437, with permission from Blackwell Science).

Early-stage (unfavourable) disease

Patients with stage I or II presenting with bulky disease, B symptoms or with more than two sites of disease are considered to be poor risk if treated with radiotherapy alone. B symptoms are any of the following symptoms: unexplained loss of weight, unexplained fever, drenching night sweats. These patients are treated with four to six cycles of combination chemotherapy, for example, ABVD, and radiotherapy (20–30 Gy) to sites of bulky disease. Patients should be considered for entry into the NCRI 18–30 study.

Advanced disease

Patients with advanced disease (stages III and IV) are treated with combination chemotherapy. The first widely used combination chemotherapy regimen was MOPP (mechlorethamine, vincristine (Oncovin), procarbazine and prednisolone) which produced a response rate of 80% and long-term disease-free survival of approximately 50%. ABVD has replaced MOPP chemotherapy as the regimen of choice as it is as effective but less toxic in terms of fertility, haematological toxicity, and the development of acute leukaemia and myelodysplasia. Six to eight cycles of ABVD is considered the current standard treatment for advanced disease.

Despite advances in HL, 30–40% of patients progress or relapse and respond poorly to salvage chemotherapy. A number of regimens have been investigated to both increase dose intensity and density of treatment, for example, BEACOPP (bleomycin, etoposide, Adriamycin (doxorubicin), cyclophosphamide, vincristine, procarbazine, prednisolone) and escalated BEACOPP (Table 51.1). In a trial comparing escalated BEACOPP, standard BEACOPP and COPP-ABVD, escalated BEACOPP demonstrated increased overall survival compared with the other two treatment arms but at the cost of significant toxicity (Engert et al., 2009). First-line escalated BEACOPP can only be recommended currently as part of a clinical trial. A study to investigate the role of BEACOPP and PET imaging in patients with advanced HL is under way and will close in 2012 (UK Clinical Research Network Study Portfolio, 2010).

Table 51.1 Combination chemotherapy regimens effective in the treatment of Hodgkin’s lymphoma

Regimen Dose and route Frequency
ABVD (28-day cycle)
Doxorubicin 25 mg/m2 i.v. Days 1 and 15
Bleomycin 10,000 iu/m2 i.v. Days 1 and 15
Vinblastine 6 mg/m2 i.v. Days 1 and 15
Dacarbazine 375 mg/m2 i.v. Days 1 and 15
BEACOPP escalated (21-day cycle)a
Bleomycin 10,000 iu/m2 i.v. Day 8
Etoposide 200 mg/m2 i.v. Days 1–3
Adriamycin (doxorubicin) 35 mg/m2 i.v. Day 1
Cyclophosphamide 1250 mg/m2 i.v. Day 1
Vincristine 1.4 mg/m2 i.v. (max. 2 mg) Day 8
Procarbazine 100 mg/m2 orally Days 1–7
Prednisolone 40 mg/m2 orally Days 1–14
BEACOPP standard dose (21-day cycle)a
Bleomycin 10,000 iu/m2 i.v. Day 8
Etoposide 100 mg/m2 i.v. Days 1–3
Adriamycin (doxorubicin) 25 mg/m2 i.v. Day 1
Cyclophosphamide 650 mg/m2 i.v. Day 1
Vincristine 1.4 mg/m2 i.v. (max. 2 mg) Day 8
Procarbazine 100 mg/m2 orally Days 1–7
Prednisolone 40 mg/m2 orally Days 1–14
ChlVPP
Chlorambucil 6 mg/m2 orally Days 1–14
Vinblastine 6 mg/m2 i.v. Days 1 and 8
Procarbazine 100 mg/m2 orally Days 1–14
Prednisolone 40 mg/m2 orally (max 60 mg) Days 1–14

a Escalated BEACOPP and standard BEACOPP have shown activity in Hodgkin’s lymphoma, but their usage is not standard in the UK.

Other options for patients unlikely to tolerate ABVD include ChlVPP (chlorambucil, vinblastine, procarbazine, prednisolone) and CHOP (cyclophosphamide, doxorubicin (hydroxydaonorubicin), vincristine (Oncovin), prednisolone, rituximab.

Salvage therapy for relapsed disease

Relapsed disease refers to disease progression after completion of primary treatment which resulted in a complete remission. Depending on previous treatment, options include salvage radiotherapy, salvage chemotherapy or high-dose chemotherapy with autologous stem cell support. In this procedure, stem cells are collected from the patient and returned following high-dose chemotherapy. Patients who relapse after initial radiotherapy alone have a good chance of cure with combination chemotherapy, at least equal to that of patients initially treated with chemotherapy for advanced disease. Occasionally, radiotherapy is used if the disease is localised and previously non-irradiated. Those who relapse after combination chemotherapy have a worse prognosis, although durable remissions can be obtained with further conventional therapy.

Length of remission following first-line chemotherapy influences the success of subsequent salvage therapy and so failure of chemotherapy can be used to classify disease and determine appropriate therapy. If the duration of remission was greater than 12 months (late relapse), then the patient can be re-treated with their initial chemotherapy, salvage regimen or considered for high-dose chemotherapy with autologous transplantation.

Commonly used chemotherapy salvage regimens are listed in Table 51.2. If relapse occurs less than a year after treatment (early relapse), then high-dose chemotherapy with autologous stem cell support should be considered. A patient who has never achieved complete remission (primary refractory disease) should receive high-dose chemotherapy with autologous stem cell support.

Table 51.2 Salvage chemotherapy regimens effective in the treatment of lymphoma

Regimen Dose and route Frequency
DHAP
Cisplatin 100 mg/m2 i.v. Days 1
Cytarabine 2000 mg/m2 i.v. 12 hourly Day 2
Dexamethasone 40 mg orally Days 1–4
ESHAP
Etoposide 40 mg/m2 i.v. Days 1–4
Methylprednisolone 500 mg/m2 i.v. Days 1–5
Cytarabine 2000 mg/m2 i.v. Day 1
Cisplatin 25 mg/m2 i.v. Days 1–4
ICE
Ifosfamide 5000 mg/m2 i.v. Day 2
Carboplatina AUC 5 i.v. Day 2
Etoposide 100 mg/m2 i.v. Days 1–3
IVE
Epirubicin 50 mg/m2 i.v. Days 1
Etoposide 200 mg/m2 i.v. Days 1–3
Ifosfamide 3000 mg/m2 i.v. Days 1–3

AUC, area under the curve; GFR, glomerular filtration rate.

a Carboplatin dose (mg) = target AUC (mg/mL × min) × (GFR (mL/min) + 25).

