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Recommended treatment for lymphoblastic lymphomas, a highly aggressive, relatively rare lymphoma entity predominantly seen in teenagers and young adults, includes acute lymphoblastic leukemia (ALL)-like induction chemotherapy. Whether these patients should be consolidated with maintenance chemotherapy or autologous stem cell transplantation (Auto-SCT) and the use of radiotherapy are matters of debate.We reviewed treatment and outcome for 25 consecutive patients above the age of 15 years with lymphoblastic lymphoma (T-lineage; T-LBL, n = 19; B-lineage; B-LBL, n = 6) seen at a single center during a 12-year period (1999-2011). Patients were given an ALL-like chemotherapy induction regimen, and responding patients were consolidated with Auto-SCT and local radiotherapy when applicable.Median age at diagnosis was 33 years (range 15-65). Seventeen of the T-LBL patients had a mediastinal mass, three patients had central nervous system (CNS) involvement. Chemotherapy with intensified CNS prophylaxis induced an overall response rate of 92% (CR 84%, PR 8%). In total 23/25 (92%) patients underwent Auto-SCT in first remission while 13 of 14 eligible patients with mediastinal involvement received local radiotherapy. Twenty percent of the patients had hepatotoxicity grade 3-4 and 32% thromboembolic events (TE). Two patients (8%) died of treatment-related toxicity. One patient had progressive disease and died of lymphoma. Three patients have relapsed, but two of these (both B-LBL) are currently alive in second CR after Allo-SCT. With a median follow-up of 98 months (range 1-163) the 5- and 8-year PFS and OS are 76% and 84%, respectively.Combined intensive ALL-like induction and early consolidation chemotherapy followed by Auto-SCT and local radiation therapy resulted in high sustained cure rates.

Background High-dose therapy with autologous stem cell support (HDT) has been a treatment option for lymphomas in Norway for 25 years. The purpose of the article was to describe the use of the therapy for lymphomas for the country as a whole and by health region, and to reveal the overall survival rate. Method All lymphoma patients ≥ 18 years who received HDT in Norway in the period 1987-2008 are included. Patients, diagnostics and treatment are identified for each hospital. Data for the population base have been retrieved from Statistics Norway. Results Altogether 726 lymphoma patients received HDT in Norway in the period 1987-2008, with an annual average of 0.72 per 100,000 inhabitants. The annual number of treatments increased until 2004 and has since been stable. The average number of treatments per 100,000 inhabitants per year was 0.94 for Northern Norway Health Region, 0.80 for South-Eastern Norway Health Region, 0.58 for Central Norway Health Region and 0.55 for Western Norway Health Region. Early mortality (death within 100 days) was 6%. Ten-year overall survival was 55% (95% CI 51-59%), and Hodgkin's lymphoma had the best survival of the lymphoma groups (p = 0.01). Interpretation The annual number of HDT increased gradually until 2004. The use of the treatment varied according to the patients' place of residence at the time of diagnosis, and was most frequently used for patients belonging to Northern Norway Health Region. More than half of the lymphoma patients are alive ten years after the treatment.

In recent decades, the prognosis of Mantle Cell Lymphoma (MCL) has been significantly improved by intensified first-line regimens containing cytarabine, rituximab and consolidation with high-dose-therapy and autologous stem cell transplantation. One such strategy is the Nordic MCL2 regimen, developed by the Nordic Lymphoma Group. We here present the 15-year updated results of the Nordic MCL2 study after a median follow-up of 114years: For all patients on an intent-to-treat basis, the median overall and progression-free survival was 127 and 85years, respectively. The MCL International Prognostic Index (MIPI), biological MIPI, including Ki67 expression (MIPI-B) and the MIPI-B including mIR-18b expression (MIPI-B-miR), in particular, significantly divided patients into distinct risk groups. Despite very long response durations of the low and intermediate risk groups, we observed a continuous pattern of relapse and the survival curves never reached a plateau. In conclusion, despite half of the patients being still alive and 40% in first remission after more than 12years, we still see an excess disease-related mortality, even among patients experiencing long remissions. Even though we consider the Nordic regimen as a very good choice of regimen, we recommend inclusion in prospective studies to explore the benefit of novel agents in the frontline treatment of MCL.

Mantle cell lymphoma (MCL) is a heterogenic non-Hodgkin lymphoma entity, with a median survival of about 5 years. In 2008 we reported the early - based on the median observation time of 4 years - results of the Nordic Lymphoma Group MCL2 study of frontline intensive induction immunochemotherapy and autologous stem cell transplantation (ASCT), with more than 60% event-free survival at 5 years, and no subsequent relapses reported. Here we present an update after a median observation time of 6·5 years. The overall results are still excellent, with median overall survival and response duration longer than 10 years, and a median event-free survival of 7·4 years. However, six patients have now progressed later than 5 years after end of treatment. The international MCL Prognostic Index (MIPI) and Ki-67-expression were the only independent prognostic factors. Subdivided by the MIPI-Biological Index (MIPI + Ki-67, MIPI-B), more than 70% of patients with low-intermediate MIPI-B were alive at 10 years, but only 23% of the patients with high MIPI-B. These results, although highly encouraging regarding the majority of the patients, underline the need of a risk-adapted treatment strategy for MCL. The study was registered at www.isrctn.org as ISRCTN 87866680.

Background: From 1999, Norwegian guidelines recommend two escalated (esc) BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) followed by six standard (s) BEACOPP for patients with advanced-stage classical Hodgkin lymphoma (HL) with an international prognostic score (IPS) ‡4. We evaluated retrospectively the experience with this recommendation at the Norwegian Radium Hospital, also including all IPS 3 patients treated with the same regimen. Patients and methods: Forty-seven patients were treated between June 1999 and December 2008. IPS was 3 in 10 patients and ‡4 in 37. Results: Thirty-five patients received eight cycles of BEACOPP, 12 patients received one to six cycles only, mainly due to toxicity. Sixty percent of patients had dose reductions. With median follow-up of survivors of 89 months, 5-year progression-free and overall survival are 84% [95% confidence interval (CI) 73% to 95%] and 91% (95% CI 82% to 100%), respectively. Toxicity was considerable with grade 3 or more infections/febrile neutropenia in 66% of patients, including one death and three cases of Pneumocystis jiroveci pneumonia. Of note, 10 patients (21%) experienced symptomatic aseptic osteonecrosis, of whom 3 have had hip replacement surgery after treatment. Conclusion: Two escBEACOPP plus six sBEACOPP is efficacious in advanced-stage high-risk HL. We document a high incidence of aseptic bone necrosis, possibly related to prednisolone.

We present a prospective phase II study of patients with relapse after chemotherapy showing transformation of follicular lymphoma to diffuse large B-cell lymphoma, performed before rituximab was included in standard treatment. Patients in complete (CR) or partial remission (PR) after salvage chemotherapy were eligible for high-dose chemotherapy with autologous stem cell support (HDT). Forty-seven patients from five Norwegian centres were included, of whom 30 (63%) received HDT. Eighteen (60%) achieved CR, seven (23%) PR and five (10%) had progressive disease following HDT. Median follow-up for the surviving patients was 75 months; median progression-free (PFS) and overall survival (OS) were 26 and 47 months, respectively. Median OS for all patients was 43 months, compared to only 10 months for patients not eligible for HDT. Patients receiving CD34(+) enriched/B-cell depleted grafts had inferior PFS and a trend for inferior OS compared to patients receiving non-purged grafts (Log Rank 0·025 and 0·151, respectively). In conclusion, two thirds of patients with transformation of follicular lymphoma were eligible for HDT. The majority of patients achieved CR and a considerable number had prolonged OS. The use of in vitro purged grafts did not result in a survival benefit compared to that of non-purged grafts.

