Abstract
Diffuse large B-Cell Lymphoma (DLBCL) is the most common subtype of maligant lymphoma (ML). The incidence rate is about 10–15 of 100,000 people in the US and in Europe per year. Men are more frequently affected than women [1]. The incidence of DLBCL in people over the age of 65 years is rapidly rising. In the elderly (75 years or older), rates of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma increased 1.4 %. According to the SEER cancer statistics review 2000–2011, 9 per 100,000 of those younger than 65 years develop the disease, compared to 90 per 100,000 in those aged older than 65 years. The 5-years relative survival rates decreases from 78 % in those younger than 65 years to 62 % in those older than 65 years. The occurrence of all Non-Hodkgin’s Lymphomas (NHL) has been rising from 10 to over 20 newly diagnosed patients per 100,000 from 1975 to 2010. For patients over 75 years of age, incidence rates have doubled (50–100 per 100,000) since 1975. Thus DLBCL is predominantly a disease of older individuals, with a median age of diagnosis at approximately 70 years of age. As demographic changes result in an increasing number of older people the occurrence of NHL in this older patient population will pose an increasing problem [2].
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Keywords
- Follicular Lymphoma
- Germinal Centre
- International Prognostic Index
- Geriatric Assessment
- Comprehensive Geriatric Assessment
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Epidemiology
Diffuse large B-Cell Lymphoma (DLBCL) is the most common subtype of maligant lymphoma (ML). The incidence rate is about 10–15 of 100,000 people in the US and in Europe per year. Men are more frequently affected than women [1]. The incidence of DLBCL in people over the age of 65 years is rapidly rising. In the elderly (75 years or older), rates of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma increased 1.4 %. According to the SEER cancer statistics review 2000–2011, 9 per 100,000 of those younger than 65 years develop the disease, compared to 90 per 100,000 in those aged older than 65 years. The 5-years relative survival rates decreases from 78 % in those younger than 65 years to 62 % in those older than 65 years. The occurrence of all Non-Hodgkin’s Lymphomas (NHL) has been rising from 10 to over 20 newly diagnosed patients per 100,000 from 1975 to 2010. For patients over 75 years of age, incidence rates have doubled (50–100 per 100,000) since 1975. Thus DLBCL is predominantly a disease of older individuals, with a median age of diagnosis at approximately 70 years of age. As demographic changes result in an increasing number of older people the occurrence of NHL in this older patient population will pose an increasing problem [2].
Classification
Diffuse large B-cell lymphoma is a heterogeneous group of Non-Hodgkin’s Lymphoma (NHL). They are classified based on the WHO-classification based on clinical data, morphology, phenotype, cytogenetics, and molecular characteristics [3]. Table 11.1 reports the classification of DLBCL.
Aetiology
Often the aetiology remains unclear. Most of the DLBCL develop as a new disease, so called primary DLBCL, others can transform from other lymphatic neoplasia, so called secondary DLBCL. Prior exposure to agents causing DNA-damage and primary and secondary immunodeficiencies are associated with an increased risk of the development of a DLBCL. Certain chronic virus infections are associated with the occurrence of DLBCL, such as HCV, HIV and EBV. In elderly patients secondary lymphoma are more common than in younger ones. The EBV positive DLBCL in elderly patients should be classified as own entity and are associated with a worse prognosis than the EBV negative one [4].
Biology
The origins of DLBCL are not well understood. Usually, it evolves from normal B cells, but it can also result from malignant transformation of other types of malignant lymphatic neoplasia.
In general DLBCL encompasses a biologically and clinically diverse group of diseases, many of which cannot be separated from one another by well-defined and widely accepted criteria. Therefore new methods of genetic analysis are used for further characterization. DLBCL, NOS can be separate in germinal centre B-like DLBCL (GCB), activated B-like (ACB) DLBCL [5]. Lymphoma cells in the germinal centre B-cell-like subgroup resemble normal B cells in the germinal centre closely, and are generally associated with a favourable prognosis. Activated B-cell-like tumour cells are named from studies showing the constant activation of physiologic B-cell- antigen pathways. They are associated with a poorer prognosis [6]. One of the important pathways involved is the NF-κB pathway, which normally helps transforming B cells into plasma cells [7]. ACB subtype is more common in older patients, but compared to other molecular changes, which loose their prognostic importance when age was added as factor, age and ACB subtype independently contributed to poor prognosis [8].
