Performance status

The Karnosky score and the Eastern Cooperative Oncology Group (ECOG) scales have been used routinely in clinical trials to assess performance status in individual patients. Despite their limitation, they have been incorporated in most prognostic indices.

Retrospective analysis of patients with lymphoma over the age of 80 years demonstrates that a patient's ability to perform activities of daily living (ADLs) (instrumental ADLs as opposed to their ECOG-performance status), is more predictive of overall survival and progression free survival.Reference Nabhan, Smith and Helenowski¹⁷

Comprehensive geriatric assessment

The decision to choose a treatment based on performance status without conducting a comprehensive geriatric assessment (CGA) may underestimate older patients’ ability to tolerate treatment, and might, in part, explain why they are offered less therapy.Reference Latta, Cygan and Fried¹⁶ CGA is a multidisciplinary evaluation of physical and psychological conditions that affect the choice of therapy for older patients with malignant disease. The CGA evaluates the nutritional status, cognitive skills, functional status and co-morbidities of older patients and helps decide the intensity and density of chemotherapy. Whilst it has resulted in excellent outcomes in patients with various cancers,Reference Merli, Luminari and Rossi¹⁸ few trials were specifically designed for lymphoma patients.

Co-morbidities

Co-morbidities are defined as chronic medical conditions that can affect a patient's life. The modified Charlson co-morbidity index has been used to estimate risk of mortality, based on pre-existing morbid conditions. Reference Charlson, Pompei and Ales¹⁹ Several studies have demonstrated how co-morbid conditions adversely affect outcomes in patients with different cancers and suggest a similar effect in lymphoma patients.Reference Pfreundschuh²⁰

Organ dysfunction

In older patients, organ dysfunction becomes more likely. Dysfunction may affect the reserve of the kidney, the liver, the heart and bone marrow.Reference Pal, Katheria and Hurria²¹ Thus older patients with lymphoma need a detailed evaluation that includes all these factors in order to offer the best treatment tailored to the baseline situation and illness.

Diffuse large B-cell non-Hodgkin lymphoma (DLBCL)

DLBCL is the most commonly diagnosed NHL in western countries, accounting for approximately 25% of all NHLs. In Europe, its incidence is approximately 3.81 cases per 100,000 person years.Reference Sant, Allemani and Tereanu¹ Like most other NHLs, there is a male predominance. Incidence increases with age, with the median age at presentation being 70.4 years.Reference Smith, Howell, Patmore, Jack and Roman²² Almost one-third of newly diagnosed patients are over the age of 75 years.

DLBCL is a heterogeneous group of tumours. A number of clinicopathological entities are now recognized that are sufficiently distinct to be considered separate diagnostic categories: T-cell-rich large B-cell lymphoma, primary mediastinal large B-cell lymphoma, intravascular lymphoma and Epstein-Barr virus positive large B-cell lymphoma. DLBCL arises from a mature B-cell, usually a centroblast or immunoblast with a diffuse pattern and high proliferation fraction. Tumour cells in DLBCL generally express pan-B cell antigens (CD19, CD20, CD22, CD79a). The majority have genetic abnormalities, but there is no single cytogenetic change that is typical or diagnostic.Reference Swerdlow, Campo and Harris⁸

It can occur de novo, but it can also arise through the transformation of many different types of low grade B-cell lymphomas.

Patients with DLBCL typically present with a rapidly enlarging symptomatic mass, most usually nodal enlargement in the neck or abdomen. Systematic ‘B’ symptoms are observed in approximately 30% of patients and the serum LDH is elevated in over half. Approximately 60% of patients present with advanced stage (III or IV). Extranodal disease occurs in up to 40% of cases. The most common site of extranodal involvement is the stomach/gastrointestinal tract.

The International Prognostic Index (IPI) and its modifications are the main prognostic tools used in patients with DLBCL^{23,Reference Ziepert, Hasenclever and Kuhnt24} (Table 3). Molecular pathology also influences the prognosis. DLBCL is classified according to expression of genes into three groups: the germinal centre B-cell-like (GCB), the activated B-cell-like (ABC) and a not-otherwise specified type 3. Patients in the GCB group have the highest 5-year survival rate.^{Reference Rosenwald, Wright and Chan25,Reference Klapper, Kreuz and Kohler26}

Table 3.