[§ share last authorship] Background: In 2000-2010, the first large prospective trials in peripheral T-cell lymphoma (PTCL) showed outcomes burdened by high failure rates during induction. Concurrently, trials with the anti-CD52 monoclonal antibody alemtuzumab (ALZ) yielded promising responses in PTCL while demonstrating the feasibility of combining ALZ with CHOP. Hence, the Nordic Lymphoma Group initiated the randomized ACT-1 trial to test, in younger patients (pts) (18-65yrs), the addition of ALZ to CHOP + autologous stem cell transplant (ASCT). Primary endpoint was the 3 years event-free survival (EFS). Here, we present the final analysis of the ACT-1 trial (ClinicalTrials.gov: NCT00646854). Patients and Methods: Overall, 136 pts were randomized (43% of planned sample size due to slow accrual), five did not receive study treatment, and 131 were analyzed (ALZ-CHOP: 65; CHOP: 66). Due to lack of tumoral CD52 expression, anaplastic large cell lymphomas (ALCL) were not included in the ACT-1 trial. An amendment tapering ALZ dose from 360 mg (30 mg on days 1+2 of each CHOP course) to 120 mg (30 mg on day 1 of CHOP courses 1-4) was introduced early on due to systemic fungal infections in 2 pts. Of the 65 pts treated with ALZ-CHOP, 4 received the pre- and 61 (94%) the post-amendment dose. Monitoring for CMV- and EBV-DNA and antimicrobial prophylaxis were mandatory. Results: The median observation time for the Full Analysis Set was 66 months and the median age 51 yrs. The ALZ-CHOP and CHOP cohorts were well balanced with regard to classical prognostic factors and histological subtypes (PTCL-NOS 58% vs 54%, AILT 21% vs 25%, other 21% vs 21%). Feasibility: Neither CHOP nor ALZ-CHOP pts experienced substantial treatment delay. ALZ exposure did not affect stem cell harvest nor hematopoietic recovery. Grade 4 leucopenia was more frequent in ALZ-CHOP pts (73% vs 35%; p=0.001), whereas the occurrence of grade 3-4 anemia and thrombocytopenia did not differ significantly. After ALZ dose amendment, the frequency of bacterial and fungal infections of grade ≥3 was similar in both treatment arms. ALZ treated pts had more viral events (22/57=42% vs 4/23=17%), mainly due to asymptomatic CMV reactivations. The ratio of serious adverse events per ALZ-CHOP treated patient dropped markedly (from 3.25 to 0.86, comparable with 0.46 for CHOP) after dose amendment. Additional toxicity was mild and similar in both arms. Treatment related mortality was 4% (5% vs 3%). Efficacy: Complete remission (CR) was 52% in ALZ-CHOP vs 42% in CHOP. Primary refractory disease occurred for ALZ-CHOP and CHOP in 23% and 38% of pts, respectively. Overall, females had a significantly better outcome than males (p=0.004), also after adjustment for classical prognostic factors. Analyzing time-related endpoints without knowledge of CD52 expression, 3-years EFS, progression-free, and overall survival (PFS, OS) did not differ significantly between ALZ-CHOP and CHOP (EFS 35% vs 26%, PFS 37% vs 26%, OS 52% vs 50%). Fig.1A shows EFS by treatment arm, by gender, and by gender and treatment arm. Although not significantly different, EFS, PFS and OS values of ALZ-CHOP treated females in the ACT-1 trial were consistently higher than those of non-ALZ treated females or of males regardless of treatment group. RNA sequencing from evaluable pre-therapeutic tumor biopsies defined a signature of differentially expressed genes to be predictive of clinical outcome in ALZ-CHOP but not CHOP treated pts (n=33). Tumor microenvironment genes were prominent in determining response to ALZ. Tumors rich in B-cell milieu showed good responses, while the opposite was observed in tumors with signatures enriched with high endothelial cell genes (p Disclosures Leppä: Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Bayer: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Silva:Gilead Sciences: Research Funding; Abbvie, Gilead Sciences, Janssen, BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche, Janssen, Celgene: Other: Travel Support; Roche, Janssen: Other: Institution's payment for consultancy. Hagberg:Roche: Honoraria. Lugtenburg:takeda: Consultancy, Research Funding; servier: Consultancy, Research Funding; roche: Consultancy; BMS: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; GenMab: Research Funding. Walewski:Roche, GSK/Novartis, Takeda, and Janssen-Cilag: Research Funding; Roche, Celgene, Takeda, Janssen-Cilag, and Servier: Honoraria; Roche, Celegene, Takeda, Janssen-Cilag, and Servier: Membership on an entity's Board of Directors or advisory committees. Hopfinger:Janssen: Honoraria; Gilead: Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Jantunen:Amgen: Honoraria; Genzyme/Sanofi: Honoraria; Takeda: Honoraria. Steidl:Seattle Genetics: Consultancy; Juno Therapeutics: Consultancy; Tioma: Research Funding; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: patent holding; Roche: Consultancy. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Celgene: Consultancy, Honoraria; Janssen: Research Funding; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding.

Mantle cell lymphoma (MCL) has a heterogeneous clinical course. The recently proposed Mantle Cell Lymphoma International Prognostic Index (MIPI) predicted the survival of MCL better than the International Prognostic Index in MCL patients treated with conventional chemotherapy, but its validity in MCL treated with more intensive immunochemotherapy has been questioned. Applied here to 158 patients of the Nordic MCL2 trial of first-line intensive immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation, the MIPI and the simplified MIPI (s-MIPI) predicted survival significantly better (P < .001) than the International Prognostic Index (P > .004). Both the MIPI and the s-MIPI mainly identified 2 risk groups, low and intermediate versus high risk, with the more easily applied s-MIPI being just as powerful as the MIPI. The MIPIB (biological), incorporating Ki-67 expression, identified almost half of the patients as high risk. We suggest that also a simplified MIPIB is feasible. This trial was registered at www.isrctn.org as #ISRCTN 87866680.

Purpose Minimal residual disease (MRD) is predictive of clinical progression in mantle-cell lymphoma (MCL). According to the Nordic MCL-2 protocol we prospectively analyzed the efficacy of pre-emptive treatment using rituximab to MCL patients in molecular relapse after autologous stem cell transplantation (ASCT). Patients and Materials MCL patients enrolled onto the study, who had polymerase chain reaction (PCR) detectable molecular markers and underwent ASCT, were followed with serial PCR assessments of MRD in consecutive bone marrow and peripheral blood samples after ASCT. In case of molecular relapse with increasing MRD levels, patients were offered pre-emptive treatment with rituximab 375 mg/m2 weekly for 4 weeks. Results Of 160 MCL patients enrolled, 145 underwent ASCT, of whom 78 had a molecular marker. Of these, 74 were in complete remission (CR) and four had progressive disease after ASCT. Of the CR patients, 36 underwent a molecular relapse up to 6 years (mean, 18.5 months) after ASCT. Ten patients did not receive pre-emptive treatment mainly due to a simultaneous molecular and clinical relapse, while 26 patients underwent pre-emptive treatment leading to reinduction of molecular remission in 92%. Median molecular and clinical relapse-free survival after pre-emptive treatment were 1.5 and 3.7 years, respectively. Of the 38 patients who remain in molecular remission for now for a median of 3.3 years (range, 0.4 to 6.6 years), 33 are still in clinical CR. Conclusion Molecular relapse may occur many years after ASCT in MCL, and PCR based pre-emptive treatment using rituximab is feasible, reinduce molecular remission, and may prevent clinical relapse.

