ALBERT

Description: Introduction: PTCL is a rare and heterogeneous group of non-Hodgkin lymphoma (NHL) comprising ~10% of cases. CHOP is frequently used first-line, but with the exception of ALK+ anaplastic large-cell lymphoma (ALCL), long term outcomes are historically poor with reported 5-yr overall survival (OS) rates of 36%. We retrospectively evaluated the outcomes following first-line chemotherapy for patients with PTCL treated at the Royal Marsden (RM) and Christie (CH) hospitals over a 10-year period. Methods: All eligible patients with PTCL aged ≥18 years and treated at the RM and CH between 1st January 2002 and 31st January 2012 were included. The study was approved by our institutional review boards. Patients were identified from hospital databases and included if they had received at least 1 cycle of first-line chemotherapy. Precursor T-cell malignancies, mycosis fungoides and adult T-cell leukaemia/lymphoma were excluded, as was cutaneous T-cell lymphoma not requiring combination chemotherapy. Clinical data were collated from electronic patient records and the diagnosis of PTCL was confirmed in all cases by an expert haematopathologist. Response was assessed using the IWG 1999 criteria. OS and progression free survival (PFS) were calculated from date of start of 1st line treatment and analysed using Kaplan Meier methods and Cox regression model. The impact of clinical factors on survival was assessed using Cox regression analysis. Results: A total of 143 (RM n=69, CH n=74)patients were evaluable and the median follow-up was 63.4 months. The median age at diagnosis was 59 yrs (range 18-89 yrs). PTCL subtypes were: PTCL not otherwise specified (NOS) (n=48), angioimmunoblastic T-cell lymphoma (AITL) (n=37), ALCL ALK- (n=24), ALCL ALK+ (n=14) and other (n=20). First-line chemotherapy included CHOP (n=97), GEM-P (gemcitabine, cisplatin and methylprednisolone) (n=16), other gemcitabine containing regimen (n=7), asparaginase (n=2) or other (n=21). OS by PTCL subtype is shown in Figure 1. Response was evaluable for 125/143 patients. Overall response (ORR) to first-line chemotherapy was 81.4% with complete response (CR) seen in 42.4%. For the entire cohort (n=143) 5-yr PFS was 20.6% and 5-yr OS was 39.6%. For CHOP treated patients ORR was 80.5% with CR in 43.7%, 5-yr PFS was 25.5% and 5-yr OS was 41.2%. ORR with GEM-P was 78.6% with CR in 50%, 5-yr PFS was 13.6% and 5-yr OS was 39.1%. No statistically significant difference between CHOP and GEM-P was seen in terms of response, OS or PFS. Autologous stem cell transplantation (autoSCT) was performed post first-line induction in 15% (n=22). For patients in CR post induction (CR1) (n=41), we compared survival for those treated with (n=12) and without (n=29) subsequent autoSCT. AutoSCT in CR1 was associated with a trend towards better PFS (HR 0.36, 95%CI 0.13-1.02; p=0.056) but not OS (HR 0.72, 95% CI 0.21-2.47; p=0.599). Uni- (UVA) and multivariate analyses (MVA) were performed to determine the impact of the following on OS and PFS: age (≤60 vs 〉 60yrs), gender, stage (I-III vs IV), performance status (PS, 0-1 vs 2), B symptoms (present vs absent), ethnicity (white vs other), LDH (normal vs elevated), IPI (low vs intermediate vs high), PTCL subtype, number of extranodal sites (0-1 vs 〉1), chemotherapy (CHOP vs gemcitabine based vs other), CR post induction (present vs absent) and autoSCT (performed vs not). Factors with a p-value of

Description: Mucosa-associated lymphoid tissue (MALT) lymphomas usually arise at sites of acquired MALT and are uncommon in native MALT (eg, Peyer patches and tonsil). Malignancy in these low-grade lymphomas is often inferred by immunoglobulin light-chain restriction and expression of CD43; molecular genetic evidence is sought only if these are in doubt. We report 6 cases (4 tonsils, 2 appendixes) of marginal zone (MZ) hyperplasia in children aged 3 to 11 years that, despite histologic and immunophenotypic features indicative of lymphoma, were polyclonal by molecular analysis. No lymphoma-directed therapy was given and patients remain alive and well (5 cases, median follow-up 35.3 months). The involved tonsil and appendix showed florid MZ hyperplasia with prominent intraepithelial B cells (IEBCs). The MZ B cells and IEBCs showed a high-proliferation fraction and a CD20+, CD21+, CD27-, immunoglobulin (Ig) superfamily receptor translocation-associated 1-positive (IRTA-1+), CD43+, multiple myeloma oncogene 1 (MUM-1), IgM+D+ phenotype. Polymerase chain reaction (PCR), cloning, and sequencing of rearranged IgH and Igλ genes (whole tissue sections [6 cases]; microdissected cells [2 cases]) showed that the MZ B cells and IEBCs were polyclonal and the IgH genes nonmutated. In contrast, MZ (intraepithelial) B cells of 6 control tonsils had a similar immunophenotype, except for expression of CD27 and polytypic light chains, whereas molecular studies showed that they were polyclonal with mutated Ig genes. (Blood. 2004;104:3343-3348)