International Prognostic Index and its modifications (adapted from the International Non-Hodgkin's Lymphoma Prognostic Factors Project ²³and Ziepert et al.Reference Ziepert, Hasenclever and Kuhnt²⁴)

One point is given for each characteristic present: age >60 years, serum lactate dehydrogenase concentration above normal, ECOG performance status >2, Ann Arbor stage III or IV, number of extranodal disease sites >1

For all types of lymphoma, one important clinical decision is whether treatment may be curative. Thus distinction can be made between older, ‘fit’ patients who can be treated as adult patients, ‘frail’ patients handled mostly with palliation, and patients in an intermediate state, or ‘vulnerable’, who are likely to be suited to adjusted or reduced chemotherapy regimens. DLBCL is a potentially curable malignancy. For patients up to 80 years, rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is the standard regimen for CD20-positive DLBCL.Reference Coiffier, Thieblemont and Van den Neste²⁷ The benefit of the addition of rituximab has been shown for all age groups to 80 years.Reference Pfreundschuh, Schubert and Ziepert¹⁴ However, patients who are frail or over 80 years of age have been excluded from clinical trials, and guidelines on how these patients should be treated are lacking. There is a need for such patients to be enrolled in prospective clinical trials specifically designed for this group. In the absence of clinical studies, the decision of how to treat is usually left to the physician's discretion.Reference Van der Poel, Mulder and Ossenkoppele²⁸ It would seem reasonable for DLBCL in stage I or II disease to be treated with an abbreviated course of chemo-immunotherapy using R-CHOP followed by involved-field radiation.Reference Odejide, Cronin, Davidoff, LaCasce and Abel²⁹ In fit patients with adequate cardiac reserve, full dose R-CHOP is recommended. In those with compromised cardiac function or other co-morbidity, a dose reduced R-CHOP (mini-R-CHOP) or non-anthracycline-based programme is recommended (e.g. rituximab plus cyclophosphamide, vincristine and prednisone (R-CVP) or rituximab plus bendamustine (R-B).^{Reference Peyrade, Jardin and Thiblemont30,Reference Weidmann, Neumann and Fauth31}

Some older patients present with a decline in their performance status that is due only to their lymphoma. In such instances, starting with a pre-phase treatment might be appropriate, to improve the patient's functional status. The German Lymphoma Study Group suggested treating patients who present with ECOG performance status of 2 or more with 7 days of prednisone and 1 mg of vincristine before the first chemotherapy administration and, if a patient's status improves, the goal of therapy may then be modified.Reference Pfreundschuh, Trumper and Kloess³²

Follicular lymphoma

Follicular lymphoma (FL) is the second most common subtype of NHL and the most common of indolent NHL. The estimated incidence of FL in Europe is 3.1 cases per 100,000 people per year.Reference Sant, Allemani and Tereanu¹ Median age at diagnosis is 60 yearsReference Smith, Howell, Patmore, Jack and Roman²² and the incidence increases with age. Most patients present with asymptomatic lymphadenopathy, whilst other frequently involved sites are spleen, bone marrow, peripheral blood, Waldeyer's tonsillar ring and extranodal sites such as the gastrointestinal tract.

FL is derived from germinal centre B-cells and morphologically is composed of centrocytes and centroblasts. The grade (1 to 3) depends on the proportion of centroblasts per high power field. Grades 1 and 2 (0 to 15 centroblasts per high power field) are indolent disease. Grade 3 is divided into grade 3a (with centrocytes present) and 3b (with a solid sheet of centroblasts). Grade 3b is more aggressive and the management of this entity must be like that for diffuse large B cell lymphoma.Reference Swerdlow, Campo and Harris⁸ FL cells express surface immunoglobulin, CD19, CD20, CD22 and are bcl-2+, bcl6+ and CD10+. The genetic characteristic of FL is the translocation t (14; 18) (q32; q21) contributing to overexpression of bcl-2.Reference Swerdlow, Campo and Harris⁸ The prognosis is calculated using the Follicular Lymphoma International Prognostic Index (FLIPI) and its modifications^{Reference Solal-Céligny, Roy and Colombat33,Reference Federico, Bellei and Marcheselli34} (Table 4).

Table 4.

