Search

Dose-dense induction and up-front consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating patients with high-risk diffuse large B-cell lymphoma. GELA designed a randomized phase 2 trial evaluating the efficacy of either rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone (R-ACVBP) or rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP14) induction and a positron emission tomography (PET)-driven ASCT or standard immunochemotherapy (SIC) consolidation in age-adjusted international prognosis index 2 (aaIPI2)-aaIPI3 patients. PET was performed at baseline, after 2 (PET2) and 4 (PET4) induction cycles, and centrally assessed using international harmonization project (IHP) criteria. PET2-/PET4- patients were assigned SIC, PET2+/PET4- patients were assigned ASCT, and PET4+ patients were treated with the investigator's choice. The primary end-point was the 2007 international working group complete response (CR) rate after induction. Change in maximum standard uptake value (ΔSUVmax) after PET assessment was explored. Two hundred eleven patients were randomly assigned to R-ACVBP (n = 109) or R-CHOP14 (n = 102). PET4-/CR rates were 53%/47% with R-ACVBP and 41%/39% with R-CHOP14 (CR 95% confidence interval [CI], 38%-67% and 28%-54%, respectively; P = .076). Consolidation in the R-ACVBP and R-CHOP14 groups was SIC in 26% and 23% of patients and ASCT in 28% and 18% of patients, respectively. PET4 positivity was higher with R-CHOP14 vs R-ACVBP (54% vs 41%; P = .08), leading to more salvage therapy (37% vs 26%; P = .07) and lower event-free survival (EFS; 4-year EFS, 31% vs 43%; P 70% was associated with better outcome (4-year PFS, 84% vs 35%; 4-year OS, 91% vs 57%; P < .0001), whatever the consolidation. Superiority of R-ACVBP over R-CHOP14 was not established, as IHP criteria did not properly reflect disease control. ΔSUVmax may help better select patients needing an alternative to SIC, including ASCT.

Introduction: There is no standard treatment of refractory or relapsed (R/R) patients (pts) with DLBCL ineligible for autologous stem-cell transplantation (ASCT). However, R-GemOx is widely used in these circumstances. We here report the results of a retrospective analysis of a cohort of patient treated in two academic centers in France. The main objectives were to evaluate the activity and safety profile of this regimen in a large series of R/R DLBCL pts in a real life setting. Methods: Patients selected had to have de novo or transformed DLBCL, R/R after at least one line of treatment containing doxorubicin and rituximab, to be ineligible for ASCT and to have received at least one cycle of R-GEMOX. Rituximab 375 mg/m2 was administered on D1, gemcitabine 1000 mg/m2 on D2 and oxaliplatin 100 mg/m2 on D2 as previously described (Mounier N. et al. Haematologica 2013; 98:1726-31). Cycles were given every 2 weeks and 8 cycles were planned if at least a partial response (PR) was obtained after 4 cycles. Results: Between May 2002 and May 2017, 196 pts were treated. Baseline characteristics were: median age: 72 y (range, 24-89), international prognostic index (IPI) 3-5: 63%, refractory state to last treatment (tx): 42%, history of indolent lymphoma: 45%, prior ASCT: 16%. The median number of previous line was 1 (range 1-7) with 112 pts having received R-GemOx in second line. One hundred and thirty-six pts received at least 4 cycles, 86 pts completed 6 cycles and 61 pts 8 cycles. After 4 cycles, the overall response rate (ORR) according to IWC (Cheson 1999 or 2007) was 54 % and the complete response (CR) rate was 23 %. At the end of treatment, the ORR and CR rates were 38 % and 33 %, respectively. With a median follow-up of 22 months, median (m) progression-free survival (PFS) and overall survival (OS) were 5 and 10 months (mo), respectively. mOS was significantly longer in case of prior history of indolent lymphoma (21 vs 8 mo, p < 0.001), age Summary/Conclusion: This real life study of R/R DLBCL, confirms the activity and safety of R-GemOx. This combination represents a platform to be combined with targeted therapies as it is currently proposed with nivolumab in the phase 3 NIVEAU trial (NCT03366272) and planned with polatuzumab vedotin (POLARGO trial). However, facing this very high unmet medical need, new approaches including CAR T-cells should also be considered in this patient population. Disclosures Belhadj: Janssen: Honoraria; Celgene: Honoraria, Other: personal fees from Celgene, personal fees from Amgen, personal fees from Takeda, personal fees from Janssen, outside the submitted work; Takeda: Honoraria; Amgen: Honoraria. Le Bras:Pfizer: Other: Travel grant; Takeda: Research Funding; Jansen: Other: Travel grant. Jardin:amgen: Honoraria; Servier: Honoraria; celgene: Honoraria; roche: Honoraria; janssen: Honoraria. Tilly:Roche: Consultancy; Celgene: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Karyopharm: Consultancy; BMS: Honoraria; Janssen: Honoraria; Gilead: Honoraria; merck: Honoraria; servier: Honoraria; roche: Membership on an entity's Board of Directors or advisory committees. Haioun:F. Hoffmann-La Roche Ltd: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Servier: Honoraria; Miltenyi: Honoraria; Takeda: Honoraria.

Introduction: Patients (pts) with HIV have a 6-fold increased risk of developing classic Hodgkin lymphoma (cHL) over the general population. The outcome of frontline therapy for HIV-associated cHL (HIV-cHL) using doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is similar to the non-HIV population. However, pts with advanced stage cHL continue to have a 30% chance of refractory/relapsed disease with ABVD. Brentuximab vedotin (BV) is an anti-CD30 antibody drug conjugate that selectively induces apoptosis of CD30+ cells. The FDA approved BV with AVD (BV-AVD) after the Echelon-1 (E1) study for advanced stage disease demonstrated improved modified progression free survival (mPFS) at 2 years compared with standard ABVD: 82% vs. 77%. Pts with HIV were excluded from both relapsed/refractory and frontline BV trials. Here we present the final results of the phase 2 trial of BV-AVD in previously untreated HIV-associated cHL, an AIDS Malignancy Consortium/LYSA collaboration (ClinicalTrials.gov ID: NCT01771107). Methods: Forty-one pts were treated on days 1 and 15 of 6, 28 day cycles, with 1.2mgs/kg of BV in combination with doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 (AVD). Eligibility criteria included untreated cHL stage II-IV, CD4 + T-cell counts ≥50 cells/mm3, and initiation of combined antiretroviral therapy (cART) at least 1 week prior to therapy. Ritonavir, zidovidine, cobisistat, and other strong CYP3A4 or P-glycoprotein inhibitors were excluded with a washout of at least 1 week being required. Hematopoietic growth factor was mandated. The primary objective was 2 year PFS. The sample size was based on providing an estimate of the PFS with a 95% CI +/- 10% under the assumption of a 2 year progression free survival (PFS) estimate of 85%. Secondary objectives included toxicity, effects on CD4/CD8 + T-cells, HIV-1 viral load, prognostic significance of post C2 and end of treatment PET-CT. Results: Forty-one pts (93% men) were treated with a median age of 48y (range 24-67). Pts presented with stage II (17%), III (27%), and IV (56%) disease. Two year PFS estimate in the overall population (N=41) was 86% (95% CI: .74, .98). The 2-year overall survival (OS) estimate was 92% (95% CI: 0.83, 1.0) with 3 deaths at the time of analysis, including 1 which was a treatment related death (Figure 1A). For pts with advanced disease (N=34), the 2-year PFS estimate was 87% (95% CI: 0.76, 0.99) with an OS estimate of 90% (95% CI: 0.8, 1.00) (Figure 1B). Safety profiles were quite similar to the BV-AVD arm in the E1 study of the pts who received growth factor. Neuropathy was higher in our study compared to E1, (49% vs. 29% for any grade, P=0.01; 9.8% vs. 5% for G3/4, p=0.06). G3 Neutropenia was greater in AMC 085 compared to E1 BV-AVD arm with growth factor: 57% vs. 29% (p Conclusions: BV-AVD in stage II-IV HIV-cHL was efficacious although neutropenia and neuropathy were increased compared to the non-HIV population. The 2-year PFS estimate was 86% for the entire cohort and 87% for advanced stage HIV-cHL. Major interactions with strong CYP3A4 inhibitors lead to toxicity and must be avoided. The etiology of the CD4 increase is under investigation and may have implications for future therapy. Disclosures Rudek: Cullinan Apollo: Research Funding; Taiho: Research Funding; RenovoRX: Research Funding; Celgene: Research Funding. Barta:Mundipharma: Honoraria; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. OffLabel Disclosure: Brentuximab Vedotin has been approved for the upfront treatment of advanced stage cHL in combination with AVD though not specifically approved for use in patients infected with HIV or stage 2 cHL.

Limited comparative data exist for the treatment of HIV-associated non-Hodgkin lymphoma. We analyzed pooled individual patient data for 1546 patients from 19 prospective clinical trials to assess treatment-specific factors (type of chemotherapy, rituximab, and concurrent combination antiretroviral [cART] use) and their influence on the outcomes complete response (CR), progression free survival (PFS), and overall survival (OS). In our analysis, rituximab was associated with a higher CR rate (odds ratio [OR] 2.89; P < .001), improved PFS (hazard ratio [HR] 0.50; P < .001), and OS (HR 0.51; P < .0001). Compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), initial therapy with more dose-intense regimens resulted in better CR rates (ACVBP [doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisolone]: OR 1.70; P < .04), PFS (ACVBP: HR 0.72; P = .049; "intensive regimens": HR 0.35; P < .001) and OS ("intensive regimens": HR 0.54; P < .001). Infusional etoposide, prednisone, infusional vincristine, infusional doxorubicin, and cyclophosphamide (EPOCH) was associated with significantly better OS in diffuse large B-cell lymphoma (HR 0.33; P = .03). Concurrent use of cART was associated with improved CR rates (OR 1.89; P = .005) and trended toward improved OS (HR 0.78; P = .07). These findings provide supporting evidence for current patterns of care where definitive evidence is unavailable.

Nasal NK/T-cell lymphoma is a rare disease entity with a poor outcome. Expression of antiapoptotic proteins has not been extensively investigated in this entity. Forty-eight patients with nasal T/NK-cell lymphoma who received first-line polychemotherapy (n = 44) or chemoradiotherapy (n = 4) were analyzed for expression of active caspase-3 (aC3), granzyme B protease inhibitor 9 (PI9), and Bcl-2 proteins. Lymphomas were CD3+/CD5−/granzyme B+ and EBV-associated. Median age was 46 years. Stage I/II disease was present in 75% of the cases and an International Prognostic Index (IPI) score less than 1 in 65%. With a median follow-up of 6.3 years, 5-year event-free survival (EFS) and overall survival (OS) rates were 39% and 49%, respectively. Apoptotic index was scored as high in 32% of cases and PI9 expression as positive in 68%, whereas 35% disclosed a high number of aC3+ tumor cells. Univariate analysis showed that absence of PI9 and low apoptotic index were associated with poor outcome, but not aC3 expression nor IPI score. By multivariate analysis, both parameters affected independently EFS (P = .02 and .08, respectively) and OS (P = .009 and .04). In view of its constitutive expression by normal NK cells, it is suggested that loss of PI9 expression in tumor cells may reflect some mechanism associated with progression.

The survival of patients with aggressive non-Hodgkin lymphoma (NHL) is increasing, but the incidence of secondary cancer and late toxicity is poorly defined for those treated with cyclophosphamide-hydroxydaunomycin/doxorubicin-Oncovin-prednisone (CHOP)-like chemotherapy. From February 1984 to January 1998, 2837 patients with aggressive NHL received the control-arm chemotherapy adriamycin-cyclophosphamide-vindesine-bleomycin-prednisone (ACVBP) in 3 consecutive Groupe d'Etude des Lymphomes de l'Adulte (GELA) studies. With a median follow-up time of 74 months, the 5-year overall and event-free survival rates were 60% and 52%. Two hundred two occurrences of nonneoplastic late toxicity were reported, resulting in a 5.35% cumulative probability of incidence at 7 years. Eighty-one second tumors developed, for which the 7-year cumulative incidence rate was 2.75%; 64 were solid tumors, and 17 were hematologic malignancies. In multivariate analysis, age was the only risk factor for the second development of cancer. Epidemiologic analysis allowed a comparison of this NHL group with the general population. Considering all tumors, no excess of second cancer was observed. In the male population, however, there was an excess of lung cancer (standardized incidence ratio [SIR], 2.45; P

Fas (CD95) is a death receptor involved in apoptosis induction on engagement by Fas ligand (CD95L). Although CD95L-mediated apoptosis has been proposed as a pathogenic mechanism in a wide range of diseases, including graft-versus-host disease, systemic CD95 engagement in mice by agonistic CD95-specific antibodies or by soluble multimeric CD95L (smCD95L), though lethal, has been reported to cause apoptosis only in a limited range of cell types, that is, hepatocytes, hepatic sinusoidal endothelial cells, and lymphocytes. Another member of the tumor necrosis factor (TNF)/CD95L family, TNF-α, induces disseminated vascular endothelial cell apoptosis, which precedes apoptosis of other cell types and lethal multiorgan failure. Here we show that systemic CD95 engagement in vivo by agonistic CD95-specific antibody or smCD95L causes rapid, extensive, and disseminated endothelial cell apoptosis throughout the body, by a mechanism that does not depend on TNF-α. Disseminated endothelial cell apoptosis was also the first detectable lesion in a murine model of acute tissue damage induced by systemic transfer of allogeneic lymphocytes and did not occur when allogeneic lymphocytes were from CD95L-defective mice. Both vascular and additional tissue lesions induced by agonistic CD95-specific antibody, smCD95L, or allogeneic lymphocytes were prevented by treatment with an inhibitor of caspase-8, the upstream caspase coupled to CD95 death signaling. Vascular lesions are likely to play an important role in the pathogenesis of allogeneic immune responses and of other diseases involving circulating CD95L-expressing cells or smCD95L, and the prevention of CD95-mediated death signaling in endothelial cells may have therapeutic implications in these diseases.