In addition, gene expression studies found out more about cells and microscopic structures that are spreading within the malignant B- cells and form the tumour microenvironment. In particular, gene expression signatures that are linked with macrophages, T cells, and remodelling of the extracellular matrix seems to be associated with an improved prognosis and better overall survival [9]. On the other hand, the expression of genes involved in enhanced angiogenesis is associated with poorer survival [7].
Only a few genetic aberrations constituted valuable prognostic factors so far. Of these, the translocation of the MYC- oncogene has been associated with inferior survival. An additional translocation in BCL2 leads to an even worse prognosis and are named “double hit lymphomas”) [10].
With the help of the above diagnostic criteria derived from primary lymphoma tissue, one can distinguish few important subtypes: the T cell/histiocyte rich large B-cell lymphoma and the Primary cutaneous DLBCL, leg type and the Epstein-Barr virus (EBV) DLBCL of the elderly for which data on modern genetic testing come up as well [11, 12]. Other additional subtypes of large- B-cell lymphomas that are diagnosed and treated in the same way are, such as primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK + large B-cell lymphoma, plasmoblastic lymphoma and follicular Lymphoma Grade 3B. The DLBCL of the central nervous system displays great differences concerning disease biology and treatment and will thus not be discussed here.
Data on age associated differences in biology of DLBCL are still limited. Patterns of gene expression are not routinely determined in clinical practice but will gain importance. However, as new therapeutic options might help to overcome negative prognostic molecular changes, the tests will become part of routine [13].
Symptoms
DLBCL is cancer of rapid growth which can occur in any part of the body. Typical first signs of this disease are fast growing masses of lymphatic tissue. Others may present as a tumour of unknown origin, with histology revealing a lymphoma instead of a carcinoma. Age associated changes in presentation have not been reported so far. Elderly patients more often present with extranodal disease [14]. In one third of the patients systemic symptoms are present at diagnosis, such as concomitant fever (>38 °C for at least 3 consecutive days), weight loss (>10 % during the 6 months prior to diagnosis), and night sweats, called B-symptoms [15].
Examination
Examination serves (a) the diagnosis of the disease, (b) the extend of the disease and (c) the judgment of the patients fitness for treatment.
The diagnosis is based on a histological examination of a biopsy, preferable from palpable lymph nodes, when ever possible as excisional biopsy. Core needle biopsy should be restricted to cases where no other surgical access is possible, without major surgery.
The procedures to diagnose the extend of the disease are listed in the following Table 11.2. They do not differ between younger and older patients.
The stage of the disease is classified according to the Ann-Arbor-Classification, see Table 11.3. No differences in staging system between younger and older patients exist.
Systemic Symptoms as fever, weight loss or night sweats are also included in the staging process: “A” means these symptoms are not present and “B” means they are.
The judgment of a patients fitness for treatment includes cardic, renal and pulmonary function test. In addition a structured geriatric assessment (GA) is recommended at least for patients aged 70 years and older [18]. A screening tool is less specific but might be an approach in a busy clinic [19]. Results of GA are associated with survival in patients with malignant lymphoma [20, 21].
A geriatric assessment was better in judging the patients prognosis than physicians. Tucci et al. included patients with newly diagnoses DLBCL in a prospective cohort trial. All patients received a geriatric assessment. The treating physician was blinded for the results of the geriatric assessment when deciding on patients´ fitness for treatment. Most of the patients were considered fit for an R-CHOP regimen, others not, they received attenuated dose regimens, corticosteroids or single agent Rituximab. The geriatric assessment classified more patients as not fit for R-CHOP. The prognosis of patients classified by physicians as fit but by assessment as unfit was identical to the prognosis of those classified as unfit by the physicians and the assessment [22].
Patients’ fitness for treatment should be assessed at the time of diagnosis and after a prophase treatment (see below) [15].
Prognostic Factors
Prognostic factors predicting overall survival can be related to the disease (stage, LDH, extranodal involvement) and to the patients (age, performance-status) and the treatment, as response after treatment is a highly predictive factor for survival.