High-dose chemotherapy plus autologous stem cell support is associated with a 40–50% 5-year survival rate. However, the significant toxicity of autologous stem cell transplantation means that it should be reserved for patients in whom there is a clear increase in chance of cure. Allogeneic transplant is an option in patients relapsing after autologous transplant (Brusamolino et al., 2009).

New agents

The anti-CD20 antibody rituximab has shown remission in 80% of cases of NLPHL, but due to short follow-up, its use is still considered experimental. Other monoclonal antibodies targeting CD30, which is expressed in the majority of classic HL cases, are being investigated. The most promising of these is a novel immunotoxin conjugate SGN-35 (Younes, 2009).

Panobinostat, a histone deacetylases (HDAC) inhibitor, has been granted orphan drug designation for the treatment of HL.

Gemcitabine has shown activity in relapsed classic HL with response rates up to 79% in a small series of heavily pretreated patients (Ng et al., 2005). Bortezomib and lenalidomide licensed for myeloma are also being investigated in those who have relapsed HL.

Non-Hodgkin’s lymphoma

The NHLs are a heterogeneous group of lymphoid malignancies ranging from indolent, slow-growing tumours to aggressive, rapidly fatal disease. Paradoxically, the more aggressive NHLs are more susceptible to anticancer therapy. The overall incidence of NHL in the UK is 11 per 100,000 per year and accounts for approximately 3% of all cancers in the UK. The disease is rare in subjects under 30 years of age and the incidence steadily increases with increasing age; the median age at presentation is about 60. NHL is slightly more common in men than in women (1.5:1).

Aetiology

The aetiology is unclear although immunosuppression, for example, following organ transplantation, may predispose to the development of lymphoma. Viruses have been implicated in the pathogenesis of NHL; for example, Burkitt’s lymphoma is one of the most common neoplasms to develop in HIV-related immunosuppressed patients, human T-lymphotrophic virus type 1 (HTLV-1) is associated with a rare type of T-cell lymphoma, the adult T-cell leukaemia/lymphoma (ATLL) and Epstein–Barr Virus (EBV) is associated with post-transplant lymphoproliferative disorder (PTLD). Exposure to certain chemicals such as pesticides and solvents can increase the risk of developing NHL. There is an increased incidence of gastro-intestinal lymphomas in patients with Crohn’s disease.

Signs and symptoms

The most common presentation of NHL is painless lymphadenopathy, frequently in the neck area in the supraclavicular and cervical regions. Spread of disease is haematogenously (via the blood), and so extranodal sites may be involved. Signs and symptoms of infection, anaemia or thrombocytopenia may be present in patients with bone marrow involvement. Hepatosplenomegaly may also be present. Patients may also present with any of the following symptoms: unexplained loss of weight, unexplained fever, drenching night sweats. These symptoms are described as B symptoms and patients without these symptoms are classified as category A. B symptoms are more commonly seen in advanced or aggressive NHL but may be present in all stages and histological subtypes.

Laboratory findings

Laboratory examinations may reveal anaemia, a raised erythrocyte sedimentation rate and a raised serum LDH level. There may be a reduction in circulating immunoglobulins, and a monoclonal paraprotein may be seen in a small number of cases. The immune disruption caused by the disease may also result in an increased susceptibility to viral infection or autoimmune haemolytic anaemia or thrombocytopenia.

Histopathology and classification

There have been many attempts to classify the NHLs into histological categories that have clinical significance. Despite this, many problems and areas of confusion remain. Approximately 85% of NHLs are of B-cell origin, while 15% are of T-cell origin or are unclassifiable.

There are two classification systems in common use. The Working formulation, developed in 1982, divides the lymphomas into low, intermediate and high grade. More recently, the revised European–American lymphoma (REAL) classification system has been developed (Table 51.3) and adopted by the World Health Organization (Box 51.3) to classify the grade of lymphoma. The REAL/WHO classification incorporates some diagnoses not included in the Working formulation and is a list of lymphomas using morphology, immunophenotype, genotype and clinical behaviour. It recognises the three major categories of lymphoid malignancies: B-cell neoplasms, T-cell/natural killer cell neoplasms and HL. However, in practice, the clinical behaviour of lymphomas informs the treatment strategies employed as these are based on the initial classification into indolent (low grade) or aggressive (intermediate and high grade) NHL. A more biologically relevant classification of lymphoma using the REAL/WHO classification and immunological and molecular characteristics increases the diagnostic specificity and improves selection and targeting of therapy.

Table 51.3 Clinical grade and frequency of lymphomas in the REAL classification

Diagnosis % of all cases
Indolent lymphomas
Follicular lymphoma 22
Marginal zone B-cell, mucosa-associated lymphoid tissue 8
Chronic lymphocytic leukaemia/small lymphocytic lymphoma 7
Marginal zone B-cell nodal 2
Lymphoplasmacytic lymphoma 1
Aggressive lymphoma
Diffuse large B-cell lymphoma 31
Mature (peripheral) T-cell lymphomas 8
Mantle cell lymphoma 7
Mediastinal large B-cell lymphoma 2
Anaplastic large cell lymphoma 2
Very aggressive lymphomas
Burkitt’s lymphoma 2
Precursor T-lymphoblastic 2
Other lymphomas 7

Box 51.3 Revised European–American lymphoma classification as adopted by the WHO (REAL/WHO classification)