Mantle cell lymphoma (MCL) is considered incurable. Intensive immunochemotherapy with stem cell support has not been tested in large, prospective series. In the 2nd Nordic MCL trial, we treated 160 consecutive, untreated patients younger than 66 years in a phase 2 protocol with dose-intensified induction immunochemotherapy with rituximab (R) + cyclophosphamide, vincristine, doxorubicin, prednisone (maxi-CHOP), alternating with R + high-dose cytarabine. Responders received high-dose chemotherapy with BEAM or BEAC (carmustine, etoposide, cytarabine, and melphalan/cyclophosphamide) with R-in vivo purged autologous stem cell support. Overall and complete response was achieved in 96% and 54%, respectively. The 6-year overall, event-free, and progression-free survival were 70%, 56%, and 66%, respectively, with no relapses occurring after 5 years. Multivariate analysis showed Ki-67 to be the sole independent predictor of event-free survival. The nonrelapse mortality was 5%. The majority of stem cell products and patients assessed with polymerase chain reaction (PCR) after transplantation were negative. Compared with our historical control, the Nordic MCL-1 trial, the event-free, overall, and progression-free survival, the duration of molecular remission, and the proportion of PCR-negative stem cell products were significantly increased (P < .001). Intensive immunochemotherapy with in vivo purged stem cell support can lead to long-term progression-free survival of MCL and perhaps cure. Registered at www.isrctn.org as #ISRCTN 87866680.

There is no consensus on the optimal chemotherapy regimen for Hodgkin's lymphoma patients > or = 60 years. We present our institution's results of 5 years, using CHOP-21 as standard for this patient group. Twenty-nine patients with a median age of 71 years (range, 60 - 91) were included in this cohort. Fifty-five percent had known co-morbidities. Stage I/IIA patients (38%) were treated with 2 - 4 cycles of CHOP followed by radiotherapy. Stage IIB - IV patients (62%) received 6 - 8 cycles of CHOP and for the majority (13/18 pts) no radiotherapy. Two treatment-related deaths occurred. Febrile neutropenia was the most common toxicity (31%). The complete response rate after CHOP +/- radiotherapy was 93%. With a median follow-up of 41 months, five patients have relapsed and four have died from Hodgkin's lymphoma. So far, no relapses have occurred after 2 years from the end of therapy. Overall survival and progression-free survival at 3 years were 79% and 76%, respectively. We conclude that CHOP-21 is a well-tolerated and effective treatment for elderly patients with Hodgkin's lymphoma.

Peripheral T-cell lymphoma (PTCL) with a nodular architecture is rare. Recently, two variants have been described with infiltration of the B-cell follicle, one variant that localizes to the marginal zone with a so-called perifollicular growth pattern, and a variant that localizes to the germinal center. These lymphomas have a CD4+ phenotype and may express Bcl-6. We have studied five similar cases of PTCL with involvement of the B-cell follicle. However, our cases differ from the cases previously described by their predominant and frequently patchy involvement of the expanded mantle zone of the B-cell follicle at onset. Later biopsies in three of the cases show diffuse infiltration of the lymph node, without features of angioimmunoblastic TCL (AILT). All cases expressed Bcl-6 in addition to CD4. Cytogenetics was available in four of the cases but revealed no recurrent chromosomal aberrations or changes associated with other types of PTCL. No mutations of the BCL-6 gene were observed. Together, the cases seem to have an intermediately aggressive clinical behavior. Whether our cases are part of a spectrum of PTCLs that encompasses previously described variants with predominant marginal zone or germinal center infiltration or they represent a separate T-cell lymphoma type remains to be demonstrated by a study of more of such cases.

Background: Burkitt’s/Burkitt-like lymphoma (BL/BLL) are highly aggressive lymphomas mainly affecting children and young adults. We report the results in adolescent and adult patients with the use of three successive regimens. Patients and methods: Forty-nine patients aged 15 –70 years admitted to the Norwegian Radium Hospital in the period 1982– 2001 with a diagnosis of BL/BLL on histological review and who were given chemotherapy with curative intent are included in this analysis. Up to 1987 patients were given doxorubicin-based chemotherapy supplemented with intravenous and intrathecal methotrexate (MmCHOP). From 1987 to 1994, patients who obtained complete remission upon this regimen were consolidated with high-dose therapy with stem-cell support (MmCHOP + HDT). In 1995 we introduced as frontline therapy the German Berlin – Frankfurt– Munster (BFM) regimen. Results: By intention to treat analyses, the progression-free survival rates for patients who received MmCHOP (n = 13), MmCHOP + HDT (n = 17) or BFM therapy (n = 19) are 30.8%, 70.6% and 73.7%, respectively. In the groups of patients who received either the BFM regimen or MmCHOP + HDT, all patients who obtained complete remission upon induction therapy are continuously disease free. There was no treatment-related death. Conclusions: BL/BLL in adolescents and adults can successfully be treated with 5-day blocks of intensified chemotherapy such as the BFM regimen or CHOP/methotrexate-based chemotherapy consolidated with high-dose therapy. Using the BFM regimen, continuous remissions are obtained without additional myeloablative chemotherapy.

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

The chemotherapy dose-intensity in two adapted German BFM paediatric protocols (BFM 90 and NHL 86) was compared in contemporaneously treated adults50 years with Burkitt lymphoma and B-cell lymphoma unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (collectively referred to as BL). In BFM 90, primary prophylaxis with Granulocyte-colony-stimulating factor was used, postinduction treatment was started at granulocytesor =0.5 x 10(9)/L (or =1.0 x 10(9)/L in NHL 86) with a higher mean methotrexate dose (2.9 g/m(2)/cycle, n = 23; 1.6 g/m(2)/cycle in NHL 86, n = 22, P0.001). Intervals between consecutive treatment-cycles were shorter in BFM 90 (P0.001) with no additional toxicity. However, the two-year failure-free survival with BFM 90 (82%) was similar to that achieved with NHL 86 (72%, P = 0.33). We conclude that BFM 90 enables safe intensification of therapy in young adults with BL compared to NHL 86, but registry-based studies are required to further evaluate the antineoplastic effects and cost-effectiveness of the two therapeutic approaches.

High dose chemotherapy with autologous stem cell transplant (HD-ASCT) is a recommended procedure for patients with transformed indolent B-cell lymphoma from the pre-rituximab era. In this retrospective single-center study, we present our experience with HD-ASCT in patients with histologically verified transformed indolent B-cell lymphoma in the rituximab era. Forty-two patients were included, of whom 28 with chemosensitive disease proceeded to HD-ASCT. Twenty patients (71%) achieved a complete response (CR) and five (18%) a partial response (PR) after HD-ASCT. With a median observation time of 49 months for the survivors, the median progression-free survival (PFS) and overall survival (OS) for patients with HD-ASCT were 39 months and 57 months, respectively. Patients who were rituximab-naive at transformation had a significantly better OS compared to patients previously treated with rituximab, both in the whole patient cohort and among the HD-ASCT-treated patients (p = 0.036 and p = 0.039, respectively). Furthermore, male sex influenced survival negatively, whereas time from diagnosis to transformation was positively associated with survival, both with borderline significance, in HD-ASCT-treated patients. In conclusion, HD-ASCT remains an effective treatment for transformed indolent lymphomas in the rituximab era.

