German High-Grade Non-Hodgkin Lymphoma Research Articles

Low serum albumin is an independent risk factor in elderly patients with aggressive B-cell lymphoma: Results from prospective trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group.

Serum albumin a well‐known risk factor predicting outcome in many solid tumors. We explore the role of low serum albumin (≤3.5 g/dL) as an independent risk factor in elderly patients with aggressive B‐cell lymphoma. Outcome of 429 patients treated with R‐CHOP‐14 in the RICOVER‐60 trial and available serum albumin were analyzed in this retrospective study. Of the 429 patients in the RICOVER‐60 trial, 137 (32%) had low and 292 (68%) had normal serum albumin levels (>3.5 g/dL). In the low albumin group, patients had significantly higher International Prognostic Index (IPI), bulky disease, extralymphatic involvement, and B‐symptoms. Event‐free survival (EFS) (P < .001), progression‐free survival (PFS) (P < .001), and overall survival (OS) (P < .001) were significantly inferior for patients with low compared to those with normal serum albumin. Multivariate analysis adjusted for IPI shows following Hazard ratios (HR) for low serum albumin: EFS (HR = 1.5; 95% confidance interval [CI] [1.1; 2.1], P = .009), PFS (HR = 1.7; 95% CI [1.2; 2.4], P = .001) and OS (HR = 1.6; 95% CI [1.1; 2.3], P = .006). Results were confirmed in 185 patients from the DENSE‐R‐CHOP‐14 and SMARTE‐R‐CHOP‐14 trials. In conclusion, low serum albumin is an independent risk factor in elderly patients with aggressive B‐cell lymphoma treated with R‐CHOP.

Clinical Impact of the Cell-of-Origin Classification and the MYC/ BCL2 Dual Expresser Status in Diffuse Large B-Cell Lymphoma Treated Within Prospective Clinical Trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group.

Purpose To explore the prognostic impact and interdependence of the cell-of-origin (COO) classification, dual expression (DE) of MYC and BCL2 proteins, and MYC, BCL2, and BCL6 translocations in two prospectively randomized clinical trials of patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Overall, 452 formalin-fixed paraffin-embedded samples from two prospective, randomized DLBCL trials (RICOVER-60, prospective, randomized study for patients > 60 years, all IPI groups; and R-MegaCHOEP, prospective, randomized study for patients ≤ 60 years with age-adjusted IPI 2,3) of the German High-Grade Non-Hodgkin Lymphoma Study Group were analyzed with the Lymph2Cx assay for COO classification, with immunohistochemistry for MYC and BCL2, and with fluorescent in situ hybridization for MYC, BCL2, and BCL6 rearrangements. Results COO classification was successful in 414 of 452 samples. No significant differences with respect to COO (activated B-cell [ABC]-like DLBCL v germinal center B-cell [GCB]-like DLBCL) were observed in event-free survival, progression-free survival, and overall survival in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the RICOVER-60 trial. Also, no differences with respect to COO were observed in multivariable analyses adjusted for International Prognostic Index factors in event-free survival (hazard ratio [HR] of ABC-like disease v GCB-like disease, 1.0; 95% CI, 0.6 to 1.6; P = .93), progression-free survival (HR, 1.1; 95% CI, 0.6 to 1.8; P = .82), and overall survival (HR, 1.0; 95% CI, 0.6 to 1.8; P = .96). Similar results were observed in the R-MegaCHOEP trial. In patients treated with R-CHOP, DE status was associated with significantly inferior survival compared with nonDE within the GCB, but not within the ABC subgroup. DE status was associated with significantly inferior outcome compared with patients with ABC-like DLBCL without DE (5-year PFS rate, 39% [95% CI,19% to 59%] v 68% [95% CI, 52% to 85%]; P = .03) and compared with patients with GCB-like DLBCL without DE. When data from patients with nonDE were analyzed separately, the outcome of patients in the ABC subgroup was inferior to that of patients in the GCB subgroup (5-year PFS rate, 68% [95% CI, 52% to 85%] v 85% [95% CI, 74% to 96%]; P = .04). Conclusion COO profiling in two prospective randomized DLBCL trials failed to identify prognostic subgroups, whereas dual expression of MYC and BCL2 was predictive of poor survival. Evaluation of prognostic or predictive biomarkers in the management of DLBCL, such as the COO, within prospective clinical trials will be important in the future.