Precursor B-cell neoplasm

Precursor B-cell acute lymphoblastic leukaemia or lymphoma

Mature (peripheral) B-cell neoplasm

B-cell chronic lymphocytic leukaemia or small lymphocytic lymphoma
B-cell prolymphocytic leukaemia
Lymphoplasmacytoid lymphoma
Splenic marginal zone B-cell lymphoma (with or without villous lymphocytes)
Hairy cell leukaemia
Plasma cell myeloma or plasmacytoma
Extranodal marginal zone B-cell lymphoma (with or without monocytoid B-cells)
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphoma
Mediastinal large B-cell lymphoma
Primary effusion lymphoma
Burkitt’s lymphoma or Burkitt’s cell leukaemia

Precursor T-cell neoplasm

Prescursor T-cell acute lymphoblastic leukaemia or lymphoma

Mature (peripheral) T-cell and natural killer neoplasms

T-cell prolymphocytic leukaemia
T-cell granular lymphocytic leukaemia
Aggressive natural killer cell leukaemia
Adult T-cell lymphoma or leukaemia
Extranodal natural killer/T-cell lymphoma
Enteropathy type T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides/Sezary syndrome
Primary cutaneous anaplastic large cell lymphoma
Peripheral T-cell lymphoma
Angio-immunoblastic T-cell lymphoma
Primary systemic anaplastic large cell lymphoma

Diagnosis

Diagnosis is based on a thorough history, physical examination and investigation of a lymph node. A definitive diagnosis of NHL can only be made by biopsy of pathological lymph nodes or tumour tissue. An expert histopathologist may need to utilise sophisticated techniques such as immunocytochemistry (e.g. CD20) or genotyping to obtain an accurate subclassification.

Chromosomal abnormalities are of diagnostic importance. Most translocations involve genes associated with either proliferation (e.g. c-MYC) or apoptosis (e.g. BCL-2).

Additional investigations should also be performed to accurately stage the disease and exclude other disease. FBC from peripheral blood and routine biochemistry and uric acid should be performed. Peripheral blood lymphocytosis (increased lymphocytes) with circulating malignant cells is common in low grade and mantle cell lymphomas. A bone marrow aspirate and trephine are required to exclude leukaemia and will detect bone marrow involvement, which is more common than in HL. CT scans of the chest, abdomen and pelvis are required to assess the extent of the disease. The use of PET scans, capable of locating sites not thought to be affected from CT scan images, is increasing. Lumbar punctures should be performed for patients at high risk of CNS involvement, for example, Burkitt’s lymphoma. Erythrocyte sedimentation rate, LDH and serum β2-microglobulin levels may indicate disease activity and can be of prognostic importance.

Staging

Determining the extent of disease in patients with NHL provides prognostic information and is useful in treatment planning. Patients with extensive disease usually require different therapy from those with limited disease. The NHLs can be staged according to the Ann Arbor classification (see Box 51.1). In this system, NHL is defined as stage I, II, III or IV, stage I being disease limited to a single lymph node and stage IV being advanced disease, with involvement of extralymphatic sites. The International Prognostic Index (Table 51.4) uses the following factors as predictors of poor prognosis: elevated LDH, stage III or IV disease, greater than 60 years of age, the higher the number of extranodal sites involved and the Eastern Co-operative Oncology Group (ECOG) performance status of two or higher. Other prognostic factors include bulky disease, presence of B symptoms and transformation from low- to high-grade disease. Prognostic indicators are important because they inform the treatment plan to avoid overtreating those with good prognosis and undertreating those with poor prognosis.

Table 51.4 International prognostic index

Factor Adverse prognosis
Age ≥60 years
Ann Arbor stage III or IV
Plasma lactate dehydrogenase level Above normal
Number of extranodal sites of involvement ≥2
Performance status ≥ECOG 2 or equivalent

ECOG, Eastern Co-operative Oncology Group.

Treatment

When designing a treatment plan for an individual patient, various factors must be taken into account. These include the patient’s age and general health, the extent or stage of the lymphoma and the particular histological subtype. Indolent (low-grade) lymphoma tends to run a slow course and although it is not curable, patients survive for prolonged periods with minimal symptoms. Aggressive (high-grade) lymphomas result in death within weeks or months if untreated. These lymphomas, however, are very responsive to chemotherapy and up to 50–60% may be cured with combination chemotherapy (Fig. 51.3).

image

Fig. 51.3 Typical treatment algorithm for non-Hodgkin’s lymphoma.

CD20 is essential for cell cycle regulation and cell differentiation. It is expressed on normal B-cells and the majority of malignant B-cell lymphomas. The introduction of rituximab, a monoclonal antibody with specificity for CD20, has changed the way patients with NHL are treated and is now incorporated into most chemotherapy regimens. The mechanism of action of rituximab is not fully understood but is thought to involve complement-mediated lysis of B-cells and antibody-dependent cellular cytotoxicity. Other potential mechanisms include induction of apoptosis and inhibition of cell cycle progression.

Indolent non-Hodgkin’s lymphoma

The median age at which patients present with indolent NHLs is 50–60 years, and generally patients have a good performance status. If left untreated, indolent NHL has a comparatively long survival (median: 9 years). Follicular lymphoma is the most common of the indolent lymphomas. For the minority of patients presenting with limited-stage disease (stage I), radiotherapy to the involved field is generally used. However, the majority (80%) of patients present with advanced disease (stages II–IV) where the aim of treatment is to reduce disease bulk and offer symptom relief. Rituximab, cyclophosphamide, vincristine, prednisolone (R-CVP) is used as the first-line treatment for advanced (stage III or IV) follicular lymphoma following the results of a study comparing R-CVP with CVP (cyclophosphamide, vincristine, prednisolone) (Marcus et al., 2005). This approach has been incorporated into national guidance (NICE, 2006). R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) can also be used as first-line treatment for young patients with aggressive disease and is an option in relapsed disease (Table 51.5).

