Lymphoma Group Trials Research Articles

Relationships, marriage, and partner abandonment among Hodgkin lymphoma survivors treated in nine EORTC-GELA Lymphoma Group trials

Relationships, marriage, and partner abandonment among Hodgkin lymphoma survivors treated in nine EORTC-GELA Lymphoma Group trials

Th1/2 Immune Response Signature Predicts Outcome after Dose-Dense Immunochemotherapy in Patients with High Risk Diffuse Large B-Cell Lymphoma - Results from Nordic Lymphoma Group Trials

Introduction: Despite better therapeutic options and improved survival of diffuse large B-cell lymphoma (DLBCL), 30-40% of the patients still relapse and have dismal prognosis. Recently, the impact of genomic aberrations, allowing lymphoma cells to escape immune recognition on DLBCL pathogenesis has been recognized. However, whether immune related signatures could be used as determinants for treatment outcome has not been rigorously evaluated. Here, our aim was to elucidate the immunologic characteristics of the tumor microenvironment, and associate the findings with outcome in patients with high-risk DLBCL.Patients and methods: We specifically examined gene expression in the tumor microenvironment, using RNA isolated from formalin fixed paraffin-embedded (FFPE) tumor samples from 81 patients with DLBCL. Gene expression analysis was conducted on the NanoString nCounter gene expression platform using a 770-gene PanCancer Immune panel. The predictive impact of the gene expression signatures was assessed using a cohort of 65 high risk DLBCL patients enrolled in the Nordic CHIC trial (Leppä et al., 2016). The findings were validated using exon array data from an independent cohort of 38 high risk DLBCL patients treated in the Nordic CRY-04 trial (Holte et al., 2013; Leivonen et al., 2017a). In both trials, the patients received dose-dense immunochemotherapy (R-CHOEP-14) and systemic central nervous system prophylaxis (HD-Mtx and HD-Ara-C).Results: Unsupervised hierarchical clustering revealed three major clusters of genes with differential expression between the patients. The clusters were enriched for the genes related to focal adhesion and extracellular matrix (ECM) receptor interactions (eg. COL3A1, ITGA, ITGB, VEGFC, VEGFA, PDGFRB, PDGFC, FN1 ), T/NK-cell signaling (eg. ICAM1, CD3, CD4, CD8 GZMB, ITGB2 ), and type 1/2 immune responses (eg. IL4, IFNL1, IFNL2, IL13, IL24 ). Interestingly, type 1/2 immune response signature correlated with survival. In the CHIC cohort, the group of patients (n=10) with high expression of type 1/2 immune response signature genes had a 4-year PFS of 60% in comparison to 91% for those (n=55) with low expression (p = 0.021). The corresponding 4 y OS rates were 64% vs 90% (p=ns). The risk of progression was 4.0 fold higher for the patients with high expression of type 1/2 immune response signature genes (95% CI 1.120-14.280, p=0.033). No differences were observed in sex, age, stage, IPI scores, or molecular subgroups between the low and high type 1/2 immune response subgroups. The prognostic impact of the signature was confirmed in the CRY-04 exon array cohort (4-y PFS; 46% vs 80%, p = 0.021, 4-y OS 62% vs 88%; p = 0.014). In the CRY-04 cohort, the risk of progression was 3.6 fold (95% CI 1.13-11.20, p=0.030) and death 4.8 fold (95% CI 1.20-19.26, p=0.027) higher for the group of patients with high expression of the type 1/2 immune response signature genes. In contrast to our data on primary testicular lymphomas (PTLs) (Leivonen et al., 2017b), T/NK cell signature did not correlate with outcome in either of the trial cohorts. Correspondingly, type 1/2 immune signature was not associated with outcome in the cohorts of PTL or DLBCL patients treated with conventional R-CHOP regimen.Conclusion: Our data suggest that immune related signatures exhibit treatment-specific roles in diffuse large B-cell lymphoma. For the high risk DLBCL patients treated with dose-dense immunochemotherapy, high expression of type 1/2 immune response signature genes predicts a poor outcome. A detailed characterization of immune cell composition in the tumor microenvironment and its impact on survival is ongoing. DisclosuresJørgensen:Roche: Research Funding. Holte:Novartis: Consultancy, Honoraria; Celgene: Consultancy; Janssen Cilag: Consultancy; Nordic Nanovector: Consultancy; Mundipharma: Consultancy. Leppa:Merck: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Research Funding; Bayer: Research Funding.