Validation of German High-Grade Non-Hodgkin's Lymphoma (DSHNHL) Prognostic Model and the Impact of Treatment on Secondary Central Nervous System (CNS) Relapse in Diffuse Large B-Cell Lymphoma (DLBCL) in a Developing Country: Report from the Nationwide Multi-Institutional Registry of Thai Lymphoma Study Group (TLSG)

Introduction: Despite improved treatment outcome of DLBCL in the immunochemotherapy era, secondary CNS relapse remains a serious and fatal complication. Several prognostic models were reported in order to define high-risk patients for CNS relapse and provide proper prophylactic strategies. There is no standard approach for CNS prophylaxis in DLBCL with more data suggesting lack of efficacy of intrathecal chemoprophylaxis. In 2013, the DSHNHL introduced a prognostic model including each international prognostic index (IPI) factor (age, lactate dehydrogenase (LDH), stage, performance status (PS), extranodal involvement (EN) and kidney/adrenal involvement) to stratify patients into 3 groups. Herein, we applied and validated DSHNHL model to DLBCL patients treated at nationwide University hospitals in Thailand including analyzing an impact of rituximab and intrathecal chemoprophylaxis on CNS relapse.Method: From the nationwide multicenter registry of 4,371 newly diagnosed lymphoma patients in Thailand between 2007 and 2014, there were a total of 2,399 DLBCL patients. We looked at the incidence and clinical predictors of CNS relapse, the effect of immunotherapy and intrathecal chemoprophylaxis on CNS relapse in DLBCL who were treated with at least one cycle of CHOP-like or intensive chemotherapy regimens.Result: After excluding patients with CNS/ocular involvement at diagnosis, 2,034 DLBCL patients were included in the analysis. Table 1 summarizes baseline characteristics of DLBCL patients. The median follow up time for living patients was 51 months (interquartile range, 22-75 months). A total of 565 patients (27.8%) progressed or relapsed after first-line induction therapy and 61 patients (3.0%) developed CNS relapse. Median time to CNS relapse was relatively shorter than non-CNS relapse (8.4 vs 10.5 months, P =0.07). A total of 729 (35.8%), 1,024 (50.3%) and 281 (13.8%) patients were classified as low-, intermediate- and high-risk groups based on DSHNHL risk model for CNS relapse. Of high DSHNHL risk group, 45 patients (16%) received intrathecal chemotherapy for CNS prophylaxis along with induction treatments. Using the competing risk regression analysis, 2-year cumulative incidence of CNS relapse was 2.7% (1.5%, 3.1%, and 4.6% for low-, intermediate- and high-risk DSHNHL group respectively). Univariate analysis showed elevated LDH, poor PS, stage III/IV, presence of B symptoms, higher risk IPI and DSHNHL risk group as risk factors of CNS relapse (Table 2). Presence of concurrent EN involvement more than one site and elevated LDH was a significant predictor of CNS relapse (Hazard Ratio [HR] 2.39, P =0.004). Kidney/adrenal gland and gonadal involvement were not associated with higher risk of CNS relapse whereas breast involvement showed a trend toward higher incidence of CNS relapse (HR 2.46, P =0.07). Either immunochemotherapy or intrathecal chemoprophylaxis was not associated with lower risk of CNS relapse; in fact patients who received intrathecal chemotherapy had more CNS relapse though this could be due to selection bias. Median survival of patients with CNS relapse was 13.2 months which was significantly worse than patients without CNS relapse (81.8 months, P<0.001).Conclusion: The 2-year cumulative incidence of CNS relapse in DLBCL in this analysis was 2.7% which was comparable to other series. Using the DSHNHL prognostic model was able to define DLBCL patients into low, intermediate and high risk for CNS relapse. The high-risk group in our series had lower incidence of CNS relapse compared to German and recently reported British Columbia cohorts. Our study confirms poor survival outcome of DLBCL patients with CNS relapse and no protective effect of immunochemotherapy or intrathecal chemoprophylaxis on the incidence of CNS relapse. Novel risk-adapted CNS prophylaxis strategies are warranted to be further investigated in prospective studies. [Display omitted] [Display omitted] [Display omitted] DisclosuresKhuhapinant:Roche: Honoraria.