The following factors have been identified as independently associated with survival and thus are included in the International Prognostic Index (IPI) scoring system. In addition an age-adapted version (aaIPI), was established, see Tables 11.4 and 11.5 [23].
As the prognostic classification according to the IPI and aaIPI was established based on data, prior to the inclusion of Rituximab into the treatment, the scores were re-evaluated based on data of patients treated with Rituximab containing regimes. The data are reported in Table 11.6. Sehn et al. suggest based on their data analysing population based data, to use three instead of four prognostic categories: very good, good, and poor; and renamed the IPI to a revised IPI [24]. The former distribution had separated only two different prognostic groups, factors 0–2 and factors 3–4. The median age of the included patients was 61 years. Ziepert et al. analysed treatment results of clinical trials including patients aged 60 years and older with DLBCL. They confirmed the prognostic value of the aaIPI regarding PFS, EFS and OS [25]. As age above 60 years is a factor of IPI, older patients per se can not be in a very good risk group.
Treatment
None or delayed treatment leads to death within weeks to few months. Treatment decision should into account the stage of the disease and the IPI in addition to patients´ fitness. Chemotherapy with CHOP is the backbone of treatment in patients with DLBCL. It was established in 1976. The initial trial included patients with a median age of 53 years [26].
As the IPI identified age, below and above the age of 60 years, as major prognostic factor, as treatment toxicity increases with age, and as in younger patients, strategies to increase dose of chemotherapy, with the hope of increased remission and survival rate, trials often used age limit of 60 years as definition of elderly patients.
1st line Treatment for Fit Patients Aged 60–80 Years
The addition of Rituximab, a chimeric CD 20 antibody, added to CHOP improved treatment results substantially, as demonstrated in different trials. Coiffer et al. were the first to show that the addition Rituximab was able to improve response rate, event-free and overall survival in patient aged 60–80 years [27]. Maintenance therapy with Rituximab following the R-CHOP regime seemed demonstrated no further improvement in outcome [28]. The RICOVER-60 trial compared different dosing intervals and numbers of therapy cycles, R-CHOP given every 14 days (R-CHOP-14) proved most effective in maximizing event free and overall survival for the same patient group [29]. The shorter interval includes obligatory application of G-CSF as part of the dose-dense protocol.
However, there is an ongoing discussion whether this data apply to patients prognostic risk groups in the age adjusted IPI. Furthermore, the application of R-CHOP-14 in this age group resulted in more frequent grade 3 and 4 neutropenia and increased number of transfusions [30, 31]. Table 11.7 summarizes the results of 1st line regimens containing R-CHOP as a treatment arm.
All in all 6–8 cycles of R-CHOP-14 or R-CHOP-21 should be the current standard of care for fit patients and according to these pivotal trials for patients aged younger than 80 years.
Prior to the start of the R-CHOP regimen a prophase treatment is recommended, consisting of a single intravenous injection of vinristin 1 mg day 1 and oral prednisolone for 7 days. Besides not being tested in a randomized fashion, toxicity in the 1st cycle reduced substantially [15].
1st Line Treatment Alternatives and Options for Patients with Comorbidities, Medically Non-Fit, or Patients or Aged More Than 80 Years
All in all data for very elderly patients, especially those aged 80 years and older are limited. Bellera at al. analysed the specific barriers to include elderly patients with malignant lymphoma (not especially patients with DLBCL) in RCTs and identified restrictive inclusion criteria, poor performance status, impaired liver and kidney function and presence of comorbidities as major reasons [32]. Therefore, data especially for these groups of patients are very limited. In addition to data from RCTs, data from cohort trials in phase II trials have to be included in the recommendations for treatment decision, as they better reflect the typical elderly patients seen in clinics or hospitals.
There is no generally agreed definition, which patient is suitable for a classical R-CHOP regimen. Age is one factor associated with increased toxicity. With the increase in age, treatment related toxicity and mortality increases. Predictors of toxicity are analysed by Ziepert et al. [33]. They separately analysed data for patients aged up to 60 years and above 60 years. Low body weight, female gender, poor PS, high LDH, and initial cytopenia where associated with increased hematological toxicity. According to the results of the RICOVER-60 trial, treatment related death rate was 4 % was patients aged 60–65 years, 6.4 % for those aged 66–70 years, 7.0 % for those aged 70–75 years, and 20.1 % for those aged 76–80 years.
