Scotland And Newcastle Lymphoma Group Research Articles

HLA-A*02:01 Is Associated with Inferior Overall Survival in EBV-Associated Classical Hodgkin Lymphoma

AbstractAbstract 1526 Introduction:The risk of developing Epstein-Barr Virus (EBV)-associated classical Hodgkin Lymphoma (cHL) shows an association with class I human leukocyte antigen (HLA) genes. HLA-A*01:01 is associated with increased risk of EBV-associated cHL whereas HLA-A*02:01 is associated with decreased risk. (Hjalgrim et. al, PNAS, 2010).The effects of these two alleles are independent of each other and the effect associated with each allele is additive i.e., possession of two HLA-A*01:01 alleles is associated with greater risk than one allele. HLA-A genes are involved in cytotoxic T cell (CTL) responses to exogenous antigens, and these data suggest that EBV-specific CTL responses are important in the pathogenesis of EBV-associated cHL. This study aimed to determine if HLA-A*01:01 and A*02:01 alleles are a factor in determining clinical outcome in EBV-associated cHL. Methods:Patients with cHL were selected from two previous studies: the Scotland and Newcastle Epidemiological Study of Hodgkin’s disease (SNEHD) (Jarrett et. al, Blood, 2005) and the “Investigation of the pathogenesis of Hodgkin lymphoma” (IPHL), an ongoing collection of patients principally from the West of Scotland. Both studies have ethical approval. Clinical follow-up data were obtained through clinical records, liaison with treating physicians or the Scotland and Newcastle Lymphoma Group (SNLG) database. Clinical treatment decisions were made by individual physicians. Cases were selected on the basis of availability of tumour EBV status, a suitable sample for HLA typing and clinical follow-up data and included 257 cases from the SNEHD study and 128 from the IPHL. HLA genotyping was performed to an intermediate resolution using allele-specific PCR (Gen-probe) and subsequent bead-based sequence specific oligonucleotide (SSO) assay (Luminex). Allele assignment was performed using Quicktype for Lifematch software (Gen-probe). Results were analysed for all cases, EBV-associated cases only, and EBV-negative cases only. Overall survival (OS) and Event-free survival (EFS) were analysed by number of HLA-A*01:01 alleles, number of HLA-A*02:01 alleles, and by the presence or absence of HLA-A*01:01 or HLA-A*02:01. Statistical analyses used Kaplan-Meier survival and Cox-regression analyses, adjusting for histological subtype, clinical stage, age and sex, and were implemented using SPSS v.19. Results:385 cases diagnosed between 1993 and 2008 were included in the analysis. 55.8% of cases were male and 128 (33.2%) had EBV-associated disease. Median follow up was 74 months (range 0–220 months). Clinical stage was available for 289 patients: stage 1 (17.9%); stage 2 (41.8%); stage 3 (22.5%); and stage 4 (17.6%). In the analysis of all cases there were no significant differences in OS and EFS by number or presence of HLA-A*02:01 and A*01:01 alleles. EBV-associated cHL cases demonstrated inferior OS with the presence of HLA-A*02:01 (p=0.04) (figure). This was corroborated by the demonstration of inferior OS with increasing number of HLA -A*02:01 alleles present (p=0.016). Increasing number of HLA -A*02:01 alleles was also associated with inferior EFS but differences were not statistically significant. HLA-A*01:01 was not associated with OS or EFS in EBV-associated cHL. There was no significant association between histological subtype and OS or EFS. When clinical stage, age, and sex were included in the Cox-regression analysis of survival in EBV-associated cases, only age (p<0.001) was significant; presence of an HLA-A*02:01 allele approached statistical significance (p =0.062). Conclusions:In this study the HLA-A*02:01 allele was associated with inferior survival in EBV-associated cHL. As HLA-A*02:01 is associated with a decreased risk of developing EBV-associated cHL, we hypothesise that cHL arising in this 'protected' group is associated with greater biological or immunological dysfunction, resulting in poorer outcome. HLA-A genotype may be helpful in identifying patients who have inferior outcomes using standard therapy, and who may benefit from novel or cellular therapies. Larger studies within the context of clinical trials are required to extend these findings. In addition, this study supports the importance of stratifying cHL cases by EBV-status in clinical studies. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

A Novel Bayesian Prognostic Index for Diffuse Large B-Cell Lymphoma: A New Powerful Tool for Prediction of Outcome.

