SEMINAR

Seminar

Non-Hodgkin lymphoma
Linda S Evans, Barry W Hancock Non-Hodgkin lymphoma is a non-specific term that includes several lymphoproliferative malignant diseases with different clinical and histological appearances. Here, we concentrate on adult lymphomas. We look at their molecular basis, at the development of a classification system based on a better understanding of the biology of the various subgroups, and at how refinement of adverse prognostic factor groupings helps in clinical management. Lymphomas can present in various ways and be difficult to diagnose. About a quarter of cases arise extranodally and might present special problems. Developments in cytotoxic chemotherapy have led to good long-term survival prospects for aggressive lymphoma; introduction of novel approaches, including monoclonal antibody therapy, offers promise for indolent lymphoma, and should further improve prognosis for aggressive tumours. Non-Hodgkin lymphomas represent about 24% of all cancers registered in England and Wales, and 26% of all cancer deaths. Prevalence rises with age and is about 50% higher in men than women. Prevalence is highest in North America and western Europe and lower in eastern Europe and Asia. For the past 20 years, the incidence has been rising steadily across all age groups and in both sexes, by about 35% per year. Reasons for this increase are unclear. In most cases of non-Hodgkin lymphoma, cause is unknown. Some subtypes are associated with infection, for example, Epstein-Barr virus in Burkitts lymphoma, patients with constitutional (Purtilos syndrome) or postorgan-transplant immune deficiencies, and human T-lymphotropic virus in adult T-cell leukaemia and lymphoma. Immunosuppression is the most clearly defined risk factor, leading to 50100-fold excess risk. microsatellite instability that is caused by defects in DNA the mismatch repair genes in some hereditary cancer predisposition syndromes and in a few sporadic solid cancers.3,4 Historically, detection of recurrent, non-random chromosomal abnormalities by karyotypic analysis of nonHodgkin lymphoma metaphases has presented the major clue towards identification and cloning of most genetic alterations in these disorders. Chromosomal translocations represent the main mechanism of proto-oncogene activation. These translocations are characterised by recurrence within a specific clinicopathological category of non-Hodgkin lymphoma and are clonally represented in each tumour. All chromosomal translocations in this disorder that have been cloned up to now share a common featureie, presence of a proto-oncogene mapping to the vicinity of one of two chromosomal recombination sites. They tend to juxtapose the proto-oncogene to heterologous regulatory sequences derived from the partner chromosome. These sequences might derive from antigen-receptor loci and from other loci that are expressed at sustained concentrations in normal cells corresponding to the differentiation stage of the lymphoma (table 2). The typical result of translocation is deregulated expression of a proto-oncogene. The two exceptions are t(2;5) of T-cell anaplastic large cell lymphoma and t(11;18) of mucosa-associated lymphoma tissue (MALT) lymphoma, which cause gene fusions coding for chimeric proteins.5,6

Biology
Most lymphoid malignancies worldwide are derived from B-lymphocytes at various stages of differentiation (figure 1). Therefore, to understand the structure, cellular composition, changes in gene expression, and molecular events implicated in the differentiation and function of normal B cells is important. Two types of lymphoid tissue exist: central (bone marrow and thymus) and peripheral (blood, spleen, lymph node, and mucosa-associated). Within central lymphoid tissue, cells arise and differentiate into mature lymphocytes; they then migrate into peripheral lymphoid tissues and recirculate throughout the body. If they encounter foreign antigen, effector and memory cells evolve. Differentiation of B cells in central and peripheral lymphoid tissues entails changes in cytological and homing mechanisms, which are correlated to genetic events and changes in gene expression (table 1). Similar to most human cancers, the genetic lesions involved in non-Hodgkin lymphoma include activation of proto-oncogenes and disruption of tumour suppressor genes.1 By contrast with many types of epithelial cancers that are characterised by generalised random instability of their genome, the genome of lymphoma cells is relatively stable.2 Furthermore, lymphomas generally do not have the
Lancet 2003; 362: 13946
Weston Park Hospital, Sheffield S10 2SJ, UK (L S Evans FRCP, Prof B W Hancock FRCP) Correspondence to: Prof B W Hancock (e-mail: b.w.hancock@sheffield.ac.uk)

Histopathological classification
Many classifications of non-Hodgkin lymphoma have been made in the past 3040 years, which can be difficult to interpret and reproduce. By understanding the origin of a lymphoma, more can be understood about disease management. Different lymphomas have various origins;

Search strategy and selection criteria

A search of published work was undertaken with MEDLINE together with the American Society of Hematology educational books, textbooks, and information gleaned from international meetings including the European Society of Haematology. Textbooks were also used, including: Souhami RL, Tannock I, Hohamberger P, Horiot JC. Oxford Textbook of Oncology, 2nd edn. Oxford: Oxford University Press, 2001; and Hancock BW, Selby PJ, MacLennan K, Armitage JO. Malignant Lymphoma. London: Arnold, 2000.