High-dose therapy with autologous stem cell support (HDT) has been a therapeutic option for lymphomas in Norway since as far back as 1987. By restoring bone marrow function through reinfusion of the patient's own stem cells, it is possible to administer cancer treatment in higher and otherwise lethal doses, and thereby achieve better treatment results. Originally stem cells were harvested from bone marrow and the high-dose therapy included total body irradiation, but since the mid 1990s stem cells have been harvested by apheresis and the high-dose therapy has consisted of chemotherapy alone (BEAM chemotherapy). In 1995 the treatment was regionalised and since then it has been performed in all health regions. The HDT procedure was introduced as an experimental treatment in clinical studies with international collaboration. The indications have changed over time, and this is now established treatment for a number of types of lymphoma.

Purpose Systemic peripheral T-cell lymphomas (PTCLs) respond poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by up-front high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) in PTCL, the Nordic Lymphoma Group (NLG) conducted a large prospective phase II study in untreated systemic PTCL. This is the final report, with a 5-year median follow-up, of the NLG-T-01 study. Patients and Methods Treatment-naive patients with PTCL age 18 to 67 years (median, 57 years) were included. Anaplastic lymphoma kinase (ALK) –positive anaplastic large-cell lymphoma (ALCL) was excluded. An induction regimen of six cycles of biweekly CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) was administered (in patients age > 60 years, etoposide was omitted). If in complete or partial remission, patients proceeded to consolidation with HDT/ASCT. Results Of 166 enrolled patients, 160 had histopathologically confirmed PTCL. The majority presented with advanced-stage disease, B symptoms, and elevated serum lactate dehydrogenase. A total of 115 underwent HDT/ASCT, with 90 in complete remission at 3 months post-transplantation. Early failures occurred in 26%. Treatment-related mortality was 4%. At 60.5 months of median follow-up, 83 patients were alive. Consolidated 5-year overall and progression-free survival (PFS) were 51% (95% CI, 43% to 59%) and 44% (95% CI, 36% to 52%), respectively. Best results were obtained in ALK-negative ALCL. Conclusion Dose-dense induction followed by HDT/ASCT was well tolerated and led to long-term PFS in 44% of treatment-naive patients with PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the study population. Therefore, dose-dense induction and HDT/ASCT are a rational up-front strategy in transplantation-eligible patients with PTCL.

The immunosurveillance hypothesis suggests that lymphocytes can recognize tumor-specific antigens expressed by transformed cells and initiate their elimination. Immunosurveillance implies that lymphocytes of naive phenotype can home to a tumor site and become activated by tumor-specific antigens. In this study, we have employed T-cell receptor transgenic mice as a source of naive, tumor-specific T cells. The transgenic, CD4+ T cells recognize a 91- to 101-residue fragment of the lambda 2(315) immunoglobulin light chain presented by I-Ed class II molecules. Such naive, idiotype-specific, CD4+ T cells protected against tumor development of a class II negative plasmacytoma (MOPC315) and a class II positive B lymphoma (F9), which both secrete lambda 2(315) immunoglobulin. Adoptive transfer experiments demonstrated that 2 x 10(6) lymph node cells were sufficient for protection against MOPC315. Depletion of T-cell subsets indicated that transgenic CD4+ cells were indispensable for tumor resistance. However, an additional role of CD8+ T cells is not ruled out. In contrast to the resistance against the secreting MOPC315 and F9 cells, transgenic mice were not protected against B lymphoma cells (F67), which do not secrete lambda 2(315) but express a truncated lambda 2(315) chain intracellularly. The results suggest that lambda 2(315) is processed and presented by host antigen-presenting cells, which in turn activate naive, idiotype-specific T cells.

We present a prospective phase II study of patients with relapse after chemotherapy showing transformation of follicular lymphoma to diffuse large B-cell lymphoma, performed before rituximab was included in standard treatment. Patients in complete (CR) or partial remission (PR) after salvage chemotherapy were eligible for high-dose chemotherapy with autologous stem cell support (HDT). Forty-seven patients from five Norwegian centres were included, of whom 30 (63%) received HDT. Eighteen (60%) achieved CR, seven (23%) PR and five (10%) had progressive disease following HDT. Median follow-up for the surviving patients was 75 months; median progression-free (PFS) and overall survival (OS) were 26 and 47 months, respectively. Median OS for all patients was 43 months, compared to only 10 months for patients not eligible for HDT. Patients receiving CD34(+) enriched/B-cell depleted grafts had inferior PFS and a trend for inferior OS compared to patients receiving non-purged grafts (Log Rank 0·025 and 0·151, respectively). In conclusion, two thirds of patients with transformation of follicular lymphoma were eligible for HDT. The majority of patients achieved CR and a considerable number had prolonged OS. The use of in vitro purged grafts did not result in a survival benefit compared to that of non-purged grafts.

A panel of independent BALB/c T cell clones responding to a peptide of the lambda 2(315) immunoglobulin light chain (residues 91-101), in the context of I-Ed, has previously been described. A monoclonal antibody (mAb; GB113) to the T cell receptor (TcR) of one of the clones, 4B2A1 (V alpha 1, J alpha 19; V beta 8.2, D beta 1.1, J beta 1.2) precipitates the alpha/beta heterodimer from 4B2A1. However, GB113 does not bind DO11-10.2 cells bearing a similar alpha/beta heterodimer (V alpha 1.1, J alpha TT11; V beta 8.2, D beta 1.1, J beta 1.1). GB113 does not cross-react with the TcR of the six other clones in the panel. Furthermore, the mAb does not bind polyclonal lambda 2(315)-specific T cell lines except 4.4% of cells of line 4 from which 4B2A1 was cloned. The mAb only binds a negligible number (0.5%) of BALB/c thymocytes and peripheral T cells. Therefore, the epitope detected by GB113 is very rarely expressed on 91-101. lambda 2(315)-specific TcR or on TcR of normal T cells. Soluble GB113 induces T cell activation [measured as proliferation and interleukin (IL) 2, IL3 and interferon-gamma production]. GB113-induced T cell activation is enhanced by soluble anti-CD4 and anti-Thy-1 mAb.

Penicillin G with an aminoglycoside is the standard initial empirical treatment in febrile neutropenia in Norway. It has been argued that giving the aminoglycoside once daily to neutropenic patients with Gram-negative bacteraemia may be hazardous when penicillin G is the beta-lactam antibiotic. We questioned this argument and hypothesized that tobramycin once daily was as efficacious as three times daily.We conducted a randomized prospective multicentre study, comparing the efficacy of tobramycin 6 mg/kg once (arm A) versus three times (arm B) daily, plus penicillin G 5 million IU x 4, in febrile neutropenic cancer patients.modification of the antibiotic regimen.One hundred and seventy-four patients were evaluable for intention-to-treat analyses. One hundred and fifty-five patients had lymphoma or leukaemia as the underlying cancer diagnosis. In arm A, 35 of 88 patients and in arm B, 34 of 86 patients, that is 40% in both arms had no modification of the antibiotic regimen. No patients died while participating in the study. Upon modification of the antibiotic regimen, all patients were successfully treated. The increase in serum creatinine was modest and similar in the two treatment groups.When administered with penicillin G, tobramycin given once daily was as efficacious and safe as tobramycin given three times daily in cancer patients with febrile neutropenia in Norway, provided the regimen was modified according to the clinical response.

We report six cases of Pneumocystis jirovecii pneumonia (PCP) verified by immunoflourescence/polymerase chain reaction of bronchoalveolar fluid among 46 lymphoma patients (13%) who received rituximab-CHOEP-14 at our institution. PCP prophylaxis should be standard management for this group of patients and also considered for patients treated with rituximab-CHOP-14, CHOP-14 or CHOEP-14.