Abstract 1666Poster Board I-692<>Diffuse large B-cell lymphoma (DLBCL) is primarily treated with Rituximab – CHOP immunochemotherapy with varying results. Improved prediction at diagnosis of outcome for an individual patient remains a key goal in DLBCL management. This would allow the selection of patients who could benefit from new therapies. A large amount of data on new immunohistochemical and molecular factors has been collected in the last decade, but the International Prognostic Index (IPI) and Revised IPI are still mostly used for identification of prognostic groups. Both of these indices have important limitations. They rely on a small number of dichotomised predictive variables and patients are assigned to one of a small number of risk groups rather than giving a direct prediction, such as a predictive survival probability or a predictive median lifetime, on a continuous scale for each patient. We have developed a new prognostic index based on Bayesian survival modelling. This has allowed an increase in the number of predictive variables and removal of the need to dichotomise them. Importantly, the new index can give predictions for patients where not all of the predictive variables are observed. It can easily be modified in the future by the addition of new variables, e.g. molecular factors or new treatment regimens. The index was developed using data on a population-based cohort of DLBCL patients prospectively registered with the Scotland and Newcastle Lymphoma Group (SNLG) between 1990 and 2003. The complete data on patients' outcomes were available for 1863 from 2025 registered patients and of this cohort 1391 patients were treated with anthracycline-based chemotherapy and the new index is based on this group. Bayesian statistical inference was used with a three-component Weibull mixture model in which both the hazard multiplier and the component membership probabilities depend on the predictive covariates. The three mixture components correspond to the following three groups: patients who will suffer from primary progressive disease or relapse within one year from diagnosis; patients who will relapse at a later point; those who will have no relapse. A novel method of modelling to deal with cases with missing covariates was used. Both time to first relapse (TFR) and overall survival (OS) were modelled. The following factors were included in the current version of the model: age, sex, performance status by ECOG, clinical stage, B-symptoms, extranodal and bone marrow involvement, Hb, WBC, lactate dehydrogenase, albumin, alkaline phosphatase and urea. The new index is available in the form of a simple computer program and can predict the outcome of patients as: a predicted TFR and OS or a probability of belonging to one of the three groups. In order to check the index, the whole cohort of patients was separated randomly with stratification by IPI into a training-prediction set (2/3 of patients) and a validation-observed set (1/3 of patients). Fig 1 shows the Kaplan-Meyer plots for TRF and OS for both sets. The index was successfully validated. Our new Bayesian prognostic index for DLBCL gives more reliable predictions at diagnosis for individual patients. In future the model can be modified for new treatment regimens or factors. Presently our group is investigating this issue for patients treated with CHOP-R. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Combination chemotherapy followed by autologous stem cell transplant for enteropathy‐associated T‐cell lymphoma

I read with interest the short report by Bishton and Haynes (2006), regarding combination chemotherapy and autologous stem cell transplantation for enteropathy-associated T-cell lymphoma (EATL). However, I believe the comment ‘use of peripheral blood stem cell transplantation in EATL has been reported anecdotally by Lymphoma Groups in unpublished findings’ does not accurately reflect the efforts of other workers in the field. On behalf of the Scotland and Newcastle Lymphoma Group (SNLG), I carried out a comprehensive review of all patients that presented with EATL/intestinal T-cell lymphoma (ITCL) in our population of 8 million people over a 5-year period (1994–1999). There were 55 such patients and with conventional treatment [mainly CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin, prednisone)-based therapy] the median survival was 7 months. Consequently, in 1999 the SNLG changed its policy for this rare group of patients and piloted an aggressive primary therapy approach using Ifosfamide, etoposide (VP16) and Epirubicin (IVE) alternating with intermediate dose Methotrexate (MTX) and consolidated with an autologous bone marrow transplant (ABMT). Data on the first eight patients to proceed to autologous transplantation were presented at the 8th International Conference on Malignant Lymphoma in Lugano in June 2002 (Lennard et al, 2002). Following the presentation and publication of the proceedings of the meeting, colleagues around the UK and in continental Europe have used the regimen, and a register of patients with ITCL who have been treated with IVE/MTX ± ABMT has been compiled. Dr Haynes has kindly contributed two of his cases to this register, which now numbers 17 patients. Subsequently, a national phase II protocol with two major aims has been developed. To register as many UK cases of ITCL as possible with review of histology and collection of treatment and outcome data. To evaluate the efficacy and toxicity of IVE/MTX/ABMT in patients considered eligible for intensive chemotherapy. The protocol has been peer reviewed and has Cancer Research UK support. The study is now proceeding through the Central Office for Research Ethics Committees and should be open in 2007. It will be supported by the National Cancer Research Network and administered by the Lymphoma Trials office in London. The short report by Bishton and Haynes (2006) confirms my conclusions from 2002: That aggressive treatment is feasible in some patients with ITCL. IVE/MTX/ABMT-treated patients have superior outcomes to conventionally treated patients. It is to be hoped that all haematologists in the UK will support the forthcoming study. The long-term goal should be to transform the outcome for these rare patients in the same way that, by national and international collaboration, we have changed the prognosis for patients with Burkitt Lymphoma in the last decade.