Description: Angioimmunoblastic T-cell lymphoma (AITL) is a systemic disease involving lymph nodes, spleen, and bone marrow. Although the histologic features have been well described, the diagnosis is often challenging, as there are no specific phenotypic or molecular markers available. This study shows that the neoplastic cells of AITL can be identified by aberrant CD10 expression. Archival material from 30 cases of AITL, 10 cases of peripheral T-cell lymphoma unspecified (PTL), and 10 cases of reactive lymphoid hyperplasia were reviewed. Single and double immunostaining for CD3, CD4, CD8, CD20, CD21, CD10, BCL6, Ki67, and LMP-1 in situ hybridization for Epstein-Barr early region and polymerase chain reaction (PCR) for T-cell receptor gamma chain gene and immunoglobulin heavy chain gene were performed. Three overlapping histologic patterns with hyperplastic follicles, depleted follicles, or without follicles were identified in AITL. Of the 30 cases of AITL, 27 contained CD10+ T cells. No CD10+ T cells were present in the cases of PTL or reactive hyperplasia. PCR confirmed a monoclonal or oligoclonal T-cell population in 29 of 30 cases of AITL and a monoclonal B-cell population in 6 cases. Analysis of microdissected CD10+ single cells showed that they belonged to the neoplastic clone. In conclusion CD10 is a phenotypic marker that specifically identifies the tumor cells in 90% of AITL, including the early cases. The presence of these cells distinguishes AITL from other PTLs. This finding provides an objective criterion for accurate and early diagnosis of AITL.

Description: Peripheral T- and NK-cell lymphomas (PTCLs) are fatal in the majority of patients, and conventional chemotherapy is minimally effective. Targeted inhibition of tyrosine kinases (TKs) might be a useful treatment strategy, but TK overexpression by PTCLs has not been well characterized (except ALK). Recently a novel translocation t(5;9) fusing the ITK and SYK genes was reported in a subset of unspecified-type PTCLs, associated with high SYK gene expression and Syk protein positivity. Syk is a non-receptor TK important in immunoreceptor signal transduction, providing proliferation and survival signals in a variety of hematopoietic cells. Syk is absent or expressed at very low levels in most normal post-thymic T cells, where this signal transduction role is fulfilled by ZAP70. Since Syk TK inhibitors are now in clinical trials for other diseases, we sought to determine the incidence of t(5;9) and Syk overexpression in PTCL. Tissue microarrays were constructed using triplicate cores from paraffin-embedded tissue blocks. Cases were studied using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Additional studies were performed using flow cytometry and Western blot. There were 141 PTCLs, including 35 angioimmunoblastic, 66 unspecified, 21 anaplastic large cell, 2 enteropathy-associated, 5 hepatosplenic, 5 extranodal NK/T, and 7 other. No evidence of t(5;9) was identified by FISH in 86 informative cases. Normal T-cell subsets from peripheral blood, spleen, and lymph node were negative for Syk by IHC, flow cytometry, and Western blot. Syk was positive by immunohistochemistry in 133 of 141 (94%) PTCLs. All 8 Syk negative cases were extranodal, cytotoxic PTCLs. Western blot on frozen tissue correlated with IHC results in paraffin. All 4 Syk-positive cases tested showed phosphorylation of tyrosine residues 525/526, known to be required for Syk activation. We conclude that Syk is overexpressed in most PTCLs, including the vast majority of nodal cases. Syk may substitute for ZAP70 in these tumors and provide ongoing proliferation and survival signaling. The overexpression of Syk and phosphorylation of its Y525/526 residues suggest Syk may be a suitable target for pharmacologic TK inhibition as a treatment option for patients with PTCL.