A physicians’ judgement, that the patient is not suitable for a standard R-CHOP regimen can be based on different criteria. Tucci et al. identified, that a geriatric assessment is better to identify patients as fit for treatment than physicians´ judgement [22].
Main strategies followed in the over 80 year old patients and in those unfit for standard R-CHOP treatment are to reduce toxicity of R-CHOP by dose reduction or to use other less toxic drugs.
A variety of studies mainly in the last decade of the last century compared different regimens to CHOP, to find a less toxic protocol. One of the most extensively studies substance, was Mitoxantrone as substitute for Doxorubicin, resulting in CNOP instead of CHOP regimen. In a meta-analysis comparing results of 9 studies, CHOP remained the superior regime regarding efficacy and CNOP was not less toxic. The studies were not restricted to elderly patients, but included a considerable number of older adults [34]. As Rituximab is a very active and less toxic agent, trials using R-Non-CHOP regimens are analysed and reported in Table 11.8.
The dose-reduced R-Mini-CHOP regime is a pragmatic alternative that has shown progression free survival rates by 47 % after 2 years [21, 39].
Most of the previously mentioned trials analysed a liposomal anthracycline. The International Society for Geriatric Oncology (SIOG) provides recommendations for the use of liposomal anthracyclines, beside other tumours in lymphoma patients by which treatment can be delivered more safely [40].
R- Bendamustine is a valuable alternative for anthracycline free treatment in patients that are ineligible for R-CHOP [41].
Patients Aged 80+
As rarely patients aged 80 years and older are included in prospective clinical trials, especially RCTs, cohort trials are an additional method to gain knowledge on treatments used, results obtained, and the value of variables of a comprehensive geriatric assessment (CGA) as prognostic tools [42, 43]. Table 11.9 summarizes articles reporting treatment results in cohorts of patients aged 80 and older.
In patients aged 80 and older, the treatment decision is mainly based on the patients fitness for treatment. A structured geriatric assessment shall help to identify patients fit for standard treatment with R-CHOP and those who should be treated with alternative protocols, when severe comorbidity, e.g. cardiac failure are present, or when the pre-existing performance-status / functional status is poor.
Trials Integrating Comprehensive Geriatric Assessment (CGA)
Only few trials are available reporting the inclusion of CGA in the care for elderly patients with DLBCL. Results of a systematic literature research are listed in Table 11.10.
In summary the trials including CGA demonstrate the prognostic significance of variable of the CGA for survival in elderly patients with DLBCL. This is true for functional scores, especially IADL score, and for comorbidities, where the CIRS-G score is the most widely used score. Randomised trials comparing CGA based treatment decision to clinical judgement are missing so far. Physician´s judgement of fitness of patients for treatment classifies more patients as fit than CGA [49].
Second Line Therapy
In patients with recurrence or resistant disease second line regimens are used. In younger once and those medically fit, high-dose chemotherapy followed by autologeous blood stem cell retransfusion is treatment of choice. It is especially effective in those patients who responded to 1st line therapy, who had an interval of at least 12 months until recurrence and who responded to second line treatment [50]. A maintenance treatment with rituximab is not beneficial [51]. However, most of elderly patients, especially those aged 70 years and older will not be fit for a high-dose regimen. A variety of treatment protocols are effective in inducing a remission, but most of the patients will have a recurrence again or will develop resistance while on treatment. The treatment approach will be non-curative in most of these patients. Main prognostic factor is the time between 1st line treatment and recurrence. A second curative approach might be possible when the interval is more than 12 months. Suggested treatment protocols are R-GemOx [52], R-ESHAP-[53] and R-mini-CHOP-Regime [21] or less toxic but less effective as well the R-bendamustine regmine [54].
Radiotherapy (RT)
Radiotherapy is an effective method in lymphoma treatment. However which role RT has as part of 1st line treatment remains unclear. Most data on involved-field RT in patients with bulky disease or residual disease after induction chemotherapy, are collected prior to the use of rituximab. The topic is discussed in more detail by Martelli et al. [15].