Survival in Young Patients (Less than 40 Years) with Follicular Lymphoma: A population Based Study by the Scotland and Newcastle Lymphoma Group

We have examined in a population-based observational study the survival of young patients (less than 40 years) with follicular lymphoma (FL) treated conventionally and followed for up to 17 years (minimum 10, median 13 years). Data were derived from the Scotland and Newcastle Lymphoma Group (SNLG) database from 1986. Histology of all available cases was reviewed to ensure that patients met the modern criteria for diagnosis of FL. Of 55 patients identified from the database, 46 were confirmed to have follicular lymphoma. There were 25 males and 21 females, median age 34 years (range 16-39). Thirty-four patients presented with advanced stage disease (Stages III and IV). The majority of patients received initial treatment with chemotherapy, though 7 had surgery (biopsy or splenectomy) alone and 7 radiotherapy alone. All 12 patients with early stage disease showed a complete response (CR) with initial therapy; 6 relapsed and 2 have died (1 of transformation to high grade non-Hodgkin's lymphoma). Overall survival of patients presenting with stage IIIA disease was 68% at 10 years, and 69% for patients in stages IIIB and IV. The SNLG prognostic index for low grade non-Hodgkin's lymphoma was predictive for overall survival. The 71% overall survival in this patient cohort at 10 years provides a baseline for comparison with the results of a more aggressive approach to treatment.

Extranodal follicular lymphoma: a clinicopathological and genetic analysis of 15 cases arising at non-cutaneous extranodal sites.

Recent studies of primary cutaneous follicular lymphoma suggest that it represents a clinicopathological entity distinct from nodal follicular lymphoma (FL). The purpose of this study was to determine if FL arising at other extranodal sites is more closely related to FL occurring in the skin or in lymph nodes. Fifteen cases of non-cutaneous extranodal follicular lymphoma (ENFL) were identified from the Scotland and Newcastle Lymphoma Group (SNLG) database. All were stage 1E at presentation and involved the tonsil (n = 3), palate (n = 3), skeletal muscle (n = 2), ileum (n = 2), duodenum (n = 1), stomach (n = 1), thyroid gland (n = 1), submandibular gland (n = 1) and fallopian tube (n = 1). Polymerase chain reaction for t(14;18) using primers to the major breakpoint cluster region was performed on 14 cases of ENFL and the incidence of the translocation compared with that found in 16 cases of stage 1 nodal FL. Clinical and follow-up data were obtained from the SNLG database for the 15 cases of ENFL and 87 cases of stage 1 nodal FL, and a comparison of outcomes made. Only 2/14 cases of ENFL had detectable t(14;18) compared with 9/16 stage 1 nodal FL (P < 0.01). Freedom from progression and disease-specific survival was similar for the 15 cases of ENFL and 87 cases of stage 1 nodal FL. However, 13/15 patients with ENFL were disease free at the end of follow-up compared with 49/87 stage 1 nodal FL (P < 0.02). The low incidence of t(14;18) and favourable outcome encountered in ENFL in this study is similar to that previously found for primary cutaneous FL. These results support the concept of a subtype of FL lacking t(14;18) involving the major breakpoint cluster region, and with a propensity to arise at extranodal sites. Despite a high relapse rate, patients with ENFL are more likely to achieve complete remission and may ultimately have a more favourable long-term prognosis than those with equivalent nodal disease.