Caloric restriction (CR) is proposed to decrease tumorigenesis through a variety of mechanisms including effects on glycolysis. However, the understanding of how CR affects the response to cancer therapy is still rudimentary. Here, using the Eµ-Myc transgenic mouse model of B-cell lymphoma, we report that by reducing protein translation, CR can reduce expression of the prosurvival Bcl-2 family member Mcl-1 and sensitize lymphomas to ABT-737-induced death in vivo. By using Eµ-Myc lymphoma cells lacking p53, we showed that CR mimetics such as 2-deoxyglucose led to a decrease in Mcl-1 expression and sensitized lymphoma cells to ABT-737-induced death independently of p53. In keeping with this, Eµ-Myc lymphoma cells lacking the BH3-only proapoptotic members Noxa, Puma, or Bim were also sensitized by CR mimetics to ABT-737-induced death. Remarkably, neither the loss of both Puma and Noxa, the loss of both Puma and Bim, nor the loss of all three BH3-only proteins prevented sensitization to ABT-737 induced by CR mimetics. Thus, CR can influence Mcl-1 expression and sensitize cells to BH3 mimetic-induced apoptosis, independently of the main BH3-only proteins and of p53. Exploiting this may improve the efficiency of, or prevent resistance to, cancer therapy.

bcl-xL, a member of the Bcl-2 family, exerts an antiapoptotic effect on lymphocytes. To assess its clinical significance in patients with follicular lymphoma, realtime quantitative reverse transcription–polymerase chain reaction (RT-PCR) analysis of bcl-xL gene expression was investigated in whole lymph node sections and laser-microdissected lymphoma cells of 27 patients. Compared with 10 patients with reactive follicular hyperplasia, the bcl-xL gene was overexpressed in patients with follicular lymphoma at a higher level in microdissected lymphoma cells. The bcl-xL gene level correlated with the number of apoptotic lymphoma cells labeled by terminal deoxytransferase-catalyzed DNA nick-end labeling (TUNEL) assays (r = -0.7736). Clinically, a high bcl-xL level was significantly associated with multiple sites of extranodal involvement (P = .0020), elevated lactate dehydrogenase level (P = .0478), and an International Prognostic Index indicating high risk (P = .0235). Moreover, bcl-xL gene overexpression was linked to short overall survival times (P = .0129). The value of bcl-xL gene expression as a prognostic marker in follicular lymphoma should thus be considered.

Approximately 5-10% of diffuse large B-cell lymphomas (DLBCL) harbor a 8q24/MYC rearrangement (MYC+). We determined the prognostic significance of MYC rearrangement in patients with relapsed/refractory DLBCL prospectively treated by R-ICE or R-DHAP followed by high-dose therapy and autologous stem cell transplantation. Twenty-eight (17%) of the 161 patients analyzed presented a MYC+ rearrangement, targeted as either simple hit (25%) or complex hits (n=75%) including MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6. Results were statistically highly concordant in matched primary and relapsed biopsies (n = 45). Compared to the MYC− DLBCL patients, the MYC+ DLBCL patients presented with a more elevated lactico-deshydrogenase level (P = .0006) and a more advanced age adjusted international prognostic index (P = .0039). The 4-year PFS and OS were significantly lower in the MYC+ DLBCL patients than those in the MYC− DLBCL patients, with rates of 18% vs 42% (P = .0322), and of 29% vs 62% (P = .0113), respectively. Type of treatment, R-DHAP or R-ICE, had no impact on survivals, with 4-year PFS rates of 17% vs 19% and 4-year OS rates of 26% vs 31%. In conclusion, MYC rearrangement is an early event in DLBCL. MYC+ DLBCL patients have a significant inferior prognosis than MYC− DLBCL patients. Their outcome was not influenced by the proposed salvage therapy.

Introduction and Methods: Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT) is standard care for relapsed/refractory DLBCL. In the CORAL study, 477 patients were assigned to one of two salvage regimens (R-DHAP or R-ICE). Only the 240 responding patients underwent per protocol ASCT and were randomly assigned to rituximab or observation. The four-year event-free survival (EFS) post ASCT were 52 and 53% for the rituximab and observation groups, respectively (p=.7). Secondary IPI (sIPI) independently predicted EFS, PFS and OS after ASCT (Gisselbrecht et al, JCO 2010 & 2012). Outcome data are limited in DLBCL patients who relapse after ASCT, with reported overall survival (OS) of 9.9 months in rituximab-pretreated patients (Nagle et al, AJH 2013). To shed more light on outcome and prognostic factor in this population, 75 patients included in the CORAL study who relapsed after scheduled BEAM/ASCT were reviewed. Results: Median time between ASCT scheduled in CORAL and relapse was 7.1 months (range 3.1-61.9) with 32.9% relapsing > 12 months. Median age was 56.1y (range 20.9-67.7), M/F ratio 51/24, sIPI 0-2 in 71.6%, >2 in 28.4%. 49.3% were in the rituximab and 45.3% in the observation arm of the CORAL. All patients had previously received rituximab. Third-line therapy consisted of ICE-type (17.3%), DHAP-type (24%), gemcitabine-containing (28%), CHOP-like (13.3%), and miscellaneous regimens (17.3%). Overall response rate to third-line chemotherapy was 44%, with 32% complete response (CR)/CR unconfirmed (CRu), and 12% PR. Among the 75 patients, 16 (21.6%) could eventually be transplanted 3 ASCT and 13 allogeneic SCT with conditioning regimens including fludarabine. Median OS, calculated from time of relapse until death, was 10.0 months (95% CI 6.6-12.6; min: 0.9-max: 55.2 months; median follow-up: 32.8 months) with an estimated 1-y OS of 39.1%. Median OS was statistically different (p=.0007) according to sIPI at CORAL failure: sIPI 0-2: 12.6 months (1-y OS 51.3%), sIPI > 2: 5.3 months (1-y OS 21.6%, HR 2.805). Median OS in patients achieving CR/CRu, PR, or no response after third-line regimen was 37.7 m (1-y OS 90.5%, p 6 and < 12 months (11.3 months, n=21) or > 12 months after ASCT (12.6 months, p=0.01, fig. 1)). In multivariate Cox analysis (with the following variables entered: age, sex, sIPI, response to third line and time between CORAL ASCT and relapse), sIPI >2 (HR 2.464, p=0.01), achievement of CR (HR 0.1, p Conclusions: Overall, the outcome of DLBCL patients relapsing after second-line R-DHAP/R-ICE followed by ASCT is poor. However, prognostic factors predicting better outcome in this group are late (> 6 months) relapse, lower sIPI and achieving at least PR after third-line salvage followed by transplantation. In the transplanted patients (allo SCT or second ASCT) a 2-year OS of 50% was observed. Thus, new salvage regimens can be a bridge to transplantation in patients with late relapse and/or low sIPI,. New drugs improving salvage efficacy are urgently needed, especially for patients relapsing < 6 months following ASCT. Figure 1. OS (months) in DLBCL patients relapsing after CORAL-scheduled ASCT according to interval between ASCT and relapse ( 12 months) Figure 1. OS (months) in DLBCL patients relapsing after CORAL-scheduled ASCT according to interval between ASCT and relapse ( 12 months) Disclosures Schmitz: Roche, Takeda, Gillead, Riemser und ctilifesciences: Other: Advisory board, Speakers Bureau. Gill:Sanofi Aventis: Research Funding; Roche: Honoraria; AbbVie: Honoraria; Roche: Research Funding. Milpied:Celgene: Honoraria, Research Funding. Briere:St. Louis Hospital, Paris, France: Employment. Thieblemont:St. Louis Hospital, Paris, France: Employment. Salles:Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy. Gisselbrecht:roche: Research Funding, Speakers Bureau.

Peripheral T-cell lymphomas (PTCLs) are rare and have a dismal prognosis. The most frequent subtype is PTCL, unspecified. Epstein-Barr virus (EBV) has been detected in around 40% of cases, but its prognostic significance is not fully established. Lymph node samples from 110 patients with PTCL, unspecified included in LNH87 and LNH93 trials were available. EBV status was studied by EBV-encoded small RNA in situ hybridization (EBER-ISH). EBER-ISH showed positive cells in 45 (41%) of 110 patients. Pretreatment characteristics were comparable between positive and negative cases, except for male sex (80% versus 60%, respectively, P = .02). Only 50% of patients achieved complete remission with a 5-year event-free survival (EFS) and overall survival (OS) of 21% and 30%, respectively. EBER-ISH positivity was the sole factor linked with worse EFS, with a 5-year probability of 11% for positive patients. In univariate analysis, factors affecting OS were EBER-ISH positivity, high LDH level, and age older than 60 years. In multivariate analysis, EBER-ISH was associated with a worse OS in the elderly population. Time-dependent analysis showed that the negative impact of EBV was essentially seen in the first 2 years following diagnosis. These results warrant further studies regarding pathogenesis and specific treatment approaches for EBV-associated PTCL patients.

The purpose of this study is to compare our standard chemotherapy regimen (CHVP [cyclophosphamide, doxorubicin, teniposide, and prednisone]) plus interferon with 4 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by high-dose therapy with autologous stem cell transplantation (ASCT) in treatment-naive patients with advanced follicular lymphoma. Four hundred one patients were included from July 1994 to March 2001: 209 received 12 cycles of CHVP plus interferon α for 18 months (CHVP-I arm) and 192 received 4 cycles of CHOP followed by high-dose therapy (HDT) with total body irradiation and ASCT (CHOP-HDT arm). Overall response rates were similar in both groups (79% and 78% after induction chemotherapy, respectively). One hundred thirty-one of the 150 patients eligible for HDT underwent transplantation (87%). Intent-to-treat analysis after a median follow-up of 7.5 years showed that there was no difference between the 2 arms for overall survival (P = .53) or event-free survival (P = .11). Patients with a complete response at the end of the induction therapy had a statistically longer event-free survival and overall survival (P = .02 and < .001, respectively). After long-term follow-up, our study showed that there was no statistically significant benefit in favor of first-line high-dose therapy in patients with follicular lymphoma. High-dose therapy should be reserved for relapsing patients.

We aimed to compare AIDS risk–adapted intensive chemotherapy in AIDS-related lymphoma (ARL) patients before and after the advent of highly active antiretroviral therapy (HAART). A total of 485 patients aged from 18 to 67 years were randomly assigned to chemotherapy after stratification according to an HIV score based on performance status, prior AIDS, and CD4+ cell counts below 0.10 × 109/L (100/mm3). A total of 218 good-risk patients (HIV score 0) received ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisolone) or CHOP (doxorubicin, cyclophosphamide, vincristine, and prednisolone); 177 intermediate-risk patients (HIV score 1), CHOP or low-dose CHOP (Ld-CHOP); and 90 poor-risk patients (HIV score 2-3), Ld-CHOP or VS (vincristine and steroid). The 5-year overall survival (OS) in the good-risk group was 51% for ACVBP versus 47% for CHOP (P = .85); in the intermediate-risk group, 28% for CHOP versus 24% for Ld-CHOP (P = .19); and in the poor-risk group, 11% for Ld-CHOP versus 3% for VS (P = .14). The time-dependent Cox model demonstrated that the only significant factors for OS were HAART (relative risk [RR] 1.6, P < .001), HIV score (RR 1.7, P < .001), and the International Prognostic Index (IPI) score (RR 1.5, P < .001) but not chemotherapy regimen. Our findings indicate that in ARL patients, HIV score, IPI score, and HAART affect survival but not the intensity of the CHOP-based chemotherapy.