Detailed Long-Term Follow-Up of Patients Who Relapsed After the Nordic Mantle Cell Lymphoma Trials: MCL2 and MCL3.

Mantle cell lymphoma (MCL) is an incurable disease with a highly variable clinical course. The prognosis after relapse is generally poor, and no standard of care exists. We investigated the postrelapse outcomes of 149 patients who were initially treated in the Nordic Lymphoma Group trials, MCL2 or MCL3, both representing intensive cytarabine-containing frontline regimens including autologous stem cell transplant. Patients with progression of disease before 24 months (POD24, n = 51, 34%) displayed a median overall survival of 6.6 months compared with 46 months for patients with later POD (n = 98, 66%; P < 0.001). MCL international prognostic index, cell proliferation marker, blastoid morphology, and TP53 mutations showed independent prognostic value irrespective of POD24, and in a combined, exploratory risk score, patients with 0, 1, 2-3, or 4-5 high-risk markers, respectively, displayed a 5-year overall survival of 62%, 39%, 31%, and 0%. By a comparison of median progression-free survival of the different salvage therapies in the relapse setting, bendamustine-rituximab was superior to all other combination chemotherapy regimens; however, it was also associated with longer responses to last line of therapy. Collectively, we confirm the prognostic impact of POD24 and highlight the relevance of other biomarkers, and we emphasize the importance of novel therapies for patients with high-risk features at first POD.

Absolute B cell counts in blood predict long-term response in follicular lymphoma patients treated with rituximab without chemotherapy

Rituximab monotherapy is widely used for follicular lymphoma. However, there are no established predictors for response or response duration. We analyzed the long-term prognostic relevance of pre-treatment absolute blood counts of lymphocytes with subsets and monocytes in 265 follicular lymphoma patients, uniformly treated with rituximab without chemotherapy, in two Nordic Lymphoma Group trials. There were 265 previously untreated, stage II–IV follicular lymphoma patients with a median follow-up of over 10 years. Absolute B cell counts ≥ median (0.09 × 109/L) were an independent predictor for shorter time to next treatment or death (multivariable analysis P = 0.010). In univariate analysis, absolute monocyte counts ≥ median (0.5 × 109/L) did not correlate with time to next treatment or death, but with inferior overall survival (P = 0.034). Absolute T cell or T cell subset counts were not predictive for outcome. High absolute B cell counts, possibly reflecting circulating lymphoma cells, have an unfavorable impact on time to next treatment or death in patients treated with rituximab without chemotherapy.

Chemotherapy-Free Initial Treatment of Advanced Indolent Lymphoma Has Durable Effect With Low Toxicity: Results From Two Nordic Lymphoma Group Trials With More Than 10 Years of Follow-Up.

For indolent lymphoma, the optimal timing, sequence, and choice of therapeutic regimens remain a matter of debate. In two Nordic Lymphoma Group randomized trials, symptomatic or clearly progressing patients were treated first line with a rituximab-containing regimen without chemotherapy. The purpose of this study was to assess long-term survival, risk of transformation, and need of new therapies. Data were collected at cross-sectional follow-up for 321 patients with indolent lymphoma (84% with follicular lymphomas [FL]) included in one of two Nordic Lymphoma Group trials (accrual 1998 to 1999 and 2002 to 2008). All patients received first-line therapy with one or two cycles of four weekly infusions of rituximab 375 mg/m2, and 148 were randomly allocated to the addition of interferon alfa-2a. Follow-up data were retrieved from initial trial databases and medical records on repeated clinical evaluations. At the end of follow-up, 73% of patients were alive, with a median follow-up after random assignment of 10.6 years. Among all, 36% (38% with FL) had never needed chemotherapy. For patients with FL who required new therapy within 24 months because of early disease progression, the 10-year survival rate was 59% versus 81% for those with longer remission. Interferon was not shown to improve long-term outcome. Transformation was diagnosed in 20% of all patients (2.4% per person-year) and in 18% with FL. An additional malignancy was found in 12%. Approximately one third of patients with symptomatic indolent lymphoma (30% with FL, 23% without FL) did not need new therapy in the long term after first-line rituximab without chemotherapy. In the entire cohort, 10-year survival was excellent with no major safety issues, which suggests that chemotherapy can be delayed safely in the majority of patients.