THE LANCET Vol 362 July 12, 2003 www.thelancet.com

139

SEMINAR

entities on the basis of morphological appearances, which were lent support by immunophenotype and genetic Marginal/ Germinal features. Publication of this mantle centre classification was followed by rigorous zone clinical assessment to establish its validity and reproducibility. It was recorded to be 85% reproducible among pathologists, and it defined new A diseases with distinctive clinical features DLBCL and responses to treatment, thereby MZL MCL FL SLL convincing oncologists to accept it.8 In Precursor Extranodal 2001, the classification system was BCL tissue updated under the auspices of WHO by the Society for Haematopathology and the European Association of Haematopathology (table 3).9 B Peripheral TCL For doctors who treat lymphomas, Precursor clinical differences between the most TCL common diseases are easily Node appreciatedlarge B-cell lymphoma, Thymus follicular lymphoma, chronic lymphoGerminal cytic leukaemia, and Hodgkins disease. centre Many recognised diseases are also clinically distinctive: MALT lymphoma and mantle-cell lymphoma are strikingly different from each other and from ALCL chronic lymphocytic leukaemia and small lymphocytic lymphoma, and need Figure 1: Cellular origins of representative non-Hodgkin lymphomas (A) B cell; (B) T cell. ALCL=anaplastic large-cell lymphoma; BCL=B-cell lymphoma; DLBCL=diffuse different approaches to treatment. large B-cell lymphoma; FL=follicular lymphoma; MCL=mantle-cell lymphoma (pre-germinal centre); Peripheral T-cell lymphomas consist of MZL=marginal zone (MALT) lymphoma (post-germinal centre); SLL=small lymphocytic lymphoma; many distinctive categories that differ in TCL=T-cell lymphoma. their natural history from B-cell lymphomas. As practitioners begin to see patients with these they have diverse clinical behaviour and prognosis. A diseases, their characteristic clinical features will provide a classification system that is constantly updated when new real-life rationale for learning the new categories. informationboth clinical (prognosis, treatment) and The most typical lymphomas are of diffuse large B-cell pathological (histology, immunology, genetics)becomes type (33%) followed by B-cell follicular lymphoma (22%). available is important. In 1993, the International All other types of lymphoma have a frequency of less than Lymphoma Study Groupconsisting of eminent 10% (table 3).8 An algorithm can be used to establish histopathologists from the USA, Europe, and Asiamet and subsequently published the revised Europeandiagnosis on the basis of gene expression, American classification of lymphoid neoplasms (REAL immunophenotype, morphology, homing patterns, and classification).7 Lymphomas were identified as specific proliferation fraction (panel 1).10
Bone marrow Node
B cells Foreignantigen independent Stem cell Immunoglobulin genes Germ line Somatic mutations None Immunoglobulin protein None Marker CD34 Corresponding lymphoma Affected tissues Bonemarrow

Pro B cell Pre B cell Immature B cell Mature naive B cell

Germ line IgH rearrangement, -chain (cytoplasm) IgL/IgH rearrangements, IgM (membrane) IgL/IgH rearrangements, IgM and IgD (membrane)

None None None None

None Ig IgM (membrane) IgM/IgD

Foreignantigen dependent

CD19, CD79a, BSAP, CD34, CD10, TdT CD19, CD45R, CD79a, BSAP, CD34, CD10, TdT CD19, CD20, CD45R, CD79a, CD10, BSAP CD19, CD20, CD45R, CD79a, BSAP, CD5

B-LBL/ALL

Germinal IgL/IgH rearrangements, centre class switch (centroblastic and centrocytic) Memory IgL/IgH B cell rearrangements Terminal Plasma cell differentiation IgL/IgH rearrangements

Introduction of somatic mutations Somatic mutations Somatic mutations

Immunoglobulin (minimal or absent) IgM

CD19, CD20, CD45R, CD79a, BSAP, CD10, BCL6 CD19, CD20, CD45R, CD79a, BSAP CD38, Vs38c, MUM-1CD138

IgG>IgA>IgD

B-chronic Peripheral lymphocytic lymphoid leukaemia, tissues mantle cell lymphoma Burkitts lymphoma, follicle cell lymphoma, diffuse large B-cell lymphoma Marginal zone lymphoma, B-chronic lymphocytic leukaemia Plasmacytoma/ myeloma

ALL=acute lymphoblastic leukaemia; B-LBL=B-lymphoblastic lymphoma. Adapted from Harris NL, Stein H, Coupland SE, et al. New approaches to lymphoma diagnosis. Hematology 2001: 194220. http://www.asheducationbook.org/cgi/content/full/2001/1/194 (accessed March 13, 2003), with permission of the American Society of Hematology.

Table 1: B-cell development and corresponding lymphomas derived at each stage

140

THE LANCET Vol 362 July 12, 2003 www.thelancet.com

SEMINAR

NHL histological type Lymphoplasmacytic lymphoma Follicular lymphoma

Translocations observed t(9;14)(p13;q32)

Cases affected 50%

Proto-oncogene involved PAX5

Mechanism behind protooncogene activation Transcriptional deregulation

Proto-oncogene function Transcription factor regulating B cell proliferation and differentiation Negative regulator of apoptosis

Mantle-cell lymphoma MALT lymphoma Diffuse large B-cell lymphoma Burkitts lymphoma

t(14;18)(q32;q21) t(2;18)(p11;q21) t(18;22)(q21;q11) t(11;14)(q13;q32) t(11;18)(q21;q21) t(1;14)(p22;q32) der(3)(q27) t(8;14)(q24;q32) t(2;8)(p11;q24) t(8;22)(q24;q11) t(2;5)(p23;q35)

8090%

BCL2

Transcriptional deregulation

70% 50% Rare 35% 80% 15% 5% 60% adult, 85% childhood

BCL1/cyclin D1 API2/MLT BCL10 BCL6 c-MYC

Transcriptional deregulation Fusion protein Transcriptional deregulation Transcriptional deregulation Transcriptional deregulation

Cell-cycle regulator Antiapoptosis Antiapoptosis? Transcriptional repressor Transcription factor regulating proliferation and growth

Anaplastic large T-cell lymphoma

NPM/ALK

Fusion protein

ALK is a tyrosine kinase

Adapted from Harris NL, Stein H, Coupland SE, et al. New approaches to lymphoma diagnosis. Hematology 2001: 194220. http://www.asheducationbook.org/cgi/content/full/2001/1/194 (accessed March 13, 2003), with permission of the American Society of Hematology.