Table 51.5 Chemotherapy regimens effective in the treatment of non-Hodgkin’s lymphoma

Drug Dose and route Day of administration
R-CHOP (21-day cycle)
Cyclophosphamide 750 mg/m2 i.v. Day 1
Doxorubicin (hydroxydaunorubicin) 50 mg/m2 i.v. Day 1
Vincristine (Oncovin) 1.4 mg/m2 (max 2 mg) i.v. Day 1
Prednisolone 100 mg orally Days 1–5
Rituximab 375 mg/m2 i.v. Day 1
R-CVP (21-day cycle)
Cyclophosphamide 750 mg/m2 i.v. Day 1
Vincristine (Oncovin) 1.4 mg/m2 (max 2 mg) i.v. Day 1
Prednisolone 100 mg orally Days 1–5
Rituximab 375 mg/m2 i.v. Day 1
FC (28-day cycle)
Fludarabine 40 mg/m2 orally Days 1–3
Cyclophosphamide 250 mg/m2 daily orally Days 1–3
CHOP (21-day cycle)
Cyclophosphamide 750 mg/m2 i.v. Day 1
Doxorubicin (hydroxydaunorubicin) 50 mg/m2 i.v. Day 1
Vincristine (Oncovin) 1.4 mg/m2 (max 2 mg) i.v. Day 1
Prednisolone 100 mg orally Days 1–5

For patients who are asymptomatic at diagnosis, adopting a ‘watch and wait’ policy with active monitoring and initiating treatment when symptomatic is an option. Patients could be considered for recruitment to clinical trials; there are on-going studies comparing R-CVP with R-FC (rituximab, fludarabine, cyclosphosphamide) followed by rituximab maintenance and investigating the benefit of bendamustine compared to R-CVP. If patients fail to tolerate the standard treatment options, an oral alkylating agent, for example, chlorambucil, with or without a steroid can be used. Repeated courses may be given.

Relapsed indolent non-Hodgkin’s lymphoma

Relapsed patients may be re-treated with rituximab if the time to relapse post-rituximab is greater than 6 months (NICE, 2008). If the time to relapse is less than 6 months, Yttrium-90 labelled ibritumomab tiuxetan (Zevalin®) may be considered. Zevalin® is a new therapeutic development that utilises monoclonal antibodies as tumour-specific vehicles to deliver systemic radiation therapy concurrent with immunotherapy to the targeted tumour. However, for some resistant or relapsing patients, particularly if their condition is too poor to merit further radical chemotherapy, palliation will be appropriate. Radiotherapy may be an option in this situation and this is being evaluated through an ongoing clinical trial.

Aggressive non-Hodgkin’s lymphoma

The median age of presentation of aggressive NHL is 60–70 years when 50–60% of patients will present with an advanced stage of the disease. The most common presentation is diffuse large B-cell lymphoma (DLBCL), and therefore the treatment strategies described later refer to this alone. Other aggressive lymphomas, for example, mantle cell, are managed differently. The most important strategy when treating this group of patients is to maintain the dose intensity of chemotherapy and minimise any delay in chemotherapy administration. Treatment is given with curative intent.

The treatment for advanced-stage aggressive NHL is six cycles of the combination of R-CHOP chemotherapy (NICE, 2003). Doxorubicin can cause cardiotoxicity and patients with a reduced cardiac ejection fraction or co-morbidities may not tolerate R-CHOP. The use of gemcitabine (R-GCVP) is currently being investigated for this patient group as part of a clinical trial. The addition of bortezomib to R-CHOP in DLBCL is also being investigated as a clinical trial for patients with high-risk disease.

Relapsed aggressive non-Hodgkin’s lymphoma

Combination chemotherapy with R-CHOP probably cures 40–60%. This, therefore, implies that over half of all patients have refractory disease or relapse after first treatment.

In younger patients with aggressive NHL, the aim will be to introduce remission with further chemotherapy, using an alternative, salvage regimen, and then to consolidate remission with high-dose therapy (HDT). HDT is usually supported by mobilised peripheral blood stem cells (PBSCs) and an autologous PBSC transplantation (auto-PBSCT). Lymphoma is the most frequent indication for auto PBSCT in Europe. The European Group for Blood and Marrow Transplantation (EBMT) suggests that the upper age limit for autologous transplantation is 65 years. HDT, with autologous stem cell support, is also used as part of primary treatment for younger patients with indolent lymphoma. Patients who receive HDT after their initial treatment can have progression-free survival rates of around 50% at 5 years.

To induce a remission in patients with aggressive lymphoma and relapsed disease, it may be reasonable to use the same or similar regimen used for front-line chemotherapy. However, in most cases, the regimen chosen introduces new agents that are potentially not cross-resistant with those used in the initial treatment regimen. There are several salvage regimens in use and they generally have response rates of between 40% and 70%. Examples of salvage regimens are ICE (ifosfamide, carboplatin, etoposide), ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) and DHAP (cisplatin, cytarabine, dexamethasone) (see Table 51.2). Gemcitabine, a pyrimidine analogue, may be of benefit for patients with relapsed or refractory disease after two lines of treatment. Gemcitabine is used in combination with other agents, such as cisplatin and methylprednisolone. Rituximab can also be added to these salvage regimens. PBSCs are usually harvested after the second course of the salvage regimen. Patients then receive a high-dose regimen such as BEAM (carmustine, etoposide, cytarabine, melphalan) (Table 51.6) conditioning prior to stem cell infusion (autograft). Patients should only undergo an autograft if they have demonstrated a response to salvage chemotherapy.

Table 51.6 Conditioning chemotherapy for autologous transplantation

Drug Dose and route Day of administration
BEAM
Carmustine 300 mg/m2 i.v. 6 days before reinfusion
Etoposide 200 mg/m2 i.v. 5–2 days before reinfusion
Cytarabine 200 mg/m2 12 h i.v. 5–2 days before reinfusion
Melphalan 140 mg/m2 i.v. 1 day before reinfusion
Reinfusion of stem cells   Day 0
LACE
Lomustine 200 mg/m2 orally 7 days before reinfusion
Etoposide 1000 mg/m2 i.v. 7 days before reinfusion
Cytarabine 2000 mg/m2 6–5 days before reinfusion
Cyclophosphamide 1800 mg/m2 i.v. 4–2 days before reinfusion
Reinfusion of stem cells   Day 0

CNS prophylaxis for diffuse large B-cell lymphoma

Approximately 5% of patients with DLBCL develop CNS disease. The optimum approach to CNS prophylaxis is uncertain, and it usually involves a course of intrathecal chemotherapy.

