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PEREIRA, JULIANA/0000-0002-0655-2821; ZINZANI, PIER LUIGI/0000-0002-2112-2651; Trotman, Judith/0000-0001-8009-4593 WOS: 000462407900001 PubMed: 30707661 PURPOSEThe aim of this open-label, first-in-setting, randomized phase III trial was to evaluate the efficacy of alisertib, an investigational Aurora A kinase inhibitor, in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL).PATIENTS AND METHODSAdult patients with relapsed/refractory PTCLone or more prior therapywere randomly assigned 1:1 to receive oral alisertib 50 mg two times per day (days 1 to 7; 21-day cycle) or investigator-selected single-agent comparator, including intravenous pralatrexate 30 mg/m(2) (once per week for 6 weeks; 7-week cycle), or intravenous gemcitabine 1,000 mg/m(2) or intravenous romidepsin 14 mg/m(2) (days 1, 8, and 15; 28-day cycle). Tumor tissue (disease subtype) and imaging were assessed by independent central review. Primary outcomes were overall response rate and progression-free survival (PFS). Two interim analyses and one final analysis were planned.RESULTSBetween May 2012 and October 2014, 271 patients were randomly assigned (alisertib, n = 138; comparator, n = 133). Enrollment was stopped early on the recommendation of the independent data monitoring committee as a result of the low probability of alisertib achieving PFS superiority with full enrollment. Centrally assessed overall response rate was 33% for alisertib and 45% for the comparator arm (odds ratio, 0.60; 95% CI, 0.33 to 1.08). Median PFS was 115 days for alisertib and 104 days for the comparator arm (hazard ratio, 0.87; 95% CI, 0.637 to 1.178). The most common adverse events were anemia (53% of alisertib-treated patients v 34% of comparator-treated patients) and neutropenia (47% v 31%, respectively). A lower percentage of patients who received alisertib (9%) compared with the comparator (14%) experienced events that led to study drug discontinuation. Of 26 on-study deaths, five were considered treatment related (alisertib, n = 3 of 11; comparator, n = 2 of 15). Two-year overall survival was 35% for each arm.CONCLUSIONIn patients with relapsed/refractory PTCL, alisertib was not statistically significantly superior to the comparator arm. Millennium Pharmaceuticals, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited Funded by Millennium Pharmaceuticals, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Background Optimal upfront therapy for posttransplant lymphoproliferative disease (PTLD) arising after solid organ transplant remains contentious. Rituximab monotherapy (R-Mono) in unselected patients has shown a lack of durable remissions. Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-based chemotherapy confers improved response rates, although concerns exist about toxicity. Methods This multicenter retrospective study reports outcomes for adults with biopsy-proven B-cell PTLD treated initially with R-Mono or Rituximab plus CHOP (R-CHOP). Selection of therapy was made according to physician preference. Results Among 101 patients, 41 received R-Mono and 60 had R-CHOP. Most (93%) had undergone renal or liver transplantation. R-CHOP showed a trend toward improved complete (53% versus 71%; P = 0.066) and overall (75% versus 90%; P = 0.054) response rates. In the R-Mono group, 13 of 41 (32%) subsequently received chemotherapy, while 25 of 41 (61%) remained progression-free without further therapy. With median follow-up of 47 months, overall survival (OS) was similar for R-Mono and R-CHOP, with 3-year OS of 71% and 63%, respectively (P = 0.722). Non-PTLD mortality was 3 of 41 (7%) and 4 of 60 (7%) within 12 months of R-Mono or R-CHOP, respectively. The International Prognostic Index was statistically significant, with low- (0-2 points) and high-risk (≥3 points) groups exhibiting 3-year OS of 78% and 54%, respectively (P = 0.0003). In low-risk PTLD, outcomes were similar between therapies. However, in high-risk disease R-Mono conferred an inferior complete response rate (21% versus 68%; P = 0.006), albeit with no impact on survival. Conclusions Our data support R-Mono as initial therapy for PTLD arising after renal or liver transplantation. However, upfront R-CHOP may benefit selected high-risk cases in whom rapid attainment of response is desirable.

In the original version of this article, the mention of ‘ifosfamide 1500 mg/m2 days 1–3’ should, in fact, read ‘ifosfamide 1500 mg/m2 bd days 1–3’. This has now been updated in the original version of the article.

BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas.METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152.FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group.INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile.FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

Background Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas (NHL). PTCL accounts for approximately 10% of all NHL cases in the US and Europe, and may be as high as 24% in Asia. The most common frontline treatment of PTCL is anthracycline-based chemotherapy with CHOP or CHOP-like regimens which do not produce durable remissions in the majority of subtypes, including ALK+ systemic anaplastic large cell lymphoma (sALCL) with high International Prognostic Index (IPI) scores. Brentuximab vedotin is an antibody-drug conjugate directed against CD30 currently approved for the treatment of relapsed or refractory sALCL with demonstrated antitumor activity in frontline PTCL. A phase 1 trial combining brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisone (CHP [CHOP without vincristine to eliminate additive neurotoxicity]) as frontline treatment of PTCL demonstrated estimated 5-year progression-free survival (PFS) and overall survival (OS) rates of 52% and 79% (Fanale 2018). Based on the encouraging activity and manageable safety profile of the combination, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin in combination with CHP (A+CHP) versus standard CHOP for the treatment of patients (pts) with PTCL (ClinicalTrials.gov No. NCT01777152). Here we report the blinded, pooled analyses per investigator of the ECHELON-2 trial. Methods ECHELON-2 is a phase 3, randomized, double-blind, active-controlled, multicenter study. Adults with newly diagnosed CD30+ (≥10% of neoplastic cells by local review) PTCL were enrolled. Pts with ALK+ sALCL were required to have an IPI ≥2. The primary endpoint of ECHELON-2 is PFS per an independent review facility. Pts were randomized 1:1 to receive 21-day cycles of either CHOP or A+CHP for 6 to 8 cycles. Consolidative SCT or radiotherapy was permitted at the investigator's discretion after end of treatment. Results A total of 452 pts across 17 countries were randomized between January 2013 and November 2016 in Europe (44%), North America (29%), and other (26%) regions including Asia and Australia. The median age was 58 years (range, 18-85) and 63% were male. Most pts were white (62%) or Asian (22%). Most pts entering the study had an ECOG performance status of 0 or 1 (39% each) and the remaining 22% of pts had a performance status of 2. Most pts had advanced-stage disease (Stage III [27%] or IV [53%]) at diagnosis and 78% had IPI scores ≥2 (2 [34%], 3 [29%], 4 [12%]. 5 [3%]). PTCL subtypes included sALCL (316 pts [70%]: ALK+ 98 pts [22%]; ALK- 218 pts [48%]), PTCL - not otherwise specified (72 pts [16%]), angioimmunoblastic T-cell lymphoma (54 pts [12%]), adult T-cell leukemia/lymphoma (7 pts [2%]), and enteropathy-associated T-cell lymphoma (3 pts [1%]). Of the 452 randomized pts, 449 received at least 1 dose of study treatment and all pts had either completed (82%) or discontinued treatment as of April 2017. Treatment was discontinued for adverse events (AEs) (7%), progressive disease (7%), investigator decision (2%), and patient decision (2%). Preliminary results by investigator assessment, show an overall blinded pooled objective response rate (ORR) following completion of the frontline treatment of 79% (95% CI: 75.4-83.1) with 64% achieving a complete response (CR) (95% CI: 59.1-68.2). With a median follow-up of 35.2 mos, the 3-year PFS and OS for all pts were 52.9% (95% CI: 47.7-57.7) and 73.1% (95% CI: 68.3-77.2). The incidence of AEs was consistent with the known safety profiles of brentuximab vedotin and CHOP chemotherapy, including the AE of interest, peripheral sensory neuropathy (43%). Grade 3 or higher AEs reported in ≥10% of pts were neutropenia (33%), febrile neutropenia (17%), and anemia (12%). Conclusions ECHELON-2 is the largest prospective, randomized, double-blind study to compare the efficacy and safety of standard CHOP with an alternative regimen that includes a CD30-targeted agent in frontline treatment of sALCL and other CD30+ PTCLs. Blinded pooled data from ECHELON-2 show that the treatment was well tolerated with encouraging 3-year PFS and OS rates. The primary analysis by treatment regimen will be unblinded prior to the meeting and presented at the conference. Disclosures Horwitz: Seattle Genetics: Consultancy, Research Funding; Aileron Therapeutics: Consultancy, Research Funding; Innate Pharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Corvus: Consultancy; Mundipharma: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Trillium: Consultancy; Celgene: Consultancy, Research Funding; Portola: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Spectrum: Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding. O'Connor:Seattle Genetics: Research Funding; Celgene: Research Funding; ADC Therapeutics: Research Funding. Pro:kiowa: Honoraria; Takeda Pharmaceuticals: Honoraria, Other: Travel expenses; Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding; portola: Honoraria. Illidge:Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria. Fanale:Amgen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Merck & Co: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding. Advani:Agensys: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Merck: Research Funding; Janssen: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Celgene: Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Research Funding; Kura: Research Funding; Celgene: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Millenium: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Forty Seven Inc.: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board. Bartlett:KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImaginAB: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck & Co: Research Funding; Immune Design: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Affimed: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; Millennium: Research Funding. Christensen:Seattle Genetics: Research Funding. Morschhauser:Janssen: Other: Scientific Lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Domingo-Domenech:Affimed: Research Funding. Rossi:Novartis: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Janssen: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Mundipharma: Honoraria; Sandoz: Honoraria; Seattle Genetics: Research Funding; Alexion: Other: Travel expenses. Feldman:Portola: Research Funding; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; KITE: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Janssen: Speakers Bureau. Lennard:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Belada:Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Illés:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Tobinai:Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; SERVIER: Research Funding; Abbvie: Research Funding; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; HUYA Bioscience International: Consultancy, Honoraria; Chugai Pharma: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Tsukasaki:Celgene: Honoraria; Eisai: Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA: Consultancy, Research Funding; Ono Pharma: Consultancy; Daiich-Sankyo: Consultancy; Mundy Pharma: Honoraria; Kyowa-hakko/Kirin: Honoraria; Seattle Genetics: Research Funding. Yeh:GNT Biotech & Medicals Crop.: Research Funding. Shustov:Seattle Genetics: Research Funding. Hüttmann:Roche: Other: Travel expenses; Celgene: Other: Travel expenses. Savage:Verastem: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Servier: Consultancy. Yuen:Seattle Genetics: Research Funding. Zinzani:MSD: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hua:Takeda Pharmaceuticals International Co.: Employment. Little:Takeda Pharmaceuticals: Employment. Rao:Seattle Genetics: Employment, Equity Ownership. Woolery:Seattle Genetics: Employment, Equity Ownership. Manley:Seattle Genetics: Employment, Equity Ownership. Trümper:Seattle Genetics: Research Funding.