Table 2: Chromosomal translocations of non-Hodgkin lymphoma

Clinical presentation and staging

Presentation depends on site of involvement, natural history of the lymphoma, and presence or absence of B symptoms (weight loss >10%, night sweats, fever). Indolent lymphomas frequently present with peripheral lymphadenopathy, which generally waxes and wanes over time and is usually asymptomatic unless it causes
Frequency (%)* B-cell neoplasms Precursor B-cell neoplasms Precursor B-lymphoblastic leukaemia/lymphoma (precursor B-cell lymphoblastic leukaemia) Mature (peripheral) B-cell neoplasms Chronic lymphocytic leukaemia/B-cell small lymphocytic lymphoma B-cell prolymphocytic leukaemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma (splenic lymphoma with villous lymphocytes) Hairy cell leukaemia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma (MALT lymphoma) Nodal marginal zone B-cell lymphoma Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphomas Burkitts lymphoma/leukaemia T-cell and NK-cell neoplasms Precursor T-cell neoplasm Precursor T-lymphoblastic leukaemia/lymphoma (precursor T-cell acute lymphoblastic leukaemia) Blastoid NK-cell lymphoma Mature (peripheral) T-cell neoplasms T-cell prolymphocytic leukaemia T-cell large granular lymphocytic leukaemia Aggressive NK-cell leukaemia Adult T-cell lymphoma/leukaemia (HTLV1+) Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/Sezary syndrome Primary cutaneous anaplastic large cell lymphoma Peripheral T-cell lymphoma, not otherwise specified Angioimmunoblastic T-cell lymphoma Primary systemic anaplastic large cell lymphoma

8 2 22 6 33 2

compression, for instance of ureter, orbit, or spinal cord. With aggressive lymphomas, rapid tumour growth takes place, and patients might quickly become very ill. The standard staging system for non-Hodgkin lymphoma is the same as that proposed for Hodgkins disease at the Ann Arbor conference in 1971.11 Its main use is to distinguish localised stage 1 and 2 disease from the disseminated stages 3 and 4. For some subtypes, especially indolent lymphomas, widespread disease is typical without necessarily conferring poor prognosis. Also, staging does not take into account certain prognostic factors or some prognostically important sites of involvementespecially bone marrow and central nervous system. Patients can present with lumps almost anywhere. Fewer than a quarter present with a lump in the neck. About a quarter of patients present with disease at an extranodal site, the main sites being gastrointestinal tract, head and neck, and skin, but virtually any tissue or organ can be affected.12 Presentation might also be multifocal. Occasionally, a patient could present with symptoms only (for example fatigue, night sweats, or weight loss) and no mass that is easy to biopsy (table 4). According to UK Department of Health referral guidelines for suspected cancer,13 patients with the symptoms in panel 2 should be urgently referred. All patients with, or who potentially have, lymphoma should have their management discussed by a multidisciplinary team.14 This discussion, together with informed entry into clinical trials, is essential for the patients own optimum treatment and for the contribution to the evidence-base for future improvements in care.15 Treatment of lymphoma should be continually evolving. Investigations are as in panel 3.

Prognostic factors
Management of patients with non-Hodgkin lymphoma is mainly affected by tumour type and extent, patients performance status, and previous medical history. Indicators to determine prognosis have been avidly investigated. Clinical prognostic features are mainly a surrogate for disease bulk. Factors that have generally been accepted as being associated with a poor prognosis include age older than 60 years, poor performance status, B symptoms, disseminated stage, an abdominal mass more than 10 cm in diameter, three or more extranodal sites of disease, bone-marrow involvement, concentration in serum of lactate dehydrogenase above normal, and transformation from previous low-grade histology.

*For subtypes with frequency of 1%. All other lymphomas account for remaining 7% of total. Adapted from Harris NL, Stein H, Coupland SE, et al. New approaches to lymphoma diagnosis. Hematology 2001: 194220. http://www.asheducationbook.org/cgi/content/full/2001/1/194 (accessed March 13, 2003), with permission of the American Society of Hematology.

Table 3: The REAL/WHO classification of non-Hodgkin lymphomas and their frequency

THE LANCET Vol 362 July 12, 2003 www.thelancet.com

141

SEMINAR

Panel 1: Algorithm for use of special techniques in lymphoma diagnosis

Morphology: small lymphoid cells (1) Benign vs malignant Immunoglobulin light chains (kappa and lambda)* BCL2 protein in follicles* Kappa/lambda polyclonal or Bcl2 follicles=reactive Kappa/lambda monoclonal or Bcl2+ follicles=small B-cell lymphoma (2) Classification of small B-cell lymphoma CD5+: CLL/SLL vs mantle-cell lymphoma Cyclin D, dim surface immunoglobulin expression, CD23+=CLL/SLL* Cyclin D+, bright surface immunoglobulin expression, CD23=mantle-cell lymphoma* CD5: follicular lymphoma vs marginal zone lymphoma (MALT) CD10+=follicular lymphoma CD10=marginal zone lymphoma vs CD10 follicular lymphoma Bcl6+, CD43, Bcl2+ follicles=follicular lymphoma Bcl6, CD43+, Bcl2 follicles=marginal zone lymphoma Morphology: large lymphoid cells (1) Lymphoma vs non-lymphoid tumour CD45 (leukocyte common antigen), pan-B antigens and pan-T antigens, immunoglobulin light chains, cytokeratin, melanoma markers (2) Subclassification of medium-sized and large cell lymphomas Pan-B antigens (CD20, CD79a)+=B-cell lymphoma Ig+=mature B-cell lymphoma (DLBCL vs Burkitts) CD10+, Bcl2, Ki67 >99%= favours Burkitts CD10-, Bcl2+, Ki67 <90%= favours DLBCL Ig=mature B cell vs lymphoblastic lymphoma TdT+, CD10+=precursor B-lymphoblastic lymphoma TdT, CD10/+=DLBCL Pan-T antigens (CD3, CD2, CD45RO)+=T-cell/NK-cell lymphoma TdT+=precursor T-lymphoblastic TdT =mature T-cell/NK-cell lymphoma CD21+, FDC, CD10+=angioimmunoblastic T-cell lymphoma CD30+, ALK+=anaplastic large-cell lymphoma
CLL/SLL=chronic lymphocytic leukaemia/small lymphocytic lymphoma; MALT=mucosa associated lymphoid tissue; Ig=immunoglobulin; DLBCL=diffuse large B-cell lymphoma; NK=natural killer cell; TdT=terminal deoxynucleotidyl transferase; ALK=anaplastic lymphoma kinase. *Can be detected by gene expression (immunophenotype) or gene rearrangement (genetic techniques). Adapted from Harris NL, Stein H, Coupland SE, et al. New approaches to lymphoma diagnosis. Hematology 2001: 194220. http://www.asheducationbook.org/cgi/content/full/2001/1/194 (accessed March 13, 2003), with permission of the American Society of Hematology.