Follicular lymphoma International prognostic index (FLIPI) (adapted from Solal-Celigny et al.Reference Solal-Céligny, Roy and Colombat³³)

One point is given for each characteristic present: age >60 years, serum lactate dehydrogenase concentration above normal, haemoglobin level <12 g/dl, Ann Arbor stage III or IV, number of involved nodal areas >4

Treatment options for FL depend on the disease stage, age and co-morbidities of the patient and if there is symptomatology associated with the disease. In early stages (I/II), radiotherapy is a treatment option that may increase survival, but one that produces toxicity, so that the observation is a reasonable option if there are co-morbidities and expected toxicity of radiotherapy is considered likely to be significant.Reference Pugh, Ballonoff, Newman and Rabinovitch³⁵ In advanced stages (III/IV) that are still asymptomatic, observation is a reasonable option until there is disease progression and does not worsen survival.Reference Ardeshna, Smith and Norton³⁶ For patients with symptomatic advanced stage or high-volume disease, treatment is chemoimmunotherapy: R-CHOP or bendamustine-rituximab (B-R). B-R can be considered as a first-line treatment because of increased progression-free survival (PFS) and fewer side-effects.Reference Rummel, Niederle and Maschmeyer³⁷ R-CVP can be used in patients with heart disease, but the response rate is lower.Reference Marcus, Imrie and Solal-Celigny³⁸ For ‘oldest old’ or unfit patients, rituximab 375 mg/m² weekly for four doses, or treatment with single agents (e.g. chlorambucil or cyclophosphamide) with or without rituximab, can be options.³⁹ Patients who have achieved a good response can be treated with rituximab maintenance therapy to improve PFS.Reference Salles, Seymour and Offner⁴⁰ Currently, there are clinical trials of new drugs with promising results, such as 90Y-ibritumomab tiuxetan.Reference Scholz, Pinto and Linkesch⁴¹

Mantle cell lymphoma

Mantle cell lymphoma (MCL) is a mature B-cell NHL that accounts for approximately 7% of adult NHL. In Europe the incidence is 0.45 cases per 100,000 people per year.Reference Sant, Allemani and Tereanu¹ It is more prevalent in males than females. Median age at diagnosis is around 74 years and the incidence increases with age.Reference Smith, Howell, Patmore, Jack and Roman²² Frequently, MCL patients present at an advanced stage of disease (III or IV), with lymphadenopathy, hepato-splenomegaly and bone marrow infiltration. The diagnosis is made by lymph node biopsy, bone marrow aspiration, or even with identification of an immunophenotype in peripheral blood. The lymphoid cells are positive for CD20, CD5 and FMC7. Cyclin D1 and translocation t (11:14) (q13:32) identifies MCL.Reference Swerdlow, Campo and Harris⁸

The clinical course of MCL is very heterogeneous. Most cases have an aggressive course and poor prognosis, with short duration of remission following standard therapies. However, there is a small percentage of patients that have an indolent course and do not need treatment for several years. The prognostic index for MCL is the Mantle Cell International Prognostic Index (MIPI)Reference Hoster, Dreyling and Klapper⁴² (Table 5). Other factors associated with worse prognosis in MCL are high proliferative activity or increased Ki-67 staining, blastoid variant, inactivation of p53 and secondary chromosomal aberrations.

Table 5.

Mantle cell lymphoma international prognostic index (MIPI) (adapted from Hoster et al.Reference Hoster, Dreyling and Klapper⁴²)

One to three points is given for each characteristic present: age (<50: 0; 50 to 59: 1; 60 to 69: 2; >70: 3), ECOG performance status (0 to 1: 0; 2 to 4: 2), lactate dehydrogenase:upper limit of normal (LDH:ULN) ratio (<0.67: 0; 0.67 to 0.99: 1; 1.00 to 1.49: 2; >1.50: 3), white blood cells 10⁹/l (<6.7: 0, 6.7 to 9.9: 1; 10.0 to 14.9: 2; >15.0: 3)

The choice of treatment in MCL older patients is difficult. For patients with asymptomatic low MIPI, older MCL and indolent MCL, the strategy of ‘watch and wait’ should be considered.Reference Martin, Chadbum and Christos⁴³ R-CHOP should remain an important consideration in older patients,Reference Kluin-Nelemans, Hoster and Hermine⁴⁴ despite the cardiotoxicity associated with anthracycline. B-R has been associated with a longer PFS as it is less toxic and is not associated with cardiac toxicity.Reference Rummel, Niederle and Maschmeyer³⁷ Therefore, B-R is a reasonable first option. Purine analogues have been used for the treatment of MCL in older patients, but the outcomes are poorer than with R-CHOP.Reference Kluin-Nelemans, Hoster and Hermine⁴⁴ Rituximab maintenance after induction chemotherapy may improve the overall survival.Reference Kluin-Nelemans, Hoster and Hermine⁴⁴ More intensive treatments, such as hyper-CVAD regimens, have significantly more toxicity in older patients than in younger patients. Other recent studies have combined bendamustine and rituximab with other agents such as bortezomib, lenalidomide and cytarabine.Reference Visco, Finotto and Zambello⁴⁵ However, further clinical trials including older patients and the monitoring of existing studies are needed before these treatments can be recommended outside the context of clinical trials. New treatments such as ibrutinib are being investigated with promising results.Reference Zucca and Bertoni⁴⁶