Liposomal Formulation of Vincristine Allows for Doubling the Dose Compared to Conventional Vincristine: Results of the First Futility Analysis of the OPTIMAL>60 Study of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)

Background: Cumulative neurotoxicity is a major issue and dose limiting factor of vincristine in the treatment of diffuse large B-cell-lymphoma (DLBCL) and other malignancies, especially in elderly patients. In the RICOVER-60 trial of the German High Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) [Pfreundschuh et al., Lancet Oncol. 2008] only 59% of patients received full-dose vincristine at cycle 6, 22% of patients received no vincristine at cycle 6 and 36% at cycle 8 due to the neurotoxicity of the drug. Thus, vincristine-induced polyneuropathy is a long-term toxicity that heavily affects the quality of life of successfully treated elderly patients with lymphoma, because of slow and often incomplete recovery. Moreover, retrospective analyses suggest that dose reductions of vincristine lead to a considerable loss of efficacy [Fisher et al., Am J Med. 1977; De VV et al., Cancer Res. 1987]. Since preclinical and clinical studies suggest a high activity and excellent tolerability of liposomale vincristine, a randomized comparison of the two formulations is warranted.Methods: In the OPTIMAL>60 study elderly patients with DLBCL (61- to 80 years-old, ECOG 0-4, IPI 1 [age>60] with bulk, or IPI 2-5) are randomized to receive eight 2-week applications or an optimized schedule of 12 application of rituximab in combination with 6 cycles of CHOP-14. In a 2x2 factorial design, patients receive a second randomization into conventional vincristine (1.4 mg/m2, capped at 2 mg) or liposomal vincristine (2mg/m2, uncapped). One secondary endpoint of the OPTIMAL>60 trial of the DSHNHL is the determination of the median dose of either conventional or liposomal vincristine, that can be given to patients applying identical dose reduction rules. Neurotoxicity was determined as polyneuropathy according to the Common Terminology Criteria for Adverse Events (CTCAE v. 4.03).Results: In this planned futility analysis of the OPTIMAL>60 trial, we investigated the cumulative dose of liposomal (VLIP, Marqibo®) and conventional vincristine (VCR) and the neurotoxic effect of the first 105 patients. Fifty-three patients received VCR and 52 patients VLIP. In comparing the median cumulative dose received for each group. The median cumulative dose of VLIP group (10.09mg/m2) was nearly double the median cumulative dose of VCR group (5.42mg/m2) (p<0.001). Since identical dose reduction rules were applied, we expected equal neurotoxic effects with VLIP and VCR, which was indeed the case. Before initiation of therapy 100% of patients receiving VCR showed PNP grade 0 while 15.2% of patients in the VLIP-group showed PNP grade 1 (84.8% grade 0) which was significantly worse (p=0.018). After cycles 1 and 2 the median grade of polyneuropathy was 0 in both groups, which increased to a median toxicity of grade 1 after cycles 3, 4, 5 and 6. The maximum grades of polyneuropathy observed in both groups were not significantly different (p=0.865). In the VLIP group no liposomal vincristine was administered in 18 patients (34.62%) , in the VCR arm group no vincristine in 14 patients (26.42%) in at least one cycle of therapy (p=0.361). Due to polyneuropathy no VLIP was given in 16 patients (30.77%), no VCR in 12 patients (22.64%) for the minimum of one cycle of therapy (p=0.346).Conclusions: With nearly twice the dose of VLIP achieved in elderly patients treated in the OPTIMAL>60 study, the preset goals were met and the study will continue as planned. A total recruitment of 864 patients is necessary to demonstrate whether the double dose of VLIP will translate into a significantly improved outcome in 3-year PFS (HR 0.68 or 9% with an alpha=5% and a power of 80%). Acknowledgment: This study was supported by Spectrum, Amgen and Roche. DisclosuresViardot:Amgen Inc.: Membership on an entity’s Board of Directors or advisory committees, Travel support Other; Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Travel support, Travel support Other; Janssen: Membership on an entity’s Board of Directors or advisory committees; Gilead: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria, Travel support Other. Pfreundschuh:Amgen: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Roche: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Spectrum: Research Funding.