A population-based study of intensive multi-agent chemotherapy with or without autotransplant for the highest risk Hodgkin's disease patients identified by the Scotland and Newcastle Lymphoma Group (SNLG) prognostic index. A Scotland and Newcastle Lymphoma Group study (SNLG HD III)

The aim of the study was to identify all patients with poor risk Hodgkin's disease (HD) using a numerical prognostic index in a defined population and to recruit them into a trial of intensive chemotherapy prednisolone, vinblastine, doxorubicin, chlorambucil, etoposide, bleomycin, vincristine, procarbazine (PVACE-BOP)×3+autotransplant (Arm A) versus PVACE-BOP×5 (Arm B) in first remission. In 10 years, the Scotland and Newcastle Lymphoma Group (SNLG) registered 930 patients with HD of whom 178 (19%) were identified as ‘poor risk’ by the SNLG index and were aged 16–59 years. 126/178 (71%) entered the study. Of the 120 confirmed poor risk HD cases, all completed PVACE-BOP×3 with a 93% Complete Response/unconfirmed Complete Response (CR/CRu) rate. Only 65/107 in CR accepted the randomisation. With a median follow-up of 6 years, both arms of the trial have a similar time to treatment failure (TTF) (Arm A 79%±11 versus 85%±7 Arm B, P=0.35). Advanced stage ‘good risk’ patients not included in the trial receiving standard therapy with CLVPP or ABVD had a 75% 5-year survival. The study demonstrates that PVACE-BOP therapy in the poorest risk group (58% had an IPI⩾3) produces excellent CR rates (93%) and overall survival with minimal toxicity, and that the substitution of autotransplant in first CR does not improve outcome. The use of the objective SNLG index accurately helped in the selection of the poorest risk group in this population study. The placing of a randomised control trial within the context of a population-based study of HD enhances the validity of the outcome.

Evidence for a seasonal variation in the presentation of Hodgkins disease.

An analysis by month of diagnosis was made of 1359 cases of Hodgkins disease (HD) on the Scotland and Newcastle Lymphoma Group (SNLG) registry 1979-1992 to look for evidence of seasonality. A March peak was evident when all cases were analysed (p < 0.01). The histological subtypes nodular sclerosing (NS) and mixed cellularity (MC) showed a similar pattern (p < 0.05) while lymphocyte depleted (LD) and lymphocyte predominant (LP) had no demonstrable seasonal variation. In a breakdown by age and sex there was evidence of seasonality in both sexes but only under the age of 40. This provides further evidence for the heterogeneity of HD and supports the hypothesis that different factors are involved in the aetiology of this condition in younger compared to older patients.

Autologous transplantation in poor risk Hodgkin's disease using high dose melphalan/etoposide conditioning with non-cryopreserved marrow rescue

This study aimed to assess the safety and efficacy of using high dose melphalan and etoposide followed by autologous, non-cryopreserved marrow rescue in advanced Hodgkin's disease (HD). Seventeen patients with poor risk Hodgkin's disease from a single centre underwent autologous bone marrow transplant (ABMT) using high dose melphalan and etopside conditioning. Two patients had primary progressive resistant disease (PD), two were in fourth relapse, six in second or third complete remission (CR), one patient had good partial response (GPR) (> 75% reduction in initial bulk) to primary therapy and six were in first complete remission. The patients transplanted in first CR all has a Scotland and Newcastle Lymphoma Group (SNLG) Prognostic Index (Proctor et al., 1991) which indicated they were in a poor risk prognostic group. Melphalan and etoposide both have a short half life enabling ABMT to be accomplished using unmanipulated marrow stored at 4 degrees C. The marrow was returned to the patient within 56 h of harvest. Complete haematological reconstitution occurred in 16/17 patients, the rate of engraftment reflecting the amount of previous chemotherapy. One patient died of progressive Hodgkin's disease before full engraftment could occur. In patients autografted in first remission, the median number of days with neutropenia (< 0.5 x 10(9) l-1 neutrophils) was 19 (range 9-33) and, in those in subsequent remission, 27 days (range 18-36). The median number of days to 50 x 10(9) l-1 platelets in the same groups were 29 (21-80) and 50 (41-74) respectively. The number of days in hospital post transplant in both groups was similar; median 22 (15-27) and 23 (17-37) respectively. There were no procedural deaths and none of the patients transplanted in first, second or third CR have relapsed (median follow up 21 months). The two patients transplanted with progressive disease showed only temporary responses. The two patients transplanted in fourth relapse went into CR; one is still alive and in CR 15 months post transplant, but the other relapsed 18 months post transplant. This form of intensification therapy with marrow rescue has been shown to be effective and of low toxicity and now forms part of a randomised controlled trial in poor risk Hodgkin's patients as identified by the SNLG index (Proctor et al., 1992).

