ALBERT

Description: The SHIELD program for Hodgkin lymphoma in patients 60 years of age or older, prospectively evaluated clinical features and outcome in a large patient cohort (n = 175). The central element was a phase 2 study of VEPEMB chemotherapy (n = 103, median age 73 years) incorporating comorbidity assessment. A total of 72 other patients were treated off-study but registered prospectively and treated concurrently with: ABVD (n = 35); CLVPP (n = 19), or other (n = 18). Of VEPEMB patients, 31 had early-stage disease (stage 1A/2A) and received VEPEMB 3 times plus radiotherapy. Median follow-up was 36 months. Complete remission (CR) rate (intention-to-treat) was 74% and 3-year overall survival (OS) and progression-free survival (PFS) were 81% and 74%, respectively. A total of 72 patients had advanced-stage disease (stage 1B/2B/3 or 4) and received VEPEMB 6 times. CR rate was 61% with 3-year OS and PFS of 66% and 58%, respectively. Of patients achieving CR, 13% with early-stage and 5% with advanced-stage disease progressed. Overall treatment-related mortality was 7%. In patients treated with curative intent with VEPEMB, ABVD, and CLVPP (n = 157), CR linked to several factors in univariate analysis. In a Cox regression model only, obtaining CR remained significant for OS and CR plus comorbidity and age for PFS. RS-EBV status had no significant effect on outcome.

Description: SGN-30 is a monoclonal antibody directed against the CD30 antigen expressed on some hematologic malignancies. Based on encouraging phase I data, a multicenter phase II study was conducted treating patients with refractory or recurrent CD30-positive ALCL with an ECOG performance status of ≤ 2. Thirty-nine patients (24M, 15F) with ALCL were enrolled, with a median age of 57 (range 23–82) and a median of 3 prior therapies (range 2–5). Nine patients had previously received a stem cell transplant. Eighty-five percent of tumors were negative for ALK, a poor prognostic factor. SGN-30 was administred at 6 mg/kg/wk (90 minute infusion, premedications were not required) for 6 consecutive weeks. After 24 patients were enrolled, the dose was escalated to 12 mg/kg/wk in subsequent patients. (Patients with stable disease or objective response were eligible to receive additional cycles of SGN-30. Five patients received ≥ 2 cycles of SGN-30.) Response assessments, as determined by CT scans, were performed 2 weeks after the last infusion. Best response is shown below: CR PR SD PD Pending Eval ORR *Both CRs have ongoing durations of 〉365 days; both patients received additional cycles of SGN-30. **PRs had durations of 27, 53, 139 and 167 days; two additional patients have ongoing durations of 86+ and 25+ days. ***Three SDs have ongoing durations of 96+, 365+, and 365+ days. Two additional patients had SD for 71 and 174 days. 2* 6** 5*** 24 2 21% Three drug-related toxicities ≥ Grade 3 were reported (each was considered possibly related to SGN-30): 1) lymphopenia, 2) catheter related infection and 3) urticaria. No other significant hematologic or biochemical toxicities have been observed. There was one definitely related serious adverse event (Grade 2) in a patient who experienced a transient exacerbation of his cutaneous lesions after 2 doses of SGN-30 but achieved a partial response after continuing on study. This phase II study represents one of the largest prospectively designed trials in relapsed/refractory ALCL and demonstrates good tolerability and clinically meaningful antitumor activity of SGN-30, especially in ALK negative patients who have a particularly poor prognosis.

Description: Abstract 1666 Poster 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. Fig1 Kaplan-Meyer plots for TFR and OS in training-prediction (TFRP and OSP) and validation-observed set (TFRO and OSO). Fig1. Kaplan-Meyer plots for TFR and OS in training-prediction (TFRP and OSP) and validation-observed set (TFRO and OSO). Disclosures No relevant conflicts of interest to declare.

Description: Background: A large phase III randomised control trial (Marcus et al, Blood2005, 105;4) has demonstrated that rituximab plus CVP compared with CVP alone improved time to treatment failure (p