The Impact of Upfront Autologous Transplant on the Survival of Adult Patients with ALCL and PTCL-NOS According to Their ALK, DUSP22 and TP63 Gene Rearrangement Status - a Joined Nordic Lymphoma Group and Mayo Clinic Analysis

Introduction: Recent results from two independent patient series have shown that chromosomal rearrangements of DUSP22 (DUSP22r+) and TP63 (TP63r+) can predict outcome in ALK-negative anaplastic large cell lymphoma (ALK-ALCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) with morphologic features resembling ALK-ALCL (Parilla-Castellar E, Blood 2014; Pedersen MB, Blood 2017). While DUSP22r+ is predictive for excellent survival similar to that of ALK+ALCL after CHOP/CHOP-like therapy, the rarely occurring TP63r+ is associated with an aggressive clinical behavior and poor outcome. The largest subgroup, i.e. patients with neither ALK nor DUSP22 nor TP63 rearrangements (triple negative), show a 5 year (yr) overall survival (OS) intermediate between that of ALK-/DUSP22r+ and ALK-/TP63r+ patients.The aim of the present study was to assess the impact of upfront high-dose therapy with autologous stem cell transplant (HDT/ASCT) on outcome in adult ALCL and PTCL-NOS patients according to their ALK, DUSP22 and TP63 status. The survival results from the two published series were pooled with those of a Nordic Lymphoma Group trial, the NLG-T-01 (d'Amore et al, JCO 2012), where patients were treated with 1st line CHOEP/CHOP followed, in chemosensitive cases, by upfront HDT/ASCT.Methods: Fluorescence in situ hybridization was performed on sections of previously constructed tissue microarrays using break-apart probes for the DUSP22-IRF4 and TP63 loci and a dual-fusion probe for TBL1XR1/TP63 fusion [inv(3)(q26q28)]. Evaluation of DUSP22 and TP63 rearrangements was performed in a blinded fashion without knowledge of PTCL subtype, clinical course, or outcome. Three independent patient cohorts were included: (i) one from Mayo Clinic consisting of 31 DUSP22r-, ALK-ALCL and PTCL-NOS (triple negative: 25; TP63r+: 6); (ii) one from Denmark consisting of 93 DUSP22r-, ALK-ALCL and PTCL-NOS (triple negative: 90; TP63r+: 3); and one from the NLG-T-01 trial consisting of 46 ALK-ALCL and PTCL-NOS (triple negative: 37; TP63r+: 1; DUSP22r+: 8), leading to a total study population of 170 patients. ALK+ ALCL was not included in the analysis, since no patients with this histology entered the NLG-T-01 trial. Association of genetic subtype with OS was assessed using Kaplan-Meier curves and Cox proportional models for hazard rate ratios (HR). Significant differences were defined as P <0.05.Results: The eight DUSP22r+ patients (7 ALK-ALCL and 1 PTCL-NOS) from NLG-T-01 had a 5-yr OS of 83%, (95%CI 27-97), similar to that reported for DUSP22r+ in the Mayo and Danish cohorts (90% and 80%, respectively). No lymphoma-related events were observed in this subset. The only event was a septic death due to HDT-induced cytopenias in a patient who was in complete remission (CR). Among the 162 patients with DUSP22r-, ALK-ALCL and PTCL-NOS, those consolidated with HDT/ASCT (n=47) had a significantly better outcome (5-yr OS: 45%) than those treated with induction chemotherapy alone (5-yr OS: 30%) (n=115) (P=0.01). The patients in the HDT/ASCT group were younger (P<0.001) and had more advanced stage disease (P=0.002). The improvement in OS persisted when the analysis was limited to transplant eligible patients and adjusted for age and stage (HR 0.52 95%CI 29-91, P=0.023) or International Prognostic Index (IPI) groups (HR 0.49, 95%CI 20-82, P=0.006). Of the 10 TP63r+ patients found within the pooled cohort, 6 were transplant eligible. Of these, 5 were not transplanted (intention-to-treat) while one was (Nordic trial). The latter patient achieved a still ongoing long-term CR, while all others died of lymphoma progression.Conclusion: In ALK-ALCL and PTCL-NOS patients from the NLG-T-01 trial, DUSP22r+ was associated with a very good outcome, similar to that seen in DUSP22r+ patients who had not undergone upfront autologous transplant. This observation supports the impression that upfront HDT/ASCT may not be of benefit in these patients. TP63r+ predicted poor outcome in non-transplanted patients. The impact of HDT/ASCT in the TP63r+ setting could not be adequately evaluated, since only one patient from the NLG-T-01 trial cohort was found to be TP63r+. Notably, this patient was the only survivor of the TP63r+ subset. For DUSP22r-, ALK-ALCL and PTCL-NOS patients taken as one group, those who received upfront HDT/ASCT had a superior survival compared to their age- and IPI-matched non-transplanted counterparts. DisclosuresEllin:ROCHE: Consultancy, Research Funding; CTI: Consultancy. Mannisto:Roche: Honoraria, Other: Travel expence; Takeda: Honoraria, Other: Travel expence; Amgen: Other: Travel expence; Novartis: Other: Travel expence; Celgene: Other: Travel expence; Gilead: Other: Travel expence; Pfizer: Honoraria; SOBI: Honoraria. Cerhan:Janssen: Other: Scientific Advisory Board (REMICADELYM4001); Janssen: Other: Multiple Myeloma Registry Steering . Toldbod:Takeda Pharma: Honoraria.