In diffuse large B-cell lymphoma (DLBCL), the combination of rituximab and CHOP (cyclophosphamide, doxorubicine, vincristine, prednisone; R-CHOP) has been shown to be more effective than CHOP for the treatment of elderly patients. Bcl-2 protein expression has been associated with poor prognosis in patients with DLBCL. To establish whether or not rituximab reduces bcl-2-assoclated treatment failure, we studied bcl-2 protein expression and clinical outcome in patients included in the Groupe d'Etude des Lymphomes de l'Adulte LNH-98-5 trial. Patients between 60 and 80 years of age were randomized to receive 8 cycles of either CHOP or R-CHOP every 3 weeks. Of the 399 patients included, 292 with histologically proven DLBCL had material available for bcI-2 study. Tumors were considered positive when at least 50% of tumor cells expressed bcl-2 protein. There were 193 (66%) bcl-2(+) patients and 99 (34%) bcl-2 patients. The response rates for R-CHOP and CHOP were, respectively, 78% and 60% (P = .01) in bcl-2(+) patients and 76% and 73% (P = .7) in bcl-2- patients. At a median of 2 years of follow-up, R-CHOP was significantly associated with a better overall survival than CHOP in bcl-2(+) patients (67% +/- 9% versus 48% +/- 11%, P = .004). In bcl-2- patients there was no statistically significant difference ( 72% +/- 12% versus 67% +/- 14%, P = .6). In addition, R-CHOP was associated with significantly better event-free survival than CHOP in bcl-2(+) patients (58% +/- 10% versus 32% +/- 10%, P < .001) but not in bcl-2- patients (60% +/- 13% versus 40% +/- 15%, P = .13). Multivariate analysis confirmed the significant benefit for survival and event-free survival of R-CHOP in bcl-2(+) patients. These results suggest that rituximab is able to prevent chemotherapy failure in patients with bcl-2 protein overexpression. (C) 2003 by The American Society of Hematology.

Introduction Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare entity with distinct clinico-pathological features accounting for 5% of all Hodgkin lymphomas. Its optimal management is still debated, including the place of therapeutic abstention, and the role of rituximab. With the aim to report the management of the disease in a large series of patients (pts), we performed a retrospective study describing the characteristics of NLPHL at diagnosis, the therapeutic strategies, outcomes and the risk of late complications, including secondary malignancies. Methods We retrospectively analyzed adult pts with NLPHL treated in the Lymphoma Study Association (LYSA) centers between 1974 and 2012. Survival analysis were made according to the log-rank regression model. We also performed a competing risk analysis in order to better assess the risks of death, progression and secondary malignancies. Results 314 pts, out of a total of 366 were retained for further analysis. Median age at diagnosis was 38 years. Most pts (82.5%) presented with localized, Ann Arbor stage I-II disease. Watchful waiting (WW) was the most frequent attitude at diagnosis, and concerned 114 pts (36%), mainly with localized disease (104 pts). 200 pts received a treatment, which comprised chemotherapy +/- rituximab for 68 pts (34% of pts with treatment), radiotherapy for 63 pts (31.5%), combined modality treatment (CMT, chemotherapy +/- rituximab followed by radiotherapy) for 40 pts (20%), and rituximab alone for 28 pts (14%). Among 155 pts with localized disease who received initial treatment, radiotherapy alone was delivered to 62 pts (42 with stage I, 20 with stage II disease), mainly on the cervical, supra-clavicular or axillar areas. The radiotherapy fields included the mediastinum in 7 localized pts treated by CMT. Among 55 pts with disseminated disease receiving initial treatment, chemotherapy +/- rituximab was administered to 32 pts. Most of them received anthracycline-based chemotherapy, and ABVD-derived chemotherapies were the preferred regimens with 19 pts; 8 pts received CHOP-like regimens. With a median follow-up of 55.8 months, 112 pts relapsed or progressed. Among them, 37 pts (33%) received chemotherapy +/- rituximab, 27 pts (24%) radiotherapy alone, 19 pts (17%) rituximab alone, 7 pts (6%) CMT, and 2 pts rituximab + radiotherapy. WW concerned 19 pts (17%) at first relapse/progression. The overall response rate (ORR) for the whole population was 83%, with 200 pts (79%) reaching CR or CRu, 3 months after diagnosis. The CR/CRu rate according to the different treatment modalities were 95% for radiotherapy alone, 89% for rituximab alone, 87% for chemotherapy +/- rituximab and 91% for CMT, respectively. In localized disease, 40 pts had persistent CR/CRu after radiotherapy alone. In disseminated disease, 45 pts who attained CR/CRu after chemotherapy +/- rituximab did not subsequently relapse. The median PFS for the whole population was 112.1 months. There was no impact of Ann Arbor stage on PFS, but the attitude at diagnosis had a powerful impact. Compared to WW, the risk of progression was significantly reduced for pts treated by radiotherapy alone (Hazard ratio: 0.345 [95% CI: 0.196; 0.610], p = 0.0002), chemotherapy +/- rituximab (HR: 0.476 [0.266; 0.855], p = 0.0129), or CMT (HR: 0.292 [0.148; 0.577], p = 0.0004), but not with rituximab alone. The risk reduction remained significant for pts who had complete surgical resection of the initial lesions and received any additional treatment vspts who were just watched after surgery (HR: 0.344 [0.122; 0.974], p = 0.0444). The estimated OS at 72 months is 96.9%. OS was not different according to the attitude at diagnosis, including WW. 10 pts died, 1 due to lymphoma progression, 5 of secondary malignancies and the remaining 4 of accident or unknown causes. The competing risk analysis model confirmed that the risk of relapse/progression was significantly reduced with radiotherapy in stage I-II pts (HR : 0.474 [0.277; 0.812]), and with a treatment combining chemotherapy +/- rituximab +/- radiotherapy in the whole population (HR: 0.388 [0.234; 0.643]). Conclusion Our study supports the use of radiotherapy in localized disease, and of treatments combining chemotherapy +/- rituximab +/- radiotherapy, to improve disease control in adult patients with NLPHL. Disclosures No relevant conflicts of interest to declare.

Background: Human Immunodeficiency Virus (HIV) infection is associated with an increased risk of classical Hodgkin (cHL) and non-Hodgkin lymphomas (NHL). In the combined antiretroviral therapy (cART) era, while the incidence of NHL has declined, HL incidence has remained stable. In comparison to their HIV-negative counterpart, HIV-associated HLs present frequent high-risk characteristics: 1- mixed cellularity histological subtype, 2- advanced stage, presence of B symptoms and higher International Prognostic Score (IPS). Methods: The national prospective cohort of HIV-related lymphomas (ANRS CO16 Lymphovir cohort sponsored by Inserm-ANRS) enrolled adult patients in 40 centers since July 2008. Pathological materials were centralized and reviewed. Diagnoses were based on World Health Organization criteria. Patients have been followed every 6 months during 5 years. HIV HL patients were compared to a series of HIV-negative adult patients consecutively diagnosed with HL during the same period in Paris Saint-Louis hospital. Results: Among 159 HIV-infected patients, 68 (43%) were diagnosed with cHL. Mixed cellularity (MC) subtype was predominant (n=42), followed by nodular sclerosing (11). Fifteen cases could not be subclassified mainly because of small needle biopsies. Median age was 44 years (ranging from 20 to 65), male/female ratio was 5.8. Most patients (75%) had advanced clinical stage (III/IV). HIV infection had been diagnosed for a median of 13 years (maximum of 26 years) before the diagnosis of cHL. Median CD4 T-cell count was 380/μl (range 37-1742) and plasma HIV RNA was < 50 in 78% of the patients. All except one patient had been treated with cART prior to cHL diagnosis. They were all treated with cART after diagnosis. Front-line chemotherapy with standard anthracyclin based regimen (ABVD) was given to 64 out of 68 patients, BEACOPP in 4 patients. ABVD was followed by radiotherapy in limited stages. Five patients died from early disease progression (n=2), sepsis during chemotherapy (1) and after relapse (2). Two-year overall survival and Progression Free Survivals (PFS) were 94% [95%CI 88, 100] and 89% [82, 97], respectively. The only factor associated with PFS was age with a relative risk of 8.09 [0.97; 67.18] above 45 years (Table). IPS and CD4 count were not significantly associated with PFS. In comparison with HIV-negative patients, patients with HIV infection displayed higher risk features for all prognostic factors of HL (older age, male predominance, MC subtype, more advanced stages, lower lymphocytic counts). Treatment of HIV-negative patients was similar to HIV-positive patients: ABVD (79%), BEACOPP (21%), with addition of radiotherapy in limited stages. Overall, the outcomes of the HIV-infected patients did not differ significantly from those of HIV-negative patients (Figure). Conclusion : Although high risk features still predominate in HIV-HL, the prognostic of these patients has markedly improved in the recent cART era. We report 2-years OS and PFS of 94% and 89%, respectively, in patients mainly treated with cART and ABVD. The outcome of HL in HIV infected patients now resembles to those of non HIV infected patients. Table: Univariate analysis of Progression Free Survival in HIV associated Hodgkin Lymphoma (Cox model) (N=68) N Progression or Death, N RR 95 % CI p-value Gender 0.95 F 9 1 1 M 59 6 0.94 [0.11 ; 7.77] Age 0.05 =40 18 1 1 0.2 45 4 1 ≤0.2 21 3 1.64 [0.37 ; 7.32] RR: Relative Risk CI: Confidency interval *: 3 missing values **: 8 missing values ***: 2 missing values Median follow-up: HIV(-) cHL: 37 months (IQR=37) Lymphovir: 33 months (IQR=34) 2- year PFS: HIV(-) cHL: 0.86 CI95%=[ 0.82, 0.90 ] Lymphovir: 0.89 CI95%=[ 0.82, 0.97 ] Figure: Progression free survival (PFS) of HIV associated Hodgkin’s Lymphoma (N= 68) compared with HIV negative patients (N=336) Figure:. Progression free survival (PFS) of HIV associated Hodgkin’s Lymphoma (N= 68) compared with HIV negative patients (N=336) IQR: Interquartile range CI: Confidency interval Disclosures Brice: Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Roche: Honoraria.

Introduction and Methods Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT) is the standard of care for relapsing/refractory DLBCL. In the CORAL study, there was no difference between two randomized second line regimens (R-DHAP or R-ICE) and only half of the patients (pts) eventually underwent per protocol ASCT (Gisselbrecht et al, JCO 2010 & 2012). Because outcome data are limited in DLBCL pts failing second-line strategy, 145 pts included in the CORAL study who failed R-DHAP or R-ICE and could not proceed to scheduled ASCT were herein reviewed. Results Median age was 56y (range 20-67, 31% > 60y), M/F ratio 91/54, IPI 0-1 in 30%, 2-3 in 56%, and 4-5 in 14%. Third-line therapy consisted of ICE-type (19%), DHAP-type (19%), gemcitabine-containing (16%), CHOP-like (8%), dexaBEAM (8%), and miscellaneous (31%) regimens with or without rituximab according to centre policy. Overall response rate to third-line chemotherapy was 43%, with 21% complete response (CR), 8% CR unconfirmed (CRu), and 14% PR. CR/CRu and PR rates among pts treated with ICE-type, DHAP-type, gemcitabine-containing, or CHOP-like regimens were 23 and 23%, 35 and 8%, 9 and 4%, 25 and 25%, respectively. Among the 145 patients, 64 (44%) could eventually be transplanted (ASCT 56, allogeneic SCT 8). Median overall survival (OS), calculated from time of second failure until death, was 5.9 months (95% CI 4.6-7.5; min: 0.0-max: 68.8 months; median follow-up: 32.8 months) and was not influenced by the type of third-line regimen (p=.49). OS was statistically different (p 2: 3.7 months (1-y OS 7.7%, HR 3.021). OS in pts achieving CR/CRu, PR, or no response after third-line regimen was 63.6 m (1-y OS 72.1%, p Conclusions Outcome of DLBCL pts failing second-line R-DHAP or R-ICE is overall poor. However, response to third-line therapy occurs, and 44% of the pts can be further transplanted. Long-term disease control can be observed, especially in pts achieving CR after third-line. This approach (salvage chemotherapy aiming at achieving response followed by transplantation) should then be encouraged in these patients, although there is obviously an urgent need for new drugs improving salvage efficacy. Disclosures: Gisselbrecht: Roche: Consultancy, Research Funding; Baxter: Research Funding; Chugai Pharma: Research Funding. Trneny:Roche: Honoraria, Research Funding. Radford:Roche: Consultancy. Shpilberg:Roche: Consultancy, Honoraria, Research Funding. Dührsen:Roche Pharma: Honoraria, Research Funding. Moskowitz:Genentech: Consultancy, Research Funding. Glass:Roche: Honoraria, Research Funding.