Background Studies in patients with rheumatoid arthritis and advanced follicular lymphoma have shown that CT-P10, a rituximab biosimilar, has equivalent or non-inferior efficacy and pharmacokinetics to rituximab. We aimed to assess the therapeutic equivalence of single-agent CT-P10 and rituximab in patients with newly diagnosed low-tumour burden follicular lytnpliorna. Methods In this ongoing, randomised, double-blind, parallel-group, active-controlled, phase 3 trial, adult patients W.8 years) with stage II-IV low-tumour-burden follicular lymphoma were randomly assigned (1:1) using an interactive web or voice response system stratified by region, stage, and age to CT-P10 or US-sourced rituximab. Patients received CT-P10 or rituximab (375 mg/m(2) intravenous) on day 1 of four 7-day cycles (induction period). Patients who had disease control after the induction period continued to a maintenance period of CT-P10 or rituximab administered every 8 weeks for six cycles and, if completed, a second year of maintenance therapy of additional CT-P10 (every 8 weeks for six cycles) was offered. The study was partially unmasked after database lock (Feb 23, 2018) for all data up to 7 months (before cycle 3 of the maintenance period). The primary endpoint was the proportion of patients who achieved an overall response by 7 months in the intention-to-treat population. Efficacy equivalence was shown if the two-sided 90% CIs for the treatment difference in the proportion of responders between CT-P10 and rituximab was within the equivalence margin of 17%. This trial is registered with ClinicalTrials.gov, number NCT02260804. Findings Between Nov 9, 2015, and Jan 4, 2018, 402 patients were assessed for eligibility, of whom 258 were randomly assigned: 130 to CT-P10 and 128 to rituximab. 108 (83%) of 130 patients assigned to CT-P10 and 104 (81%) of 128 assigned to rituximab achieved an overall response by month 7 (treatment difference estimate 1-8%; 90% CI 6-43 to 10 20). Therapeutic equivalence was shown (90% CIs were within the prespecified margin of 17%). The most common grade 3 or 4 treatment-emergent adverse events were decreased neutrophil count (two grade 3 in the CT-P10 group) and neutropenia (one in each group); all other grade 3 or 4 treatment-emergent adverse events occurred in one patient each. Six (5%) of 130 patients who received CT-P10 and three (2%) of 128 who received rituximab experienced at least one treatment-emergent serious adverse event. Interpretation CT-P10 was equivalent to rituximab in terms of efficacy and was well tolerated. CT-P10 monotherapy is suggested as a new therapeutic option for patients with low-tumour-burden follicular lymphoma. Copyright (C) 2018 Elsevier Ltd. All rights reserved.

The prognosis of patients with primary central nervous system lymphoma (PCNSL) has improved in recent years. This has partly been achieved by remission induction protocols incorporating high-dose methotrexate (HD-MTX) and rituximab. Given the high rates of relapse, consolidation therapy is usually considered in first response. Whole brain radiotherapy may prolong PFS but appears to confer no long-term survival advantage and is associated with significant neurocognitive dysfunction. Attempts to improve efficacy and reduce neurotoxicity of consolidation therapy have included thiotepa-based high-dose chemotherapy and autologous stem cell transplant (HDC-ASCT). This multi-centre, retrospective study reports the outcome of 70 patients undergoing HDC-ASCT for PCNSL in the United Kingdom. The median age at diagnosis was 56 years and all patients received HD-MTX-containing induction regimens. All patients underwent HDC-ASCT in first response. The rate of complete response increased from 50% before HDC-ASCT to 77% following HDC-ASCT. Treatment-related mortality was 6%. At a median follow-up of 12 months from HDC-ASCT, the estimated 1- and 2-year PFS rates were 71.5% and overall survival 86.4% and 83.3%, respectively. These data are comparable to published studies of HDC-ASCT for PCNSL, supporting its feasibility and efficacy.