Response at Interim Evaluation Predicts Survival after Autologous Stem Cell Transplantation in Nodal Peripheral T-Cell Lymphoma; A Nordic Lymphoma Group Study

Introduction: In the Nordic Lymphoma Group trial NLG T-01, patients with newly diagnosed peripheral T-cell Lymphoma (PTCL) were treated with six courses of CHOEP (up to 60 yrs) or CHOP (61-67 yrs) followed by high-dose chemotherapy (BEAM) and autologous stem cell transplantation (ASCT). At 5 years median follow-up, the progression-free survival of the trial cohort was 44%. On this background, the NLG-T01 treatment strategy has become the recommended first-line treatment for younger fit patients in the Nordic countries and in the latest ESMO guidelines for PTCL. Despite this intensive approach with up-front ASCT a fraction of patients still relapses. In an attempt to find factors predictive for survival after up-front ASCT we aimed to analyze the impact of radiologic response at the first interim evaluation on long-term survival.Methods: All NLG T-01 patients (TrialP) with "nodal" PTCL, i.e. anaplastic large cell lymphoma, ALK-negative (ALCL), angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma not otherwise specified (PTCL NOS), that actually received the planned ASCT were included. Using national (Sweden and Denmark) or site-specific (Finland and Norway) registries, additional patients (RegP) who received the same treatment schedule, but off-protocol, were identified, and data for these patients was collected retrospectively. Overall survival (OS) was calculated from date of stem cell reinfusion until death from any cause. The first interim computed tomography (iCT) scan was performed after 3 cycles of chemotherapy. Response assessment in the NLG-T-01 trial was based on the 1999 International Working Group criteria for response, which allowed for complete remission unconfirmed and these patients have been grouped with CR in the present analysis. Progressive Disease (PD) was defined as increase of ≥25% of any lesion.Results: Altogether, 132 patients were included in the present study (TrialP n= 92; RegP n=40). The clinical characteristics are presented in the Table. The 5-year OS among all the patients was 58%. Response at iCT was CR, partial remission (PR) and SD in 44%, 53% and 3% respectively. Of the four patients with SD at iCT, all four patients attained PR after completing six cycles of chemotherapy prior to ASCT. Kaplan-Meier estimates for OS are illustrated in the Figure and the 5-year OS was identical, 61%, for patients in CR and PR but 0%for patients with SD. Using log-rank comparisons patients achieving SD at iCT had a significantly worse survival compared to patients with CR or PR (p=.01).Discussion: This study is to our knowledge the first to analyze whether interim treatment response can predict long-term OS in "nodal" PTCL patients treated with CHOEP or CHOP consolidated by up-front ASCT. Patients with SD after three cycles of chemotherapy had a very poor survival compared to patients with PR or CR. This was an expected finding, and it confirms the importance of chemo-sensitive disease as a necessary pre-requisite in order to benefit from up-front high-dose consolidation. Using CT, there was no survival