The updated national guidance for the safe administration of intrathecal chemotherapy (DH, 2008) sets out the minimum requirements of a hospital providing an intrathecal chemotherapy service.

Very aggressive lymphoma

Burkitt’s lymphoma is a rare form of B-cell NHL which occurs most commonly in children and young adults. The median age of adult patients is 30 years. Untreated, survival is measurable in days or weeks, and it is widely accepted that combination chemotherapy should be urgently commenced. Intensive chemotherapy is necessary, together with CNS prophylaxis, and cure is possible in a high proportion of cases.

Multi-agent chemotherapy regimens including high-dose methotrexate, high-dose cytarabine, etoposide and ifosfamide are used and a schedule such as CODOX-M (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate)/IVAC (ifosfamide, etoposide, high-dose cytarabine) is common.

There is an on-going debate about the value of adding rituximab to the CODOX-M/IVAC regimen.

Lymphoblastic lymphomas/leukaemia

Lymphoblastic lymphomas comprise about 2% of adult NHLs. Patients are often treated with the same regimens used in acute lymphoblastic leukaemia (ALL). Despite a very high rate of complete responders, long-term survival remains poor. Patients who fail after first-line chemotherapy have a long-term disease-free survival of less than 10%. These cases are subsequently treated as leukaemias (see Chapter 50).

Patient care

The chemotherapy regimens used to treat HL and NHL (see Tables 51.1 and 51.5) are usually administered on a hospital outpatient basis with the patient visiting the clinic regularly for assessment and treatment. The patient is monitored by FBCs carried out before each cycle of chemotherapy and at the ‘nadir’ between cycles. The nadir is when the blood count is at its lowest point, usually 10–14 days after the first day of chemotherapy. The interval between each cycle of chemotherapy enables normal body cells to recover before the patient receives further treatment. Disease response to treatment is monitored by repeating some of the diagnostic investigations, such as CT, at suitable intervals and the use of PET. If there is little or no response to treatment, a different chemotherapy regimen will be used or a decision made to withdraw from active therapy and provide optimum supportive care.

Counselling and support

Counselling is an essential part of the care of the cancer patient and involves not only the explanation of drug therapy and investigations but also the provision of psychological support for the patient and family. Prior to treatment with chemotherapy, the patient will be counselled by the doctor, chemotherapy nurse and, increasingly, by oncology pharmacists. It is necessary to explain how the chemotherapy is to be given and discuss both potential and inevitable side effects. The probability of successful treatment must be weighed against the prospect of serious and life-threatening adverse effects. Patients must be made aware of the long-term complications of chemotherapy and radiotherapy, such as secondary malignancy.

The support available to the cancer patient, to help cope with both the illness and its treatment, has improved dramatically in recent years. Multidisciplinary teams working within specialised units have become skilled in anticipating the problems of lymphomas and their treatment. In addition, many charities provide care, support and advice such as Macmillan Cancer Support (www.macmillan.org.uk) and the Lymphoma Association (www.lymphoma.org.uk).

Patient-specific treatment modifications

The selection of appropriate therapy must also take into consideration the individual patient. Factors include the patient’s age, renal and hepatic function and underlying medical conditions, such as heart disease, diabetes or chronic pulmonary disease. The patient’s tolerance of side effects and complications of therapy may then be predicted. The decision is based on an understanding of the pharmacodynamics and pharmacokinetics of the drugs being used as well as the clinical condition of the patient.

Supportive care

During a course of chemotherapy, the patient requires supportive care to minimise the adverse effects of treatment. The common adverse effects of the chemotherapy regimens discussed in this chapter are outlined in Table 51.7. These will occur to varying degrees depending on the combination of drugs and the doses used as well as individual patient factors.

Table 51.7 Adverse effects associated with chemotherapy regimens used in the lymphomas with supportive measures and counselling points

image

Nausea and vomiting

Nausea and vomiting is the most distressing and most feared adverse effect of chemotherapy. Its effect on the patient should not be underestimated, and its treatment is an important part of supportive care. The severity will depend on the combination of drugs used. For example, oral chlorambucil is generally well tolerated by almost all patients and requires no antiemetic cover. Regimens such as ABVD, which is highly emetic, will make most patients vomit if no antiemetics are given. Aprepitant, an NK1 receptor antagonist, is licensed for cisplatin chemotherapy regimens and may be useful for managing emesis with DHAP, ESHAP, etc. The patient should be counselled on the appropriate use of prescribed antiemetics (see Table 51.7).

Tumour lysis syndrome

The lymphomas are, in general, highly sensitive to chemotherapy. The resulting lysis of cells which occurs following initiation of chemotherapy may lead to hyperuricaemia, hyperkalaemia and hypocalcaemia in patients with bulky disease, and result in urate nephropathy. There is a high incidence of tumour lysis syndrome (TLS) in tumours with high proliferation rates and tumour burden such as Burkitt’s lymphoma and T-lymphoblastic lymphoma. The mainstay of TLS prevention is hydration with the patient encouraged to maintain a high fluid intake. Hyperuricaemia is controlled with allopurinol and close monitoring of renal function, serum urate levels and electrolytes. Allopurinol must be commenced before chemotherapy and continued until the tumour load has reduced and serum urate levels are normal. In aggressive forms of NHL, rasburicase, a recombinant urate oxidase, may be indicated as prophylaxis. Allopurinol should not be prescribed concurrently with rasburicase because it will inhibit the production of uric acid, the substrate for rasburicase.

Rasburicase can also be used to treat TLS but will only correct hyperuricaemia. Treatment of TLS should include vigorous hydration and diuresis. Historically alkaline diuresis has been recommended, but overzealous alkalinisation can lead to problems such as metabolic acidosis (Cairo and Bishop, 2004). Hypocalcaemia should be corrected if the patient is symptomatic, but this may increase calcium phosphate deposition. Hyperkalaemia and hyperphosphataemia should be corrected; patients may require haemofiltration or dialysis.