Aggressive craniofacial lymphoma in the pre-rituximab and rituximab era.

8038 Background: Among 4,165 patients treated in trials of the German High Grade Non-Hodgkin Lymphoma Study Group (DSHNHL), 316 pts had craniofacial involvement by their lymphoma. Methods: To analyze clinical characteristics and response to therapy of 316 pts with craniofacial lymphomas treated with CHOP-like chemotherapy with and without rituximab (R). A retrospective analysis was performed to compare characteristics and treatment outcome of pts with craniofacial lymphoma to all the other pts of these trials. Results: Of the 316 pts, 32 had orbital, 101 paranasal sinus, 44 main nasal cavity, 109 mouth, 28 tongue and 57 salivary gland involvement. Pts with craniofacial lymphoma presented with a significantly lower LDH, better performance status, lower Ann Arbor Stage and less bulky disease compared to the entire population (elevated LDH: 16.8% vs. 35.9%, p=<0.001; ECOG >1: 2.8% vs. 10.1%, p=<0.001; stage III/IV: 28.2% vs. 40.7%, p=<0.001; bulky disease: 14.9% vs. 39.3%, p=<0.001). 3-year event free survival (70.4% vs. 60.5%, p=<0.001) and 3-year overall survival (81.2% vs. 75.6%; p=0.044) were better in pts with craniofacial involvement compared to the entire population of these trials. Multivariate analysis confirmed all IPI-relevant risk factors as significant and independent. With respect to different treatment strategies, the addition of rituximab to CHOP-14 in the RICOVER-60 trial reduced the relative risk to 0.6 for EFS and 0.5 for OS. This is clinically very relevant, but not significant due to the limited number of patients. In contrast, additive Rx to the craniofacial involvement for pts in CR/CRu or PR at the end chemo- or immunochemotherapy, which was given to 178 pts had no influence on the outcome of these pts compared to pts not receiving additive Rx (n=68). The relative risk for EFS was 1.0 (p=0.863) and 1.5 (p=0.315) for OS in patients receiving additional Rx compared to pts receiving systemic therapy only. Conclusions: Pts with craniofacial lymphoma present with favorable prognostic parameters and treatment results are better in this population compared to the whole population. Our results do not support the addition of radiotherapy to systemic therapy in these patients.

Favorable impact of the interleukin-4 receptor allelic variant I75 on the survival of diffuse large B-cell lymphoma patients demonstrated in a large prospective clinical trial

BackgroundRecently published data indicate that host germline variations in immune genes can influence the outcome of lymphoma patients. Interleukin (IL)-4 and IL13 are crucial immune factors and may influence the course of the disease. Both cytokines signal through the interleukin-4 receptor (IL4R). Therefore, we investigated whether polymorphisms of IL4, IL13 and IL4R genes could predict the outcome of diffuse large B-cell lymphoma (DLBCL) patients. MethodsIn 228 DLBCL samples of the German High-Grade Non-Hodgkin's Lymphoma Study Group, the polymorphisms of IL4 (-524CT, rs2243250), IL13 (-1069CT, rs1800925) and IL4R (I75V, rs1805010; S503P, rs1805015; Q576R, rs1801275) were analyzed and the soluble interleukin-4 receptor (sIL4R) serum level was measured before the start of chemotherapy. ResultsPatients harboring IL4R V75 (IL4RI75V-AG and IL4RI75V-GG) had shorter overall survival (OS) (P=0.044) and event-free survival (EFS) (P=0.056) periods compared with I75 carriers (IL4RI75V-AA). Multivariate analysis adjusted to the International Prognostic Index revealed a relative risk of 1.9 for carriers of the IL4R V75 (P=0.011) in relation to OS. DLBCL patients homozygous for the IL4R I75 and low sIL4R serum levels have the most favorable OS and EFS. ConclusionsThese data support the role for host germline gene variations of immunologically important factors like the IL4R I75V gene variation to predict the survival in DLBCL patients.