Hodgkin lymphoma

Hodgkin lymphoma is a B-cell neoplasm that represents approximately 10% of all lymphomas. The incidence in Europe is around 2.49 cases per 100,000 people.Reference Sant, Allemani and Tereanu¹ HL has a bimodal age distribution with one peak in young adults around 20 years and one peak in older age around 65 years. Histologically, HL consists of neoplastic cells called Reed-Sternberg cells and their variants on an inflammatory background. There are two groups: nodular lymphocyte predominant HL (NLPHL) and classical HL (CHL). CHL is divided into four groups based on the appearance of the tumour cells and the composition of the reactive background: nodular sclerosis, mixed cellularity, lymphocyte rich and lymphocyte depleted. Usually CHLs express CD15 and CD30, variably express CD20 and do not express CD3 and CD45.Reference Swerdlow, Campo and Harris⁸ The main prognostic index for HL is the International Prognostic Score for Hodgkin Lymphoma^{Reference Hasenclever and Diehl47,Reference Moccia, Donaldson and Chhanabhai48} (Table 6).

Table 6.

The International Prognostic Score for Hodgkin lymphoma (adapted from Hasenclever et al.Reference Hasenclever and Diehl⁴⁷ and Moccia et al.Reference Moccia, Donaldson and Chhanabhai⁴⁸)

One point is given for each characteristic present: serum albumin <4 g/dl; haemoglobin<10.5 g/dl; male gender; age >45 years; stage IV disease; white blood cell count >15,000/µl; absolute lymphocyte count <600/µl and/or <8% of the total white blood cell count

The percentage of HL patients aged over 60 years is approximately 15–35%. Older patients have biological and histological features associated with poor prognosis. Mixed cellularity, EBV positive HL, B symptoms, infra-diaphragmatic disease and advanced stage of disease are other features more commonly observed in older than younger patients. However, a bulky mediastinal mass is infrequent in older patients.^{Reference Björkholm, Svedmyr and Sjöberg49,Reference Halbsguth, Böll, Borchmann and Diehl50}

The most common treatment for HL is ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) with or without radiotherapy, but this regimen can be very toxic in older patients. Patients aged 60–70 years with a good performance status and without co-morbidities can receive ABVD. The number of courses depends on stage of the disease and presence of favourable or unfavourable features. Use of granulocyte colony stimulation factor (GCS-F) with bleomycin regimens increases the risk of bleomycin toxicity,Reference Martin, Ristow, Habermann, Colgan, Witzig and Ansell⁵¹ so GCS-F should be avoided in these cases. In patients aged 60–70 years with co-morbidities and in patients older than 70 years, ABVD may be poorly tolerated and adjustments of doses could be needed.Reference Björkholm, Svedmyr and Sjöberg⁴⁹ The Stanford V or BEACOPP regimens are very toxic in HL older patients. There are other regimens – PVAG (prednisone, vinblastine, adriamycin and gemcitabine)Reference Böll, Bredenfeld and Görgen⁵² and VEPEMB (vinblastine, cyclophosphamide, procarbazine, prednisone, etoposide, mitoxantrone and bleomycinReference Proctor, Wilkinson and Jones⁵³ – that provide satisfactory disease control in early and advanced stages of disease with acceptable toxicity.

Nodular lymphocyte predominant HL (NLPHL) constitutes less than 5% of all HL cases, express CD20, are often localized, have a male predominance and the median age just over 30 years.Reference Swerdlow, Campo and Harris⁸ Thus NLPHL is rarely seen among older patients. Moreover, the treatment of this disease differs from CHL.³⁹ PET/CT is used for the early evaluation of response in order to adapt the subsequent intensity and duration of treatment.Reference Ansell⁵⁴

Brentuximab-vedotin is an anti-CD30 antibody that has been used in patients with relapsing or refractory disease and has a favourable safety profile and long term response.^{Reference Younes, Gopal and Smith55,Reference Younes, Bartlett and Leonard56}