Description: Enteropathy associated T-cell lymphoma (EATL) is a rare disease with dismal prognosis. At present there are no standardised diagnostic or treatment protocols. The SNLG collected 5yrs of prospective data which uniquely enables us to describe the disease in a population-based setting. Additionally, we introduce results from a novel approach with aggressive chemotherapy (CT) and autologous stem cell transplantation (ASCT). From 1994 – 1998 all pts diagnosed with lymphoma in Scotland and the Northern region of England were prospectively registered. Pts with a diagnosis of EATL were evaluated for clinical features, treatment and outcome. The novel regimen was piloted from 1997 for new pts eligible for intensive treatment. This therapy delivers one cycle of CHOP, followed by 3 courses of IVE (ifosfamide, etoposide, epirubicin), alternating with intermediate dose methotrexate (MTX). Stem cells are harvested after IVE and complete remissions (CR) are consolidated with myeloablative ASCT. During the study period, 4542 pts were diagnosed with non-Hodgkin-lymphoma and of these 54 pts (1.2%) had features of EATL. In the population of 7.6 million, this equates to an overall incidence of 0.14/100,000 per yr. The median age at diagnosis was 57 yrs, 61% of pts were male. 40% of pts presented with Lugano clinical stage (CS) IIE (serosal penetration involving adjacent organs and tissues), 17% CS IV (disseminated extranodal involvement or supradiaphragmatic nodal involvement), 15% CS I (confined to GI-tract), 15% CS II1 (local abdominal involvement) and 12% CS II2 (distant abdominal involvement). Two pts had bone marrow involvement. Diagnosis of EATL was made at laparotomy in 91% of pts. Tumour was arising from the small bowel in 96% of pts; in one case involved the duodenum and in another the iliocaecal region. Pain was the most common presenting symptom (81%), followed by weight loss, visceral perforation, nausea/vomiting, bowel upset and subacute obstruction. Symptoms were present less than a month before diagnosis in 33% of pts and between 1–6 months in 55%. 92% of pts had co-existing coeliac disease (diagnosed prior to diagnosis of EATL in 35% of pts and co-incidently in 58%). 30 pts (56%) were treated with surgery and CT, 19 pts (35%) with surgery alone and 5 pts (9%) with CT alone. Of those pts treated with CT the majority (31/35) received CHOP-like regimens. There were no statistically significant differences between treatment groups with the exception of higher number of elderly pts treated with surgery alone. 44 pts died, mostly due to lymphoma or complications. For all pts, median progression free survival (PFS) was 3.4 months and overall survival (OS) 7 months. 5yr PFS and OS for pts treated with CHOP-like CT was 20% and 22%, respectively and no pts treated with surgery alone survived. 18 pts were subsequently treated with the new regimen. The median age was 52.5 yrs, 67% of pts were male, 39% presented with Lugano CS II1, 22% CS I, 22% CS IV, 11% CS IIE, 6% CS II2+E. The bone marrow was involved in one pt. Site of disease was small bowel in 83% of pts and two patients had involvement of stomach and duodenum and one of small bowel and colon. In all except one pt the diagnosis was made at laparotomy. 12 pts (67%) completed all planned treatment, 3 pts had progressing disease during treatment, two other did not received ASCT due to poor general condition and one pt declined further treatment. Most common severe toxicities were pancytopenia, infection, nausea/vomiting and obstruction/perforation. Treatment results were compared with historical control group treated with CHOP-like CT. There was no difference between the groups according to age, sex and features at presentation. Compared to pts treated with CHOP-like CT, those in the IVE/MTX group had improved CR at final evaluation (42% vs 72%), 5yr PFS (20% vs 56%; p=0.008) and 5yr OS (22% vs 67%; p=0.001). Additionally, in the IVE/MTX group fewer patients died than in the CHOP-like CT group (33% vs 81%; p=0.002). There were no treatment related deaths. In a population-based study of EATL we describe the natural history of the disease in the context of current treatments. We propose a new protocol with significantly improved outcome and acceptable toxicities. In conclusion, pts with EATL should be treated with systemic CT and where feasible an aggressive treatment like IVE/MTX – ASCT. We recommend patients should be entered into national studies such as (NCRI 1418) to evaluate this approach further.

Description: Abstract 2727 Introduction: Chronic lymphocytic leukemia (CLL) is a B-cell lymphoproliferative disease which follows a heterogeneous clinical course. Although the two staging systems, based on clinical parameters, have been effective in stratifying patients into different risk groups, they both fail to identify the early stage patients who will progress rapidly and therefore benefit from an early or more intensive therapy. This is important as most patients present at an early stage of disease. A number of biological markers have been identified to date to aid prediction. These include the IgVH mutational status, CD38 and Zap-70 expression. Although these parameters provide fairly accurate prognostic information, neither marker alone or combined can identify either Binet stage A patients who are going to progress, or the stage B or C patients who may require alternative treatment at the onset. It is therefore important to identify new predictive markers which may provide additional or better prognostic information. The microRNAs are endogenous, non-coding RNAs that play key regulatory roles in a diverse range of pathways, including development, cell proliferation, differentiation and apoptosis. These 18–24 nucleotide single-stranded RNAs are involved in post-transcriptional gene regulation, by binding to complimentary sites in the 3' UTR of messenger RNAs (mRNA), usually resulting in gene silencing. A number of findings early on in the history of microRNAs suggested their potential role in human cancer, and in 2006 Calin et al directly associated de-regulated expression of miR-15 and -16 in the development of CLL. Since this time, a number of microRNAs have been implicated in CLL lymphomagenesis, including miR-92, which is a mature member of the miR-17-92 cluster. The miR-17-92 is located on chromosome 13q31 and shown to act in an oncogenic capacity (oncomiR-1). With respect to CLL, although the expression levels of mature microRNAs of the miR-17-92 cluster have been assessed, the role of such expression in predicting disease outcome has never been examined. Methods and Results: We used qRT-PCR to assess the expression levels of mature microRNAs of the miR-17-92 cluster, relative to normal CD19+ B-cells. We report that, despite being transcribed from the same parental cluster, the expression levels of all mature microRNAs vary, with miR-17-5p and -18 showing significantly higher levels than the other members of the cluster (p =