Background: CT-P10 is the first biosimilar to innovator rituximab (RTX) approved for all indications by the European Medicines Agency. The pharmacokinetics (PK) equivalence and non-inferior efficacy of CT-P10 compared with RTX in patients with newly diagnosed advanced follicular lymphoma (FL) was previously demonstrated when used with combination chemotherapy of cyclophosphamide, vincristine and prednisone (CVP) (Kim WS et al,. 2017). Objectives: This is an ongoing, phase 3, randomized, double blind, active controlled study to demonstrate similarity of efficacy and safety between CT-P10 and RTX as monotherapy in patients with newly diagnosed FL with low tumor burden (NCT02260804). The results of efficacy as determined by overall response rate (ORR), PK, pharmacodynamic, safety and immunogenicity up to 7 months (prior to Maintenance Cycle 3) are presented here. Methods: Patients with FL with stage II-IV, Grade 1-3a and low tumor burden as assessed by GELF criteria were randomized in a 1:1 ratio to receive either CT-P10 or RTX (375mg/m2 i.v.) monotherapy weekly for 4 weeks as induction therapy, followed by maintenance therapy every 2 months for 2 years. Patients who had complete response (CR), unconfirmed CR, partial response or stable disease after the induction therapy were eligible for maintenance therapy. The primary endpoint was ORR over 7 months according to the IWG criteria and was assessed by the independent review committee as central review and by the site investigator as local review. Results: In total, 258 patients were randomized to either the CT-P10 (n=130) or RTX (n=128) group with well-balanced baseline characteristics. Overall, 231 patients (n=119/130 [92%] and n=112/128 [88%] in the CT-P10 and rituximab groups, respectively) completed up to 7 months. Therapeutic similarity between CT-P10 and RTX was established by meeting the predefined margin of ±17% for the primary efficacy endpoint of ORR in the intent-to-treat (ITT) and per-protocol (PP) population (Figure 1). An ORR of 83.1% and 81.3% for CT-P10 and RTX, respectively, was observed over 7 months. The ORR difference was 1.8% and 90% confidence interval (CI) of the treatment difference estimate was entirely within the equivalence margin; 90% CI (-6.43, 10.20). Similar PK profiles were shown in the CT-P10 and RTX. Maximum and trough concentration of CT-P10 or RTX at each cycle were similar between the two groups. Median number of B-cells decreased to the lower limit of quantification ( CT-P10 was well tolerated and the safety profile of CT-P10 over 7 months was consistent with that of RTX, with no new, unexpected safety findings. Treatment-emergent adverse events (TEAEs) were reported in 71% and 67% patients in the CT-P10 and RTX, respectively. Adverse events of special interest included infections and infusion-related reactions occurred in a similar proportion of patients in each treatment group (Table 1). Neither progressive multifocal leukoencephalopathy nor Hepatitis B virus reactivation was reported in either group. The proportion of patients with positive anti-drug antibody were similar between 2 groups (0.8% vs. 2.3%) over 7 months. Among them, neutralizing antibody were detected in one patient in the CT-P10 group. Conclusions: This study demonstrates therapeutic equivalence of CT-P10 to RTX in previously untreated LTBFL. CT-P10 was well-tolerated and the safety profile including immunogenicity of CT P10 was comparable to that of RTX over 7 months. Disclosures Ogura: SymBio: Research Funding; Mundi Pharma: Consultancy; Celltrion: Consultancy, Research Funding; Takeda: Honoraria; Cellgene: Honoraria; MeijiSeika Pharma: Consultancy. Sancho:SERVIER: Honoraria; SANOFI: Honoraria; CELGENE: Honoraria; KERN FHARMA: Honoraria, Speakers Bureau; GILEAD: Honoraria, Research Funding; JANSSEN: Honoraria, Speakers Bureau; ROCHE: Honoraria, Speakers Bureau; MUNDIPHARMA: Honoraria. Lennard:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Jurczak:European Medicines Agency: Consultancy; Astra Zeneca/Acerta: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Afimed: Research Funding; Bayer: Research Funding; Beigene: Research Funding; Celgene: Research Funding; Epizyme: Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Servier: Research Funding; Roche: Research Funding; TG Therapeutics: Research Funding. Coiffier:CELGENE: Consultancy, Membership on an entity's Board of Directors or advisory committees; MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees; CELLTRION: Membership on an entity's Board of Directors or advisory committees; MORPHOSYS: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees. Buske:Roche: Honoraria, Research Funding; Bayer: Research Funding; Janssen: Honoraria, Research Funding. Lee:Celltrion, Inc: Employment.

International audience; BACKGROUND: Patients with indolent non-Hodgkin lymphoma who fail to achieve adequate disease control with rituximab-based treatment have few treatment options and a poor prognosis. We aimed to assess a combination of obinutuzumab (GA101), a novel glyco-engineered type II anti-CD20 monoclonal antibody, and bendamustine in this patient population. METHODS: In this open-label, randomised, phase 3 study (GADOLIN), patients aged 18 years or older with histologically documented, CD20-positive indolent non-Hodgkin lymphoma refractory to rituximab were enrolled at 83 hospital and community sites in 14 countries in Europe, Asia, and North and Central America. Patients were randomly assigned (1:1) using a hierarchical dynamic randomisation scheme stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographical region, to receive induction treatment (six 28-day cycles) with obinutuzumab plus bendamustine or bendamustine monotherapy, both given intravenously. Obinutuzumab plus bendamustine dosing was obinutuzumab 1000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2-6) plus bendamustine 90 mg/m(2) per day (days 1 and 2, cycles 1-6), and bendamustine monotherapy dosing was 120 mg/m(2) per day (days 1 and 2, all cycles). Non-progressing patients in the obinutuzumab plus bendamustine group received obinutuzumab maintenance (1000 mg every 2 months) for up to 2 years. The primary endpoint was progression-free survival in all randomised patients, as assessed by an independent review committee. Safety was assessed in all patients who received any amount of obinutuzumab or bendamustine. This study is registered with ClinicalTrials.gov, number NCT01059630, and has stopped recruiting patients. FINDINGS: Between April 15, 2010, and Sept 1, 2014, when the study was stopped after a pre-planned interim analysis, 396 patients were randomly assigned (194 to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy). After a median follow-up time of 21.9 months (IQR 12.1-31.0) in the obinutuzumab plus bendamustine group and 20.3 months (9.5-29.7) in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached [95% CI 22.5 months-not estimable]) than with bendamustine monotherapy (14.9 months [12.8-16.6]; hazard ratio 0.55 [95% CI 0.40-0.74]; p=0.0001). Grade 3-5 adverse events occurred in 132 (68%) of 194 patients in the obinutuzumab plus bendamustine group and in 123 (62%) of 198 patients in the bendamustine monotherapy group. The most frequent grade 3 or worse adverse events were neutropenia (64 [33%] in the obinutuzumab plus bendamustine group vs 52 [26%] in the bendamustine monotherapy group), thrombocytopenia (21 [11%] vs 32 [16%]), anaemia (15 [8%] vs 20 [10%]) and infusion-related reactions (21 [11%] vs 11 [6%]). Serious adverse events occurred in 74 patients (38%) in the obinutuzumab plus bendamustine group and in 65 patients (33%) in the bendamustine monotherapy group, and deaths due to adverse events occurred in 12 patients (6%) and 12 patients (6%), respectively. Three (25%) of 12 adverse event-related deaths in the obinutuzumab plus bendamustine group and five (42%) of 12 in the bendamustine monotherapy group were treatment related. INTERPRETATION: Obinutuzumab plus bendamustine followed by obinutuzumab maintenance has improved efficacy over bendamustine monotherapy in rituximab-refractory patients with indolent non-Hodgkin lymphoma, with manageable toxicity, and is a new treatment option for patients who have relapsed after or are no longer responding to rituximab-based therapy. FUNDING: F Hoffmann-La Roche Ltd

Summary We present case of Anaplastic Large Cell Lymphoma discovered as an incidental finding whilst revising an implant based breast reconstruction in a 55 year old woman, whom previously had undergone risk reduction mastectomies and immediate reconstruction. During the procedure a presumed seroma was present but this was macroscopically atypical giving a ‘milky' coloured appearance with a pink tinge to it. The atypical fluid was sent for analysis and the diagnosis of ALCL confirmed. Treatment consisted of unilateral capsulectomy on the affected side and bilateral removal of implants with staging scans suggesting the disease being confined to the capsule. She remains in remission 12 months following the original procedure.

Enteropathy associated T-cell lymphoma (EATL) is a rare type of peripheral T-cell lymphoma. At present, there are no standardized diagnostic or treatment protocols for EATL. We describe EATL in a population-based setting and evaluate a new treatment with aggressive chemotherapy and autologous stem cell transplantation (ASCT). From 1979 onward the Scotland and Newcastle Lymphoma Group prospectively collected data on all patients newly diagnosed with lymphoma in the Northern Region of England and Scotland. Between 1994 and 1998, records of all patients diagnosed with EATL were reviewed, and 54 patients had features of EATL. Overall incidence was 0.14/100 000 per year. Treatment was systemic chemotherapy (mostly anthracycline-based chemotherapy) with or without surgery in 35 patients and surgery alone in 19 patients. Median progression-free survival (PFS) was 3.4 months and overall survival (OS) was 7.1 months. The novel regimen IVE/MTX (ifosfamide, vincristine, etoposide/methotrexate)–ASCT was piloted from 1998 for patients eligible for intensive treatment, and 26 patients were included. Five-years PFS and OS were 52% and 60%, respectively, and were significantly improved compared with the historical group treated with anthracycline-based chemotherapy (P = .01 and P = .003, respectively). EATL is a rare lymphoma with an unfavorable prognosis when treated with conventional therapies. The IVE/MTX-ASCT regimen is feasible with acceptable toxicity and significantly improved outcome.