difference between patients with CR or PR at the first interim evaluation. A larger cohort might reveal further differences in subgroups, particularly if PET/CT based remission evaluation should confirm itself as a useful tool also in nodal PTCL. At present our study indicates that failure to achieve PR after three cycles of CHOEP/CHOP identifies patients at high risk of relapse/progression that are in need of a different therapeutic strategy than continuing with CHOEP/CHOP towards an ASCT. [Display omitted] [Display omitted] DisclosuresMannisto:Gilead: Other: Travel expenses; Celgene: Other: Travel expenses; Novartis: Other: Travel expenses; Amgen: Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses; Roche: Honoraria, Other: Travel expenses; Pfizer: Honoraria; SOBI: Honoraria.

Net antitumoral immunity and the predictive power of conventional prognosticators in diffuse large B-cell lymphoma.

8542 Background: Immunity represents a balance between immune-effectors and immune-checkpoints. In DLBCL, circulating lymphocyte:monocyte ratios are prognostic, implicating them as surrogate immune-effectors and immune-checkpoints within the tumor microenvironment (TME). Detailed assessment of blood would enable identification of the optimal TME immune-effector and monocyte/macrophage-checkpoints to assist sub-stratification of conventional prognosticators. Methods: Blood from 140 R-CHOP treated DLBCL patients in the NHL21 Australasian Leukaemia and Lymphoma Group trial were analysed. A circulating immune-effector:monocyte-checkpoint signature segregating interim-PET/CT positivity was identified. Intratumoral applicability was tested in two independent R-CHOP treated DLBCL cohorts, with cell-of-origin (COO) and international prognostic index (IPI) as co-variates. Results: Patient monocytes suppressed T-cell proliferation and NK-cell rituximab-ADCC. Both CD14+HLA-DRlo monocytoid-myeloid derived suppressor ...

Higher World Health Organization grades of follicular lymphoma correlate with better outcome in two Nordic Lymphoma Group trials of rituximab without chemotherapy

A common treatment for follicular lymphoma is rituximab monotherapy. To identify patients for whom this regimen is adequate as first-line therapy, we applied the World Health Organization (WHO) classification for grading follicular lymphoma in a prospective central pathology review of the biopsies of previously untreated patients in two randomized trials of rituximab without chemotherapy. In the first trial (n1 = 53), higher WHO grades correlated with longer time to next treatment, independently of clinical prognostic factors (p = 0.030); the finding was replicated in the second trial (n2 = 221; p = 0.019). Higher grades were associated with better treatment responses (p = 0.018). Furthermore, also grades externally confirmed by independent local pathologists correlated with time to next treatment (p = 0.048). Flow cytometry in a separate patient series showed that the intensity of CD20 increased with the malignant cell size (p < 0.00005). In conclusion, WHO grade 1 follicular lymphoma correlates with inferior outcome after rituximab monotherapy. WHO grading might provide a clinically useful tool for personalized therapy.

