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[§ 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.

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.

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.

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.

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.