Purpose To perform an updated analysis of the randomized phase III GADOLIN trial in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated with obinutuzumab (GA101; G) and bendamustine (B). Patients and Methods Patients with histologically documented, rituximab-refractory CD20+ indolent non-Hodgkin lymphoma received G 1,000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2 to 6) plus B 90 mg/m2/d (days 1 and 2, all cycles) or B 120 mg/m2/d monotherapy. Patients who did not experience disease progression with G-B received G maintenance (1,000 mg every 2 months) for up to 2 years. The primary end point was progression-free survival (PFS). Results Of 413 randomly assigned patients (intention-to-treat [ITT]: G-B, n = 204; B monotherapy, n = 209), 335 had follicular lymphoma (FL; G-B, n = 164; B monotherapy, n = 171). After a median follow-up of 31.8 months, median PFS in ITT patients was 25.8 months (G-B) and 14.1 months (B monotherapy; hazard ratio [HR], 0.57; 95% CI, 0.44 to 0.73; P < .001). Overall survival (OS) also was prolonged (HR, 0.67; 95% CI, 0.47 to 0.96; P = .027). PFS and OS benefits were similar in patients with FL. Grade 3 to 5 adverse events (AEs) were reported by 148 (72.5%) and 133 (65.5%) patients in the G-B and B monotherapy arms, respectively, most commonly neutropenia (G-B, 34.8%; B monotherapy, 27.1%), thrombocytopenia (10.8% and 15.8%), anemia (7.4% and 10.8%), and infusion-related reactions (9.3% and 3.4%). Serious AEs occurred in 89 G-B patients (43.6%) and 75 B monotherapy patients (36.9%); fatal AEs occurred in 16 (7.8%) and 13 (6.4%), respectively. Conclusion This updated analysis confirms the PFS benefit for G-B shown in the primary analysis. A substantial OS benefit also was demonstrated in the ITT population and in patients with FL. Toxicity was similar for both treatments.

Imatinib mesylate (IM, STI 571, Glivec) can induce a high rate of complete cytogenetic response (CCR) in chronic myeloid leukaemia (CML) patients, although to date the majority of patients continue to have detectable disease by sensitive reverse transcription polymerase chain reaction (RT-PCR). It is therefore possible that these patients may ultimately relapse and require treatment such as autologous peripheral blood stem cell transplant (APBSCT). We attempted mobilization of haemopoietic progenitor cells from 58 patients in CCR using recombinant human granulocyte colony-stimulating factor [rHu-G-CSF; 10 micro g/kg/d subcutaneously (s.c.) for at least 4 d] alone, while continuing IM treatment. The median d 5 (peak) CD34+ count was 11.5/ microl (range 0-108/ microl), and 43/58 (74%) patients underwent a median of two (range 1-3) apheresis procedures. A median dose of 2.1 x 10(6)/kg CD34+ cells (range 0.1-6.5 x 10(6)/kg) was collected. Some 84% of 31 collections analysed were negative for the Philadelphia (Ph) chromosome or breakpoint cluster region and Abelson murine leukaemia viral oncogene homologue (BCR-ABL) translocation by cytogenetics or fluorescent in situ hybridization respectively. No toxicity was reported with the regimen. Overall, the target CD34+ dose (2 x 10(6)/kg CD34+) was attained in 23/58 (40%) patients who entered the study. In summary, we have demonstrated that successful mobilization of Ph- CD34+ cells from IM-treated patients in CCR is possible using rHu-G-CSF alone.

The Northern Region Lymphoma Group is a population-based group covering 3.1 million people in Northern England. From 1991 total data collection for all Hodgkin's disease patients for this population has been in place and it has been possible to demonstrate that the overall survival for Hodgkin's disease for younger patients within this population has moved from 80% pre- 1988 to 87% post- 1988. This improvement has been brought about by the introduction of clinical trials for advanced stage disease and effective salvage regimens. This report describes the outcome of 51 patients treated with the ifosfamide, etoposide and epirubicin (IVE)schedule and includes 28 males and 23 females with a median age of 34 years. Overall 43 of 51 patients responded to treatment (84%) with 31 achieving a complete response, four a good partial response and eight a partial response. Thirty-one proceeded to autologous stem-cell transplantation. In total, with a median follow-up of 24 months (range 6-51), 26 patients remain alive and in continuous remission. Haematological toxicity,in particular neutropenia WHO grade 4, was observed in all cases but improved over the three courses of treatment. Non-haematological toxicity was not a major problem, with no significant cardiac, hepatic, renal or neurotoxicity. We conclude that the high-dose ifosfamide-containing regimens should be prospectively evaluated in the various types of non-responsive and relapsing Hodgkin's disease.

Introduction The incidence of BIA-ALCL is on the rise. It is a recognised rare risk of breast implants. It commonly presents with a sudden, dramatic seroma around an implant, or occasionally a breast mass. Diagnosis is based on cellular morphology and staining positive for CD30 and negative for anaplastic lymphoma kinase (ALK). The aetiology and management of BIA-ALCL remains unclear. Clemens et al. suggest the conventional Ann-Arbor staging system and aggressive local and systemic treatments may not be appropriate. In the majority of cases, BIA-ALCL is confined to the seroma or the inner aspect of the capsule, so total capsulectomy alone may be sufficient. Systemic therapy may only be required in the minority where disease extends beyond the capsule. We present the UK BIA-ALCL data using the new specific staging system. Results We report 11 cases of BIA-ALCL from seven regional centres. Treatment was multidisciplinary between breast/plastic surgery and haemato-oncology and based on best available evidence and expert opinion. Mean lead-time from implant to diagnosis was 10 years. Using the new classification, eight Stage I cases that presented with recurrent seroma were treated successfully with implant removal and total capsulectomy. Four patients had bilateral breast augmentation (BBA); two had bilateral risk-reducing mastectomies (RRM) with implant reconstruction; two had a unilateral mastectomy and implant reconstruction for breast cancer, one of which had previously received adjuvant chemo- radio- and endocrine therapy. All but one patient with bilateral implants had surgery to remove both implants and ipsilateral total capsulectomy. Of these, three also had contralateral capsulectomy and the pathology was benign. One patient had unilateral capsulectomy and bilateral exchange of implants. Three patients presented with Stage IIA disease. One had previous RRM and implant reconstruction and presented with a mass. Treatment was CHOP+ (Echelon2 trial), radiotherapy and implant removal, she remains well at two years. One patient with previous BBA following a routine implant exchange developed a BIA-ALCL mass at the drain site. She was treated with local excision, adjuvant CHOP and radiotherapy. She is well at four years. The third patient had BBA and presented with a mass adjacent to the implant and progressed rapidly through neoadjuvant CHOP to develop life threatening chest wall/thoracic cavity involvement. She achieved complete pathological response with six cycles of Brentuximab followed by bilateral total capsulectomy and implant removal. This is the first reported case of neo-adjuvant antibody therapy in BIA-ALCL. Discussion Our data support the published literature demonstrating the majority of BIA-ALCL is stage I/II and can be safely managed with surgery alone. Chemotherapy was targeted at patients with more advanced local disease. Brentuximab, a monoclonal antibody is not licenced for BIA-ALCL but is used in refractory in ALCL. BIA-ALCL related death, although rare, is due to uncontrolled local disease progression. Conclusion BIA-ALCL cases must be staged according to the new system to avoid overtreatment. Brentuximab should be considered first line therapy for locally advanced BIA-ALCL. Citation Format: Johnson L, O'Donoghue J, Stark H, Collis N, Lennard A, Butterworth M, McLean N, Youssef M, Gui G, Lyburn I, Bristol J, Hurren J, Smith S, Jacklin R, Cunningham D, MacNeill F. Breast implant associated anaplastic large cell lymphoma (BIA-ALCL)– The UK experience and first reported case of neoadjuvant brentuximab [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-03-02.

