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 symptomsB: fever, drenching sweats, weight lossX: bulky disease>one-third width of the mediastinum>10 cm maximal dimension of nodal massE: involvement of a single extranodal site, contiguous or proximal to known nodal siteCS: clinical stagePS: 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

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