Description: It is now well known that the initial phase of graft-versus-host disease (GVHD) involves cytokine release during preconditioning of the recipient of an allogeneic bone marrow transplant (BMT). Tumor necrosis factor  (TNF), in particular, has been implicated in pathological damage and is released pretransplant due to irradiation and cytotoxic preconditioning regimens. Interleukin-10 (IL-10), a natural immunosuppressant of TNF , may be involved in downregulation of these responses, which may be an individual patient-specific effect. In this study, we determined the genotype for polymorphisms associated with TNF and IL-10 in 80 potential allo-BMT recipients and correlated the genotype with the severity of GVHD in 49 patients for whom clinical data relating to GVHD was available. The widely studied TNF −308 polymorphism does not show any significant associations, but the d3 homozygous allele of the TNFd microsatellite is preferentially associated with grade III/IV GVHD (7 of 11 patients) compared with its occurrence in 8 of 38 patients with grade 0/II GVHD (P = .006). Alleles of the IL-10 −1064 promoter region microsatellite polymorphism that possess greater numbers of dinucleotide (CA) repeats also significantly associate with more severe GVHD. This region has been demonstrated to be important in the regulation of the IL-10 promoter. Eighteen of 38 patients with grade 0-II GVHD possessed alleles with greater numbers (12 or more) of dinucleotide repeats, compared with 9 of 11 cases with grade III-IV GVHD (P 〈 .02). Of the 38 patients with grade 0-II GVHD, 3 of 38 had a both TNFd3/d3 and IL-10 (12-15) genotype, compared with 6 of 11 patients with grade III-IV GVHD (P 〈 .001). There was no association of either the TNFd or IL-10 microsatellite polymorphisms with mortality (P = .43 and .51, respectively). Our results suggest that patient cytokine gene polymorphism genotypes may influence GVHD outcome by affecting cytokine activation during the pretransplant conditioning regimens, and these results are the first to suggest a genetic predisposition to this important transplant-related complication.

Description: Chromosomal abnormalities are increasingly used to risk stratify adults with acute lymphoblastic leukemia. Published data describing the age-specific incidence of chromosomal abnormalities and their prognostic relevance are largely derived from clinical trials. Trials frequently have age restrictions and low recruitment rates. Thus we investigated these factors in a population-based cohort of 349 patients diagnosed during the course of 19 years in the northern part of England. The incidence of most chromosomal abnormalities varied significantly with age. The incidence of t(9;22)(q34;q11) increased in each successive decade, up to 24% among 40- to 49-year-old subjects. Thereafter the incidence reached a plateau. t(4;11)(q21;q23) and t(1;19)(q23;p13) were a rare occurrence among patients older than 60 years of age. In contrast, the frequency of t(8;14)(q24;q32) and t(14;18)(q32;q21) increased with age. High hyperdiploidy occurred in 13% of patients younger than 20 years of age but in only 5% of older patients. The incidence of low hypodiploidy/near-triploidy and complex karyotype increased with age from 4% (15-29 years) to 16% (≥ 60 years). Overall survival varied significantly by age and cytogenetics. Older patients and those with t(9;22), t(4;11), low hypodiploidy/near-triploidy, or complex karyotype had a significantly inferior outcome. These population-based results demonstrate the cytogenetic heterogeneity of adult acute lymphoblastic leukemia. These data will inform the delivery of routine clinical services and the design of new age-focused clinical trials.

Description: The aim of this study was to evaluate the influence of duration of first remission (FR) on overall survival (OS) of patients (pts) with DLBCL in a population-based setting, and further to assess the possible differences in clinical features or IPI between pts with different duration of FR. We analyzed all DLBCL pts registered on the database of the Scotland and Newcastle Lymphoma Group. Further inclusion criteria were age 〉18 yrs and defined clinical stage (CS) at presentation, treatment with anthracycline based chemotherapy, and no immunotherapy or stem cell transplantation in first line treatment. According to duration of FR four groups were defined; “refractory”-pts who did not respond to first line treatment or relapsed within 9 months from diagnosis, “early relapse”-pts who relapsed within 9–18 months from diagnosis, “late relapse”-pts who relapsed after 18 months from diagnosis and “no relapse”-pts who did not relapse. From 1990 to 2003, 2025 DLBCL pts were registered within the database and 1391 pts fulfill inclusion criteria. The median age at diagnosis was 64 yrs, 40% of pts were aged ≤60yrs, 51% of pts were male, 79% of pts had ECOG 60 yrs 46%, 7%, 9% and 38%, respectively. 5 yrs OS was 8% in “refractory–group”, 16% in “early relapse–group”, 50% in “late relapse–group” and 90% in “no relapse–group”, differences between the groups were statistically significant, p