Purpose: Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal non–Hodgkin lymphoma with a poor, though variable prognosis. The International Prognostic Index (IPI) and the prognostic index for peripheral T-cell lymphoma (PIT) have limited predictive value for outcome of EATL. The purpose of this study was to develop and validate a prognostic model for EATL, which can identify high-risk patients who need more aggressive therapy. Experimental Design: This retrospective multicenter study was based on 92 patients and included 45 patients diagnosed with EATL between 1999 and 2009 from the Netherlands and 47 patients from England and Scotland, diagnosed with EATL between 1994 and 1998. A new EATL prognostic index (EPI) was constructed using the RPART (recursive partitioning and regression trees) procedure. Validation was performed applying the bootstrap method. Results: Three risk groups were distinguished (P < 0.0001): a high-risk group, characterized by the presence of B-symptoms [median overall survival (OS) of 2 months]; an intermediate-risk group, comprising patients without B-symptoms and an IPI score ≥ 2 (7 months); and a low-risk group, representing patients without B-symptoms and an IPI score of 0 to 1 (34 months). Internal validation showed stability of statistical significance and prognostic discrimination. In contrast with the IPI and PIT, the EPI better classified patients in risk groups according to their clinical outcome. Conclusions: Our new, validated, prognostic model EPI accurately predicts survival outcome in EATL and may be used for patient selection for new therapeutic strategies and evaluation of clinical trials. Clin Cancer Res; 21(13); 3013–9. ©2015 AACR.

Patients with Hodgkin's disease (HD) refractory to first line chemotherapy and those who have rapid or multiple relapses have a very poor prognosis. With the increasing use of hybrid chemotherapy these patients will have been exposed to many of the drugs active in HD so it is important to develop salvage regimens that are novel and demonstrate activity in this group of patients. We report the use of a continuous high dose infusion of 'ifosfamide at a dose of 9g/m2 over 3 days in combination with etoposide and epirubicin followed by autologous stem cell transplant with either BEAM or Melphalan/VP16 conditioning in this difficult group. Forty six patients (28M18F) with a median age of 28 years (range 13–45) were treated. Overall 39 out of 46 (85%) patients responded to treatment, with 17 achieving complete remission and 11 a good partial remission; 28 proceeded to autologous bone marrow/stem cell transplantation. In total, 23 patients are alive and in continuous remission with a follow up of between 12 and ...

Thirty unselected patients with chronic granulocytic leukaemia (CGL), age range 22-59 years, were treated with intensive chemotherapy and G-CSF to mobilize peripheral blood progenitor cells (PBPC). Chemotherapy was well tolerated and PBPC were collected by leukapheresis early during white cell recovery. PBPC collections considered adequate for engraftment were collected in 21 patients. Cytogenetic analysis of all collections in these patients showed >75% Ph negativity (range 79-100%) in 10. Successful collections, ie those >75% Ph negative and with total cell count of >1 x 10(6) CD34+ve cells/kg or >20 x 10(4) CFU-GM/kg were further analysed by Southern blot or RT-PCR. All samples were positive for the bcr/abl transcript. Patients with a low Sokal score (

The purpose of this cooperative study was to evaluate the quantity and quality of Ph1-negative progenitor cells mobilized in the peripheral blood of patients with chronic myelogenous leukaemia soon after aplasia induced by chemotherapy. 32 patients ineligible for allografting who were cytogenetically refractory to interferon-alpha (IFN-alpha) were entered into this study. The chronic phase varied widely, with a median duration of 17 months (range 3-90 months). All patients were treated with intensive conventional chemotherapy regimens and recombinant human granulocyte colony-stimulating factor (rhuG-CSF, lenograstim). Peripheral blood progenitor cells (PBPC) were harvested by leukaphereses during early recovery from chemotherapy-induced aplasia. A total of 119 leukaphereses were performed. Median numbers of CD34+ cells and CFU-GM collected were 2.04 x 10(6)/kg and 2 9 x 10(4)/kg, respectively. There was a significant correlation between white cell count and number of CD34+ cells in the leukaphereses (P = 0.0001, r2 = 0.41, n = 104). A strict correlation between the number of CD34+ cells and CFU-GM in the leukapheretic product (P = 0.0001, r2 = 0.39, n = 110) was observed. 21% of evaluable patients (6/29) achieved a complete cytogenetic remission in the leukapheretic product and the other four patients achieved a major cytogenetic response for an overall response of 35% (10/22 patients). To date, 16 patients have been autografted and are alive. Five of them are Ph1-negative (three patients) or partially Ph1-negative (two patients). In conclusion, despite the high-risk characteristics of this study population, Ph1-negative PBPC were successfully mobilized in more than one-quarter of patients using a chemotherapy plus rhuG-CSF regimen. The importance of this achievement is increased by the current lack of other practical methods of rescuing Ph-negative cells in such patients.

Between May 1984 and October 1995 we performed 114 autologous stem cell transplants for lymphoma in our centre; 77/114 (68%) were transplanted after primary therapy. The conditioning regimen varied according to diagnosis; 26 patients were conditioned with melphalan and total body irradiation, 66 received melphalan and etoposide and the remainder (50) were conditioned with melphalan alone. The median follow-up is 62 months. Only two new haematological malignancies have occurred, both in patients with Hodgkin's disease. One patient developed Ph+ chronic myeloid leukaemia 18 months post-transplant. In this case, because of the timing of the haematological disorder, we considered the malignancy to be concurrent with or to have preceded the transplant. A second patient developed acute myeloid leukaemia 20 months post-transplant. She had been treated for Hodgkin's disease for 10 years and was transplanted in third complete remission. Cytogenetic analysis in this case showed trisomy 11. We believe this to have been an unequivocal second malignancy. Our finding of a 1.1% incidence of secondary haematological malignancy (95% CI 0.02-4.96) from a census population adds weight to the hypothesis that haematological problems post-transplant reflects prior chemotherapy rather than toxicity from the transplant procedure itself.

The aim of this study was to test whether survival for patients with high-grade non-Hodgkin's lymphoma (NHL) can be improved with a non-cross-resistant regimen as compared to a CHOP-based regimen. This is a multicentre study comprising 325 adult patients, median age 58 years, with high-grade non-Hodgkin's lymphoma: patients of any age and performance status were eligible provided they were able to receive the drugs in the regimens. Patients were randomised to either B-CHOP-M (bleomycin, cyclophosphamide, doxorubicin, vincristine, prednisolone and methotrexate) or PEEC-M (methylprednisolone, vindesine, etoposide, chlorambucil and methotrexate) alternating with B-CHOP-M. At a median follow-up of 9 years, there was no significant difference in overall survival or disease-free survival between the two arms. Toxicities for the two regimens were equivalent. This study confirms that for relatively unselected patients with high-grade non-Hodgkin's lymphoma, an alternating multidrug regimen does not improve upon the results obtained with B-CHOP-M.

As more centres consider autologous bone marrow and peripheral blood stem cell transplantation for patients with high risk Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) in first complete remission (CR1) the long term sequelae of such treatments have to be considered. One of the most important side effects of such intensive treatment is loss of fertility. Sperm banking before treatment commences is available for males but unfortunately cryopreservation of ova/ovarian tissue is not yet possible for females. We have transplanted 30 women, 23 were under 40 years and report ten females who have had successful pregnancies (including two twin pregnancies and one triplet pregnancy), leading to live births following autologous bone marrow transplantation (ABMT) for poor prognosis HD and NHL in first or second complete remission. None of these children have shown evidence of birth defects (median follow up of two years). Of the twenty one pregnancies reported to the European Bone Marrow Transplantation Registry (EBMTR) following ABMT for lymphoma, eight of the seventeen unassisted cases came from our centres. The Newcastle/SNLG autotransplant differs from the approach in many EBMTR centres in that it uses melphalan or melphalan/etoposide alone instead of the more common four drug containing regimens and yet sustained complete remission rates indicate that the non-ablative approach is equally effective as more aggressive regimens on the disease with the huge advantage of preserved fertility in females. This approach to conditioning for ABMT should be considered when treating women in the reproductive age group.