Mucositis

Chemotherapy may cause mucositis, which is inflammation of or damage to the surface of the gastro-intestinal tract. In the mouth, this may lead to painful ulceration, local infection and difficulty in swallowing. Dependent on the severity of mucositis, patients may require analgesia from benzydamine mouthwash to systemic opiates. Disruption of the mucosal barrier will give bacteria and fungi easier systemic access. A mouth care regimen should therefore be instituted with myelosuppressive therapy. This involves good oral hygiene, for example, gentle brushing with a toothbrush to remove plaque or rinsing with saline to remove debris. An antiseptic mouthwash such as chlorhexidine 0.2% should also be used regularly to prevent infection. Palifermin, keratinocyte growth factor (KGF), may have a role in autologous haemopoietic stem cell support.

Bone marrow suppression

Myelosuppression is usually the dose-limiting factor with these regimens, and it is necessary to carry out FBCs before treatment to confirm that recovery has occurred. Each chemotherapy protocol should be referred to so as to ensure appropriate management. Generally, if the platelet count is below 100 × 109 L−1 and/or the absolute neutrophil count (ANC) is less than 1 × 109 L−1, the subsequent dose may be reduced or treatment delayed by a week.

Anaemia is treated with blood transfusions and thrombocytopenia with platelet transfusions as necessary. Erythropoietin administration reduces blood transfusion requirements and can improve quality of life. However, the evidence suggesting improvement in patient survival is inconclusive.

Neutropenia is the most life-threatening acute toxicity; the neutropenic patient is at constant risk from infections. Seemingly minor infections such as cold sores can spread rapidly, and infections not seen in the normal population, such as systemic fungal infections, can occur. Supportive measures involve reducing the risks and the aggressive treatment of any infectious episodes. The patient is counselled to avoid contact with people with infection or those who may be carriers. Most infections, however, are from an endogenous source such as the gut or skin. The patient is educated on the importance of good personal hygiene, mouth care, how to monitor body temperature and to report any febrile episodes immediately. Co-trimoxazole 960 mg may be prescribed as prophylaxis against Pneumocystis pneumonia in patients receiving chemotherapy for lymphomas, particularly in those receiving a regimen containing fludarabine. Thorough and frequent hand washing helps to prevent the transmission of opportunistic infection to the neutropenic patient.

Febrile neutropenia

A febrile episode in the neutropenic patient is an indication for immediate treatment with broad-spectrum intravenous antibiotics. Susceptibility to infection is likely when the neutrophil count is less than 1 × 109 L−1 with increasing risk at levels less than 0.5 × 109 L−1 and 0.01 × 109 L−1. Fever, usually defined as a temperature above 38 °C maintained for 1 h or 38.3 °C on one occasion, may be the only sign of infection. The patient should be assessed to determine the site of infection, if possible. Blood cultures from all venous access ports and any other appropriate cultures, for example, midstream urine sample and stool sample, are taken and then antibiotic therapy commenced. Blood cultures are taken prior to starting antibiotics to increase the likelihood of obtaining a positive culture. Infection with Gram-negative bacilli, for example, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, and Gram-positive cocci, for example, coagulase-negative staphylococci, β-haemolytic streptococci, enterococci, and Staphylococcus aureus is probable in this situation. First-line therapy should cover these common pathogens. Options include carbapenems, a third-generation cephalosporin or antipseudomonal penicillin with or without an aminoglycoside. If the patient does not respond to this combination within 24–48 h, then second-line therapy, which may include a glycopeptide for Gram-positive cover, is commenced.

Gram-positive infections are becoming more common with the use of indwelling intravenous catheters. If positive microbiological cultures are found, the appropriate antibiotic can be prescribed on the basis of sensitivities; however, if the patient is responding to empiric therapy, the antibiotics should not be changed. Only one-third of suspected infections are ever confirmed, and the pathogen may not be isolated. The febrile episode may not be due to infection; non-infectious causes include blood transfusion and underlying disease.

Growth factor support

Patients with persistent neutropenia or those who have repeated admissions for neutropenic sepsis may be supported with granulocyte-colony-stimulating factor (GCSF). There is evidence that patients with lymphomas receiving a reduced dose of chemotherapy as a consequence of myelosuppression have a worse prognosis when compared with patients who receive full doses. GCSF is indicated as primary prophylaxis, before any episode of febrile neutropenia, for regimens where there is a high (>40%) incidence of febrile neutropenia. GCSF has been investigated as a prophylactic measure to increase the dose intensity of chemotherapy in regimens such as CHOP-14 (cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), prednisolone at 14-day intervals) and BEACOPP-14 (bleomycin, etoposide, Adriamycin (doxorubicin) cyclophosphamide, vincristine, procarbazine, prednisolone at 14-day intervals).

Case studies

Case 51.1

Mr RB is a 50-year-old man receiving a course of fludarabine and cyclophosphamide (see Table 51.5) for mantle cell lymphoma. He has no other medical problems and has normal renal and hepatic function.

Questions

1. What are the key counselling points for the oral chemotherapy drug fludarabine?
2. What antibacterial agent would you expect to see prescribed with fludarabine?
3. What antiemetic regimen would you recommend with the fludarabine and cyclophosphamide?

Answers

1. Immunocompromised patients, for example, those receiving purine analogues, fludarabine, cladribine and pentostatin, are at risk of developing transfusion-associated graft versus host disease (TAGVHD), a rare but usually fatal complication of transfusion.
Viable T-lymphocytes in donated blood can recognise the recipient as ‘foreign’, leading to fever, skin rash, hepatitis and bone marrow involvement. Death occurs in 90% of cases, predominantly due to infection.
γ-Irradiation of cellular blood components is the mainstay of TAGVHD prevention. Patients should be given an appropriate patient information leaflet and an alert card. The risk of TAGVHD is minimised by informing transfusion staff and the patient of their need for irradiated blood products.
2. Mr RB should be prescribed co-trimoxazole prophylactically to prevent Pneumocystis jiroveci infection.
3. Chemotherapy drugs are grouped by how likely they are to cause emesis if antiemetics are not given, called emetogenic potential. Antiemetic regimens are then prescribed to prevent the degree of vomiting expected for each group.
Fludarabine is rarely emetogenic and oral cyclophosphamide is moderately emetogenic. Therefore, the regimen should be classified and treated as moderately emetogenic. Dexamethasone, granisetron and metoclopramide are frequently employed for moderately emetogenic regimens. Guidelines for antiemetic use in oncology are available (American Society of Clinical Oncology, 2006). As corticosteroids are associated with immunosuppression, some clinicians prefer not to use them for emesis prevention with FC chemotherapy.