Description: Background: High-grade transformation (HT) of follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL) occurs at a rate of 3% per year and has been associated with a very poor prognosis, with a median overall survival (OS) of 1 year reported by Montoto et al in the pre-rituximab era. Treatment often includes upfront autologous or allogeneic stem cell transplantation (SCT) due to the poor prognosis, but rarely maintenance rituximab despite evidence in FL. These patients are excluded from the majority of clinical trials and hence the role of SCT in the rituximab era and maintenance rituximab are not well evaluated. Methods: We performed a retrospective analysis of all patients aged ≥18 years with histologically proven transformed follicular lymphoma (TFL) diagnosed and treated (≥1 cycle of chemotherapy) at our institute in the 10-year period 2003-2013. Histopathology databases were searched to identify patients diagnosed with DLBCL and FL (grade 1-3a). Clinical data were collated from electronic patient records. Patients with grade 3b FL were excluded. A minimum interval of 6 months between the diagnosis of FL and development of HT was required for inclusion to outrule a discordant lymphoma. All histological specimens were reviewed by an expert haematopathologist. The study was approved by our institutional review board. Results: Between March 2003 and May 2013, a total of 56 patients were diagnosed with TFL (to DLBCL) and received first-line induction treatment +/- autologous/allogeneic SCT. The median follow-up was 5.6 years. The median time from diagnosis of FL to HT was 5.3 (range 0.6-29.3) years with a median age at diagnosis of TFL of 61 years (range 34-85). 59% (n=33) had received prior chemotherapy for FL. At diagnosis of TFL 89% (n=50/56) of patients received chemotherapy +/- radiotherapy (IFRT) without subsequent SCT. Upfront autologous or allogeneic SCT post induction was performed for 4 (7%) and 2 (3.5%) patients respectively. 91% of patients (n=51/56) received rituximab containing (R) chemotherapy and 68% (n=38/56) were treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). 16.1% (9/56) received IFRT post induction. 14.3% (8/56) patients received R-maintenance following first-line treatment for TFL. For patients treated with R-chemotherapy alone (n=46) the 2 and 5-year OS and PFS (for TFL) were 84.5% and 70.9% and 58.7% and 49.3% respectively. In patients aged 〉65 years (n=17) 5-year OS was similarly 71.6%. Patients treated with R-CHOP had 2 and 5-year OS of 89% and 76% and PFS (TFL) rates of 59.5% and 51.7% respectively. Patients who received R-chemotherapy induction followed by R-maintenance (n=8) had both 2-year OS and PFS (TFL) of 100%. 82% of all patients (46/56) underwent FDG-PET on completion of induction treatment +/- SCT. A negative PET (n=30) was associated with 2 and 5-year OS rates of 90% and 74.1% and PFS (TFL) of 60% and 49.2%. Conclusion: The outcome for TFL has significantly improved with the advent of rituximab. In our analysis the 2 and 5-year OS rates of 84.5% and 70.9% with R-chemotherapy alone are superior to reported OS for patients undergoing upfront autologous/allogeneic SCT, while PFS rates are comparable to those quoted for upfront autologous SCT. Although the numbers are small (n=8) and follow-up shorter, the outcomes for patients treated with R-chemotherapy followed by R-maintenance (2-yr OS and PFS of 100% and 100%) are particularly encouraging while offering minimal additional toxicity. In conclusion our data indicate that upfront SCT may no longer be required for TFL in the rituximab era. Rituximab maintenance should be considered in the management of these patients. Disclosures Hawkes: Roche: Travel grant Other. Peckitt:Sanofi: Membership on an entity's Board of Directors or advisory committees. Dearden:Roche: Membership on an entity's Board of Directors or advisory committees. Cunningham:Astra Zeneca: Research Funding; Novartis: Research Funding; Merck Serono: Research Funding; Sanofi: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Roche: Research Funding.