Monocytes Are Associated with Impaired T-Cell Immunity and Residual Interim-PET/CT Avidity After 4 Cycles of CHOP-R In Patients with High-Risk DLBCL,

Abstract 3673 Background:Impaired systemic immunity is an established risk factor for the development of B-cell lymphoma. However current understanding of the underlying mechanisms of cell-mediated immune evasion and how this varies during chemo-immunotherapy remains rudimentary. Studies have been hampered by retrospective analysis of heterogenous cohorts containing both new and relapsed patients, with a variety of indolent/aggressive histological subtypes, treated with different treatment regimens. Methods:We performed detailed analysis of circulating immune cell populations in 33 patients (mean age 53 years, range 31 – 69, F:M 11:22) with newly diagnosed high-risk diffuse large B-cell lymphoma (DLBCL) enrolled in a prospective multi-centre Australasian Leukaemia & Lymphoma Group trial. They received 3 cycles of CHOP-R-14, and then after a 4th cycle underwent an interim-PET/CT with centralized review performed at day 17–20 (to enable risk-stratification). Pegylated-GCSF was given on day 2 after each cycle. PET/CT metabolic response categorisation used the harmonisation criteria. 10/33 evaluable patients remained interim-PET/CT avid. Blood samples were taken pre-treatment and on day 21 post-cycle 4, and compared to 23 age/gender-matched healthy control subjects. Results were correlated with interim-PET/CT response status. Laboratory investigators were blinded to clinical results. Results:CD3+, CD8+ and CD4+ T-cells (p=00.21, p=0.005, p=0.0017) among patients with DLBCL were all reduced at pre-treatment compared to controls. After 4 cycles, CD4+ lymphocytes were reduced further (p=0.0003) whereas CD3+ and CD8+ counts remained unchanged. However, CD3+, CD8+ and CD4+ proliferative responses to CD28/CD3 stimulation were equivalent to healthy subjects at both time-points, indicating the absence of an intrinsic functional T-cell defect in response to stimulation. Nor were regulatory T-cells (CD4+CD25hiCD127−) or myeloid-derived suppressor cells (CD33+CD14−HLA-DR−) altered between time-points or as compared to healthy subjects.Circulating monocytes are key regulators of inflammation/ immunity. Absolute monocyte counts were strikingly elevated at pre-treatment compared to healthy subjects (p=0.007), and had a predominantly CD14+HLA-DR−/lo phenotype. Importantly, pre-treatment values for absolute monocytes (p=0.04), monocyte % (p=0.004), CD14+HLA-DR−/lo monocytes (p=0.03), mean fluorescent intensity of HLA-DR on CD14+ monocytes (p=0.025) and CD3+ T-cells (p=0.0374), were all associated with persistent interim-PET/CT avidity. However, all were independent of the international prognostic index (IPI) score, and IPI did not segregate with interim-PET/CT status. Post-cycle 4 monocyte % (p=0.048) and CD3+ T-cells (p= 0.029) were also related to interim-PET/CT avidity.The CD14+HLA-DR−/lo phenotype has been described as immunosuppressive (Lin, Blood 2011). Consistent with this, in-vitro depletion of monocytes from pre-treatment (p=0.03) and post-cycle 4 (p=0.04) samples enhanced CD4+ proliferation. By contrast, monocyte depletion from control samples did not influence CD4+ proliferation. Post-cycle 4 monocytes rose above pre-treatment levels (p=0.0301) as did fluorescent intensity of HLA-DR on CD14+ monocytes (p=0.0027). In line with the post-cycle 4 reduction of the CD14+HLA-DR−/lo ratio (p=0.0135), plasma arginase was reduced relative to pre-treatment (p=0.0035), suggesting that suppression was mediated in part through arginine metabolism. HLA-DR expression on monocytes at the interim time-point was up-regulated from pre-treatment (p=0.01), and accompanied by a relative increase in ex-vivo blood myeloid dendritic cells (BMDCs; p=0.044), suggesting the CD14+HLA-DR−/lo phenotype is associated with an impaired ability to differentiate into BMDCs in-vivo. Conclusion:Monocytes in DLBCL mediate immunosuppression of T-cells and both appear to be associated with interim-PET/CT avidity. Although the role of interim-PET/CT in DLBCL patients treated with chemo-immunotherapy is an area of considerable activity, the study of biological predictors of metabolic response has been relatively neglected. To the best of our knowledge, this is the first prospective study to find an association between cellular markers of inflammation/ immunity and interim-PET/CT avidity in a cohort of uniformly treated high-risk DLBCL patients. Disclosures:No relevant conflicts of interest to declare.