Case 51.2

Mrs BC is a 72-year-old widow who has been newly diagnosed with low-grade NHL. She has been seen in the hospital outpatient haematology clinic and has brought a prescription to the pharmacy for chlorambucil 10 mg daily for 14 days. When she hands in her prescription, she expresses concern about the side effects of the tablets. The doctor who saw her had spent a lot of time talking to her about her treatment, but she feels confused with all the information given.

Questions

1. What are the side effects of chlorambucil?
2. How would you counsel this patient?

Answers

1. Chlorambucil, an alkylating agent, is generally well tolerated. The major side effect is bone marrow suppression. Other side effects are uncommon and include nausea and vomiting, rash, mucositis and diarrhoea. Hepatotoxicity and jaundice have been reported. Mrs BC is an elderly patient and is thus more likely to experience toxicity because of deteriorating renal and hepatic function and underlying medical conditions.
2. Mrs BC may be distressed by her diagnosis and may not have been able to absorb all the information she was given in the clinic. She may also be seeking confirmation of information.
Mrs BC should be counselled to complete the course of tablets as prescribed. She should be told that she will probably feel tired and be more prone to infection because the tablets lower the blood count and resistance to infection. She should be advised to inform the haematologist if she feels unwell. Chlorambucil is unlikely to make her feel nauseous, but if this occurs she should inform the doctor, who will be able to prescribe an antiemetic.

Case 51.3

Mr F is 56 years old and was diagnosed with stage III high-grade NHL (DLBCL) over 10 weeks ago. Since then, he has received three cycles of R-CHOP and has come to the hospital for his nadir blood count. He complains of painful mouth ulcers and a sore throat. On examination, he has mucositis and oropharyngeal candidiasis. He has a white blood cell count (WCC) of 3.2 (normal range: 3.5–11 × 109 L−1) with ANC of 0.8 × 109 L−1.

Questions

1. How would you treat Mr F’s Candida infection?
2. How would you counsel this patient?

Answers

1. Mr F has an ANC of 0.8 × 109 L−1 and is therefore neutropenic (ANC <1.0 × 109 L−1). Localised candidal infections can spread rapidly in the immunosuppressed patient, so local therapy with an antifungal mouthwash will be inadequate therapy. A course of fluconazole, 100 mg daily for at least 7 days, should be prescribed. Therapy should continue for a further 7 days if Mr F is still neutropenic or if the thrush has not completely resolved.
An antibacterial mouthwash, such as chlorhexidine 0.2% 10 mL four times daily, should be used. As Mr F is complaining of pain, an analgesic should be added. Benzydamine mouthwash, a locally acting analgesic, could be prescribed initially. If this does not give adequate pain relief, then systemic analgesics such as dihydrocodeine should be given.
2. Regular mouth care reduces the risk of infection but does not entirely remove it. It is not necessarily a reflection of how well the patient has adhered to his mouth care regimen. Chlorhexidine mouthwash should be used first, held in the mouth as long as possible, ensuring the entire mucosa is covered before spitting out. The mouthwash should be used after meals and at bedtime. He should not eat or drink for at least half an hour after using the mouthwash.
The benzydamine mouthwash should be used before meals as Mr F will probably find eating painful. He should be advised to use a soft toothbrush, to eat soft foods and to avoid hot and spicy dishes. He may be reassured that once his blood count recovers, his mouth ulcers should resolve and that the fluconazole should relieve his sore throat.

Case 51.4

Mr D, 38 years old with advanced HL, is admitted to the haematology ward at the local hospital as an emergency. He had a temperature of 39 °C on the morning of admission, feels generally unwell but has no specific symptoms. It is 12 days since he started his third cycle of ABVD. On admission, he is taking the following medication:

• co-trimoxazole 960 mg twice daily on 3 days a week
• chlorhexidine 0.2% mouthwash 10 mL four times daily

Blood cultures are taken and piperacillin + tazobactam 4.5 g i.v. three times daily and gentamicin 480 mg i.v. once daily are prescribed, to be commenced immediately. Blood biochemistry results are normal; his FBC was Hb 10.8 (normal range: 13.5–18.0 g/dL for men), WCC 2.5 (normal range: 3.5–11 × 109 L−1), neutrophil count 0.6 (normal range: 1.5–7.5 × 109 L−1) and platelets 150 (normal range 150–400 × 109 L−1). Mr D weighs 86 kg and is 186 cm tall.

Questions

1. Comment on the rationale for the antibiotic therapy prescribed.
2. How would you monitor this patient?
3. What would be an appropriate second-line regimen if he remains pyrexial?
4. What modifications would need to be made to subsequent cycles of chemotherapy?