Description: Introduction: Primary mediastinal B Cell Lymphoma (PMBL) is a high-grade non-hodgkin lymphoma with distinct clinical and biological features. Optimal chemotherapy for this lymphoma is not established but some centres favour more intensive regimes such as DA EPOCH-R over R-CHOP. The role of consolidation radiotherapy is yet to be clarified and whether it can be omitted in those patients with a negative end-of-treatment PET scan (EOT PET) regardless of induction chemotherapy. Furthermore, the occurrence of false positive EOT PET scans may lead to overtreatment. The aim of this study was to establish the outcomes of patients (pts) with PMBL who had been treated in a single centre. Methods: Pts diagnosed with PMBL between 2003 and 2015 in Royal Marsden Hospital were included. Data was collected from electronic patient records and PET CT images review. Survival was defined from date of diagnosis until date of death or date of last follow up. Results: Thirty-four pts were identified with characteristics as shown in the table. Median diameter of the mediastinal mass was 12cm (range 5.5 - 24cm); 25 (74%) pts had a mass of ≥ 10cm. The majority of pts received R-CHOP chemotherapy (2 had 14 day cycles, 30 had 21 day cycles), 1 R-GCVP and another R-PACEBOM. Median number of cycles of chemotherapy was 6 (range 1-8). Seven out of 32 (22%) pts received involved field radiotherapy (IFRT). EOT PET was available for 30 pts. Median time to obtaining EOT PET from completion of chemotherapy was 31 days (20-81). Twenty-three out of 30 pts had EOT PET negative disease with a Deauville score (DS) of 1-3. Twenty-one of these 23 pts did not receive IFRT. Two of these 21 pts relapsed in the mediastinum and were treated with salvage chemotherapy followed by autologous stem cell transplant (ASCT) of whom 1 died due to their lymphoma. The 2 patients who received consolidation radiotherapy remain in remission. Seven out of 30 pts had a positive EOT PET (DS 4-5); of whom 5 received IFRT. Two out of 5 patients relapsed and proceeded with further chemotherapy of whom 1 died due to treatment-related causes while the other 4 patients were alive at time of last follow-up. Two pts with a positive EOT PET did not have IFRT, 1 proceeded with salvage chemotherapy but died due to lymphoma and the other patient was followed up with serial PET scans and ultimately the residual avidity was considered to be due to thymic hyperplasia. Conclusion: Our analysis demonstrates that for the 23 patients who achieved a complete metabolic response on EOT PET the risk of relapse was low (9%) (despite that only 2 patients received consolidation radiotherapy) and only one patient (4%) died of lymphoma. Thus the majority of patients with a negative EOT PET scan following R-CHOP chemotherapy may not need consolidation radiotherapy. This finding should be taken into account when considering the risk/benefit of adding radiotherapy treatment to patients who are already in metabolic CR after chemotherapy. Consolidation radiotherapy is currently being investigated in a prospective IELSG37 trial, NCT01599559. Table. Table. Disclosures Chau: Eli-Lilly: Honoraria, Other: Advisory Board, Research Funding; Bristol Meyers Squibb: Other: Advisory Board; MSD: Other: Advisory Board; Bayer: Other: Advisory Board; Roche: Other: Advisory Board; Merck Serono: Other: Advisory Board, Research Funding; Five Prime Therapeutics: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Janssen-Cilag: Research Funding; Sanofi Oncology: Research Funding. Cunningham:Roche pharmaceuticals: Research Funding.

Description: Angioimmunoblastic T-cell Lymphoma (AITL) is a rare Peripheral T-cell lymphoma that primarily affects the elderly, presenting as advanced disease characterized by aggressive behaviour and very poor outcome. Despite the unfavourable prognosis, the best approach for treating patients with AITL is still unknown. We report a retrospective multicentre study of 64 AITL patients (37 male, 27 female) who were diagnosed as AITL in our institution based on typical histology and molecular clonality analysis between 1995 and 2004. The median age at diagnosis was 60 years (range 25 to 87). Fifty-two patients (81%) presented with advanced stage III–IV disease, 41 (64%) had B symptoms and 49 (76%) elevated LDH. ECOG performance status was 1 for 40%, 2 for 53% and 3 for 9% of the patients. Based on IPI risk factors 12% of the patients were classified as low risk, 17% low intermediate, 29% high intermediate and 42% as high risk. Six patients developed autoimmune haemolytic anaemia. Therapeutic approach varied from no treatment to high dose therapy (HDT). The majority of the patients had received CHOP chemotherapy. Overall 19 patients (30%) had received 1 treatment line, 20 (31%) had 2, 19 (30%) 3, 4 patients (6%) were treated with ≥4 and 2 (3%) were not eligible for any treatment. Twenty patients (31%) proceeded to an autologous and 2 to allogeneic transplantation after achieving CR (n=12), PR (n=7) while 3 had progressive disease. Following first line therapy 37 patients (58%) achieved CR, 15 (23%) PR and 10 (16%) had primary refractory disease. Median time to relapse or progression was 6 months (1 to 89). Interestingly three patients relapsed as EBV driven DLBCL, 1as DLBCL and 2 as EBV driven Hodgkin’s lymphoma. With a median follow-up of 19 months (1 to 119) twenty-six patients (41%) were alive. Eighteen (28%) of these patients were in CR, and 8 in PR (13%). Thirty-seven patients (58%) died, 29 (45%) from disease progression. Twelve patients developed toxic complications -infectious complications (n=8), haemorrhage (n=1), thrombosis (n=1) myocardial infarction (n=2). The estimated PFS rates at 1 and 2 years were 33% and 27% respectively. Overall survival rates were estimated at 55% and 28% at 2 and 4 years. By univariate and multivariate analyses, no response to first line therapy (p=0.035) and male sex (p=0.0161), were significantly associated with higher relapse rate. Application of HDT resulted to significantly superior PFS (p=0.002). Poor performance status at presentation was the only factor found to be significant for the OS (p= 0.0317). In conclusion analysis of the results of this large cohort of AITL patients showed that although the initial overall response rate was 73% this was short lived. It is estimated that less than 30% of the patients will survive and remain disease free at 4 years. Considering the dismal outcome with current therapeutic approaches, new strategies using novel agents to improve further and most importantly maintain initial response are needed. The role of frontline HDT either autologous or allogeneic for eligible AITL patients is worth exploring in prospective collaborative studies.