Background AZA is currently the first line treatment for intermediate-2 and high-risk IPSS myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) with 20 to 30% of marrow blasts. We have previously reported that cells from AZA-resistant patients exhibit impaired mitochondrial apoptosis but maintain functional autophagy (Cluzeau et al. Cell Cycle 2011, Oncotarget 2012). Acadesine (ACA), also known as AICAR or Aica-Riboside is a nucleoside analogue that has been shown to trigger autophagy in AZA resistant cells. Methods In vitro effect: We used an AZA-resistant MDS/AML cell line (SKM1-R) as a tool to decipher AZA resistance. Cells were treated with increasing doses of ACA (0.5-2mM) or with a maximally efficient dose of AZA (1µM) and induction of cell death was assessed by cell metabolism and Propidium Iodide (PI) assays. In vivo effect: The effect of ACA was also assessed in a mouse xenograft model of SKM1-R cells. When tumors reached 100 mm3, mice were treated daily with an intra-peritoneal injection of the vehicle alone, 5 mg/kg AZA, or 200 or 400 mg/kg ACA. Ex vivo effect: We finally used primary bone marrow cells from AZA-resistant MDS or AML-resistant patients (n=12) (clinicalTrials.gov identifier: NCT01210274) to perform cell metabolism assays. Results In vitro effect: Only a slight decrease of cell metabolism and a moderate increase of PI staining were detected following stimulation with 1µM AZA confirming the resistance of SKM1-R cells to AZA. In identical conditions, ACA induced a robust increase of cell death in AZA-resistant cells with a maximal effect at 2mM. Induction of cell death by ACA was independent of apoptosis but relied on autophagy induction, as shown by the conversion of LC3-I to LC3-II and an increase of cathepsin B activity, that are respectively early and late markers of autophagy. In vivo effect: As expected, AZA failed to trigger tumor regression of AZA-resistant SKM1-R cells in vivo compared to vehicle alone, whereas ACA was found to induce a statistically significant inhibition of tumor growth at both tested concentrations. Ex vivo effect:Bonferroni’s Multiple Comparison Test performed in 6 AZA-resistant MDS patients showed significant reduction of cell metabolism between ACA and untreated cells (66% and 78% at 1 and 2 mM of ACA) and between ACA and AZA-treated cells (60% and 72% at 1 and 2mM of ACA,). Identical results were found in 6 AML AZA-resistant AML patients with a significant reduction of cell metabolism between ACA and untreated cells (63% and 81% at 1 and 2mM of ACA) and ACA and AZA-treated cells (56% and 75% at 1 and 2 mM of ACA). Conclusion Our results show the high efficacy of Acadesine in vitro, in vivo and ex vivo in AZA-resistant MDS and AML cell lines and patient’s bone marrow cells. Induction of cell death by autophagy seems to be the main mechanism by which ACA circumvents AZA resistance in MDS and AML cells. These encouraging results prompted us to initiate a multicenter phase I/II clinical trial with the French MDS Group (GFM) to assess the safety and efficacy of ACA in MDS and AML patients with 20 to 30% of marrow blasts not responding or relapsing after AZA treatment (clinicalTrials.gov identifier: NCT01813838). Disclosures: Cluzeau: Advancell: Research Funding. Robert:Advancell: Research Funding. Auberger:Advancell: Research Funding.

Background Single-agent studies of lenalidomide in relapsed/refractory follicular lymphoma (FL) have demonstrated significant activity. Recent studies reported that the combination of lenalidomide and rituximab yields high response rates in patients with FL. Three recent phase 1 studies have shown that lenalidomide administered on 10 to 14 days of 21-day cycle of R-CHOP could be safe in the initial treatment of aggressive or indolent B-cell lymphomas. Two of these studies determined 25 mg of lenalidomide as the recommended daily dose. This multicenter, open label, phase 2 trial (NCT01393756) investigated the combination of lenalidomide with R-CHOP in patients (pts) with high burden FL. Methods Pts with previously untreated FL grade 1, 2 or 3a and a high tumor burden according to GELF criteria were eligible. Pts received an induction therapy with 6 cycles of R2-CHOP given every 3 weeks (25 mg oral lenalidomide on days 1-14) followed by two additional rituximab infusions. Pegfilgrastim was administered on day 4 and oral aspirin prophylaxis (100 mg) was given daily during the cycles. Lenalidomide dose was adapted to toxicities. Pts responding to induction therapy received rituximab maintenance every 8 weeks for 2 years. The primary endpoint was the complete remission (CR/CRu) rate, according to IWRC 99, at the end of induction treatment. Secondary endpoints were safety, progression free survival, duration of response and overall survival. Results Eighty pts were enrolled from 16 LYSA centres between December 2010 and January 2012. Median age was 57 y (range 29-71); 50% were male; 92% Ann Arbor stage III-IV; 28% B symptoms, 69% ECOG performance status = 0; 25% mass >10cm; 53% bone marrow involved; 40% LDH elevated; 63% FLIPI 3-5. Sixty-eight pts (85%) received the complete induction regimen. Median interval between R2-CHOP cycles remained 21 days during treatment. Thirty-three pts (41%) experienced at least one dose reduction of lenalidomide. The complete remission (CR/CRu) rate was 74% (CI 95%: 63%-83%) and ORR was 94% (CI95%: 86%-98%).Current median follow-up is 13 months. So far, 9 pts (11%) experienced a progression/relapse. Hematologic toxicity was in the range of that observed with R-CHOP regimen with 65% grade 4 neutropenia; 12.5% grade 4 thrombocytopenia; 7.5% febrile neutropenia and no toxic death. Grade 1-2 sensory neuropathy was observed in 28 pts (36%), one pt had a grade 3 neuropathy. Twenty-nine pts (36%; grade 1-2: 27; grade 3: 2) had reversible skin toxicity, usually during the course of the first cycle. Five episodes of thrombosis occurred during treatment or follow-up, 3 were related to venous access devices and only one required discontinuation of lenalidomide. Three cases of neoplasm were observed during follow-up. Conclusion The combination of 25mg of lenalidomide for 14 days with 21-day R-CHOP cycles is well tolerated and yields a high rate of complete remission in patients with high tumor burden follicular lymphoma. Disclosures: Tilly: Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Honoraria; Amgen: Research Funding. Off Label Use: Use of lenalidomide to enhance R-CHOP efficacy in follicular lymphoma. Morschhauser:Celgene: advisory boards Other, Honoraria, Research Funding, Speakers Bureau. Casasnovas:ROCHE: Consultancy, Honoraria, Research Funding. Molina:Merck: Honoraria. Salles:roche: Consultancy, Honoraria, Research Funding; Celgene: Honoraria. Haioun:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Abstract 2813 Background: Myelodysplastic syndroms (MDS) are an heterogenous diseases. In order to define prognosis of differents subgroups, several scoring are elaborated. The most used was IPSS score including pourcentage of blasts, number of cytopenia and cytogenetics. Recently, IPSS was revised. IPSS-R includes new cytogenetics subgroups, anemia, thrombocytopenia, neutropenia and pourcentage of blasts. These score were defined in untreated MDS and Acute Myeloid Leukemia (AML) with less 30% of blasts patients. IPSS-R score was evaluated in MDS untreated population included AML with 20–29% of blasts. Only 16% of patients were higher-risk IPSS MDS in this study (Greenberg et al., Blood 2012). Azacitidine (AZA) prolongs survival when used as first line treatment of higher-risk MDS and AML with 20–29% bone marrow (BM) blasts (Fenaux et al., Lancet Oncology 2009). The aim of this study is to evaluate efficacy of AZA in higher IPSS-R MDS and AML with 20–99% BM blasts. Methods: We analyzed retrospectively MDS and AML patients treated by AZA in 6 centers. Patients having received ≥ 1 cycle of AZA and who had BM evaluation after ≥ 4 cycles, or who died or progressed before completion of 4 cycles were considered évaluable (the last 2 groups were considered as treatment failures). Responses were scored according to IWG 2006 criteria for MDS and to Cheson et al. (JCO 2003) for AML. Results: The study population included 149 patients: F/M: 65/84; median age 70 (range 35–88). Median number of cycle of AZA treatment was 6 (range 1–42). Diagnosis at AZA was (RAEB-1 n=1, RAEB-2 n=69, AML n=79). Median overall survival (OS) was 11 months. For MDS population excluding AML with 20–29% of blasts, IPSS score was intermediate-1 in 16 patients, intermediate-2 in 29 patients and high in 25 patients. In using IPSS-R score, we observed IPSS-R good in 2 patients, IPSS-R intermediate in 20 patients, IPSS-R poor in 29 patients and IPSS-R very poor in 19 patients. If we applied IPSS-R score in WHO-AML population, we observed IPSS-R intermediate in 11 patients, IPSS-R poor in 39 patients and IPSS-R very poor in 29 patients. In all cohort population, we observed a significant difference in median OS between « intermediate + poor » group versus very poor group (12 months vs 9 months respectively, p=0.01). In MDS sub group analysis excluding AML with 20–30% of blasts, we observed no significant difference in median OS between these 2 groups (13 months vs 9 mois respectively, p=0.39). Nevertheless, we still observed a significant difference in median OS between these 2 groups in AML population (12 months vs 6 months respectively, p=0.02). Conclusion: Our results suggest that AZA cancels prognostic impact of IPSS-R score in MDS patients treated by AZA. IPSS-R score could be applied in AML population and keep his prognostic impact in AML patients treated by AZA. IPSS-R score should be evaluated in larger cohort of MDS and AML patients treated by AZA in order to confirm these results. Disclosures: No relevant conflicts of interest to declare.

Abstract 2723 Introduction: Elderly patients with diffuse large B-cell lymphoma (DLBCL) frequently receive reduced dose-intensity (DI) chemotherapy (Lyman GH et al. J Clin Oncol 2004) but impact on outcome in the era of classical or dose-dense immunochemotherapy is unknown. Final results of the LNH03–6B did not show any difference in PFS (HR: 0.99 [95%CI: 0.78–1.26]; p=0.90) and OS (HR: 0.96 [95%CI: 0.73–1.26]; p=0.75) between R-CHOP14 and R-CHOP21 (Delarue et al. ASCO 2012). Methods: Patients between 60 and 80 years old with DLBCL and aaIPI≥1 were eligible. They were randomized between R-CHOP14 and R-CHOP21 for 8 cycles. Dose-intensity (DI) was calculated for all patients for cyclophosphamide (CPM), doxorubicin (DOX) and rituximab (RTX) and patients were separated into 4 quartiles for each of these drugs. Outcome (PFS and OS) according to final DI was evaluated for all patients and in R-CHOP14 and R-CHOP21 arms. Results: 602 pts were randomized, 600 were evaluable, 304 with R-CHOP14 and 296 with R-CHOP21. Median age was 70 years. Patient characteristics were similar in both arms. The percentage of cycles administered with G-CSF was 89% in R-CHOP14 and 66% in R-CHOP21. Median interval between 2 cycles was 14 d [9–94] in R-CHOP14 arm and 21 d [15–66] in R-CHOP21 arm. Median dose-intensity was 88% in R-CHOP14 and 97% in R-CHOP21 for CPM, and 88% in R-CHOP14 and 96% for R-CHOP21 for DOX. There was no difference of median dose-intensity for CPM and DOX according to G-CSF use at C1 in R-CHOP14 arm. In the R-CHOP14 arm, the increase of DI at the end of treatment, calculated according to 3-week interval as a reference, was 133% for CPM and DOX. When separating patients in 4 quartiles according to final dose intensity, there was no impact for CPM, DOX and RTX for the entire cohort in term of PFS and OS. Moreover, decreased DI for CPM, DOX and RTX did not impact negatively PFS and OS in patients randomized in the R-CHOP14 arm. On the other hand, for patients included in the R-CHOP21 arm, PFS was negatively impacted by lower DI of CPM (p=0.02), DOX (p=0.007) and RTX (p=0.006). OS was also negatively impacted by lower DI of CPM (p=0.0002), DOX (p Conclusion: While low DI has a major impact on PFS and OS in patients who receive conventional dose immunochemotherapy, consequences for patients receiving dose-dense immunochemotherapy seem less pronounced. As a consequence, immunochemotherapy could be safely decreased for elderly patients who receive R-CHOP14 and experienced adverse events. Disclosures: No relevant conflicts of interest to declare.