Presentation group Nodal

Site or symptoms Tends to be non-contiguous; 25% have mediastinal involvement; abdominal lymph node involvement is common with bulky disease Main sites of occurrence: gastrointestinal tract, Waldeyer's ring, skin Present with non-specific symptoms of fatigue, night sweats, or weight loss

Cases 5575%

Extranodal

2040%

Symptomatic

About 5%

Table 4: Clinical presentation of lymphomas

phenotype has been shown for large-cell lymphoma, other than anaplastic, and should be taken into consideration when choosing treatment.18 In the future, we can expect that new biological prognostic factors will be identified and that their importance will be compared with the clinical IPI. In follicular lymphoma, genomic aberration might contribute substantially to prognostic risk assessment,19 and in diffuse B-cell lymphoma is possible to identify gene expression subgroups with differing survivals by molecular profiling.20 The importance of treatment-related factors is not very clear. Results of several reports suggest a good cure rate in lymphoma patients who respond most rapidly to chemotherapy.21

Treatment
Mainstays of treatment for non-Hodgkin lymphoma have been chemotherapy or radiotherapy. However, we are now entering an exciting era when use of novel treatments, including monoclonal antibodies, is being assessed and put into everyday practice. Indolent lymphomas Follicular lymphoma Only a few patients with follicular lymphoma have localised disease potentially curable by radiotherapy, with complete remission in 98% and an estimated 10-year disease-free survival for 47%.22 Most have disseminated disease at diagnosis. This disease tends to be chronic relapsing and remitting, and standard chemotherapy is not curative. Regimens include: oral chlorambucil; cyclophosphamide, vincristine, and prednisolone (CVP); fludarabine; or anthracycline-containing regimens. They differ in toxic effects but none affects overall survival. For a patient with no major symptoms or organ dysfunction, a watch-and-wait policy can be undertaken, which usually delays initiation of chemotherapy by 2 or 3 years. However, for most patients, this disease is incurable, and new treatments need to be assessed. Rituximab is a chimeric human-murine IgG1 monoclonal antibody that binds specifically to the B-cell surface antigen

Discrepancies in different series, and recognition of the importance of prognostic factors, led to an overview analysis of more than 3000 patients with diffuse large B-cell lymphoma treated with conventional chemotherapy between 1982 and 1987.16 In multivariate analysis, five features independently contributed to prognosis: age, stage, number of extranodal sites, performance status, and serum concentration of lactate dehydrogenase. Patients could be divided into four groups with decreasing complete response rates and shortened survival. This model has been called the International Prognostic Index (IPI) and has been validated by many groupseg, in patients treated with doxorubicin, cyclophosphamide, vindesine, and bleomycin (ACVB).17 Moreover, it is applicable to various histological subtypes. This study was unable to include other markers such as immunophenotyping, 2 microglobulin, or BCL2 protein expression. Prognostic importance of T-cell immuno-

Panel 2: Symptoms of non-Hodgkin lymphoma needing urgent referral

Lymphadenopathy (>1 cm persisting for 6 weeks) Hepatosplenomegaly q Three or more of the following symptoms: q Fatigue q Night sweats q Weight loss q Itching q Breathlessness q Bruising q Recurrent infection q Bone pain
q q

142

THE LANCET Vol 362 July 12, 2003 www.thelancet.com

SEMINAR

Panel 3: Investigations done before initiation of treatment

Essential procedures q A full history, recording growth rate, symptoms present, performance status q A detailed physical examination, with special attention to all node-bearing areas including Waldeyers ring q Adequate surgical biopsy specimen, allowing immunophenotyping and examined by a skilled pathologist q Laboratory procedures: q Full blood count, including erythrocyte sedimentation rate q Serum lactate dehydrogenase, calcium, uric acid, proteins and electrophoresis, alkaline phosphatase q Assessment of renal and liver function q Radiological studies: q Chest radiograph q Thoracic and abdominal-pelvic CT scan q Bone-marrow aspirate and trephine, to include molecular genetic analysis if available Optional procedures, depending on clinical picture q 2 microglobulin q Endoscopy, eg, for gastric MALT lymphoma q Plain radiographs, bone scan, or MRI q Positron electron tomography (PET) q Head or spinal MRI for neurological symptoms q Cerebrospinal fluid analysis in patients at risk

the same as that for high-grade lymphoma, if the patient is fit enough. The results are, however, much worse than for patients presenting de novo with high-grade lymphoma. Chronic lymphocytic leukaemia and small lymphocytic lymphoma This slowly progressive form of lymphoma, as its name implies, shows considerable overlap with B-cell chronic lymphocytic leukaemia. Most patients are adults older than 60 years who present with generalised lymphadenopathy and bone marrow, liver, spleen, and peripheral-blood involvement. A conservative approach to treatment similar to that in follicular lymphomais usual; when salvage chemotherapy is needed these tumours are more likely than follicular lymphomas to respond to purine analogues of adenosine arabinoside (fludarabine or cladribine). Mantle-cell lymphoma With standard treatment (including CHOP), median survival for patients with this disorder is about 3 years, far shorter than that for patients with other indolent lymphomas; for this reason, mantle-cell lymphoma must now be regarded as an aggressive disorder.38 Attempts to improve survival have used new treatments, such as highdose treatment with autologous stem-cell rescue, allogeneic transplantation, and immune therapy with either free or radiolabelled monoclonal antibodies.39 One novel approachpioneered at the M D Anderson Cancer Centreis the hyper-CVAD regimen (high-dose cytarabine and methotrexate with rituximab).40 As yet, no randomised controlled trial evidence is available to show that such approaches are better than conventional treatments. Aggressive lymphoma Diffuse large B-cell lymphoma Historically, radiotherapy to the involved field has been the treatment of choice for patients with localised disease. However, this therapy is insufficient and, even after adequate dosage, about 15% of patients will develop in-field relapse and others will relapse with disease outside the radiation field. Therefore, in the past 15 years, two strategies have been developed for patients with stage 12 disease (without poor prognostic factors): chemotherapy