Structural aberrations affecting the MYC locus indicate a poor prognosis independent of clinical risk factors in diffuse large B-cell lymphomas treated within randomized trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL)

Recent retrospective studies of heterogeneously treated patients have suggested that chromosomal aberrations of the MYC gene locus indicate an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL). Here, we investigated the prognostic impact of MYC aberrations analyzed by interphase fluorescence in situ hybridization in 177 patients with de novo DLBCL treated within the two prospective, randomized trials non-Hodgkin's lymphoma NHL-B1 and NHL-B2. MYC aberrations were detected in 14 DLBCL (7.9%). In a univariate analysis compared with MYC-negative DLBCL, MYC-positive cases showed a significantly shorter overall survival (OS) (P=0.047) and relevantly, though not significantly, shorter event-free survival (EFS) (P=0.062). In a Cox model adjusted for the international prognostic index, the presence of a MYC gene rearrangement was the strongest statistically independent predictor of OS (relative risk 3.4, P=0.004) and EFS (relative risk 2.5, P=0.015), and this also held true when the cell-of-origin signature detected by immunohistochemistry was included in the model.

CNS-Disease in Elderly Patients Treated with Modern Chemotherapy (CHOP-14) with or without Rituximab: An Analysis of CNS Events in the RICOVER-60 Trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL).

Background CNS recurrence of aggressive lymphoma remains a distressing and usually incurable event. In an analysis of patients on protocols of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL) between 1990 and 2000, the CNS relapse rate was 2.2% in 1693 patients treated with modern chemotherapy but without rituximab (Boehme et al., Ann. Oncol. 2007). We now analyzed the incidence and prognostic factors for CNS recurrence in the RICOVER-60 study (Pfreundschuh et al., Blood abstract 2006) where patients had been randomized to 6 or 8 courses of CHOP-14 +/- rituximab. Patients and Methods From 2000–2005, 1242 patients (pts.) between 61 and 80 years with CD20+ aggressive lymphoma were randomized to receive 6 or 8 cycles of CHOP-14 chemotherapy with or without 8 courses of rituximab. Twenty patients were excluded because of missing or retracted informed consent, leaving 1222 pts. for the intention-to-treat analysis. For patients with suspected or confirmed lymphoma manifestation in testes, bone marrow, upper cervical nodes, sinuses or other extranodal involvements in the cranial region the protocol asked for intrathecal (i.th.) prophylaxis with 15 mg methotrexate twice in the first two cycles of treatment.Results 1217 patients were evaluable, of whom 58 patients (4.8%) after a median time of 8 months (1–39) developed relapse or progression to the CNS with a median time of survival of 3 months (0.1–38). Multivariate Cox regresssion analysis identified involvement of more than one extranodal site (RR = 3.4; p< 0.001), the presence of B-symptoms (RR = 1.9; p = 0.025) and increased LDH values (RR = 1.5; p = 0.146) as relevant predictors of CNS recurrence. Patients with these three characteristics had a CNS relapse rate of approximately 24% at 2 years, about 6-fold the incidence rate observed in all other patients. The addition of rituximab to chemotherapy reduced the risk of CNS recurrence (RR = 0.5; p = 0.025), whereas the number of treatment cycles (6 vs. 8) did have no influence on the CNS-specific outcome. 273 of 1217 patients (22%) received i.th. prophylaxis at least during one cycle and 202 of 273 prophylaxis patients (74%) were treated intrathecally in full compliance with the protocol, thus reducing the rate of CNS complications (RR = 0.3; p = 0.023). The majority of these patients had involvement of testes, bone marrow, sinuses or upper skeletal and/or nodal sites.Conclusion The incidence of CNS relapse in 1217 patients treated for aggressive lymphoma with CHOP-14 with or without rituximab was low (4.8%) but slightly higher than reported in other recent series. The prognostic factors for CNS-disease and the poor prognosis of CNS relapse remain largely unchanged although rituximab significantly reduced the incidence of CNS disease (3.6 vs. 5.9%) and the risk of CNS recurrence (RR 0.5; p = 0.025). Prophylactic i.th. therapy given to patients with distinct extranodal involvement reduces the risk of CNS disease in these individuals. Due to the low overall incidence general prophylactic strategies cannot be recommended.