Abstract 4936 Background: Azacitidine (AZA) has changed the outcome of patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia with multi-lineage dysplasia (AML-MLD) unfit for intensive chemotherapy. AZA is a hypomethylating agent providing about 50% of responses in MDS and AML with low blast count (Fenaux et al., Lancet Oncol 2009, JCO 2010). IPSS-R scoring was evaluated in MDS and AML with 20–29% of blasts untreated patients. Conventional cytogenetic have major prognostic interest in this score (Schanz et al., JCO 2012). To date, SNP array analysis are not included in scoring system and no markers of AZA response have been identified with this analysis. Methods: This analysis included MDS and WHO-AML-MLD (>30% blasts) patients treated by AZA in 6 centers. Genomewide single nucleotide polymorphism (SNP) analysis using SNP 6. 0 arrays (Affymetrix, High Wycombe, U. K) was performed on bone marrow (BM) samples. Patients having received ≥ 1 cycle of AZA and who had bone marrow evaluation after ≥ 4 cycles, or who died or progressed before completion of 4 cycles were considered evaluable (the last 2 groups were considered as treatment failures). Responses were scored according to IWG 2006 criteria for MDS and to Cheson et al. (JCO 2003) for AML. DNAs were extracted for hybridization according to the manufacturers' recommendations (Qiagen). Affymetrix CEL files for each sample were analyzed using the Genotyping Console software (v3. 0. 2). Genotyping was performed using Birdseed V2 algorithm. Unpaired Copy Number and LOH analysis was performed with Regional GC correction. For each patient, size of all deletions (loss) find with GC was added to have a total deletion size. The same was performed for total gain size. Results: The study population included 51 patients: F/M: 23/28; median age 73 (range 42–88). Diagnosis at AZA onset was RAEB-2 in 19 patients (IPSS int-1 in 4, int-2 in 10, high in 5) and WHO-AML-MLD in 32 patients. Cytogenetic according to IPSS-R was good in 23, intermediate in 9, poor in 7 and very poor in 12. IPSS-R score was good in 1 patient, intermediate in 4 patients, poor in 25 patients and very poor in 21 patients. Median number of cycles was 7 (range 1–42). All patients received the approved (75mg/m2 for 7 days every 4 weeks) or a reduced AZA schedule (75 mg/m2 for 5 days every 4 weeks). Median overall survival (OS) of our cohort was 11 months. DNA samples from all patients were available for SNP analysis. In using smoothing spline Cox model analysis, we observed that relative risk (RR) of worse OS increased above 4 megabases (Mb) of total chromosomal loss size detected with SNP array. Increase of RR was found in IPSS-R intermediate, poor and very poor. OS of patients treated by AZA with more than 4 Mb of genomic loss detected by SNP array was significantly different of OS of patients with less than 4 Mb (6 months vs 14 months respectively, p=0. 0012). Negative effect of genomic loss above 4 Mb was mainly observed in IPSS-R very poor group. In IPSS-R very poor subgroup, we observed significant difference in OS between patients with more than 4 Mb of genomic loss versus patients with less than 4Mb (3 months vs 10 months respectively, p=0. 01). In our cohort, total genomic gain has no impact on OS. Conclusion: New tools such as SNP array are not used in current practice. Therefore, prognostic impact of molecular karyotype is unclear in MDS/AML treated by AZA; our data suggest that total genomic loss superior to 4 Mb could be a worse prognosis, mainly in IPSS-R very poor patients. Impact of SNP array should be studied in larger cohort of patients treated by AZA in order to validate these results. Starczynowski et al. (Blood 2008) showed that total genomic alterations superior to 3Mb were associated with a poor OS in low-risk MDS. Taken together, these data are in favor of the use of SNP array's parameters in future prognosis scoring system. Disclosures: No relevant conflicts of interest to declare.

Abstract 2147 Background: Human Immunodeficiency Virus (HIV) infection is associated with an increased risk of Hodgkin lymphoma (HL) and B-cell non-Hodgkin lymphoma (NHL). Increased risk of NHL is strongly correlated to the severity of the underlying immunodeficiency. Introduction of combined antiretroviral therapy (cART) has reduced the incidence of NHL -but not of HL's- among HIV-infected individuals. Outcomes are reported to be poorer among HIV-infected patients with HL or NHL than among non-HIV-infected patients. We carry out a cohort with the aim to study the characteristics and outcome of HIV-related lymphomas. Methods: The multicentric prospective Cohort of HIV related lymphomas (ANRS-CO16 Lymphovir cohort) enrolled 116 adult patients in 32 centers between October 2007 and April 2012. Investigations were performed after approval of the ethic committee. Patients were included at diagnosis of lymphoma (n=108) or at first relapse (1 HL, 7 NHL). Data collection concerned HIV infection history, clinical, biological and histological presentation, treatment and evolution of lymphoma. Pathological materials were centralized and 91 cases were reviewed. Diagnoses were based on World Health Organization criteria. Each patient was followed every 6 months during 5 years. Results: Among the 116 patients, 39.7% (46) were diagnosed with HL and 60.3% (70) with NHL. Median age was 43.5 years (ranging from 20 to 61) among patients with HL and 47 years (23 to 67) among those with NHL. Gender (male/female) ratio was 8.2 (41/5) among patients with HL, 1.7 (44/26) among those with NHL. The histological distribution of NHL were diffuse large B-cell lymphoma (DLBCL) 54.3% (38), Burkitt lymphomas (BL) 18.6% (13), plasmablastic lymphoma 10% (7), marginal zone/lymphoplasmocytic lymphoma 7.1% (5), others 10%: PTLD- like lymphoma (2), primary effusion lymphoma (1), follicular lymphoma (1), anaplastic lymphoma (1), unclassified (2). There was a predominance of clinical stages III/IV versus I/II among HL (76.7%, 33/43) and NHL patients (73.5%, 50/68). Among patients with DLBCL, LDH level was elevated in 68.4% (26/38) and performance status altered (2–4 versus 0–1) in 38.5% (15/39). HIV infection had been diagnosed for a median of 151 months (0 to 312) among HL patients and 117 (0 to 327) among those with NHL. The interval between diagnoses of HIV infection and lymphoma was shorter than 3 months for 2 patients with HL and 13 with NHL. All other patients except 6 NHL patients had been treated with ART at diagnosis of lymphoma. Median durations of ARV were 128 months (2 to 238) among HL patients and 119 months (1 to 236) among those with NHL. Patients with HL had a median CD4 T-cell count at diagnosis of lymphoma of 353/mm3 (range 37–1120), those with NHL, 261/mm3 (range 7–1322)]. The median interval between lymphoma occurrence and last follow-up was 21 months (range 0–41). During follow-up, all patients were treated with ARV. Among first-line HL patients, 39 out of 40 were treated with ABVD. Out of 40 patients with DLBCL or BL, 30 received chemotherapies combined with rituximab. At 24 months, overall survival is 95% among patients with HL and 78% among those with NHL (Figure 1). Two HL patients died during follow-up: one HL patient included in relapse from progression, another from a second cancer. Sixteen NHL patients died during follow-up: there were 10 early deaths ( Conclusions: The present study points out the high proportion of HL among HIV infection with lymphoma in the cART era and their favourable outcome compared to previous reports. This study also strengthens the heterogeneity of HIV-related lymphomas and the frequency of early deaths among patients with NHL. Disclosures: No relevant conflicts of interest to declare.

Abstract 4428 The Fas death receptor (CD95/TNFSFR6) conveys death and non-death signals through binding to its cognate ligand, FasL (CD95L)1,2. Fas is expressed constitutively in CD34+ cells of patients with chronic myeloid leukemia3. In order to explore the implication of Fas in CML patient's response, we aimed at analyzing expression and function of Fas in the imatinib-sensitive human Bcr-abl+ Fas+ AR 230S cell line, and in its imatinib-resistant counterpart AR 230R. We analysed the Fas-mediated apoptosis of AR230S and showed that not only imatinib (Figure 1) but also nilotinib and dasatinib (data not shown) potentiate Fas-L mediated apoptosis. This potentiation is dose dependent (Figure 2). Interestingly, there is no potentiation of TKI-mediated apoptosis by FasL in the imatinib-resistant counterpart AR 230R which is Fas negative. The Fas knockdown with a lentivirus-expressing a FAS-shRNA in AR 230S was associated with a disappearance of potentiation effect, whereas the up regulation of Fas expression in AR230 S cell line using lentivirus-expressing human Fas (hFas) induced an emphasized potentiation effect confirming the pivotal role of Fas in the potentiation of TKI-mediated apoptosis. Notably, IFN-α is able to enhance expression of Fas on CD34+ cells from CML patients3. We thus explored the action of IFN-α on the Fas potentiation of TKI-mediated apoptosis. We observed that preincubation with IFN-α increased potentiation in a dose-dependant manner (Data not shown). In conclusion, our preliminary results demonstrate the pivotal role of Fas in the potentiation of TKI-mediated apoptosis and highlight the role of IFN-α in the design of CML treatments. Figure 1: Percentage of FasL-mediated apoptosis in AR230 cell line. Apoptosis induced by FasL in presence or in absence of imatinib was analyzed by propidium iodide staining of cellular DNA content and shown as percentage of sub-G1 to the whole population. Figure 1:. Percentage of FasL-mediated apoptosis in AR230 cell line. Apoptosis induced by FasL in presence or in absence of imatinib was analyzed by propidium iodide staining of cellular DNA content and shown as percentage of sub-G1 to the whole population. Figure 2: Dose-dependentof FasL mediated apoptosis in absence or in combination with imatinib. Apoptosis induced by FasL in presence or in absence of imatinib analyzed by propidium iodide staining of cellular DNA content and shown as percentage of sub-G1 to the whole population. Each point represents the mean ± S.E.M. of 3 experiments. Figure 2:. Dose-dependentof FasL mediated apoptosis in absence or in combination with imatinib. Apoptosis induced by FasL in presence or in absence of imatinib analyzed by propidium iodide staining of cellular DNA content and shown as percentage of sub-G1 to the whole population. Each point represents the mean ± S.E.M. of 3 experiments. Disclosures: Legros: Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau.

Abstract 3682 Background: Non-Hodgkin Lymphoma (NHL) remains the most common malignancy in patients with HIV infection, but there are few randomized phase II or III trials that provide level 1 evidence regarding the optimal treatment. We previously reported a pooled analysis of 16 trials including 1,144 patients with HIV–associated NHL (ASCO 2012, abstract 8005), and herein report the updated final analysis of 1,546 patients enrolled on 19 trials. Our objective was to assess lymphoma-, HIV-, and treatment-specific factors and their influence on response and survival. Methods: We performed a systematic review to search for prospective clinical phase II or III trials that assessed therapeutic interventions for HIV-associated NHL and assembled individual patient data from 19 trials published between 1993 and 2011 including 1,546 patients (median N=61/trial, range 14–467). Treatment factors included rituximab use (N=542) and type of chemotherapy (CHOP, N=632; EPOCH, N=166; CDE, N=191; dose-intense (intensive) regimens, N=155; ABCVP-based regimens, N=158; low-dose CHOP, N=165; VS, N=41; oral regimens, N=38). Endpoints included complete response (CR), progression-free survival (PFS), and overall survival (OS). We used logistic regression and Cox proportional hazard models adjusted for age, sex, histological subtype, age-adjusted international prognostic index (aaIPI), CD4 count at baseline, prior history of AIDS, type of chemotherapy, use of rituximab, concurrent use of GCSF and combination antiretroviral therapy (cART) with chemotherapy, and enrollment period. Results: The majority of patients were enrolled in the cART era (75%), were male (84%), had DLBLC (69%; BL/BLL 26%; other 6%), had high risk disease (aaIPI≥2; 59%) and a baseline CD4 count ≥50 cells/μl (86%). CHOP was the most commonly prescribed regimen (41%). Among the lymphoma- and HIV-specific covariates evaluated, lower baseline CD4 count and higher aaIPI score were associated with inferior CR rates (CD4: p Conclusions: In this pooled analysis including 1,546 patients with HIV-associated NHL, the addition of rituximab to chemotherapy was associated with significantly improved CR rate, PFS, and OS. Rituximab use did not result in a higher risk of infectious or HIV-related death. Treatment with infusional EPOCH was also more effective than CHOP for patients with DLBCL. Concurrent use of cART was associated with better outcomes. Disclosures: No relevant conflicts of interest to declare.

Abstract 594FN2 Background . Approximately 5% to 10% of DLBCLs harbor a MYC/8q24 oncogene rearrangement. We determined the prognostic significance of MYC+ DLBCL in a selected population of patients with relapsed/refractory DLBCL included in the CORAL and prospectively treated by RICE or RDHAP followed by BEAM and ASCT1. METHODS. Among the 396 patients included, 150 patients were analysed with break-apart FISH probes for MYC/8q24, BCL2/18q21, and BCL6/3q27. Correlations with clinical characteristics at diagnosis and at relapse, immunohistochemistry (IHC) for CD10, BCL6, MUM1, FOXP1, and BCL2 expression, cell of origin determined according to different IHC algorithms2-5 and by transcriptomic analysis, response to treatment and survivals were analysed considering presence or absence of MYC rearrangement. RESULTS. Twenty-four (16%) cases exhibited a MYC rearrangement, associated in 87.5% (n=21) of the cases with a BCL2/18q21 rearrangement (n=16), with a BCL6/3q27 rearrangement (n=4), and with both BCL2/18q21 and BCL6/3q27 rearrangements (n=4). Among the matched cases analysed (n=57), biological characteristics including tumor immunophenotype and breakpoints occurrence, were identical between primary and secondary biopsies. Presence of MYC+ rearrangement was significantly associated with CD10 expression (p= 0.0067) and a GC phenotype, based either on Hans algorithm (p Disclosures: No relevant conflicts of interest to declare.