CD20 (figure 2). The glycosylated protein consists of the constant regions of human IgGs combined with the variable region from murine IgGs, and is produced by Chinese hamster ovary cells in suspension culture.23 The antibody induces both complement-mediated and antibodydependent cytotoxic effects on CD20-positive cells. It has also been reported to induce apoptosis and sensitise chemoresistant human lymphoma cell lines to cytotoxic chemotherapy.2325 The antibody is well tolerated and its main toxic effect is either haematological (thrombocytopenia and neutropenia) or infusion-related. Prevalence of human antichimeric antibody is less than 10%.2628 It has important single-agent efficacy, giving remission rates of 4050% in the treatment of relapsed indolent lymphoma,2931 and has now received UK National Institute for Clinical Excellence approval for patients who have failed standard chemotherapy. Rituximab acts via many effector mechanisms, which are quite distinct from those of standard chemotherapeutic drugs. It activates complement-mediated23 and antibodydependent cytotoxicity.32 As a result, a trial combining rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) in patients with indolent lymphoma has been undertaken.33 This regimen gave an overall response rate of 95% (40 patients studied), with 55% achieving a complete response. At present, median duration of response and time to progression for these patients has not been reached after 50 months of follow-up. Rituximab has also been assessed in combination with fludarabine,34,35 since results of a phase 2 study in 49 patients investigating fludarabine as first-time treatment for follicular lymphoma indicated a response rate of 65%, with a complete response rate of 37% and median relapse-free survival of about 16 months.36 Results seem to be similar to CHOP plus rituximab. Transformed indolent lymphoma Indolent lymphomas of different types can transform into high-grade malignancies. This change happens in up to 40% of patients and leads to death.37 Treatment needs to be

Anti-CD20 CD20 antigen B cell

Radiolabel (90Y131I) Anti-CD20 CD20 antigen B cell Direct effect B cell

B cell

Bystander effect

Figure 2: Anti-CD20 antibodies for therapy in non-Hodgkin lymphoma

(A) antibody alone; (B) radiolabelled antibody.

THE LANCET Vol 362 July 12, 2003 www.thelancet.com

143

SEMINAR

alone with a doxorubicin-containing regimen, eg, CHOP; or a shortened course of chemotherapy followed by involved-field radiotherapy. In one study, 78 patients with stage 12 disease (IPI 0) received three courses of CHOP followed by involved-field radiotherapy. The response rate was 99%, with long-term survival of 85% for these patients.41 In another study, three cycles of CHOP plus radiotherapy (200 patients) was compared with eight cycles of CHOP (201 patients). Patients receiving both treatments had longer progression-free survival (77%) and better overall survival (82%) than those treated with CHOP alone (64% and 72%, respectively).42 In patients with extranodal localisation in the abdomen and in older patients with Waldeyers ring involvement, radiotherapy can be avoided to keep the risk of sequelae to a minimum. For patients with advanced-stage disease, the most effective treatment is chemotherapy. Results show that patients with advanced-stage bulky disease do not consistently relapse at sites of major initial disease, at least when they have received modern aggressive chemotherapy.43 Many combination-chemotherapy regimens have been developed. CHOP has been the standard first-line treatment in most centres and is curative in at least a third of patients with large-cell lymphomas, as confirmed by 12 years of follow-up. Long-term follow-up is indeed necessary, since results have shown that relapses can happen many years after completion of chemotherapy.44 Addition of rituximab to CHOP has been shown in one large phase 3 study (in patients age older than 60 years),45 and in several phase 2 trials, to improve response rates and survival. New chemotherapy regimens are also being assessed, which include either rapid alternation of different drugs or dose escalation. With the availability of growth-factor support, maximally tolerated non-myeloblative doxorubicin-based regimens have been developed for advanced disease. Two approaches are being investigated: to escalate dose of CHOP while maintaining a schedule every 3 weeks;46 or to administer standard CHOP on a shortened schedule, every 2 weeks.47 With both regimens, the dose-limiting factors were severe infection, associated with neutropenia, and nonhaematological toxic effects. To date, response rates have been unremarkable, the major problem being in attainment of the planned dose intensity, but data are still immature. The future lies with development of different protocols for various risk groups and combination with novel treatments. Burkitts lymphoma Burkitts lymphoma is most frequent in childhood, and adult cases of disease are treated as for the childhood form. Clinical assessment is different from other lymphomas, and if one of the following symptoms is present, the patient is deemed high risk: stage 34 disease, raised lactate dehydrogenase concentration, poor performance status, and a mass greater than 10 cm. Patients receive intensive chemotherapy together with repeated intrathecal treatments, which gives a survival of about 80%.48 Lymphoblastic lymphoma This lymphoma is also very aggressive and is treated with regimens based on strategies for acute lymphoblastic leukaemia, with due attention also being paid to the central nervous system as a potential sanctuary site. Peripheral T-cell lymphoma This type of lymphoma is rare in western populations but is most frequentand generally related to HTLV-1 virus infectionin Asia. It is made up of a heterogeneous group of neoplasms, some very rare, that differ by their

morphology, phenotype, clinical presentation, and outcome.49 Overall however, these are aggressive tumours with a median survival of less than 4 yearsworse than with aggressive tumours of the B-cell phenotype.50 Extranodal lymphomas Extranodal lymphomas in general should be treated as for nodal disease. Aggressive lymphomas are usually treated with combined chemoradiotherapy, producing an 80% 5-year survival, a 2030% improvement on treatment with radiotherapy alone.51 Certain extranodal lymphomas present special clinical management problems. Gastric lymphoma of MALT type Although MALT-type marginal-zone lymphomas arise at other sites (such as salivary gland, lung, and thyroid), gastric MALT lymphomas are uniquely related to previous infection with Helicobacter pylori. Eradication with appropriate antibiotics results in regression of the lymphoma in three-quarters of patients,52 although fewer than half achieve sustained molecular remission.53 The 10-year survival is about 90%, although transformation to diffuse large B-cell lymphoma can happen. Lymphoma of the central nervous system Primary lymphoma of the central nervous system is an aggressive tumour (usually of diffuse large B-cell type) arising in brain, leptomeninges, or eye. Its prevalence has risen strikingly in the immunocompetent population. Traditionally, radiotherapy was the treatment of choice,54 but tumour recurrence was common, and chemotherapy (with high-dose methotrexate-based regimens), combined with irradiation, has strikingly enhanced average survival to up to 5 years.55 However, late neurotoxic effects are a typical complication of this approach, and chemotherapy alone is being tested. Testicular lymphoma Although rare, primary testicular lymphoma is the most frequent testicular malignancy in men older than age 60 years. Pathology is usually of diffuse large B-cell type, and despite apparently localised presentation, prognosis is worse than with most other sites with the same histological findings. A high frequency of central nervous system relapse has been noted,56 so much so that prophylactic intrathecal chemotherapy has been advocated in addition to CHOP and adjuvant radiotherapy. However, as yet no hard evidence exists to justify routine use of this approach. Overall, about a quarter of testicular lymphomas are cured.57