Patients with Special Comorbidities
Cardiac failure: R-CEOP might be a treatment option when the use of antracyclines is not possible [55]. However liposomal agents are available and effective [40].
Renal failure: Some case reports on treatment of elderly patients with end-stage renal failure on dialysis treated with chemotherapy such as R-mini-CHOP or R-bendamustine are available.
References
Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood. 2006;107(1):265–76.
Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol. 2009;27(17):2758–65.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. WHO classification of tumors of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008.
Oyama T, Yamamoto K, Asano N, Oshiro A, Suzuki R, Kagami Y, Morishima Y, Takeuchi K, Izumo T, Mori S, Ohshima K, Suzumiya J, Nakamura N, Abe M, Ichimura K, Sato Y, Yoshino T, Naoe T, Shimoyama Y, Kamiya Y, Kinoshita T, Nakamura S. Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients. Clin Cancer Res. 2007;13(17):5124–32.
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson Jr J, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503–11.
Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, Xu W, Tan B, Goldschmidt N, Iqbal J, Vose J, Bast M, Fu K, Weisenburger DD, Greiner TC, Armitage JO, Kyle A, May L, Gascoyne RD, Connors JM, Troen G, Holte H, Kvaloy S, Dierickx D, Verhoef G, Delabie J, Smeland EB, Jares P, Martinez A, Lopez-Guillermo A, Montserrat E, Campo E, Braziel RM, Miller TP, Rimsza LM, Cook JR, Pohlman B, Sweetenham J, Tubbs RR, Fisher RI, Hartmann E, Rosenwald A, Ott G, Muller-Hermelink HK, Wrench D, Lister TA, Jaffe ES, Wilson WH, Chan WC, Staudt LM. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med. 2008;359(22):2313–23.
Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med. 2010;362(15):1417–29.
Klapper W, Kreuz M, Kohler CW, Burkhardt B, Szczepanowski M, Salaverria I, Hummel M, Loeffler M, Pellissery S, Woessmann W, Schwanen C, Trumper L, Wessendorf S, Spang R, Hasenclever D, Siebert R. Patient age at diagnosis is associated with the molecular characteristics of diffuse large B-cell lymphoma. Blood. 2012;119(8):1882–7.
Linderoth J, Eden P, Ehinger M, Valcich J, Jerkeman M, Bendahl PO, Berglund M, Enblad G, Erlanson M, Roos G, Cavallin-Stahl E. Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma. Br J Haematol. 2008;141(4):423–32.
Niitsu N, Okamoto M, Miura I, Hirano M. Clinical features and prognosis of de novo diffuse large B-cell lymphoma with t(14;18) and 8q24/c-MYC translocations. Leukemia. 2009;23(4):777–83.
Ahn JS, Yang DH, Duk Choi Y, Jung SH, Yhim HY, Kwak JY, Sung Park H, Shin MG, Kim YK, Kim HJ, Lee JJ. Clinical outcome of elderly patients with Epstein-Barr virus positive diffuse large B-cell lymphoma treated with a combination of rituximab and CHOP chemotherapy. Am J Hematol. 2013;88(9):774–9.
Pham-Ledard A, Prochazkova-Carlotti M, Andrique L, Cappellen D, Vergier B, Martinez F, Grange F, Petrella T, Beylot-Barry M, Merlio JP. Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma. Mod Pathol. 2014;27(3):402–11.
Witzig TE. Origins research in large cell lymphoma-time for action? Lancet Oncol. 2014;15(7):674–5.
Kuper-Hommel MJ, van de Schans SA, Vreugdenhil G, van Krieken JH, Coebergh JW. Undertreatment of patients with localized extranodal compared with nodal diffuse large B-cell lymphoma. Leuk Lymphoma. 2013;54(8):1698–705.
Martelli M, Ferreri AJ, Agostinelli C, Di Rocco A, Pfreundschuh M, Pileri SA. Diffuse large B-cell lymphoma. Crit Rev Oncol Hematol. 2013;87(2):146–71.
Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res. 1971;31(11):1860–1.
Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, Rosenberg SA, Coltman CA, Tubiana M. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol. 1989;7(11):1630–6.