The interleukin-10 gene promoter polymorphism −1087AG does not correlate with clinical outcome in non-Hodgkin's lymphoma

The Interleukin 10 (IL-10) gene is highly polymorphic, and the IL-10(-1087AG) (rs1800896) gene variation is the only so far studied intensively in association with certain diseases. Conflicting data have been published about an association of IL-10(-1087AG) gene variation with lower rates of complete remission and lower overall survival (OS) in patients with diffuse large B-cell lymphoma. To further investigate this in malignant lymphoma, we established the IL-10 genotypes in patients from the NHL-B1/ B2 studies from the German High-Grade Non-Hodgkin's Lymphoma Study Group. In our study, allele frequencies of lymphoma patients are comparable as in healthy controls. No increase of IL-10(-1087G) alleles was found. In addition we did not find any difference in OS or event-free survival between patients with IL-10(-1087AA) and the other genotypes. Comparable results were obtained for the IL-10 loci at -3538 (A/T), -1354 (A/G), -824 (C/T) and -597 (A/C) (rs1800890, rs1800893, rs1800871 and rs1800872).

Incidence and risk factors of central nervous system recurrence in aggressive lymphoma—a survey of 1693 patients treated in protocols of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL)

Central nervous system (CNS) relapse is a devastating and usually fatal complication of aggressive lymphoma. The extent of the disease, the proliferation rate and the sites of extranodal involvement have been discussed as risk factors. We analyzed the patients treated on protocols of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL) between 1990 and 2000, evaluated the rate and prognostic factors for CNS recurrence and developed a risk model trying to identify subsets of patients suitable for future prophylactic strategies. From 1993 to 2000, 1399 patients [<or=60 years with normal lactate dehydrogenase (LDH) and >60 years irrespective of LDH] were randomized to receive six cycles of combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-21, CHOP-14 or six cycles of CHOP+etoposide (CHOEP)-21, CHOEP-14 in a 2x2 factorial study design in the NHL-B1/B2 studies. From 1990 to 1997, 312 patients<or=60 years with an elevated LDH were randomized to five cycles CHOEP+involved field (IF) radiotherapy or three cycles CHOEP followed by high-dose BCNU, etoposide, cytarabine and melphalan (BEAM) and autologous stem-cell transplantation (NHL-A study). A total number of 1711 patients were initially eligible for this study, of whom 18 patients had to be excluded due to primary CNS involvement. In the remaining 1693 assessable patients, 37 cases of relapse or progression to the CNS (2.2%) were observed. The protocol asked for an intrathecal (i.th.) prophylaxis in patients with lymphoblastic lymphoma only (n=17), but overall 71 patients (71 of 1693=4.2%) received prophylaxis by decision of the treating physicians. Multivariate Cox regression analysis identified increased LDH (P<0.001) and involvement of more than one extranodal site (P=0.002) as independent predictors of CNS recurrence in the NHL-B1/B2 study population. Treatment with etoposide also evolved as a prognostic factor because the risk of CNS failure was significantly reduced after CHOEP (P=0.017). Elderly patients presenting with both an elevated LDH and lymphoma involvement in liver, bladder or adrenals had an up to 15-fold risk of spread of the disease to the CNS. The incidence of CNS relapse in 1693 patients treated for aggressive lymphomas on DSHNHL protocols from 1990 to 2000 was low (2.2%), although CNS prophylaxis was administered to <5% of patients. Thus, a general prophylaxis for all patients is not warranted, the less so since the effectiveness of i.th. prophylaxis itself is judged controversially. Increased LDH and involvement of more than one extranodal site were confirmed as independent risk factors. A cumulative 20% incidence of CNS disease in certain prognostic subgroups of elderly patients may render these candidates for i.th. prophylaxis; however, this approach would imply a potential overtreatment of approximately 80% of these patients deemed at high risk.