New approaches
High-dose chemotherapy For aggressive lymphoma in first remission High-dose treatment with autologous stem-cell transplantation has the potential to improve the cure rate of chemosensitive disease.58 One of the greatest challenges is to identify patients who will fail to respond to standard chemotherapy or whose responses will be short-lived. The IPI still seems to be a robust indicator of at-risk patients. Several investigators have therefore taken an at-risk subgroup (usually with at least two adverse IPI factors) and looked at giving these patients high-dose therapy when they have achieved a good response with first-line treatment that is, in an adjuvant setting. The GELA group have shown a disease-free survival advantage associated with high-dose chemotherapy for poor-risk patients in first remission,59 but this finding does not accord with those of other studies,6062 which might be because patients

144

THE LANCET Vol 362 July 12, 2003 www.thelancet.com

SEMINAR

subsequently relapsing after standard treatment are salvaged by high-dose treatment at a later date. Further studies are underway, looking at timing of the procedure, different chemotherapy regimens, use of antibodies, and high doses of chemotherapy given in sequential fashion rather than all at once.63 For refractory or relapsed aggressive high-grade lymphoma Until a few years ago, patients with aggressive lymphoma who relapsed or failed to achieve a complete response had a life expectancy of between 3 and 4 months. Various salvage regimens have now been developed that achieve an overall survival at 2 years of 2030%. High-dose chemotherapy has been shownby workers on a randomised controlled studyto substantially improve survival to over 50%.58 A total of 215 patients in first or second relapse were studied; after two courses of salvage treatment patients were randomised to continue salvage therapy or have high-dose treatment with autologous stem-cell transplantation. The response rate after high-dose treatment was 937% versus 425%, and event-free survival at 5 years was 53% versus 32% in the salvage alone arm. Patients selected for this study had previously been in complete response and had no bone marrow or central nervous system involvement or T-cell morphology. For indolent lymphoma Single-centre studies have shown promising results. Large multicentre trials are underway and results of these are awaited. Allogeneic stem-cell transplantation Allogeneic transplantation for lymphoma can result in extended survival, which is unfortunately offset by considerable transplant-related mortality (40%) and morbidity.64 At present, therefore, insufficient evidence exists to consider this treatment outside clinical studies, even in patients who cannot receive or have failed autologous stem-cell transplantation. If reductions in transplant mortality can be achieved, it is anticipated that the role of allografting for lymphoma will become more important. In this context, reports of non-myeloablative regimens that aim to keep graft-versus-lymphoma effect to a maximum but reduce transplant-related mortality (so-called mini allografting) seem promising.65 Radiolabelled monoclonal antibody treatments Many radioisotopes are under investigation, the two main contenders being iodine-131 and yttrium-90, usually in association with anti-CD20 monoclonal antibody (figure 2). These isotopes have usually been given in nonmyeloablative doses, but also in myeloablative doses as part of transplant procedures.66 Radiolabelled antibodies can have an important role in treatment of refractory or transformed low-grade lymphomas. In a study by Kaminski and colleagues,67 60 patients were reported who had been treated previously with at least two chemotherapy regimens, the last being at least 6 months before. Every patient received one course of tositumomab. 39 patients (65%) responded, and median duration of response had not been reached after follow-up of more than 47 months. Only one patient was admitted with neutropenic fever, five developed human antimurine antibodies, and one had raised concentration of thyroid-stimulating hormone after treatment. In a randomised trial comparing 90 Y ibritumomab tiuxetan with rituximab alone, the overall response rate was higher for the radiolabelled antibody (80% vs 56%, p=0002, 143 patients).68 However, more studies are needed to assess longer-term effects.