Abstract 877 Introduction: Patients with follicular lymphoma (FL) usually respond well to immuno-chemotherapy as initial treatment and can have long survival times. However, a small proportion of patients are refractory or have early relapses. Early identification of this subgroup of patients could lead to early therapeutic changes and, potentially, to a better prognosis. [18F]Fluorodeoxyglucose-Positron Emission Tomography (FDG-TEP) is widely used for the staging and restaging of aggressive lymphoma patients but little is known about the use of FDG-PET in patients with FL, except that FL is almost uniformly FDG-avid. FDG-PET is not recommended today as a routine procedure in FL patients (Cheson et al. J Clin Oncol 2007). In this first prospective, multicentric study, we evaluated the prognostic value of FDG-PET performed at mid-treatment and at the end of treatment in patients with high-tumor mass FL treated with immuno-chemotherapy in first line. Patients & methods: Patients with previously untreated FL (grades 1–3A) presenting with a high tumor burden as defined by the GELF criteria, were treated with 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus 2 cycles of rituximab, given every 21 days. Patients did not receive rituximab maintenance. A FDG-PET was performed before treatment, after 4 cycles of R-CHOP (interim FDG-PET: I-PET), and at the end of treatment (final PET: F-PET). FDG-PET scans were first interpreted in each centre, then centrally reviewed by 3 investigators blinded to clinical data. Positivity or negativity was rated according to the Deauville visual semi-quantitative criteria (Meignan M: Leuk Lymphoma 2009), positivity being defined as a fixation at level 4 (FDG uptake superior to that of the liver) or 5 (uptake clearly superior to liver and/or new sites of disease). Results: 121 patients were included. The median age was 57 years and the male-to-female ratio was 1.12. Ninety-three percent had Ann Arbor stage III–IV. Ninety-seven percent had a good performance status (ECOG score 0–1). The repartition according to the FLIPI was: 0–1 factors: 15%; 2 factors: 43%; 3–5 factors: 42%. The Kappa coefficient indicated a good degree of concordance between the 3 PET reviewers. The initial FDG-TEP was positive in all except 1 case out of 118 centrally reviewed cases. After central review, I-PET (n=111) was negative in 76% of patients and F-PET (n=106) was negative in 78%. With a median follow-up of 23 months, 2-year-progression-free survival rates for I-PET negative versus positive and for F-PET negative versus positive were I-PET 86% versus 61% (p=0.0046); F-PET 87% versus 51% (p Conclusion: In FL patients treated in first line, FDG-PET performed either after 4 cycles of R-CHOP or at the end of immunochemotherapy induction is strongly predictive of outcome. Therapeutic intervention based on TEP results during inductive treatment should be evaluated in the future. Disclosures: Salles: Roche and/or Genetech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Membership on an entity's Board of Directors or advisory committees; Calistoga/Gilead: Membership on an entity's Board of Directors or advisory committees.

Abstract 993 Purpose: Cell of origin (COO) has a major prognostic impact in DLBCL. However this impact has never been analysed in the context of relapsed/refractory DLBCL. The purpose of this study was to evaluate the prognostic value of COO immunohistochemical markers and BCL2, BCL6 and c-MYC translocations in a well-defined cohort of patients included in the CORAL trial1. Methods: Enrolled patients had CD20+ DLBCL in first relapse or refractory after upfront therapy. Treatment was randomized to either R-ICE (rituximab, ifosfamide, etoposide, carboplatin) or R-DHAP (rituximab, dexamethasone, aracytine, cisplatin). Responding patients had high-dose chemotherapy and ASCT. Paraffin-embedded tumor samples of 249 patients were analysed by immunochemistry for CD10/MME, BCL6, MUM1/IRF4, FOXP1, BCL2 expression and for BCL2, BCL6 and c-MYC breakpoints by FISH, and were categorized according to different COO algorythms2-5. Primary biopsy at diagnosis and relapse biopsy were available for 189 and 147 patients respectively, including 87 matched pairs. Results: With a median follow-up at 27 months, there was no significant difference between R-ICE and R-DHAP for 2-year progression-free survival (PFS) (56.7%+/−5% vs 60%+/−5%, p=0.24) or overall survival (OS) (46%+/−5% vs 60%+/−5%, p=0.24). We confirmed that early relapse, prior rituximab exposure and secondary aaIPI had adverse prognostic value. In univariate analysis, absence of bcl6 expression, non-GC phenotype2, ABC phenotype4, at diagnosis were associated with an unfavourable PFS (p=0.038, p=0.0044, p=0.044, respectively), whereas only non-GC phenotype2 was associated to a worse OS (p=0.027). At relapse, expression of Foxp1 and bcl2, c-MYC breakpoint, ABC phenotype4, immunoFISH index5 was associated with an unfavourable PFS (p=0.02, p=0.027, p=0.03, p=0.032, p=0.02, respectively), and c-MYC breakpoint was associated with a worse OS (p=0.01). Tumor immunophenotype and FISH analysis at diagnosis and at relapse were statistically concordant in matched pairs (Wilcoxon's test between 0.42 and 1). In the whole group, only c-MYC breakpoint present in 13% of the patients was correlated with worse PFS (p= 0.02) and OS (p =0.04). Statistical interaction were found between GC/non-GC classification2 and the treatment R-ICE vs R-DHAP. Patients with GC B-cell like DLBCL subtype treated with R-DHAP have a better 2-year PFS (64% +/−7%) than those with GC B-cell like DLBCL treated with R-ICE (42% +/−7%), and the patients with ABC B-cell like DLBCL treated either with R-DHAP (35%+/−7%) or R-ICE (45%+/−7%) (p= 0.04). In multivariate analysis, only GC/non-GC phenotype2 interaction with the treatment, FOXP1 expression, prior rituximab exposure, secondary aaIIPI, time to relapse were statistically significant. Preliminary results of gene expression profiling seem to confirm these data and are currently under validation. Conclusion: COO remains a major factor in relapsed patients with a better response to R-DHAP salvage chemotherapy in GC-B DLBCL, underlying the importance of molecular DLBCL subtyping. Treatment of ABC subtype is still unsatisfactory. Disclosures: Schmitz: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gisselbrecht:Roche: Research Funding.

Abstract 1817 Azacitidine (AZA) is the first line treatment for IPSS (index prognostic scoring system) high-risk myelodysplastic syndrome (HR-MDS). To date, only Khan et al. (Exp Hematol. 2008) and Hollenbach et al. (PLoS One. 2009) have reported apoptosis as a mechanism of AZA effect on MDS cell lines. Nevertheless, approximately 40% of patients treated with AZA are refractory to this molecule. To investigate the possible mechanisms of AZA resistance in MDS cells, we developped AZA-resistant cell clones (AZA-R) from the well-characterized MDS cell line SKM1. The bulk resistant SKM1 cell line (AZA-R) was obtained following long time exposure of cells to iterative and increasing doses of AZA ranging from 0.1 to 8mM. We first showed that AZA triggered loss of cell metabolism in SKM1 parental cells but not in their AZA-resistant counterpart at a maximally effective dose of 1mM. AZA-mediated loss of cell metabolism accounted mainly for induction of apoptosis as judged by both an increase in caspase 9 and 3 activities triggered by this compound and by a significant protection in the presence of the pan-caspase inhibitor Z-VAD-fmk in SKM1 parental cells. Conversely, no or very few activation of caspases and apoptosis were detected in AZA-R cells strongly suggesting that apoptosis is impaired in AZA-R SKM1 cells. Finally, unlike in SKM1 cells, AZA failed to induce mitochondrial membrane permeabilization in AZA-R SKM1 cells. Importantly, basal autophagy was increased in AZA-R versus AZA-S cells as shown by LC3-I cleavage into LC3-II, p62/SQSTM1 protein expression, cathepsin B activation, mTOR and S6 ribosomal protein dephosphorylation and finally electronic microscopy experiments. In addition, Acadesine, an adenosine derivative and AMPK agonist which targets autophagy was capable to circumvent AZA resistance in both AZA-R SKM1 cells and in medullary cells from five MDS patients resistant to AZA after 6 cycles of Azacitidine. In conclusion, targeting autophagy appears as an attractive therapeutical strategy to circumvent AZA resistance in both established MDS cell lines and cells from MDS patients. Therefore, drugs capable of inducing autophagy or autophagic cell death, such as Acadesine (Robert et al., PLoS One. 2009) which is currently in phase II clinical trials for the treatment of Chronic Lymphoblastic Leukemia could be also beneficial for HR-MDS patients resistant to AZA. Disclosures: Cluzeau: Celgene: Consultancy. Raynaud:Celgene: Consultancy.

Abstract 2929 Background: Azacitidine (AZA) has changed the outcome of patients (pts) with myelodysplastic syndromes (MDS) or acute myeloid leukemia with multi-lineage dysplasia (AML-MLD) unfit for intensive chemotherapy. AZA is a hypomethylating agent providing about 50% of responses in MDS and AML with low blast count (Fenaux et al., Lancet Oncol 2009, JCO 2010). To date, no consensus genetic predictor of response has been reported. Methods: In MDS (including RAEB-t) and AML-MLD (>30% blasts) patients treated by AZA in 5 centers, we performed genomewide single nucleotide polymorphism (SNP) analysis using SNP 6.0 arrays (Affymetrix, High Wycombe, U.K.) on bone marrow (BM) samples. Patients having received ≥ 1 cycle of AZA and who had bone marrow evaluation after ≥ 4 cycles, or who died or progressed before completion of 4 cycles were considered evaluable (the last 2 groups were considered as treatment failures). Responses were scored according to IWG 2006 criteria for MDS and to Cheson et al. (JCO 2003) for AML. DNA were prepared for hybridization according to the manufacturers' recommendations. Affymetrix CEL files for each sample were analyzed using the Genotyping Console software (v3.0.2). Genotyping was performed using Birdseed V2 algorithm. Unpaired Copy Number and LOH analysis was performed with Regional GC correction. Copy number and UPD were also analyzed using the Copy Number Analyzer for GeneChip (CNAG version 3.3.0.1) algorithm (http://www.genome.umin.jp/CNAGtop2.html). Results: The study population included 92 pts: F/M: 41/51; median age 72 (range 35–88). Diagnosis at AZA onset was MDS in 54 (RAEB-1 n=6, RAEB-2 n=37, RAEB-t=11, IPSS int-1 in 7, int-2 in 15, high in 32, undetermined in 2) and AML-MLD in 38 pts. Cytogenetic according to IPSS was favorable in 33, intermediate in 19, unfavorable in 28, unknown in 11. Median number of cycles was 6 (range 1–41). All pts received the approved (75 mg/m2 for 7 days every 4 weeks) or a reduced AZA schedule (75 mg/m2 for 5 days every 4 weeks). Median overall survival (OS) of our cohort was 22 months. DNA samples from 52 patients were available for SNP analysis. There were no significant differences between the SNP and no SNP subgroups in term of median age, sex ratio, disease status at AZA onset, cytogenetic according to IPSS, median number of cycles, responses and OS. We listed aneuploidies (CNA) and uniparental disomies (UPD) detected by SNP analysis in the samples, and focused on 18 chromosomal bands (1p13.2, 2q34, 3p14.2, 3q26, 4q24, 5q33.1, 5q35, 6p21.3, 7q36.1, 9p21.3, 11p13, 11q23.3, 13q12.2, 15q21, 15q26.2, 20q11.21, 21q22.1) containing genes implicated in MDS or AML. Preliminary results show correlations between some CNA/UPD and response to AZA and OS, such as 1/a UPD at 9p21 (6% of patients) associated to a better hematologic improvement (X2, p=0.037), 2/an amplification at 20q11.21 (8% of patients) correlated with a poorer response (X2, p=0.048) and a trend toward poorer OS (Log-Rank, p=0.091), and 3/deletion and UPD at 15q21 (6% of patients) strongly correlated to poorer OS (Log-Rank, p=0.001). Several additional CNA and UPD of potential interest are presently under investigation. Conclusion: SNP analysis using SNP 6.0 is a powerful tool to decipher genome complexity in BM samples of MDS and AML patients treated with AZA. Our data suggest that this approach could allow characterizing profiles of responder versus non responder pts. Our study must be extended to a larger cohort and relevant anomalies must be confirmed by more sensitive techniques such as high-scale sequencing. Disclosures: Cluzeau: Celgene: Consultancy. Raynaud:Celgene: Consultancy.