Background We evaluated the long-term results of radiotherapy for patients with gastric marginal zone lymphoma (GMZL). Patients and methods We carried out a retrospective, multi-centre study of patients with low-grade GMZL treated by radiotherapy between 17 July 1981 and 25 March 2004. Results There were 102 eligible patients. Fifty-eight patients were previously untreated and 44 had recurrent/residual disease after prior treatment (HP eradication, chemotherapy and surgery in 35, 9 and 8 patients, respectively, and 7 had >1 prior therapy). Radiation fields included the stomach /involved nodes in 61 patients and whole abdomen in 41. The median radiotherapy dose to stomach was 40 Gy (range 26–46 Gy) in a median 22 fractions. With a median follow-up after radiotherapy of 7.9 years (range 0.3–24 years), 10- and 15-year freedom from treatment failure (FFTF) was 88% (95% CI 82%–95%). Risk factors for TF were a large-cell component (P = 0.036) and an exophytic growth pattern (P = 0.042). Radiotherapy field size, radiotherapy dose, and failure of prior therapy were not associated with inferior FFTF. Ten-year overall survival was 70% (95% CI 60%–82%). Conclusions Radiotherapy achieves cure for the majority of patients with low-grade GMZL, including patients who have had prior therapy. Several features may predict a poorer outcome.

We report the safety and efficacy of autologous bone marrow transplantation (ABMT) in 30 patients with high-grade non-Hodgkin's lymphoma (NHL) in first complete remission (CR1) following remission induction chemotherapy. Two patients relapsed prior to ABMT. All patients were conditioned with high-dose melphalan. In Addition, ten received fractionated total body irradiation, one hemi-body irradiation and four high-dose etoposide. Unmanipulated non-cryopreserved autologous marrow was reinfused within 56 h of harvesting. Engraftment occurred in all patients with a median of 11 days of neutropenia (< 0.5 x 10(9) l-1), a median requirement for platelet transfusion of 3 days and packed red cell transfusion of 2 units, with a median hospital stay of 18 days post transplant. There was no procedure-related mortality and only minor morbidity was observed. Two patients relapsed at 1 and 2 months post transplantation, and one patient died of carcinoma of the lung 33 months after transplantation. The remaining 25 patients remain alive, well and in CR1 with a median follow-up of 44 months. The event-free survival at 3 years for all patients considered for ABMT was 83%. We conclude that ABMT for high-grade NHL in CR1 with non-cryopreserved marrow results in rapid haematological recovery without growth factor support. It is safe and is associated with high survival when used as consolidation of CR in high-risk patients.

Enteropathy-associated T-cell lymphoma (EATL) is a rare non-Hodgkin lymphoma of T-cell origin. The recent 2008 World Health Organization classification of hematologic malignancies distinguishes between two types of EATL. The disease is associated with celiac disease, particularly with its late, adult onset. Currently, there are no standardized diagnostic or treatment protocols for EATL, mostly because of its rarity. Historically, the patients have been treated with anthracycline-based chemotherapy with or without surgery. The outcome of patients with EATL treated with these approaches is poor. The reported death rates in the biggest studies are approximately 80–84%, with median progression-free survival (PFS) of 3.4–6.0 months and overall survival of 7.1–10.0 months. The 5-year PFS ranged from 3.2% to 18% and OS from 19.7% to 20%. The results of a novel induction regimen with ifosfamide, etoposide, and epirubicin alternating with intermediate-dose methotrexate followed by autologous stem cell transplantation (ASCT) are more promising, with a 5-year PFS of 52% and OS of 60%. The alternative approach, with a more common induction with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone followed by ASCT has also delivered promising results, with a 3-year PFS of 52% and OS of 47%. This review summarizes recently published data on epidemiology and clinical features, as well as standard and novel treatments including high-dose chemotherapy with ASCT and their outcome in EATL.

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).

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.Nintey-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

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.

Therapy-related acute promyelocytic leukemia (t-APL) with t(15;17) translocation is a well-recognized complication of cancer treatment with agents targeting topoisomerase II. However, cases are emerging after mitoxantrone therapy for multiple sclerosis (MS). Analysis of 12 cases of mitoxantrone-related t-APL in MS patients revealed an altered distribution of chromosome 15 breakpoints versus de novo APL, biased toward disruption within PML intron 6 (11 of 12, 92% vs 622 of 1022, 61%: P = .035). Despite this intron spanning approximately 1 kb, breakpoints in 5 mitoxantrone-treated patients fell within an 8-bp region (1482-9) corresponding to the “hotspot” previously reported in t-APL, complicating mitoxantrone-containing breast cancer therapy. Another shared breakpoint was identified within the approximately 17-kb RARA intron 2 involving 2 t-APL cases arising after mitoxantrone treatment for MS and breast cancer, respectively. Analysis of PML and RARA genomic breakpoints in functional assays in 4 cases, including the shared RARA intron 2 breakpoint at 14 446-49, confirmed each to be preferential sites of topoisomerase IIα-mediated DNA cleavage in the presence of mitoxantrone. This study further supports the presence of preferential sites of DNA damage induced by mitoxantrone in PML and RARA genes that may underlie the propensity to develop this subtype of leukemia after exposure to this agent.

Background: Primary diffuse large B-cell lymphoma (DLBCL) of breast is rare. We aimed to define clinical features, prognostic factors, patterns of failure, and treatment outcomes. Patients and methods: A retrospective international study of 204 eligible patients presenting to the International Extranodal Lymphoma Study Group-affiliated institutions from 1980 to 2003. Results: Median age was 64 years, with 95% of patients presenting with unilateral disease. Median overall survival (OS) was 8.0 years, and median progression-free survival 5.5 years. In multifactor analysis, favourable International Prognostic Index score, anthracycline-containing chemotherapy, and radiotherapy (RT) were significantly associated with longer OS (each P ≤ 0.03). There was no benefit from mastectomy, as opposed to biopsy or lumpectomy only. At a median follow-up time of 5.5 years, 37% of patients had progressed - 16% in the same or contralateral breast, 5% in the central nervous system, and 14% in other extranodal sites. Conclusions: The combination of limited surgery, anthracycline-containing chemotherapy, and involved-field RT produced the best outcome in the pre-rituximab era. A prospective trial on the basis of these results should be pursued to confirm these observations and to determine whether the impact of rituximab on the patterns of relapse and outcome parallels that of DLBCL presenting at other sites.

Disease relapse is a major cause of treatment failure after reduced-intensity allografts and while donor lymphocyte infusions (DLIs) can be effective salvage therapy they are associated with severe graft-versus-host disease (GVHD) when administered early after transplantation. We have therefore examined whether imatinib mesylate can delay relapse and postpone the requirement for DLI in 22 patients with chronic myeloid leukemia (CML) allografted using a reduced-intensity regimen. Imatinib was commenced on day + 35 and continued until 1 year after transplantation. Posttransplantation imatinib was well tolerated and abolished the risk of relapse during this period. Twenty-one patients completed 11 months of imatinib therapy, 15 of whom subsequently relapsed and received DLI. Ten patients to date have achieved molecular remission after DLI. Adjunctive targeted therapy allows the kinetics of disease relapse after a reduced-intensity allograft to be manipulated and represents a novel strategy by which outcome may be improved in patients who undergo transplantation for CML and other leukemias.