Vaccine treatments These treatments have been mainly aimed at follicle-centre lymphomas, since the idiotype determinants of the immunoglobulin synthesised by these cells are known to be unique and can serve as a tumour-specific antigen. Kwak and colleagues69 reported use of purified autologous immunoglobulin as vaccine for patients with follicular lymphoma. 12 patients were vaccinated after high-dose chemotherapy; ten patients mounted idiotype-specific humoral or specific responses and seven have had lengthened remissions.70 Idiotypic vaccination is timeconsuming and dependent on good laboratory backup. These results are promising but preliminary.
References
1 Dalla-Favera R, Gaidano G. Molecular biology of lymphomas. In: DeVita VTJ, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. Philidelphia: Lippincott Williams, and Wilkins; 2001: 221535. Mitelman F, Mertens F, Johansson B. A breakpoint map of recurrent chromosomal rearrangements in human neoplasia. Nat Genet 1997; 15: 41774. Eshleman JR, Markowitz SD. Micro satellite instability in inherited and sporadic neoplasms. Curr Opin Oncol 1995; 7: 8389. Gamberi B, Gaidano G, Parsa N, et al. micro satellite instability is rare in B-cell non-Hodgkins lymphomas. Blood 1997; 89: 97579. Morris SW, Kirstein MN, Valentine MB, et al. fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in NHL. Science 1994; 263: 128184. Dierlamm J, Baens M, Wlodarska I, et al. The apoptosis inhibitor gene AP12 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;21) associated with MALT lymphomas. Blood 1999; 93: 360109. Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 136192. Anonymous. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkins lymphoma. Blood 1997; 89: 390918. Jaffe ES, Harris NL, Vardiman JW, Stein H. Pathology and genetics: neoplasms of the haematopoietic and lymphoid tissues. In: Kleihaus P, Sobin L, eds. World Health Organization classification of tumours. Lyon: IARC Press, 2001. Harris NL, Stein H, Coupland SE, et al. New approaches to lymphoma diagnosis. Haematology 2001; 1: 194231. Carbone PP, Kaplan HS, Mushoff K, et al. Report of the committee on Hodgkins Disease Staging Classification. Cancer Res 1971; 31: 186061. Dobson LS, Hancock H, Bright N, et al. Localised non-Hodgkins lymphoma: The Sheffield Lymphoma Group experience (19701995). Int J Oncol 1998; 13: 131318. Anonymous. Referral guidelines for suspected cancer. London: Department of Health, London, 2000. Birtwhistle MB, Hancock BW. Common clinical errors, and service deficiencies and their classification in the investigation and management of NHL: key advances in the effective management of NHL symposium. In Marcus R, Cunningham D, Miles A, eds. The effective management of non-Hodgkins lymphoma, 2nd edn. London: Aesculapius Medical Press, 2003. Hancock BW. Management of patients with lymphoma: the way forward. Clin Oncol 2001; 13: 242. The International Non-Hodgkins Lymphoma Prognostic Factors Project. A predictive model for aggressive NHL. N Engl J Med 1993; 329: 98794. Mounier N, Morel P, Haioun C, et al. A multivariate analysis of the survival of patients with aggressive lymphoma. Cancer 1998; 82: 195262. Gisselbrecht C, Gallard P, Lepage E, et al. Prognostic significance of T-cell phenotype in aggressive non-Hodgkins lymphoma. Blood 1998; 92: 7682. Viardot A, Moller P, Hogel J, et al. Correlations of genomic gains and losses in follicular lymphoma. J Clin Oncol 2002; 20: 452330. Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large B cell lymphoma. N Engl J Med 2002; 346: 193747. Armitage JO, Cheson BD. Interpretation of clinical trials in diffuse largecell lymphoma. J Clin Oncol 1988; 6: 133547. Vaughan Hudson B, Vaughan Hudson G, MacLennan KA, et al. Clinical stage 1 non-Hodgkins lymphoma: long term follow-up in

3 4 5

10 11

12

13 14

15 16

17

18

19 20

21 22

THE LANCET Vol 362 July 12, 2003 www.thelancet.com

145

SEMINAR

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37 38

39

40

41

42

43

44

45

patients treated by the British National Lympohma Investigation with radiotherapy alone as initial therapy. Br J Cancer 1994; 69: 108893. Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994; 83: 43545. Demidem A, Lam T, Alas S, et al. Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biother Radiopharm 1997; 12: 17786. Ghetie MA, Bright H, Vitetta ES. Homodimers but not monomers of rituximab (chimeric anti-CD20) induce apoptosis in human Blymphoma cells and synergize with a chemotherapeutic agent and an immunotoxin. Blood 2001; 97: 139298. Liu AY, Robinson RR, Murray ED, et al. Production of a mouse-human chimeric monoclonal antibody to CD20 with potent Fc-dependent biologic activity. J Immunol 1987; 139: 352126. LoBuglio AF, Wheeler RH, Trang J, et al. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci USA 1989; 86: 422024. Mueller BM, Romerdahl CA, Gillies SD, et al. Enhancement of antibody-dependent cytotoxicity with a chimeric anti GD2 antibody. J Immunol 1990; 144: 138286. Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkins lymphoma. Blood 1997; 90: 218895. McLaughlin P, Grillo-Lopez J, Link BK, et al. Rituximab chimeric antiCD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16: 282533. Feuring-Buske M, Kneba M, Unterhalt M, et al. IDEC-C2BB (rituximab) anti-CD20 antibody treatment in relapsed advanced stage follicular lymphomas: results of a phase-II study of the German LowGrade Lymphoma Study Group. Ann Haematol 2000; 79: 493500. Maloney DG, Smith B, Applebaum FR. The anti-tumor effect of monoclonal anti-CD20 antibody (mAb) therapy includes direct antiproliferative activity and induction of apoptosis in CD20 positive nonHodgkins lymphoma (NHL) cell lines. Blood 1996; 88: 637a. Czuczman MS, Grillo-Lopez AJ, White CA, et al. Treatment of patients with low grade B-cell lymphoma with the combination of chimeric antiCD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999; 17: 26876. Czuczman MS, Jonas C, Stephan M, et al. Pilot study of rituxan in combination with fludarabine chemotherapy in patients with low-grade or follicular non-Hodgkins lymphoma. Proc Am Soc Clin Oncol 1999; 18: 61. http://www.asco.org. Czuczman MS, Fallon A, Scarpace A, et al. Phase II study of rituximab in combination with fludarabine in patients with low-grade or follicular B-cell lymphoma. Blood 2000; 96: 729a. Solal-Ceigny P, Brice P, Brousse N, et al. Phase II trial of fludarabine monophosphate as first-line treatment in patients with advanced follicular lymphoma: a multicentre study by the Groupe dEtude des Lymphomes de lAdulte. J Clin Oncol 1996; 14: 51419. Lennert K, Feller AC. Histopathology of non-Hodgkins lymphomas. Berlin: Springer, 1992. Vandenberghe E, Wolf-Peeters C De, Vaughan Hudson G. The clinical outcome of 65 cases of mantle cell lymphoma initially treated with nonintensive therapy by the British National Lymphoma Investigation Group. Br J Haematol 1997; 99: 84247. Press OW. Treatment of mantle cell lymphoma: stem cell transplantation, radio-immunoassay, and management of mantle cell lymphoma subsetseducational book. Alexandria, VA: American Society of Clinical Oncology, 2002: 40715. Khouri I, Romaguera J, Kantarjian H, et al. Hyper CVAD and high dose methotrexate/cytarabine followed by stem cell transplantation: an active regimen for aggressive mantle cell lymphoma. J Clin Oncol 1998; 16: 380309. Connors JM, Klimo P, Fairey RN, Voss N. Brief chemotherapy and involved field radiation therapy for limited-stage, histologically aggressive lymphoma. Ann Intern Med 1987; 107: 2530. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localised intermediate and high grade non-Hodgkins lymphoma. N Engl J Med 1998; 339: 2126. Shipp MA, Klatt MM, Yeap B, et al. Patterns of relapse in large-cell lymphoma patients with bulky disease: implications for the use of adjuvant radiotherapy. J Clin Oncol 1989; 7: 61318. Coltman CA Jr. CHOP is curative in thirty percent of patients with large cell lymphoma: a twelve-year Southwest Oncology Group follow-up: advances in chemotherapyupdate on treatment for diffuse large cell lymphoma. Skarin AT, ed. In: Proceedings of the Symposium; Nov 1417, 1985, Marco Island, FL. New York: John Wiley, 1986: 7182. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus Rituximab compared with CHOP alone in elderly patients with diffuse large B cell lymphoma. N Engl J Med 2002; 346: 23542.