Rituximab (R) combined with CHOP improves complete remission rate and PFS, OS in DLBCL pts. More intensive regimen followed by HDC have been used in patients < 60y with with 2–3 adverse age-adjusted International-Prognostic-Index (aa-IPI) factors, providing a 5y OS of 65% (CI 60–68%), (Haioun LNH 98-3B ASCO 2007). The objective of the study was to see if combining R (375 mg/m2) to the dose intense ACVBP (Doxorubicin 75 mg/m2 d1, Cyclophosphamide 1,200 mg/m2 d1, Vindesine 2 mg/m2 and Bleomycin 10 mg d1 and d5, prednisone 60 mg/m2 d1–d5) translates into an improvement of response rate and also PFS, OS, EFS in pts under 60y with DLBCL and aaIPI 2 or 3. Four cycles of R-ACVBP were delivered every 15 days supported by G CSF. Responding pts received a consolidative BEAM and peripheral blood stem cell rescue. From 01/2004 to 12/2005, 209 DLCBL pts were enrolled. Median age was 49 years (range: 18–60), 22 % with aa-IPI 3, 19 % with bone marrow involvement, 93% with LDH> 1N and 54 % with extranodal sites > 1. Based on International Workshop Criteria, CR+CRu rate after induction treatment was 61%, PR rate 24%, stable disease 2% and progressive disease 1% heading an overall response rate of 84% (176pts). Deaths occurred in 4% of the pts. Hematological toxicity was similar to that observed in previous GELA trials using ACVBP. Collection failure after the 3rd and/or 4th R-ACVBP cycle was observed in 18 pts (10%), Consequently 157 pts were responders and had successful mobilization. Among responding pts, 155 pts received HDC, representing 75% of the whole population. Four patients died without progression during the HDC procedure. At the end of treatment, the overall response rate was 81% with 150 pts (72%) considered in complete remission, 9% in PR and 4% progressed. With a median follow-up of 27 months, using the updated IWC 2007, three-year PFS was 76% (CI 69–81%), and 85% for pts submitted to HDC; OS was 81% (CI 75–86%) and 90% for pts submitted to HDC, finally EFS was 60% (CI 53–66%), and 83% for pts submitted to HDC. For pts with IPI 2 or 3, 3 y PFS were 84%–92% and OS 89%–95% respectively without significant difference. There was no significant difference between pts in CR or PR before transplant. No other prognostic factors could be isolated in multivariate analysis. We conclude that with R-ACVBP induction regimen, 75% of the patients could received HDC. There is an increase of complete remission rate after HDC according the criteria used. An impressive PFS of 76% and OS 81% were observed even in patients with 3 adverse factors. Comparison with previous study without rituximab in induction suggests a major improvement which needs confirmatory prospective randomized study.

Even with the introduction of rituximab, some patients with lymphoma continue to relapse or progress during treatment. To better define these patients, we looked at all patients with aggressive lymphoma included in the GELA trials during the last 20 years or 4 generations of studies: LNH-87, -93, -98, and -03. Each study generation comprise several randomized studies according to different groups of patients, i.e., young or old, low or high risk. ACVBP, the high-dose regimen used by GELA since 1984 was usually one of the 2 arms, except in elderly patients. Rituximab was first introduced in the LNH-98.5 study and was part of nearly all arms in the LNH-03 study. A total of 7806 patients were included in this retrospective analysis, 3116 being treated with ACVBP and 4880 with other regimens. Two analyses were done: one for the 7198 patients treated without rituximab and one for the 608 patients treated with rituximab. Only patients included in a published study were included explaining the lower number for rituximab-treated patients, most of the LNH-03 studies being not yet published. 4 groups of patients were defined: refractory or non-responding pts (NR, progression during treatment); patients in PR at the end of treatment (persisting lymphoma cells or PET fixing tumor); relapsing pts with early relapses (ER, during the first year) and late relapses (LR, after one year). 7-year OS was 56% and 7-year PFS was 47.5%, meaning that only 8.5% of the patients were rescued by any treatment at time of progression. Identical results were found in all study generations with 2 groups of patients: those with PR or LR with 7-year OS at 38%, and those with NR or ER, 7-year OS at 12%. Therefore, all generations were grouped (see figure 1). Patients treated with rituximab had a gain of 9% in OS at 6 years (69% vs. 60%). However, they had the same pattern for progression: 6-year OS around 40% for PR and LR patients and around 20% for NR and ER patients. The difference between patients treated with or without rituximab being the percentage of patients in each group: 61% vs. 50% for those without progression and 16% vs. 29% for those with NR or ER. The IPI score does not allow the identification of these poor risk patients. A study is ongoing to characterize the NR+ER patients at diagnosis. This analysis allowed recognizing 2 patterns of failing therapy. Patients with PR and LR have a disease sensible to chemotherapy while NR and ER pts have a disease not responding to treatment. These patients probably must be treated differently with the introduction of new therapeutic agents into the first line regimen. Figure Figure

Autologous stem cell transplantation (ASCT) remains the treatment of choice for patients (pts) with diffuse large B-cell lymphoma (DLBCL) that relapse after first line chemotherapy (CT). Nevertheless, the impact of the use of the anti-CD20 monoclonal antibody (Rituximab®) (RTX) with combination CT on the ulterior results of the transplantation procedure has to be determined. One of the main factors affecting survival after ASCT is a short first remission duration. This study was designed to evaluate the benefit of this strategy, in pts with DLBCL achieving after salvage CT a 2nd complete remission (CR2), by retrospectively comparing for each pt the progression free survival (PFS) after ASCT with the duration of the previous CR. Adult DLBCL pts with MEDB information available autografted in CR2 between 1990 and 2005 in EBMT centres were included in the analysis. A total of 386 pts (224 males, median age 47 (18–71) years] were evaluated. 294 pts (74%) did not receive RTX prior to ASCT, 67 pts (17%) did receive it at all and in 34 pts (9%) this information is missing. Duration of CR1 was 12 (3 – 142) months [median (range)]; it lasted less than 6 months in 25% of the cases and was longer than 24 months in 25% of the pts. Median time from diagnosis to ASCT was 25 (6–181) months. Peripheral blood was used as the source of hematopoietic stem cells in 311 pts (81%). The BEAM protocol was the conditioning regimen most frequently used (n = 244, 63%) and only 5.5% pts were conditioned with TBI-containing regimens. After a median follow up after ASCT for surviving pts of 42 months, overall survival (OS) was 63% and PFS 48%. 158 pts did relapse after ASCT [median (range), 10 (3–200) months] and 32 pts died from non-relapse mortality. When each patient was taken as her/his own control, PFS after ASCT was longer than CR1 (p < 0.001). During the initial phase of the disease, 74% pts experienced 1st relapse in less than 2 years, compared with only 32% of the patients who experienced 2nd relapse 2 years after ASCT. The use of RTX prior to ASCT did not impair the beneficial effects of the autologous procedure in the whole population of pts (RTX no: 66% vs 33%, p < 0.001; RTX yes: 73% vs 26%, p = 0.001). 2-years PFS after ASCT was significantly lower in patients with a CR1 < 12 months (p < 0.001). However, in this subgroup of patients PFS after ASCT was significantly longer than CR1 duration when studying each pt as his/her own control (p = 0.001). ASCT can significantly increase PFS in comparison with the duration of CR2 in DLBCL and can change disease course. The use of RTX prior to ASCT does not decrease the beneficial effect of pts autografted in CR2 when compared to their prior CR1 duration. The duration of CR1 remains one of the most important prognostic factors for ASCT outcome.

Follicular lymphoma (FL) is considered as an incurable disease but treatments have changed with the introduction of high-dose therapy with autologous stem cell transplant (HDT) then of rituximab (RTX). The effect of these 2 strategies on the outcome of FL patients is well described in first line but not for relapsing patients. We analyzed 2 cohorts of patients treated in 2 successive randomized studies with the same treatment, CHVP plus interferon, to evaluate the role of RTX and HDT in first disease progression or relapse. Of the 364 patients Salvage without rituximab without HDT (A) Salvage without rituximab with HDT (B) Salvage with rituximab without HDT (C) Salvage with rituximab * p values between A and C =0.0002 and

Salvage chemotherapy followed by high dose therapy (HDT) and autologous stem cell transplantation (ASCT) is the standard of treatment for chemosensitive relapses in diffuse large B cell lymphoma. Improvement of salvage chemotherapy was suggested with the association rituximab, Ifosfamide, etoposide, carboplatinum, R-ICE. What is the optimal chemotherapy regimen and can we reduce the post ASCT relapses rate? The ongoing CORAL trial was designed to answer these questions. DLBCL CD 20+ in first relapse or pts refractory after first line therapy were randomized between rituximab plus DHAP and R-ICE. Stratification was made on centers, prior rituximab exposure and refractory/12months, 108 refractory/early relapses; 97 pts with prior exposure to rituximab; Stage 3-4 107 pts; elevated LDH 88 pts; secondary IPI 0–1 112 pts; sIPI 2-3 63pts. The two arms were well balanced. In the prior rituximab cohort exposure more pts had refractory disease and adverse prognostic factors. However, at inclusion patients characteristics were not significantly different in the stratified subgroups. The overall response rate was 68%, with 41% complete remission rate. Toxicity was similar to what is expected with intensive therapy, 72 SAE were reported with 12 deaths during the initial salvage regimens. In univariate analysis factors significantly affecting response rate (p1 54% vs 77% and prior exposure to rituximab 54% vs 82%. In a logistic regression model only refractory/early relapse and secondary IPI remain significant for response rate. Intent to treat 2 yrs EFS and OS were 50% (CI 42–57%) and 69% (CI 61–75%) respectively. Only 107 pts in this prospective study received, per protocol ASCT. For patients transplanted, 2 yrs EFS was 75% (CI 63–84%) with OS 89%. Two yrs EFS was affected by: prior treatment with rituximab, 34% vs 66% (p=.0001); refractory/early relapse 36% vs 68% (p Conclusion: Salvage chemotherapy incorporating rituximab provide a high 82% response rate in pts not previously treated with rituximab. Patients who refractory to upfront rituximab-based chemotherapy have a poor response rate and prognosis. The study is on going to include 240 pts in the second randomisation for the EFS primary endpoint.

Background. The FL2000 study evaluated the combination of the anti-CD20 monoclonal antibody rituximab with chemotherapy plus interferon in the first line treatment of follicular lymphoma patients. Methods. Untreated follicular lymphoma patients (n=359) presenting with a high tumor burden were randomly assigned to receive either 12 courses of the chemotherapy regimen CHVP (cyclophosphamide, adriamycin, etoposide and prednisolone) plus interferon-α2a (CHVP+I arm) over 18 months or 6 courses of the same chemotherapy regimen combined with 6 infusions of 375 mg/m2 of rituximab and interferon for the same time period (R-CHVP+I arm). The primary endpoint of the study was event free survival and all results are shown as intent to treat. Results. Six months after treatment initiation, 156 out of 183 (85%) and 164 out of 175 (94%) patients had a response to therapy in the CHVP+I and R-CHVP+I study arm, respectively (P=.009). At the end of the 18 months treatment period, 59% and 75% of the patients were respectively in CR or CRu in the CHVP+I and R-CHVP+I arm (P Conclusions. These results extend our previous interim analyses and confirm that with a five year follow-up, the combination of rituximab with CHVP+I provides superior disease control in follicular lymphoma patients despite a shorter duration of chemotherapy. However, this combination appears to benefit essentially to high risk patients for whom overall survival is also significantly improved.

Autologous stem cell transplantation (ASCT) is widely used in relapsed or refractory low grade lymphoma with conditioning regimen including chemotherapy with or without total body irradiation (TBI). Radiolabelled immunotherapy 90Yttrium ibritumomab tiuxetan (Zevalin) is effective in B-cell lymphoma and delivers targeted radiation without TBI toxicity. To take advantage of this antilymphoma effect, conventional dose of 90Yttrium ibritumomab tiuxetan 15 MBq/kg (maximum 1200 MBq, total dose) was given without dosimetry day -14 before ASCT and combined to standard BEAM regimen starting at day -7. The goal of this phase II study was to evaluate efficacy and toxicity of Z BEAM. Patients < 65 years with CD20+ low grade B cell Lymphoma in 1st or 2nd relapses, or not achieving complete remission after first line treatment were included in the trial. They had to be chemosensitive to last salvage therapy, no more than three lines of treatment and eligible for ASCT. The primary end point was to detect a 2 yrs EFS at least 80%. Hematological reconstitution was evaluated after transplant and during the first year follow up. From 3/2005 to 8/2006, 77 patients were included. Patients characteristics at inclusion: 90% follicular lymphoma, median age 53 yr. (31–64), FLIPI 1G/L 12 days (9–35), time to platelets >20 G/L 12 days (3–42). Median number of platelets transfusions 4; red blood cell transfusions 2. Grade 3-4 toxicities were: infection 83%, mucositis 47%, pulmonary 4%. Safety data indicated 35 serious adverse events in 24 patients that did not appear to significantly differ from those usually seen after ASCT. No toxic death was observed. At week 12 and 42 after ASCT, median haemoglobin level were 11.6 g/dl and 11.3 g/dl, median platelets counts was 111G/L and 148 G/L, leucocytes counts 3.48 G/L and 4.80 G/L respectively. Only 5 events were reported. After a minimum follow up of one year for all patients, estimated 2 years EFS is 93%. Updated results on survival will be reported. Conclusion: Z BEAM is a safe conditioning regimen which can be used for B cell lymphoma. Longer follow up is necessary to evaluate long term toxicity and efficacy. Further randomized study are warranted.