Sperm quality before treatment in patients with early stage Hodgkin's lymphoma enrolled in EORTC-GELA Lymphoma Group trials

Although widely recommended, cryopreservation of sperm is sometimes not performed for patients with Hodgkin's lymphoma because of presumed poor sperm quality related to the disease. We investigated sperm quality and factors determining it in untreated patients with early stage Hodgkin's lymphoma. Of 2362 males who participated in EORTC H6-H9 trials, 474 (20%) had data available. Sperm quality was defined according to World Health Organization guidelines. Determining factors were studied by logistic regression analysis. The median sperm concentration was 40x10(6)/mL (range, 0-345x10(6)/mL) and the median motility 50% (range, 0-90%). Sperm quality was good (concentration >or=20x10(6)/mL and motility >or=50%), intermediate (concentration >or=5x10(6)/mL) and poor (concentration <5x10(6)/mL but >0) in 41%, 49% and 7% of patients, respectively. Three percent of the patients were azoospermic. No relation was found between sperm quality and age or clinical stage of the Hodgkin's lymphoma, but B-symptoms and elevated erythrocyte sedimentation rate predicted poor sperm quality. The odds ratios for the association of poor sperm quality with the variables examined were: presence of B-symptoms, 2.77 (95% CI, 1.50-5.12; p=0.001); erythrocyte sedimentation rate of 50 mm/h or greater, 2.35 (95% CI, 1.24-4.43; p=0.009); fever, 3.22 (95% CI, 1.41-7.33; p=0.005), and night sweats, 3.78 (95% CI, 1.97-7.26; p<0.001). There was no relation between sperm quality and pre-treatment follicle stimulating hormone level. In this large study of males with Hodgkin's lymphoma, 90% had good or intermediate sperm quality. Three percent were azoospermic. There was an association between sperm quality and the presence or absence of B-symptoms, in particular fever and night sweats. With modern fertilization techniques, in most patients with early-stage Hodgkin's lymphoma sperm quality before treatment is good enough for future fatherhood.

Selection of patients for randomised trials: a study based on the MACOP‐B vs CHOP in NHL study

Selection of patients for a clinical trial is affected by awareness of the existence of the trial, interest in the study question and clinical practices and views of the clinicians. To investigate the selectivity that may have occurred at Peter MacCallum Cancer Institute (PMCI) during the ANZ Lymphoma Group trial of MACOP-B vs CHOP in non-Hodgkin's lymphoma (NHL). NHL patients at PMCI in the study period were assessed against the trial's eligibility criteria. Comparisons were made between eligible (except for consent) non-trial patients and all patients actually randomised into the trial. Of 497 patients presenting during the trial period, 320 (64%) did not meet the specified eligibility criteria, 102 (21%) were unsuitable on other grounds (age and medical) and 75 (15%) were eligible. Of those eligible, 43 (57%) were entered into the trial and 32 (43%) were not. Four non-trial patients had inappropriate application of eligibility criteria and 13 unknown reason. Eligible non-trial patients were similar to trial patients in most patient and tumour characteristics and overall survival. Significantly more non-trial patients had higher stage disease (p = 0.02). More non-trial patients had lower grade histology, but this was not significant. Physician selectivity occurred with respect to patient entry, but trial and non-trial patients were similar in most characteristics. Eligibility criteria should specify that patients can withstand all trial drugs and patient availability for treatment and follow-up. PMCI trial accural could have been up to 33% greater. These results suggest the trial accrual period could have been 25% shorter. Patient entry into this trial by PMCI clinicians compared favourably with other centres.