46 Balzarotti M, Spina M, Arina B, et al. Intensified CHOP regimen in aggressive lymphomas: maximal dose intensity and dose density of doxorubicin and cyclophosphamide. Ann Oncol 2002; 13: 134146. 47 Itoh K, Ohtsu T, Fukada H, et al. Randomised phase II study of biweekly CHOP and dose-escalated CHOP with prophylactic use of lenograstim (glycosylated G-CSF) in aggressive non-Hodgkins lymphoma. Ann Oncol 2002; 13: 134755. 48 Magrath IT, Adde M, Shad A, et al. Adults and children with small noncleaved cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regime. J Clin Oncol 1996; 13: 92535. 49 Rudiger T, Weisenberg DD, Anderson JT, et al. Peripheral T-cell lymphoma (excluding anaplastic large cell lymphoma): results from the non-Hodgkins classification project. Ann Oncol 2002; 23: 14049. 50 Gisslebrecht C, Gaulard P, Lepage E, et al. Prognostic significance of T-cell phenotype in aggressive non-Hodgkins lymphomas Groupe dEtudes des Lymphomes de lAdulte (GELA). Blood 1998; 1: 7682. 51 Tondini C, Zanini M, Lombardi F, et al. Combined modality treatment with primary CHOP chemotherapy followed by locoregional irradiation in stage I and II histologically aggressive non-Hodgkins lymphomas. J Clin Oncol 1993; 11: 72025. 52 Wotherspoon AC, Doglioni C, Diss TC, et al. Regression of primary low grade B cell gastric lymphoma of mucosa-associated lymphoid tissue after eradication of Helicobacter pylori. Lancet 1993; 342: 57577. 53 Bertoni F, Conconi A, Capella C, et al. Molecular follow-up in gastic mucosa-associated lymphoid tissue lymphomas: early analysis of the LY03 co-operative trial. Blood 2002; 99: 254144. 54 Doreen MS, Ironside JW, Bradshaw JD, et al. Primary intracerebral lymphoma: a clinicopathological analysis of 14 patients presenting over a 10 year period in Sheffield. Q J Med 1988; 67: 387404. 55 Abrey LE, Angelis LM De, Yahalom J. Long-term survival in primary central nervous system lymphoma. J Clin Oncol 1998; 16: 85963. 56 Touroutoglou N, Dimopoulos MS, Younes A, et al. Testicular lymphoma: late relapses and poor outcome despite doxorubicin-based therapy. J Clin Oncol 1995; 13: 136167. 57 Zucca E. Cavalli F. Extranodal lymphomas. Ann Oncol 2000; 11 (suppl): 21922. 58 Philip T, Gugliemi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkins lymphoma. N Engl J Med 1995; 333: 154045. 59 Haioun C, Lepage E, Gisslebrecht C, et al. Survival benefit of high dose therapy in poor-risk aggressive NHL: final analysis of the prospective LNH87-2 protocola Groupe dEtude des Lymphomes de lAdulte study. Clin Oncol 2000; 19: 302530. 60 Gisselbrecht C, Lepage E, Molina T, et al. Shortened first-line chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 2002; 20: 247279. 61 Kaiser U, Uebelacker I, Abel U, et al. Randomized study to evaluate the use of high dose therapy as part of primary treatment for aggressive lymphoma. J Clin Oncol 2002; 20: 441319. 62 Martelli M, Gherlinzoni F, DeRenzo A, et al. Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggresive non-Hodgkins lymphoma: an Italian multicentre study. J Clin Oncol 2003; 21: 125562. 63 Gianni AM, Bregni M, Siena S, et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997; 336: 129097. 64 Ratanatharathorn V, Uberti J, Karenes C, et al. prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkins lymphoma. Blood 1994; 84: 105055. 65 Khouri IF, Keating M, Korbling, et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998; 16: 281724. 66 DeNardo GL, ODonnell RT, DeNardo SJ. Status of radioimmunoimaging and radioimmunotherapy for cancer. American Society of Clinical Oncology educational book 1999: 47282. 67 Kaminski MS, Zelenetz AD, Press OW, et al. Pivotal study of iodine I 131 tositumomab for chemotherapy refractory low-grade or transformed low-grade B-cell non-Hodgkins lymphomas. J Clin Oncol 2001; 19: 391828. 68 Witzig TE, Gordon LI, Cabanillas F, et al. Randomised controlled trial of yttrium-90-labelled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low grade, follicular or transformed B-cell non-Hodgkins lymphoma. J Clin Oncol 2002; 20: 245363. 69 Kwak LW, Campbell MJ, Czerwinski DK, et al. Induction of immune responses in patients with B-cell lymphoma against the surface immunoglobulin idiotype expressed by their tumours. N Engl J Med 1992; 327: 120915. 70 Davies TA, Hsu FJ, Caspar CB, et al. Idiotype vaccination following ABMT. Bio Blood Marrow Transplant 2001; 7: 51722.

146

THE LANCET Vol 362 July 12, 2003 www.thelancet.com