Chronic myeloid leukemia (CML) is associated increased stem cell turnover. We have previously shown that short telomeres in chronic phase (CP) predict for early progression to blast phase (BP). Poor prognostic score patients may therefore exhibit increased telomere loss at diagnosis and/or a greater than normal rate of loss during the disease course. We prospectively studied newly diagnosed CML patients for degree of telomere loss; measured telomere length in CML patients at all stages of disease; and performed follow-up sampling according to cytogenetic response to imatinib mesylate. Using flow-FISH, telomere length in peripheral blood leucocytes (PBL) from 32 consecutive newly diagnosed patients was measured (with ex-vivo expanded T-cells as an internal BCR-ABL negative control), in addition to 65 samples from all CML stages and 7 paired CP/BP samples. Fifty-five normal individuals served as a control population. Patients who attained either a complete cytogenetic response (CCR, 0% Ph ' , n = 10) or no CR (100% Ph + , n = 11) underwent follow-up measurement. All statistical tests were two sided. Telomeres in accelerated phase (AP) and BP patients were significantly shorter than in CP, and mean telomere shortening was significantly greater in high-risk score than low-risk patients (P < 0.05) at diagnosis. The rate of shortening during disease progression was 10 - 20 times the rate observed in normal granulocytes. BP samples had undergone at least 30- 60 additional divisions from baseline Ph - telomere length. Our findings show that telomere shortening in CML is greatest in high-risk score patients at diagnosis, and occurs rapidly during disease progression.

Imatinib mesylate (IM, STI 571, Glivec) can induce a high rate of complete cytogenetic response (CCR) in chronic myeloid leukaemia (CML) patients, although to date the majority of patients continue to have detectable disease by sensitive reverse transcription polymerase chain reaction (RT-PCR). It is therefore possible that these patients may ultimately relapse and require treatment such as autologous peripheral blood stem cell transplant (APBSCT). We attempted mobilization of haemopoietic progenitor cells from 58 patients in CCR using recombinant human granulocyte colony-stimulating factor [rHu-G-CSF; 10 micro g/kg/d subcutaneously (s.c.) for at least 4 d] alone, while continuing IM treatment. The median d 5 (peak) CD34+ count was 11.5/ microl (range 0-108/ microl), and 43/58 (74%) patients underwent a median of two (range 1-3) apheresis procedures. A median dose of 2.1 x 10(6)/kg CD34+ cells (range 0.1-6.5 x 10(6)/kg) was collected. Some 84% of 31 collections analysed were negative for the Philadelphia (Ph) chromosome or breakpoint cluster region and Abelson murine leukaemia viral oncogene homologue (BCR-ABL) translocation by cytogenetics or fluorescent in situ hybridization respectively. No toxicity was reported with the regimen. Overall, the target CD34+ dose (2 x 10(6)/kg CD34+) was attained in 23/58 (40%) patients who entered the study. In summary, we have demonstrated that successful mobilization of Ph- CD34+ cells from IM-treated patients in CCR is possible using rHu-G-CSF alone.

We assessed clinical results in 145 patients with chronic myeloid leukaemia in chronic phase who satisfied criteria for interferon-alpha failure and were thus eligible for treatment with imatinib at the Hammersmith Hospital. We used univariate and multivariate analyses to develop a risk score based on features defined after treatment for 3 months. We identified a low neutrophil count and poor cytogenetic response (

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-BOP5 (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-BOP3 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 IPI53) 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. # 2002 Elsevier Science Ltd. All rights reserved.

Post-transplant lymphoproliferative disease (PTLD) remains an important complication of solid organ transplantation. For B-cell PTLD, current first line therapies are Rituximab monotherapy (R-Mono) or R-CHOP. However, optimal selection of initial treatment is challenging due to concerns about the relative efficacy and toxicity of these modalities, and because of uncertainty about the prognostic value of baseline factors. This retrospective study identified 72 biopsy-proven cases of PTLD, diagnosed between 2000 and 2012, from 4 UK centres. These included 34 liver, 32 renal and 6 cardiothoracic transplant recipients. The median age at histological diagnosis was 47 years (range 16 - 72 years) and 68% were male. The median time from transplant to diagnosis of PTLD was 93 months (range 2 – 302 months), with 83% of cases occurring after 1 year. Tumour histology included 14 polymorphic and 49 monomorphic lesions (including 34 diffuse large B-cell, 5 plasmablastic, 4 Hodgkin and 1 T-cell lymphomas) whilst in 9 cases the PTLD subtype was unspecified. EBV-association was noted in 39/72 (54%) and this was significantly related to disease presenting within a year of transplant (X2 p=0.004). Initial therapy was R-Mono in 16/72 (22%) and R-CHOP in 34/72 (47%). Selection of R-CHOP versus R-Mono was significantly associated with stage ≥3 disease (odds ratio [OR] 6.7, p=0.01), onset more than 1 year after transplant (OR 7.3, p=0.03), lack of EBV association (OR 0.1, p=0.002) and monomorphic versus polymorphic histology (OR 14.0, p=0.004). In a multivariate logistic model, advanced stage (OR 11.0, p=0.06) and monomorphic histology (OR 8.5, p=0.03) retained significance. Of patients who received R-Mono, 15/16 (94%) completed at least 4 infusions, with no treatment-related deaths. Of these, 4 patients subsequently received R-CHOP for consolidation of response (2 patients) or for relapsed / refractory disease (2 patients). Of those who received R-CHOP as initial therapy, 23/34 (68%) completed at least 6 cycles, with 4 treatment-related deaths. The overall response rate to R-Mono was 81% (10 CR [complete remission], 3 PR [partial remission] and 3 NR [no remission]), similar to that of R-CHOP at 74% (19 CR, 6 PR, 5 NR and 4 undetermined; X2 p=0.67). With a median follow-up of 38 months, survival outcomes for R-Mono and R-CHOP were 2 year Event-Free Survival of 62% and 54% (p=0.77), 2 year Progression-Free Survival of 67% and 58% (p=0.48) and 2 year Overall Survival (OS) of 74% and 59% (p=0.52; Figure 1A) respectively. Amongst all study patients, significant baseline predictors of (inferior) OS were age ≥50 years (HR 2.9, p=0.006), stage ≥2 disease (HR 4.9, p=0.003), ECOG performance status ≥2 (HR 2.1, p=0.05), and elevated LDH (HR 2.2, p=0.08 borderline significance). Extra-nodal disease, histology, EBV-association and time from transplant were not predictive. In multivariate analysis, age>50 (HR 3.2, p=0.01) and advanced stage (HR 4.0, p=0.02) retained significance. Importantly, amongst those treated with R-Mono or R-CHOP, response to initial therapy was highly predictive of OS (overall response, HR 0.2, p Applying a 4 point modified prognostic index comprised of age>50, stage ≥2 disease, ECOG performance status ≥2 and elevated LDH, patients treated with R-Mono or R-CHOP with low risk disease ( We report outcomes for R-Mono versus R-CHOP as initial therapy for PTLD arising after adult solid organ transplantation. Whilst R-CHOP is associated with greater toxicity, R-Mono may deliver inferior response rates in patients with high risk disease. Survival outcomes were not significantly different between therapies. Importantly, using a modified prognostic index we identify a subset of patients with high risk disease who exhibit very poor outcome, irrespective of initial treatment, for whom novel therapeutic strategies are urgently required. Disclosures: Chaganti: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

We describe two cases of severe constrictive pericarditis arising after allogeneic BMT conditioning involving total body irradiation and melphalan to treat Philadelphia-chromosome positive ALL. Both patients required pericardectomy, resulting in marked improvement in ventricular filling. However, a degree of right-sided cardiac failure persisted in both patients secondary to restrictive cardiomyopathy. Constrictive pericarditis has not been previously described after BMT, but has been observed following thoracic radiotherapy for malignancy, usually involving a substantially higher radiation dose. Pericardial constriction and restrictive cardiomyopathy should be considered as causes of breathlessness and/or oedema occurring late after BMT. Bone Marrow Transplantation (2000) 25, 571-573.