Answers

1. Mr D’s FBC is probably at its nadir following his last course of chemotherapy. He is neutropenic and febrile; fever is often the only sign of infection in neutropenic patients. Immunosuppression is also a feature of HL and contributes to susceptibility to infection. Treatment should commence immediately after cultures have been taken, as infection can be rapidly fatal in these patients. The antibiotics selected should provide broad-spectrum cover and follow local policy as there are institutional variations in predominant pathogens and antimicrobial sensitivities. The organisms responsible for infectious episodes are constantly changing: in the 1970s, Gram-negative infections predominated but now Gram-positive organisms account for 65% of positive cultures. As Gram-negative infections are more rapidly fatal, first-line therapy should be biased towards these infections. Piperacillin, an antipseudomonal penicillin, and gentamicin therefore form an appropriate combination to use in this patient. Piperacillin + tazobactam monotherapy may be sufficient in cases of uncomplicated neutropenic sepsis.
The dose of piperacillin + tazobactam is appropriate. Infection is considered to be severe in these patients as signs and symptoms are often muted. Single daily dose gentamicin is at least as effective as multiple dosing and less nephrotoxic; it is more convenient and cost effective and overcomes deficiencies of the traditional method such as subtherapeutic dosing and inadequate monitoring. The dose is 5–7 mg/kg and has been calculated correctly for Mr D. He has normal renal function, so no dose modifications are necessary.
2. Monitor temperature, pulse and blood pressure and any patient symptoms for signs of improvement or deterioration. Blood biochemistry should be checked daily to detect any deterioration in renal function. Microbiology reports should be checked and antibiotics reviewed if any micro-organisms have been cultured. However, no change should be made to antibiotics if the patient is showing signs of improvement. The administration of gentamicin should be monitored, checking both administration and sampling time for drug levels. The results should be checked and recommendations for dose modification made where appropriate, using a method such as the Hartford monogram.
3. If the patient remains pyrexial 24–48 h after the first-line antibiotics have been commenced, consideration should be given to broadening cover, for example, adding vancomycin if the patient has mucositis or line infection. If blood cultures show growth, found in only 30–40% of neutropenic patients, the choice of antibiotics should be on the basis of sensitivities. It is important to note that febrile episodes lasting several days may involve more than one infecting organism.
The patient’s FBC should start to recover from day 14 but may be delayed by this infection. It is unusual for patients on conventional chemotherapy for HL to require more than one change to antibiotic therapy, and clinical improvement is often seen with recovery of neutrophil count. If Mr D is still pyrexial at 96 h, then the likelihood of fungal infection must be considered and an intravenous amphotericin-based product or caspofungin commenced if appropriate. The incidence of fungal infection is increasing in patients with prolonged neutropenia. As Mr D’s neutropenia is short lived, he is more likely to have a bacterial infection.
4. A dose reduction for subsequent cycles of chemotherapy may be considered. However, as this patient is being treated with curative intent, it may be more appropriate to give GCSF and maintain the dose intensity.

Acknowledgements

The authors thank Denise Blake and Mary Maclean for permission to use material originally included in their chapter that appeared in the third edition of this book.

References

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Brusamolino E., Bacigalupo A., Barosi G. Classical Hodgkin’s lymphoma in adults: guidelines of the Italian Society of Hematology, the Italian Society of Experimental Hematology, and the Italian Group for Bone Marrow Transplantation on initial work-up, management, and follow-up. Haematologica. 2009;94:550-565.

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

Department of Health. HSC 2008/001: Updated National Guidance on the Safe Administration of Intrathecal Chemotherapy. London: Department of Health. 2008. Available at: http://www.dh.gov.uk/en/Publicationsandstatistics/Lettersandcirculars/Healthservicecirculars/DH_086870

Diehl V., Thomas R.K., Re D. Part II: Hodgkin’s lymphoma – diagnosis and treatment. Lancet Oncol.. 2004;5:19-26.

Engert A., Diehl V., Franklin J., et al. Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of follow up of the GHSG HD9 Study. J. Clin. Oncol.. 2009;27:4548-4554.

Marcus R., Imrie K., Belch A., et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005;105:1417-1423.

National Institute for Health and Clinical Excellence. Rituximab for Aggressive Non-Hodgkin’s Lymphoma. London: NICE. 2003. Available at: http://guidance.nice.org.uk/TA65/Guidance/pdf/English

National Institute for Health and Clinical Excellence. Rituximab for the treatment of follicular lymphoma. London: NICE technology appraisal guidance A 110, NICE. 2006. Available at http://www.nice.org. uk/nicemedia/pdf/TA110guidance.pdf

National Institute for Health and Clinical Excellence. Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin’s lymphoma. London: NICE technology appraisal guidance 137, NICE. 2008. Available at http://www.nice.org.uk/nicemedia/pdf/TA137guidance.pdf

Ng M., Waters J., Chau I., et al. Gemcitabine, cisplatin and methylprednisolone (GEM-P) is an effective salvage regimen in patients with relapsed and refractory lymphoma. Br. J. Cancer. 2005;92:1352-1357.

Souhami R., Tobias J., editors. Cancer and Its Management. Oxford: Blackwell Science, 1998.

Younes A. Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma. Hematology (American Society Hematology Education Program). 2009:507-519.

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West of Scotland Blood Cancer Network. Clinical Management Guidelines Hodgkin’s Lymphoma Version 3.0. Available at http://www.medednhsl.com/meded/clinicalgpp/pdf/WoSCAN_CMG_Hodgkins_v3_0_August_2009.pdf, 2009.

Further reading

Dearden C., Matutes E. Non-Hodgkin’s lymphoma. Medicine. 2000;28:71-77.

Evens A.M., Winter J.N., Gordon L.I., et al. Non-Hodgkin’s lymphoma. In Pazdur R., Coia L.R., Hoskins W.J., et al, editors: Cancer Management: A Multidisciplinary Approach, 13th ed, New York: PRR Melville, 2011. Available at: http://www.cancernetwork.com/cancermanagement-12

Laport G.F., Williams S.F. The role of high-dose chemotherapy in patients with Hodgkin’s disease and non-Hodgkin’s lymphoma. Semin. Oncol.. 1998;25:503-517.

Leonard J.P., Coleman M., editors. Hodgkin’s and Non-Hodgkin’s Lymphoma. New York: Springer-Verlag, 2006.

Yahalom J., Strauss D. Hodgkin’s lymphoma. In Pazdur R., Coia L.R., Hoskins W.J., et al, editors: Cancer Management: A Multidisciplinary Approach, 13th ed, New York: PRR Melville, 2011. Available at http://www.cancernetwork.com/cancer-management-12

Provan D., Singer C.R.J., Baglin T., et al. Oxford Handbook of Clinical Haematology, third ed. Oxford: Oxford University Press. 2009.

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