Extermann M, Aapro M, Bernabei R, Cohen HJ, Droz JP, Lichtman S, Mor V, Monfardini S, Repetto L, Sorbye L, Topinkova E, C. G. A. o. t. I. S. o. G. O. Task Force on. Use of comprehensive geriatric assessment in older cancer patients: recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG). Crit Rev Oncol Hematol. 2005;55(3):241–52.
Decoster, L, Van Puyvelde K, Mohile S, Wedding U, Basso U, Colloca G, Rostoft S, Overcash J, Wildiers H, Steer C, Kimmick G, Kanesvaran R, Luciani A, Terret C, Hurria A, Kenis C, Audisio R, Extermann M (2014). Screening tools for multidimensional health problems warranting a geriatric assessment in older cancer patients: an update on SIOG recommendations. Ann Oncol. Jan 2014 [Epub ahead of print].
Winkelmann N, Petersen I, Kiehntopf M, Fricke HJ, Hochhaus A, Wedding U. Results of comprehensive geriatric assessment effect survival in patients with malignant lymphoma. J Cancer Res Clin Oncol. 2011;137(4):733–8.
Peyrade F, Jardin F, Thieblemont C, Thyss A, Emile JF, Castaigne S, Coiffier B, Haioun C, Bologna S, Fitoussi O, Lepeu G, Fruchart C, Bordessoule D, Blanc M, Delarue R, Janvier M, Salles B, Andre M, Fournier M, Gaulard P, Tilly H, i. Groupe d‘Etude des Lymphomes de l‘Adulte. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2011;12(5):460–8.
Tucci A, Ferrari S, Bottelli C, Borlenghi E, Drera M, Rossi G. A comprehensive geriatric assessment is more effective than clinical judgment to identify elderly diffuse large cell lymphoma patients who benefit from aggressive therapy. Cancer. 2009;115(19):4547–53.
The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med. 1993;329(14):987–94.
Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, Klasa R, Savage KJ, Shenkier T, Sutherland J, Gascoyne RD, Connors JM. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007;109(5):1857–61.
Ziepert M, Hasenclever D, Kuhnt E, Glass B, Schmitz N, Pfreundschuh M, Loeffler M. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(14):2373–80.
McKelvey EM, Gottlieb JA, Wilson HE, Haut A, Talley RW, Stephens R, Lane M, Gamble JF, Jones SE, Grozea PN, Gutterman J, Coltman C, Moon TE. Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer. 1976;38(4):1484–93.
Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235–42.
Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, Dakhil SR, Woda B, Fisher RI, Peterson BA, Horning SJ. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24(19):3121–7.
Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trumper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9(2):105–16.
Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, Bologna S, Ghesquieres H, Hacini M, Fruchart C, Ysebaert L, Ferme C, Casasnovas O, Van Hoof A, Thyss A, Delmer A, Fitoussi O, Molina TJ, Haioun C, Bosly A. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol. 2013;14(6):525–33.
Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013;381(9880):1817–26.
Bellera C, Praud D, Petit-Moneger A, McKelvie-Sebileau P, Soubeyran P, Mathoulin-Pelissier S. Barriers to inclusion of older adults in randomised controlled clinical trials on Non-Hodgkin’s lymphoma: a systematic review. Cancer Treat Rev. 2013;39(7):812–7.
Ziepert M, Schmits R, Trumper L, Pfreundschuh M, Loeffler M. Prognostic factors for hematotoxicity of chemotherapy in aggressive non-Hodgkin’s lymphoma. Ann Oncol. 2008;19(4):752–62.
Osby E, Hagberg H, Kvaloy S, Teerenhovi L, Anderson H, Cavallin-Stahl E, Holte H, Myhre J, Pertovaara H, Bjorkholm M. CHOP is superior to CNOP in elderly patients with aggressive lymphoma while outcome is unaffected by filgrastim treatment: results of a Nordic Lymphoma Group randomized trial. Blood. 2003;101(10):3840–8.
Visani G, Ferrara F, Alesiani F, Ronconi S, Catarini M, D'Adamo F, Guiducci B, Bernardi D, Barulli S, Piccaluga P, Rocchi M, Isidori A. R-COMP 21 for frail elderly patients with aggressive B-cell non-Hodgkin lymphoma: a pilot study. Leuk Lymphoma. 2008;49(6):1081–6.