For those patients ineligible for allogeneic bone marrow transplant and who are non-responsive to interferon, autotransplant with peripheral blood stem cells (PBSC) mobilised after intensive chemotherapy, may provide a novel approach to Improve prognosis in patients with chronic granulocytic leukaemia. PBSC harvests are assessed for CD34-positive cell numbers, which serve as an indicator of engraftment potential, and are also analysed cytogenetically to ascertain tumour cell contamination. However, a more accurate assessment of PBSC harvest contamination requires Investigation of the Philadelphia (Ph) status of the CD34 pos population, in which the cells that provide long-term engraftment are contained. In this study, we have analysed these levels in mobilised PBSC and also in bone marrow (BM) harvests, taken several weeks prior to mobilising chemotherapy. Using fluorescent in situ hybridisation for the bcr/abl gene fusion, we have shown that the median number of Ph negative cells in CD34 pos Isolated populations was 14.95% in BM compared to 79.05% in PBSC harvests and that In all PBSC samples tested, Ph positivity in CD34 pos populations was always detectable either by FISH or one round PCR methods. In paired assessments of both PBSC and BM harvests, higher levels of Ph negative CD34 pos cells (≥14%) isolated from BM harvests, taken prior to intensive chemotherapy, correlated with higher levels of Ph negative CD34 pos cells (≥78.5%) in PBSC harvests. These data may aid in the selection of patients for whom PBSC harvesting, after mobilisation, is more likely to achieve an autograft product containing predominantly Ph negative CD34 pos cells and may exclude those patients for whom the risk, morbidity and expense of stem cell harvesting may have no apparent benefit over a chronic phase BM harvest.

This report describes a patient presenting with Ph-positive ALL. RT-PCR analysis of diagnostic marrow revealed the presence of three bcr/abl transcripts; the ALL type e1a2 along with the CML types, b2a2 and b3a2. After initial induction therapy, bcr/abl transcripts were only detectable after two rounds of PCR but after MIDAC consolidation, remission samples were two-round negative. The relationship between the unusual molecular biological profile of this leukaemia and the rapid attainment of molecular remission is discussed.

Seven newly diagnosed patients with chronic myeloid leukaemia (CML), age range 22–45 years, were treated with intensive chemotherapy and G-CSF to mobilize peripheral blood progenitor cells (PBPC). Patients had previously received hydroxyurea alone to induce stable chronic phase. Cytogenetic analysis at diagnosis showed 95-100% Philadelphia (Ph) positive metaphases. PBPC were collected by leukapheresis early during white cell recovery, commencing 16-19 days after the start of chemotherapy. 2–5 daily collections were performed. CFU-GM (range 26–170xl04/kg) considered adequate for engraftment were collected in 6 patients. Cytogenetic analysis showed Ph-negative collections of >90% in 4 patients (1 patient being 100% Ph-negative). All patients achieved >60% Ph-negative collections. Southern blot (SB) analysis for the ber rearrangement confirmed cytogenetic results. RT-PCR in the 2 patients who were SB negative showed 1 patient to be negative after one round PCR (sensitivity 1 in 102–103) but positive after nested PCR (sensitivity 1 inlO5). The other patient was positive by one round PCR.

Summary. A 17-year-old white female presented with stage IVB Hodgkin's disease. After chemotherapy and radiotherapy she achieved a complete clinical remission and underwent an autologous bone marrow transplant (ABMT). 22 months later she developed chronic granulocytic leukaemia (CGL). Polymerase chain reaction (PCR) analysis of bone marrow harvested at the time of ABMT did not show any evidence of the bcr-abl sequence that was detectable at the diagnosis of CGL. This case provides further information on the kinetics of the development of CGL and adds to the small pool of data on CGL developing after treatment for Hodgkin's disease.

Abstract 1660 Poster Board I-686 Background In the past two decades we have observed improvement in the outcome of patients diagnosed with some subtypes of lymphoma. However, the prognosis of patient with peripheral T-cell lymphoma (PTCL) still remains unsatisfactory. We prospectively evaluated aggressive chemotherapy and autologous stem cell transplantation (ASCT): IVE/MTX-ASCT in patients with de-novo PTCL. Patients and methods: The regimen was piloted from 1997 for new patients eligible for intensive treatment: first for pts with enteropathy associated T-cell lymphoma (EATL) and subsequently for other types of PTCL. 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) were consolidated with myeloablative ASCT. The patients were evaluated with an intent to treat analysis for feasibility, response, progression free survival (PFS) and overall survival (OS). Results 57 patients were treated with the aggessive regimen, 26 pts had EATL and 31 other types of PTCL: 17 peripheral T-cell lymphoma NOS, 6 anaplastic T-cell lymphoma ALK positive, 4 extranodal NK/T cell lymphoma nasal type, 3 anaplastic T-cell lymphoma ALK negative and 1 hepatosplenic gamma/delta T-cell lymphoma. The median age at diagnosis was 51 years (range 23 – 69), 36/57 (63%) pts were male and 27/55 (49%) presented with ECOG >1. Early stage disease was diagnosed in 22/57 (39%) pts and advanced disease in 35/57 (61%). Bone marrow was involved in 6/53 (11%) pts and LDH was elevated in 23/46 (50%). Among pts with primary nodal disease 14/26 (54%) had at least one extranodal site involved and 6/26 (23%) bulky disease. At present, 55 pts are available for response evaluation. Eight pts discontinued treatment prematurely; 4 due to toxicity (one severe sepsis and death, one severe encephalopathy, one bone marrow failure and one bleeding from the gastrointestinal tract), and four pts due to disease progression. Of the remaining 47 pts 33 went on to receive ASCT. ASCT was omitted due to: refractory disease in 5 pts, poor general condition in 4 pts, insufficient stem cell mobilisation in 4 pts and one pt declined further treatment. The most common severe toxicities were pancytopenia, infection, nausea/vomiting and obstruction/perforation. Complete remission was confirmed in 39/55 (71%) pts, partial remission in 3/55 (5%) pts and 13/55 (24%) pts failed the treatment. The remission rates were: CR-17/26 (65%) pts and PR-1/26 (4%) for EATL and 22/29 (76%) and 2/29 (7%), respectively for other PTCL. During the study time 17/57 (30%) pts died, 15 due to lymphoma. For all pts 3-years PFS was 59% and OS 67%. For pts with EATL the 3-years PFS and OS were 52% and 60% and for other types 65% and 72%, respectively. These results were unchanged after the exclusion of anaplastic T-cell lymphoma ALK positive: (61% and 72%, respectively). Conclusions For patients with PTCL, we propose that intensive chemotherapy and ASCT significantly improves outcome compared to CHOP-like regimens, and has acceptable toxicities. In conclusion, where feasible patients with PTCL should be considered for aggressive treatments, like IVE/MTX – ASCT as primary therapy. Disclosures No relevant conflicts of interest to declare.

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.

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, p60yrs 4%, 6%, 40% and 85%, respectively, p60yrs 32%, 50%, 76% and 68%, respectively, p60yrs, however there were no statistically significant differences between “early relapsed” and “late relapse” groups. To assess the further potential differences in clinical features at presentation between “primary refractory” vs “no relapse” pts and “early relapse” vs “late relapse” pts, the groups were compared for the following factors: age, sex, CS, B-symptoms, ECOG, extranodal and bone marrow involvement, bulky disease, haemoglobin, leukocytes, LDH, albumin, urea, and alkaline phosphatase serum level. In evaluation of all pts and pts ≤60 years the “primary refractory–group” differed statistically significantly from the “no relapse group” in all evaluated factors except of sex and in evaluation of pts >60yrs in all factors. The “early relapse group” differed statistically significantly from the “late relapse group” only in ECOG performance status in evaluation of all pts, CS and bulky disease in evaluation of pts ≤60 years and age and CS in evaluation of pts >60yrs. In a population-based study of pts with DLBCL treated with anthracyclines, duration of FR defined groups of pts with statistically different OS. It was impossible to distinguish entirely by clinical features or IPI at diagnosis. We conclude, that the currently used prognostic indices based on clinical factors need to be enhanced using biological features of the tumor.