8598 Background: The aim of this study was to investigate conditional survival and standardized mortality ratios (SMR) after high-dose therapy with autologous stem-cell transplantation (HDT) for no...

CD4+ T cells can recognize a processed idiotypic peptide derived from the mouse lambda 2(315) immunoglobulin light chain. The idiotypic peptide is presented on the I-E(d) class II major histocompatibility complex molecule. Mice made transgenic for a lambda 2(315)-specific alpha beta T cell receptor have been demonstrated to be specifically resistant against a tumor challenge with the MOPC315 (alpha,lambda 2(315)) plasmacytoma (Lauritzsen, G. F., Weiss, S., Dembic, Z. and Bogen, B., Proc. Natl. Acad. Sci. USA 1994, 91: 5700). That study, however, did not rule out a role of either anti-Id antibodies or T cells expressing nontransgenic specificities due to expression of endogenous T cell receptor (TcR) alpha chains. Also, the role of different T cell subsets in protection was unclear. To remove these ambiguities, we have now made the transgenic mice homozygous for the scid mutation, known to inhibit both Ig and TcR gene rearrangements. Such transgenic SCID mice lack B cells and antibodies while they still have plenty of CD4+ and CD4-8- cells expressing the transgenic alpha beta T cell receptor. The number of CD8+ T cell is dramatically reduced. Even so, transgenic SCID mice are protected against a challenge with MOPC315 plasmacytoma cells. Therefore, B cells, as well as novel T cell receptor specificities created by rearrangements of endogenous alpha-chain genes, are both dispensable for effective immunosurveillance in our system. Surprisingly, we found that transgenic CD8+ and CD4-8- cells are idiotype-specific and I-E(d) restricted. However, these T cell subsets are not required for resistance because adoptive transfer experiments demonstrated that highly purified transgenic SCID CD4+ cells suffice for tumor protection.

Abstract 747 The outcome of mantle cell lympoma (MCL) has improved in recent years. The Nordic Lymphoma Group has since 1996 completed three consecutive phase II trials for front-line treatment of MCL patients < 66 years of age. The first trial (MCL1) showed that quality of response prior to transplant was the most important factor for outcome. Hence, in the second trial (MCL2) induction therapy was intensified by adding cycles of high-dose Ara-C and rituximab to the regimen. Despite significant improvement in overall and progression-free survival, patients who did not achieve CR pretransplant had a shorter time to progression. Therefore, the main objective of the MCL3 study was to improve the time to progression in patients who achieved only CRu or PR pretransplant by adding Zevalin to the high-dose regimen as a late intensification. Results of the – otherwise largely identical - MCL2 trial serve as the historic control. Methods: Newly diagnosed stage II-IV MCL patients < 66 years received induction immunochemotherapy with alternating cycles of R- (rituximab) maxi-CHOP and R-Ara-C to a total of 6 cycles. Evaluation of pretransplant response with CT scans and bone marrow was performed after 5 cycles. PET/CT pretransplant was recommended, but would not influence treatment. Responding patients by NCI criteria underwent in-vivo purged stem cell harvest after the 6th cycle (Ara-C + 2 doses of rituximab). Patients in CRu or PR received a standard dose Zevalin (0.4 mCi/kg) one week prior to high-dose therapy with BEAM or BEAC while CR patients received the high-dose chemotherapy without Zevalin. Follow-up included CT-scans, bone marrow and blood sampling for at least 5 years, including PCR for minimal residual disease or molecular relapse. Patients in solely molecular relapse received preemptive therapy with 4 weekly doses of rituximab, as in the MCL2 study. Results: 161 consecutive patients were included from 2005–2009, with characteristics similar to that of the MCL2 trial with a median age of 57 years (28–65), a male predominance and the majority in stage IV with bone marrow involvement. Only 12 out of 161 patients (7 %) did not receive a transplant, 6 due to stem cell harvest failure, 2 due to toxicity and 4 due to no response to induction treatment. Before transplant 50% were in CR, 17% in CRu, and 30% in PR. Only four out of 161 patients (2 %) did not respond to induction treatment. After a median follow-up of 3.2 years the projected 5-year overall and event free survival, and time to progression were 71, 55 and 65% respectively and the MCL2 and MCL3 curves were superimposable. Of the 69 candidates to Zevalin in CRu/PR according to protocol, 65 (94%) actually received this treatment. There was no significant difference in time to progression for patients in CRu and PR pretransplant between MCL2 and MCL3, indicating no effect of late intensification with Zevalin in MCL3 in this patient group. Interestingly, a positive pretransplant PET scan proved to be a strong negative predictor for outcome. Lack of benefit from addition of Zevalin to the high-dose regimen was shown for both PET-positive and PET-negative patients. In a multivariate analysis of the impact of clinical response, PET positivity and zevalin treatment, only PET positivity pretransplant had independent significance (p=0.0003 HR=3.412 (95% confidence limits 1.744 – 6.673). The treatment-related mortality was 3 %. Side-effects were similar to that previously reported for MCL2, and we did not find that Zevalin added any toxicity. Of the 3 patients who developed secondary MDS/AML posttransplant, two had received Zevalin and one had not. Conclusion: The MCL3 data confirm the good results and tolerability of the Nordic regimen. However, the late intensification with Zevalin, albeit non-toxic, did not prolong the time to progression for patients in only CRu or PR pretransplant. A positive PET prior to transplant was shown to be a strong negative predictor for outcome. The concept of late intensification may be too late in poor responders. In consequence, up-front intensification with increasing use of high-dose AraC for MIPI high-risk patients is used in the subsequent, now ongoing Nordic-British MCL5 study. Disclosures: Arne: Bayer Schering Pharma: Research Funding. Geisler:Roche, Schering: Consultancy, Research Funding.