Corazzelli G, Frigeri F, Arcamone M, Lucania A, Rosariavilla M, Morelli E, Amore A, Capobianco G, Caronna A, Becchimanzi C, Volzone F, Marcacci G, Russo F, De Filippi R, Mastrullo L, Pinto A. Biweekly rituximab, cyclophosphamide, vincristine, non-pegylated liposome-encapsulated doxorubicin and prednisone (R-COMP-14) in elderly patients with poor-risk diffuse large B-cell lymphoma and moderate to high ‘life threat’ impact cardiopathy. Br J Haematol. 2011;154(5):579–89.
Musolino A, Boggiani D, Panebianco M, Vasini G, Salvagni S, Franciosi V, Ardizzoni A. Activity and safety of dose-adjusted infusional cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with rituximab in very elderly patients with poor-prognostic untreated diffuse large B-cell non-Hodgkin lymphoma. Cancer. 2011;117(5):964–73.
Hainsworth JD, Flinn IW, Spigel DR, Clark BL, Griner PL, Vazquez ER, Doss HH, Shipley D, Franco LA, Burris 3rd HA, Greco FA, C. Sarah Cannon Oncology Research. Brief-duration rituximab/chemotherapy followed by maintenance rituximab in patients with diffuse large B-cell lymphoma who are poor candidates for R-CHOP chemotherapy: a phase II trial of the Sarah Cannon Oncology Research Consortium. Clin Lymphoma Myeloma Leuk. 2010;10(1):44–50.
Italiano A, Jardin F, Peyrade F, Saudes L, Tilly H, Thyss A. Adapted CHOP plus rituximab in non-Hodgkin’s lymphoma in patients over 80 years old. Haematologica. 2005;90(9):1281–3.
Aapro M, Bernard-Marty C, Brain EG, Batist G, Erdkamp F, Krzemieniecki K, Leonard R, Lluch A, Monfardini S, Ryberg M, Soubeyran P, Wedding U. Anthracycline cardiotoxicity in the elderly cancer patient: a SIOG expert position paper. Ann Oncol. 2011;22(2):257–67.
Weidmann E, Neumann A, Fauth F, Atmaca A, Al-Batran SE, Pauligk C, Jager E. Phase II study of bendamustine in combination with rituximab as first-line treatment in patients 80 years or older with aggressive B-cell lymphomas. Ann Oncol. 2011;22(8):1839–44.
Thieblemont C, Grossoeuvre A, Houot R, Broussais-Guillaumont F, Salles G, Traulle C, Espinouse D, Coiffier B. Non-Hodgkin’s lymphoma in very elderly patients over 80 years. A descriptive analysis of clinical presentation and outcome. Ann Oncol. 2008;19(4):774–9.
Bairey O, Benjamini O, Blickstein D, Elis A, Ruchlemer R. Non-Hodgkin’s lymphoma in patients 80 years of age or older. Ann Oncol. 2006;17(6):928–34.
Bairey O, Bar-Natan M, Shpilberg O. Early death in patients diagnosed with non-Hodgkin’s lymphoma. Ann Hematol. 2013;92(3):345–50.
Spina M, Balzarotti M, Uziel L, Ferreri AJ, Fratino L, Magagnoli M, Talamini R, Giacalone A, Ravaioli E, Chimienti E, Berretta M, Lleshi A, Santoro A, Tirelli U. Modulated chemotherapy according to modified comprehensive geriatric assessment in 100 consecutive elderly patients with diffuse large B-cell lymphoma. Oncologist. 2012;17(6):838–46.
Olivieri A, Marchetti M, Lemoli R, Tarella C, Lacone A, Lanza F, Rambaldi A, Bosi A, T Italian Group for Stem Cell. Proposed definition of ‘poor mobilizer’ in lymphoma and multiple myeloma: an analytic hierarchy process by ad hoc working group Gruppo ItalianoTrapianto di Midollo Osseo. Bone Marrow Transplant. 2012;47(3):342–51.