A numerical prognostic index for clinical use in identification of poor-risk patients with Hodgkin's disease at diagnosis. The Scotland and Newcastle Lymphoma Group (SNLG) Therapy Working Party.

The aim of this study was to assess the feasibility of using objective data obtained at the time of diagnosis of Hodgkin's disease to predict those patients who were likely to die of progressive disease within four years. Ninety-two consecutive patients from one centre (Newcastle upon Tyne) were used to construct a numerical index based on disease stage (Ann Arbor), age, haemoglobin and absolute lymphocyte count. Weight was assigned according to a predictive value from univariate and multivariate analyses based on survival. The index produced was then validated on a separate patient set (455) from other centres within the Scotland and Newcastle Lymphoma Group (SNLG) on whom the same prospective information was available. The index produced provided a useful separation of those patients destined to die of disease. In 101 patients with index > 0.5, 62 (61.4%) were dead at four years, whereas with index < 0.5, 61 (18%) of 336 patients were dead at four years. The index includes Ann Arbor stage but possesses additional practical prognostic value which allows identification of patients with early stage destined to die of disease. Of 149 patients with Stage IA and IIA disease 15 patients had index > 0.5, and 10 (60%) have died, whereas the remaining patients had survival of 90% and 85% respectively. This numerical index has now been strengthened by an added factor for bulk disease > 10 cms and in the SNLG it has replaced Ann Arbor staging for selection of patients requiring aggressive therapy. A randomized study of chemotherapy versus chemotherapy plus autotransplant in first remission using high dose melphalan and VP16 is currently in progress.

The identification of discrete prognostic groups in low grade non-Hodgkin's lymphoma

A prognostic model was developed by examination of the prospectively recorded presentation characteristics of patients presenting with low grade non-Hodgkin's lymphomas (LGL). A geographically distinct group (Edinburgh and Borders) was excluded in order to test the validity of the model based on the rest of the Scotland and Newcastle Lymphoma Group (SNLG) population. Between 1979 and 1987 506 patients presented with low grade lymphoma according to Working Formulation definition within one of each of the three main pathology categories. The median available follow-up was 47 months. In a multivariate analysis performance status, age, stage, gender and haemoglobin all contributed separately. 25% of all patients had relatively good prognosis with a median survival not reached and 84% alive at 5 years. Conversely for the worst prognostic group of 25% of patients the median survival is 18 months with only 26% surviving at 5 years. Finally for the intermediate group of 50% of all patients, median survival is 69 months with 58% alive at 5 years. These striking prognostic separations are shown also to be valid in sub-group analysis. Thus young patients within any pathology subgroup have been identified with bad prognostic lymphoma for whom novel strategies in therapy should be devised.

A numerical prognostic index for clinical use in identification of poor-risk patients with Hodgkin's disease at diagnosis

The aim of this study was to assess the feasibility of using objective data obtained at diagnosis of Hodgkin's disease to predict those patients who were likely to die of progressive disease within 4 years of diagnosis. 92 consecutive patients from one centre (Newcastle upon Tyne) were used to construct a numerical index based on disease stage (Ann Arbor), age, haemoglobin and absolute lymphocyte count. Weight was assigned according to a predictive value in univariate and multivariate analyses based on survival. The index produced was then validated on a separate patient set (455) from other centres within the Scotland and Newcastle Lymphoma Group (SNLG) on whom the same prospective information was available. The index produced provided a useful separation of those patients destined to die of disease. Of 101 patients with index higher than 0.5, 62 (61.4%) were dead at 4 years, whereas with index lower than 0.5, 61 (18%) of 336 patients were dead at 4 years. The index includes Ann Arbor stage but possesses additional practical prognostic value which allows identification of patients with early stage destined to die of disease. Of 149 patients with stage IA and IIA disease 15 patients had index higher than 0.5, and 10 (60%) have died, whereas the remaining patients had survival of 90% and 85% respectively. This numerical index is applicable to all patients at diagnosis and in the SNLG population gives better predictive survival at 4 years than stage alone, and provides a basis for selecting patients for more aggressive therapy.