Abstract 331 Background and aims: Systemic peripheral T-cell lymphomas (PTCL) are malignancies responding poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by upfront high-dose chemotherapy supported by autologous stem-cell transplantation (HDT/ASCT) in PTCL, the Nordic Lymphoma Group conducted the, so far, largest PTCL-restricted prospective phase II study in previously untreated systemic PTCL. This is the final report of the NLG-T-01 study with a 5-years median follow up. Methods: Patients with previously untreated systemic PTCL aged 18–67 years were included. ALK-positive anaplastic large cell lymphoma (ALCL) cases were excluded. An induction regimen of six cycles of bi-weekly cyclophosphamide, doxorubicin, etoposide, vincristin and prednisone (CHOEP) was given. Age-based (>60 yrs) omission of etoposide was recommended. If in complete or partial remission, patients received high-dose chemotherapy with carmustine, etoposide, cytarabine and melphalan/cyclophosphamide (BEAM/BEAC) followed by HDT/ASCT. Results: A total of 166 patients with previously untreated PTCL were enrolled. Of these, 160 were histopathologically confirmed and included the following subtypes: PTCL-not otherwise specified (PTCL-NOS) (n=62; 39%), ALK-negative ALCL (n=31; 19%), angioimmunoblastic lymphoma (AIL) (n=30; 19%), enteropathy-associated T-cell lymphoma (n=21; 13%), panniculitis-like (n=6; 4%), T/NK nasal-type (n=5; 3%), and hepatosplenic (n=5; 3%). The M/F ratio was 2.0 and the median age 57 yrs (range 22–67 yrs). The majority of the cases presented with advanced-stage disease (81%), B-symptoms (59%) and elevated s-LDH (62%). Nevertheless, 71% of all patients had a good performance score (PS) (WHO 0–1) at inclusion. With regard to the International Prognostic Index (IPI), risk factor distribution was as follows: 1 factor n=45 (28%), 2 factors n=52 (32%), 3 factors n=30 (19%), 4–5 factors n=33 (21%). Of the 160 patients, a total of 114 (71%) underwent HDT/ASCT with 90 in complete remission at 3 months post-transplant. Early failures occurred in 26% of the patients. The treatment related mortality was low (4%). At a median follow-up of 60 months, 83 patients were alive. The median follow-up for deceased patients (N=77) was 9 months. The consolidated 5-yr overall (OS) and progression-free survival (PFS) values for the entire cohort were 51% and 44%, respectively. Best results were obtained in ALK-negative ALCL with 5-yr OS and PFS of 70% and 61%, respectively. IPI was a useful overall prognostic discriminator for the low/low-intermediate vs. intermediate-high/high groups with regard to 5-yr OS (p=0,047) and 5-yr PFS (p=0,029). If applied separately to each of the four major subtypes, IPI had a predictive value for OS in AIL (p=0,02) and for PFS in both AIL (p=0,02) and PTCL-NOS (p=0,03). The clinicopathological parameters that showed a significant impact on OS and PFS were: female gender (correlated with a better outcome), age (analyzed as continuous variable), PS≥2 (correlated with adverse outcome), and cytotoxic phenotype (correlated with adverse outcome in AIL). All these parameters retained their prognostic value at multivariate level, except for cytotoxic phenotype, where multivariate analysis could not be performed because of too small numbers. Conclusions: Dose-dense induction followed by HDT/ASCT is well tolerated and leads to long-term PFS in 44% of patients with systemic PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the present study population. Therefore, based on these results, dose-dense induction and HDT/ASCT should be considered in transplant-eligible PTCL patients. Disclosures: Jantunen: Genzyme: Honoraria.

Idiotypes (Id) can serve as individual markers on B cells; therefore, cytotoxic Id-specific T cells may play a significant role in immunological surveillance of Id+ B-cell tumours. We have investigated the anti-tumour activity of CD4+ BALB/c Th1 and Th2 clones which recognize a processed Id of the syngeneic lambda 2(315) L chain in the context of the class II MHC molecule I-Ed. Id-specific T cells and A20/46 B lymphoma cells transfected with the lambda 2(315) gene were injected s.c. into the same site of BALB/c mice (Winn assay). The results show that both Th1 and Th2 clones can protect against tumour development. The protection was Id-specific because T cells did not influence tumour development by an A20/46 B lymphoma cell line transfected with the pSV2neo expression vector alone. In vitro studies showed that the Th1 clones were cytotoxic to lambda 2(315)-transfected B lymphoma cells; by contrast, the Th2 clone was not cytotoxic in 51Cr-release assay even though the Th2 cells inhibited the growth of lambda 2(315) B lymphoma cells. The anti-lymphoma properties of both the Th1 and Th2 clones appear to involve as yet undefined cytotoxic and growth inhibiting molecules.

Abstract 932 The Nordic Lymphoma Group has since 1996 conducted three consecutive phase II trials for front-line treatment of MCL patients ≤ 65 years of age. The first protocol (MCL1) 1996-2000 introduced high-dose chemotherapy with autologous stem cell support (unpurged or ex vivo purged) as consolidation after 4 cycles of intensified CHOP (maxi-CHOP). The results were disappointing, as the majority of patients relapsed. 1 Being in CR pre-transplant was the most important factor for outcome. Hence, in the second trial (MCL2) 2000-2006 induction therapy was intensified by adding high-dose Ara-C and rituximab to the regimen. Compared to MCL1 this led to significant improvement of event-free and overall survival, and the rate of PCR negative stem cell grafts and bone marrow samples.2 Again, responders in less than CR pre-transplant had a significantly poorer outcome. We therefore made a further intensification for the MCL3 study (2006-2009) by adding 90Y-Ibritumomab tiuxetan (Zevalin®) to the high-dose BEAC/BEAM to responders not in CR. Methods: As in the MCL1 and 2 studies newly diagnosed stage II-IV MCL patients ≤ 65 years were included. Induction treatment was identical to that of the MCL2 study with alternating cycles of maxi-CHOP-rituximab (3 cycles) and Ara-C-rituximab (3 cycles). Response evaluation was done after cycle 5. PET/CT was recommended, but could not influence the response evaluation, which was done according to the International Workshop criteria. Responders underwent in vivo purged harvest of stem cells after cycle 6 (Ara-C + 2 doses of rituximab). Patients in CRu or PR received a standard dose 90Y-Ibritumomab tiuxetan (0.4 mCi/kg) one week prior to the BEAM/BEAC, CR patients received BEAM/BEAC alone. Patients are followed by CT-scans, bone marrow and blood samples, including PCR for minimal residual disease or molecular relapse. For molecular relapse preemptive treatment with 4 standard doses of rituximab, as in the MCL2 study3, is given. Results: The planned accrual of 160 patients was reached in June 2009. The patient characteristics are similar to those of the MCL2 trial with a median age of 57 years (28-65), the majority male (80%) and in stage IV (89%) with bone marrow involvement (74%). The response rates pre-transplant so far compare favorably with data from MCL2 with 50% in CR, 18% in CRu, and 28% in PR. Only 4 out of 128 evaluable patients did not respond (3%) and there was one case (1%) of treatment-related mortality during induction therapy. While it is still too early to assess the impact of the 90Y-Ibritumomab tiuxetan on the progression-free survival, the side effects were similar to those of the MCL2 study including a treatment related mortality of 4%. Fifty-five patients in CRu or PR have so far been treated with 90Y-Ibritumomab tiuxetan, with no indication of any added toxicity. Only 12 out of 133 patients (10%) have not undergone transplant, 5 due to stem cell harvest failure, 3 due to toxicity and 4 due to non response to induction treatment. PET-scan prior to transplant was positive in 2% of CR patients, 20% of CRu patients and 54% of PR patients. Patients with a positive PET-scan pre-transplant had a 36% chance of achieving a molecular remission post-transplant, compared to 92% of cases with a negative PET-scan (p Conclusion: The high response rates after induction treatment achieved in the MCL2 study are confirmed in the present study. Adding 90Y-Ibritumomab tiuxetan to high-dose chemotherapy for responding patients not in CR prior to transplant is feasible and does not increase toxicity. A negative PET-scan prior to transplant predicts for a molecular remission after the transplant. References: Andersen et al, Eur J Cancer, 2002, 38: 401-408 Geisler et al, Blood, 2008, 112: 2687-2693 Andersen et al J Clin Oncol 2009 epub ahead of press Disclosures: Kolstad: Bayer Schering Pharma: Research Funding. Geisler:Bayer Schering Pharma: Research Funding.