Merli F, Luminari S, Rossi G, Mammi C, Marcheselli L, Tucci A, Ilariucci F, Chiappella A, Musso M, Di Rocco A, Stelitano C, Alvarez I, Baldini L, Mazza P, Salvi F, Arcari A, Fragasso A, Gobbi PG, Liberati AM, Federico M. Cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab versus epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab for the initial treatment of elderly “fit” patients with diffuse large B-cell lymphoma: results from the ANZINTER3 trial of the Intergruppo Italiano Linfomi. Leuk Lymphoma. 2012;53(4):581–8.
Lin TL, Kuo MC, Shih LY, Dunn P, Wang PN, Wu JH, Tang TC, Chang H, Hung YS. The impact of age, Charlson comorbidity index, and performance status on treatment of elderly patients with diffuse large B cell lymphoma. Ann Hematol. 2012;91(9):1383–91.
Wedding U, Kodding D, Pientka L, Steinmetz HT, Schmitz S. Physicians’ judgement and comprehensive geriatric assessment (CGA) select different patients as fit for chemotherapy. Crit Rev Oncol Hematol. 2007;64(1):1–9.
Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Briere J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(27):4184–90.
Gisselbrecht C, Schmitz N, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Milpied NJ, Radford J, Ketterer N, Shpilberg O, Duhrsen U, Hagberg H, Ma DD, Viardot A, Lowenthal R, Briere J, Salles G, Moskowitz CH, Glass B. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol. 2012;30(36):4462–9.
El Gnaoui T, Dupuis J, Belhadj K, Jais JP, Rahmouni A, Copie-Bergman C, Gaillard I, Divine M, Tabah-Fisch I, Reyes F, Haioun C. Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy. Ann Oncol. 2007;18(8):1363–8.
Aydin S, Duhrsen U, Nuckel H. Rituximab plus ASHAP for the treatment of patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma: a single-centre study of 20 patients. Ann Hematol. 2007;86(4):271–6.
Vacirca JL, Acs PI, Tabbara IA, Rosen PJ, Lee P, Lynam E. Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma. Ann Hematol. 2014;93(3):403–9.
Li Y, Yimamu M, Wang X, Zhang X, Mao M, Fu L, Aisimitula A, Nie Y, Huang Q. Addition of rituximab to a CEOP regimen improved the outcome in the treatment of non-germinal center immunophenotype diffuse large B cell lymphoma cells with high Bcl-2 expression. Int J Hematol. 2014;99(1):79–86.
Vitolo U, Chiappella A, Franceschetti S, Carella AM, Baldi I, Inghirami G, Spina M, Pavone V, Ladetto M, Liberati AM, Molinari AL, Zinzani P, Salvi F, Fattori PP, Zaccaria A, Dreyling M, Botto B, Castellino A, Congiu A, Gaudiano M, Zanni M, Ciccone G, Gaidano G, Rossi G, Fondazione Italiana L. Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial. Lancet Oncol. 2014;15(7):730–7.
Ruan J, Martin P, Furman RR, Lee SM, Cheung K, Vose JM, Lacasce A, Morrison J, Elstrom R, Ely S, Chadburn A, Cesarman E, Coleman M, Leonard JP. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J Clin Oncol. 2011;29(6):690–7.
Morschhauser FA, Cartron G, Thieblemont C, Solal-Celigny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large b-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013;31(23):2912–9.
Merli F, Luminari S, Rossi G, Mammi C, Marcheselli L, Ferrari A, Spina M, Tucci A, Stelitano C, Capodanno I, Fragasso A, Baldini L, Bottelli C, Montechiarello E, Fogazzi S, Lamorgese C, Cavalli L, Federico M. Fondazione Italiana Linfomi. Outcome of frail elderly patients with diffuse large B-cell lymphoma prospectively identified by Comprehensive Geriatric Assessment: results from a study of the Fondazione Italiana Linfomi. Leuk Lymphoma. 2014;55(1):38–43.
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Winkelmann, N., Wedding, U. (2015). Diffuse Large B-Cell Non-Hodgkin’s Lymphoma (DLBCL- NHL). In: Wedding, U., Audisio, R. (eds) Management of Hematological Cancer in Older People. Springer, London. https://doi.org/10.1007/978-1-4471-2837-3_11
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