Systemic PTCL, with the exception of alk-positive anaplastic large cell lymphoma (ALCL), have a poor prognosis. ASCT has been shown to have a favourable impact on relapsed PTCL. Therefore, the NLG designed a prospective multicenter phase II study to evaluate the impact of a dose-intensified induction schedule (6 courses of two-weekly CHOEP) consolidated in 1st PR/CR with high-dose therapy (BEAM) followed by ASCT in previously untreated systemic PTCL. This is the largest prospective PTCL-specific trial published so far. Newly diagnosed non-primary cutaneous PTCL cases aged 18–67 yrs were eligible for enrollment. Cases of alk-positive ALCL were excluded. From Oct 2001 to Feb 2006, 99 histologically confirmed PTCL cases were included in the study: PTCL unspecified (n=41), alk-neg ALCL (n=24), AILT (n=15), enteropathy-type (n=12), panniculitis-like (n=3), T/NK nasal-type (n=2), hepatosplenic (n=2). The M/F ratio was 1.8 and the median age 55 yrs (range 20–67 yrs). Although almost 2/3 of the cases presented with advanced-stage disease (62%), B-symptoms (61%) and/or elevated s-LDH (63%), the majority of them (65%) had a good performance score (WHO 0–1) at diagnosis. Of the 77 patients, where information was available for all 6 induction courses, 68 (88%) were in CR (31) or PR (37) after the 3rd and 66 (86%) after the 6th course. A total of 58 patients (75%) went through ASCT indicating that at least a fourth of this younger patient cohort has a primary refractory disease and fails therapy before reaching the transplant. Treatment-related toxicity after both induction and high-dose treatment was manageable. Of the 58 transplanted patients, 50 (86%) were still in remission at re-evaluation short after transplant. In 39 patients follow-up data one year post-transplant were available: 30 are still in CR and 9 have relapsed, suggesting that post-transplant relapses probably account for another 25% of the original patient cohort. In conclusion, the present data indicate that a time- and dose-intensified schedule is feasible and effective in previously untreated systemic PTCL. Continuous remissions are not uncommon, but a longer follow-up is needed to further characterize long-term remission rates and evaluate their impact on time-to-treatment failure and overall survival.

The use of short-duration intensive combination chemotherapy protocols has improved survival in adults with Burkitt/Burkitt-like leukaemia and lymphoma (BL). Systemic methotrexate (MTX) is an integral component of these regimens, but the dosage varies between treatment schedules, and the precise dose required to optimise tumour-kill without causing severe toxicity is not known. In this study of 66 adults with sporadic BL, we have investigated whether the dosing intensity of MTX can influence treatment failure (defined as disease relapse or resistance to treatment, or death due to therapy). There were 49 males and 17 females in the cohort (median age 36 years, range 16–69y), including 9 with HIV disease and 2 organ-transplant recipients. Majority of patients (66%) had St Jude stage III/IV disease. The median increase in serum LDH level relative to normal (adjusted LDH) was 1.4 (range 1–65). Patients were treated with a combination of CNS-directed and systemic chemotherapy comprising of a pre-phase [fractionated (Fr) cyclophosphamide and prednisolone], followed by a possible total of 6 cycles of alternating Fr ifosfamide, dexamethasone, vincristine, cytarabine and etoposide [Cycle A], with Fr cyclophosphamide, dexamethasone, vincristine and adriamycin [Cycle B] as outlined by the German BFM paediatric protocols. Patients received a 24h intravenous infusion of MTX on d1 of each cycle of treatment. Based on the mean MTX dose administered per cycle, patients were stratified into three dosage groups: low (1.5–3g/m2, n=34). There were 3 toxic deaths, disease was refractory in 8 patients and 9 experienced disease relapse. Durable complete responses following BFM were observed in 46/66 (70%) patients. A significantly lower proportion of patients receiving high-dose MTX (17%) experienced treatment failure compared to 45% and 50% in the intermediate and low-dose groups respectively (Fisher’s Exact p=0.01). Risk stratification on the basis of pre-treatment stage and bulk of disease, adjusted LDH and ECOG score was however unable to identify patients who may benefit from intensifying MTX dosage. These data thus uniquely highlight the impact of MTX dose in influencing outcomes in adult BL as well as the need for novel biological markers to identify patients requiring additional therapeutic strategies.

We studied six cases of a novel type of nodal peripheral T-cell lymphoma. Three cases with this disease were recently described by de Leval et al. (de Leval L, Savilo E, Longtine J, et al. Peripheral T-cell lymphoma with follicular involvement and a CD4+/bcl-6+ phenotype. Am J Surg Pathol2001;25:395–400). The entity was named peripheral T-cell lymphoma with follicular involvement because of its distinctive histological features. We report an additional six well-characterized cases and describe the molecular and cytogenetic findings. The neoplastic T-cells of this lymphoma type express CD4 and Bcl-6, and home to the B-lymphoid follicles. This suggests an origin of the lymphoma from an as yet poorly characterized subset of Bcl-6 expressing intra-follicular T-helper cells. Of interest, the cytogenetic data and/or the study of T-cell receptor gamma gene rearrangements revealed more than one clone in each case. Cytogenetics further revealed complex karyotypes without recurrent chromosomal aberrations. We also studied the presence of somatic mutations in the 5′ untranslated region of the BCL-6 gene in four of the cases but no somatic hypermutation was detected. Clinically, the cases presented with widespread lymph node involvement at diagnosis and multiple relapses occurred after treatment. All patients received a CHOP-based chemotherapy regimen, later followed by high dose chemotherapy with stem cell rescue in five patients. One patient died with lymphoma and hemophagocytic syndrome 24 months after diagnosis, one patient is alive with disease after 27 months from diagnosis, whereas the other four patients are in complete remission 12 to 124 months after diagnosis. In conclusion, we confirm that peripheral T-cell lymphoma with follicular involvement is a distinct lymphoma type and we show that the lymphoma is oligo-clonal. The clinical findings are those of an intermediately aggressive lymphoma type. Although minimal lymph node infiltration with lymphoma cells at diagnosis and oligo-clonality is also characteristic of angio-immunoblastic T-cell lymphoma, we believe that peripheral T-cell lymphoma with follicular involvement is a distinct T-cell lymphoma type. In contrast to angio-immunoblastic T-cell lymphoma it is characterized by the typical infiltration of lymphoma cells in B-lymphoid follicles, coagulation necrosis, the absence of proliferation of high endothelial venules and follicular dendritic cells in T-cell areas, as well as the absence of EBV infection. It is likely that T-cell lymphoma with follicular involvement arises from Bcl-6+ intra-follicular T-cells. No recurrent genetic defects have been identified but the oligo-clonal nature of the lymphoma is intriguing. The latter suggests that the triggering oncogenic factors are external, such as infection.

Splenic marginal zone lymphoma (SMZL) is a lymphoma type of putative marginal zone B-cell origin. No specific genetic alterations have yet been demonstrated in SMZL. Clinically, SMZL is a low-grade B-cell non-Hodgkin lymphoma. However, the presence of p53 mutation, 7q22-7q32 deletion or the absence of somatic hypermutations of immunoglobulin genes has been correlated with a worse prognosis. In this study, we analyzed genome-wide gene expression of 24 cases of SMZL using the microarray technique. The AP-1 transcription factors c-jun, junD, junB, and c-fos as well as Notch2 were found to be specifically up-regulated. These data were confirmed by real-time PCR and immunohistochemical staining of tissue sections. The absence of concordant high expression of the MAP kinases, the signaling cascade leading to AP-1 up-regulation, suggests autoregulation of the AP-1 transcription factors and an important role in SMZL oncogenesis. High expression of Notch2, a transcription factor that induces marginal zone B-cell differentiation, is highly suggestive for a marginal zone B-cell origin of SMZL. In addition, SMZL with the 7q deletion showed high expression of TGF-beta1 and low expression of the DNA helicase XPB, a crucial part of the nucleotide excision repair complex, possibly explaining the more aggressive clinical course of those cases.

Abstract 4110 Background: The ACT trial (ACT-1 and −2) tests the addition of alemtuzumab (ALZ) to 6 courses of bi-weekly CHOP (A-CHOP-14) followed, in younger patients (ACT-1), by high-dose therapy with autologous stem cell transplant (HDT/ASCT) in newly diagnosed primary systemic peripheral T-cell lymphoma (PTCL). To date, the trial has accrued a total of 131 patients (ACT-1 n=72; ACT-2 n=59). Here, we present the first planned interim safety analysis of the ACT-1 trial based on the first 51 randomized patients. Aims: The aim of the present analysis is to report on the feasibility of a dose-dense chemo-immunotherapy schedule combining ALZ and bi-weekly CHOP followed by HDT/ASCT in ‘de novo' PTCL patients. Results: Results contain two data subsets corresponding to ALZ dose levels prior and subsequent to a dose-reduction amendment tapering ALZ dose from 360 mg (30 mg on days 1 and 2 of each CHOP course) to 120 mg (30 mg on day 1 of CHOP courses 1–4), respectively. Of the 51 randomized patients, 43 had a complete set of evaluable data and represent the background for the present set of results. Of these, 5 received the higher ALZ dose, 17 the lower and 21 belonged to the antibody-void control arm. Treatment arms were well balanced with regard to histological subtypes, IPI sub-groups, and single prognostic factors. Neither of the two treatment cohorts, and for the experimental one irrespective of ALZ dose level, showed significant treatment delay. The median duration of chemotherapy (calculated for 5 bi-weekly cycles of an expected cumulative duration of 70 days) for non-ALZ vs. ALZ-treated patients was 73 vs. 81 days, respectively. No suspected unexpected serious adverse reactions (SUSARs) were reported. Grade 3–4 leucopenia and anemia were more frequent in ALZ-treated patients (71% vs 29% and 47% vs 14%, respectively), whereas no difference was seen in terms of thrombocytopenia (17% vs 18%). Non-hematological toxicity unrelated to infectious complications was similar in the two groups. At the higher ALZ dose level, two cases of systemic fungal infection were reported, of which one (verified as being aspergillosis) with fatal outcome in a patient with pre-existing type II diabetes and steroid-requiring chronic obstructive pulmonary disease. These two events prompted the ALZ dose-reduction amendment, which led to a significant drop in the number of serious adverse events (SAEs) for ALZ-treated patients (SAE/patient pre-amendment: 2.6, post-amendment: 0.76) to a level comparable with the control arm (SAE/patient pre-amendment: 0.67, post-amendment: 0.44). With regard to the types of infection (≥grade 2), there was a similar frequency in reported fungal infections between the two treatment cohorts, bacterial infections were more often reported in the standard treatment arm (55% vs 46%), while the opposite was observed for viral infections (29% vs. 35%). Among the latter, there were 8 cases of cytomegalovirus reactivation among ALZ-treated patients, of which only two were clinically symptomatic and regressed upon specific treatment. Conclusion: In conclusion, the early-on impression of a SAE decrease subsequent to the ALZ dose-reduction amendment (applied on both ACT-1 and ACT-2) has been further confirmed by a larger cohort of patients treated at the lower ALZ dose level. The number of adverse events in the two study arms is now fairly comparable and adds further useful information to the previous reports on feasibility of stem cell harvest (Blood 2010;116: 2395) and hematopoietic recovery (Ann Oncol 2011;22(s4): 476) in ‘de novo' PTCL patients treated with a dose-dense ALZ-CHOP regimen followed by HDT/ASCT. Disclosures: Walewski: 4SC AG: Consultancy. Jantunen:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract 57 Background The ACT trial (ACT-1, younger patients aged 18–60 yrs and ACT-2, elderly patients aged >60 yrs) is the first international randomized phase III trial in newly diagnosed primary systemic peripheral T-cell lymphoma (PTCL). It tests, in both younger and elderly patients, the efficacy of the addition of alemtuzumab (ALZ) to 6 courses of bi-weekly CHOP followed, only in younger patients (ACT-1), by high-dose therapy with autologous stem cell rescue. A dose reduction amendment tapering the cumulative ALZ dose from 360 mg (30 mg on days 1 and 2 of CHOP courses 1–6) to 120 mg (30 mg on day 1 of CHOP courses 1–4), respectively, was introduced early on due to two cases of systemic fungal infection (Blood 2011,118;4110). To date, the trial has accrued a total of 186 patients (ACT-1 n=98; ACT-2 n=88). Aim Here, we present the results from the first interim efficacy and safety analysis of the ACT-1 trial based on the first 68 randomized patients. Results Of the 68 patients, 63 had a complete set of treatment data. The median follow-up was 15 months (range 0.5–42 months). Thirty-two patients belonged to the experimental arm (exp) and 31 to the standard arm (std). Of the 32 patients treated according to exp, 4 received the higher dose of ALZ and 28 the lower. Treatment arms were well balanced with regard to main prognostic features such as age (std: median 53 yrs, range 21–60 yrs; exp: median 50 yrs, range 22–64 yrs; p=0.705), IPI subgroups (std: low 10%, low-intermediate 51%, intermediate-high 29%, high 10%; exp: low 12%, low-intermediate 44%, intermediate-high 19%, high 25%; p=0.392), advanced clinical stage (std: stage III-IV 94%; exp: 97%; p=0.613), performance status ECOG>1 (std: 23%; exp: 28%; p=0.613), elevated LDH (std: 68%; exp: 69%; p=0.932), presence of B-symptoms (std: 68%; exp: 75%; p=0.524), bulky disease (std: 13%; exp: 13%; p=1.0) and bone marrow involvement (std: 39%; exp: 31%; p=0.535). Histological subtypes were also similarly distributed among both treatment arms (std: PTCL-NOS 55%, AILT 23%, other 22%; exp: PTCL-NOS 56%, AILT 28%, other 16%). No cases of anaplastic large cell PTCL (regardless of ALK-protein status) were included. Neither of the treatment cohorts showed significant treatment delay. The median duration of chemotherapy (calculated for 5 bi-weekly cycles of an expected cumulative duration of 70 days) for non-ALZ vs. ALZ-treated patients was 73 vs. 81 days, respectively. No suspected unexpected serious adverse reactions (SUSARs) were reported. Grade 4 leucopenia was more frequent in ALZ-treated patients (std: 24%, exp: 69%; p=0,001), whereas grade 3–4 anemia and grade 3–4 thrombocytopenia were not significantly different between treatment arms (anemia, std: 19%, exp: 31%; p=0,278; thrombocytopenia, std: 20%, exp: 12%, p=0,682). Non-hematological toxicity unrelated to infectious complications was mild and had a similar frequency in both arms. The number of serious adverse events (SAEs) per patient was 0.86 for patients treated at post-amendment ALZ dose levels, representing a significant reduction compared to the pre-amendment value (3.25), and 0.46 for patients treated in the control arm (p=0.002). The frequency of bacterial and fungal infections (grade ≥3) was similar in both treatment arms. ALZ treated patients had more viral events (9/32; 28% vs. 3/31; 10%), mainly (6 out of 9) consisting of asymptomatic cytomegalovirus reactivations. The overall (non-arm specific) 1-year event-free survival (primary end-point), progression-free survival and overall survival were 55% (95% CI: 42%-67%), 54% (95% CI: 42%-67%) and 78% (95% CI: 67%-88%), respectively. Conclusion The safety profile of the current standard and experimental treatment schedules, as well as the interim outcome results, support a continuation of the trial. A final analysis will be performed in Q2 2015. Disclosures: Jantunen: Genzyme: Has participated in EU Leadership meeting organized by Genzyme as well as Medical Advisory Board meeting organized by Genzyme Other, Honoraria.