High amounts of intra-tumoral reactive macrophages have been reported to be associated with a poor prognosis in patients with follicular lymphoma (FL) (Blood2005;106:2169). However, this study has been retrospectively performed in a patients’ population selected before the monoclonal antibody therapeutic area, and has not been confirmed on independent series. To establish whether the intra-tumoral macrophages count (MC) is definitely able to predict the outcome of FL patients, we analysed both immunohistochemical CD68 expression and clinical outcome in patients included in the GELA-GOELAMS FL-2000 trial (ASH-2004; ASCO-2006). Patients between 18 and 75 years of age with high tumor burden FL were randomized to receive either CHVP-I or R-CHVP-I. Among the 358 patients included on the basis of histologically proven FL after reviewing by 3 hematopathologists, 194 had available biopsy specimen. Clinical characteristics of those 194 patients were not different of those of the whole population and median time to event was 43.1 months in 92 pts receiving CHVP-I arm and 54.5 months in the 102 pts receiving R-CHVP-I. Slides were stained with the anti-CD68 KP1 antibody using a standard IHC procedure, then scored on high power field (hpf) (× 400 magnification) by 3 different pathologists. Analysis of the relative risk of event according to the intra-follicular MC (IF-MC) led us to determine a single cut-off point to categorize the covariate, the best cut-off point being estimated to be 10 macrophages/hpf. The IF-MC was equal or less than 10 intra-follicular KP1+ macrophages/hpf in 53 patients, and more than 10 in 141 patients. With this cut-off of 10, a low MC was significantly associated with a better EFS for all patients (p=0.011). However, this effect was predominantly observed in patients that received CHVP-I (p=0,012, OR) but not in those receiving R-CHVP-I (p=0.15).Multivariate analysis adjusting for 10 IF-MC cut-off (p

Introduction : Assessment of therapeutic response using 18-Fluoro-deoxy-glucose (FDG) positron emission tomography (PET) is useful to determine prognosis in lymphoma. In poor prognosis lymphoma patients, it may have an important value in the pre-transplant evaluation and help to transplant-decision making. But the impact on patient outcome of post-transplant assessment is unknown. Patients and methods: In our department, between July 2004 and December 2005, 60 consecutive patients (M/F ratio= 37/23) who achieved tumor response and received high-dose chemotherapy plus autologous-stem-cell transplantation (ASCT) were prospectively explored with PET, prior to ASCT (after 3–4 chemotherapy cycles) and 100 days after ASCT. PET images were evaluated without knowledge of conventional imaging and clinical history. Presence (PET positive) or absence (PET negative) of abnormal FDG uptake was related to event-free survival (EFS) and overall survival (OS). Results :50 patients had non-Hodgkin lymphoma (20 diffuse-large-B-cell (DLBCL), 8 mantle-cell, 16 follicular, 4 T-large-cell, 2 Burkitt) and 10 Hodgkin’s lymphoma. Median age was 52 ranging from 19 to 68 years. At diagnosis, 9 patients had 2–4 performance status, 40 elevated LDH, 30 extranodal involvement and 53 staged 3–4. Tumor bulk was above 10 cm in 14 patients. 22 patients received front-line ASCT mainly after ACVBP (n=14) or CHOP. Platinum-based salvage chemotherapy (DHAP, n= 26) was the most frequently used for 27 relapses and 11 refractory diseases. 40 patients received Rituximab with chemotherapy. Prior ASCT, there were 31 complete remission (CR), 23 uncertain CR and 6 partial remission. Conditioning regimen was BEAM in 39 patients; Zevalin BEAM in11, Total Body Irradiation was used in 10. 44 patients (75%) were pre-ASCT-PET negative and 48 (80%) post-ASCT-PET negative. 6 patients (10%) converted from pre-ASCT-PET positive to post-ASCT-PET negative (2 Hodgkin, 1 mantle, 2 follicular, 1 DLBC) and 2 patients (3%) converted from pre-ASCT-PET negative to post-ASCT-PET positive (1 pulmonary infection, 1 early relapse in DLBC). One year after ASCT, 10 patients died (OS 80%) and 17 relapsed (EFS 67%). OS was estimated to 90% in pre-ASCT-PET-negative patients vs. 51 % in PET-positive (p=0.0003), EFS was 75% vs. 43%, respectively (p=0.001). OS was estimated to 87% in post-ASCT-PET-negative patients vs. 48% in PET-positive (p Conclusion: A positive PET after induction chemotherapy indicates a high risk of ASCT failure; in addition, this risk of failure is increased by a positive PET after ASCT. In pre-ASCT-PET-positive patients, more experimental approaches are needed. In pre-ASCT-PET-negative patients, post-ASCT-PET assessment may be omitted.

ACVBP induction regimen followed by HDC provides a better event-free survival (EFS) and overall survival (OS) as compared to a conventional consolidative treatment in patients (pts) with aggressive non Hodgkin’s lymphoma presenting with 2 or 3 adverse age-adjusted International-Prognostic-Index (aa-IPI) who first reached complete remission. However, complete response rate (CR +CRu) after ACVBP is not superior to 65% (ASH 2005, 677a). Besides, it is established that Rituximab (R) combined with CHOP improves complete remission rate and OS in elderly pts. The objective of the study was to see if combining R (375 mg/m2) to ACVBP (Doxorubicin 75 mg/m2 d1, Cyclophosphamide 1,200 mg/m2 d1, Vindesine 2 mg/m2 and Bleomycin 10 mg d1 and d5, prednisone 60 mg/m2 d1-d5) translates into an improvement of response rate and also EFS in pts under 60y with DLBCL and aaIPI 2 or 3. Four cycles of R-ACVBP were delivered every 15 days supported by filgrastim 5 μg/kg (d6 to d13) or pegfilgrastim (6 mg at day 3). Responding pts received a consolidative BEAM and peripheral blood stem cell rescue. From 01/2004 to 12/2005, 119 DLCBL pts were enrolled. Median age was 49 years (range: 19–60), 18% with aa-IPI 3, 22% with bone marrow involvement, 96% with LDH> 1N and 88% with extranodal sites>1. 59 pts received filgrastim and 60 pegfilgrastim. Based on International Workshop Criteria, CR+CRu rate after induction treatment was 63%, PR rate 25%, stable disease 3% and progressive disease 1%. Deaths without progression occurred in 3% of the pts, and 6% of them could not be assessed (treatment was stopped because of toxic effects or major protocol violation). Hematologic toxicity was similar to that observed in previous GELA trials using ACVBP. Collection failure after the 3rd and/or 4th R-ACVBP cycle was observed in 15 pts (13%), 4 receiving filgrastim and 11 pegfilgrastim (7 of them being further collected with filgrastim). Among the 105 responding pts, 90 received HDC, 15 pts did not (physician’s decision for 4 PET-positive pts after 4 R-ACVBP, 8 collection failures, 2 pts because of a poor performance status after induction phase and one due to sudden death). Three patients died without progression during the HDC procedure. At the end of treatment, 81 pts (68%) were considered in complete remission, 14% in PR and 6% progressed. With a median follow-up of 15 months, two-year EFS was 72% ( CI 62–68%), OS was 79% ( CI 69–86%). We conclude that R-ACVBP induction regimen is feasible and safe on such high risk pts but it does not increase the CR rate. EFS seems encouraging; a longer follow-up is needed to see whether the addition of rituximab contributes to decrease the incidence of relapse.

Background : 18Fluorodeoxyglucose-PET has been advocated as a powerful mean to evaluate response in aggressive non-Hodgkin’s lymphoma. Its relative merits compared to the widely accepted International Workshop Criteria (IWC) (Cheson, 1999. J Clin Oncol 17: 1244) have been investigated (Juweid, 2005 J Clin Oncol 23:4652), but need to be further confirmed. Materials and methods : We studied 103 patients with diffuse large B-cell lymphoma after 4 cycles of inductive CHOP or CHOP-like chemotherapy, with (n=51) or without Rituximab (n=52) using the IWC criteria and PET. The patients where also evaluated with an early PET after 2 courses, the results of which did not influence treatment decisions. PET response criteria have already been published (Haioun, Blood2005; 106). The interpretation of PET took into account the results of the early PET, in particular to define progressive disease. Results : The baseline characteristics of the patients where as follows : Median age 53y (19–78); age >60 : 25 (24%); LDH > normal : 71 (69%); > 1 extranodal site : 53 (51%); poor performance status (>=2) : 37 (36%); stage III–IV: 84 (81%). The international prognostic index (IPI) score was 0–2 in 40 pts (39%) and 3–5 in 63 (61%). The comparative response evaluation using IWC criteria or the combination of IWC criteria and PET is shown in the following table. Three years after completion of therapy, patients being in CR by PET at 4 cycles had an estimated event-free survival (EFS) of 83% if in CR/CRu by IWC criteria, and of 80% if in PR or SD by IWC. Patients not in CR by PET had an EFS of 51% when in CR/CRu by IWC criteria and of 8% when in PR, SD or PD by IWC criteria (p Conclusion : We confirm the higher predictive power of PET as compared to IWC criteria. The CRu category disappears from evaluation criteria when integrating informations delivered by PET, and PR patients can be separated into CR versus PR patients. The predictive value of PET is seen in patients treated with, as well as without Rituximab. IWC + PET Response CR CRu PR SD PD Total * 4 pts showed progression between 2 and 4 cycles on the basis of PET** 2 pts had no PET at 4 cycles because of early progression IWC CR 23 0 1 0 0 24 CRu 43 0 8 0 2 53 PR 9 0 3 0 2 14 SD 1 0 0 0 1 2 PD 0 0 1 0 5 6* Total 76 0 13 0 10 101**

Background: Angioimmunoblastic T-cell lymphoma (AITL), the second most frequent peripheral T-cell lymphoma, is characterized by a distinct clinical presentation and a spectrum of biological and morphologic features with little available data on prognostic factors in the literature. Objective: to evaluate the prognostic significance of clinical, biological and pathological features in AITL. Methods: between 1987 and 1998, 158 AITL patients were retrieved from the GELA LNH87 and LNH93 trials. Most patients received an anthracycline based polychemotherapy. Histologically, cases were reviewed by a panel of expert hematopathologists. For each case, at least 2 hematoxylin eosin slides were available for review together with an appropriate immunohistochemical staining including CD3, CD20 and CD21/CNA42. Cases were classified as “transformed” (>10% large B and/or T cells) and “classic” (including cases rich in clear cells, rich in epithelioid cells and with hyperplastic germinal centers). 62 cases were evaluated for CD10 and CXCL13 expression and scored according to the number of positive lymphoid cells. Results: there was a slight male predominance (M/F=1.53). Median age was 62 years. 81%, 50%, 67% and 39% of patients had respectively an advanced stage, a non ambulatory PS, an IPI>2 and a PIT>2 (age>60y, PS>=2, LDH>=normal and bone marrow involvement). Anemia, positive coombs test and bone marrow involvement were observed in 65%, 33% and 47% of cases respectively. Hypergammaglobulinemia, elevated LDH levels and skin rash were observed in 15%, 66% and 44% of patients respectively. 41 cases were classified as transformed and 117 as classic including 20 epithelioid-cell rich, 14 clear-cell rich and 4 with hyperplastic germinal centers. CD10 and CXCL13 were clearly positive, in a fraction of the lymphoid infiltrate, in 71% and 73% of cases respectively. CR/CRu remission was observed in 46% of patients after induction therapy. With a median follow-up of 69 months, the 5y overall survival rate was 33%, reaching a plateau level around 6 years. Concerning PIT, patients with 0–1 factors and 3–4 factors had a 5y OS of 37% and 38% respectively. In univariate analysis, absence of CR/CRu (p Conclusion: despite of various intensive regimens with an anthracycline based chemotherapy, AITL pursues an aggressive clinical course and carries a poor prognosis. Our large series emphasizes the morphologic heterogeneity of AITL, without any clinical impact, and further confirms the common expression of CD10 and CXCL13.

Introduction: Whether erythropoietin (Epo) has an impact on survival of patients (pts) with malignancies is debated. Since Dec 2003, the GELA has conducted a prospective randomized study to evaluate the safety and efficacy of Darbepoetin alfa (DA) in elderly pts with DLBCL treated by immunochemotherapy. In 2005, new recommendations about the use of Epo for patients with chemotherapy induced anemia have been published. Following these recommendations, the protocol was temporarily stopped and a first safety analysis was performed. Here we report the preliminary results on the first 130 enrolled patients. Patients and methods: pts between 66 and 80 years old with DLBCL and aaIPI ≥1 have been enrolled from Dec 2003 to Aug 2005. Pts were firstly randomised between two regimens combining Rituximab and the classical CHOP (Coiffier and al. NEJM 2002) delivered every 2 (R-CHOP14) or 3 weeks (R-CHOP21) for 8 cycles and were subsequently randomised between an investigational arm with DA (Arm 1) given in order to maintain hemoglobin (Hb) level between 13 and 15 g/dL and a conventional arm (Arm 2) with usual treatment of chemotherapy induced anemia, including transfusions and Epo according to usual practices. G-CSF was given according to physicians’decision. Results: 63 pts were randomised in Arm 1 and 67 in Arm 2. Median age is 71 y (66 – 80). Patients’characteristics were similar between arms and the percentage of patients with aaIPI 2–3 is 59%. Mean Hb level at randomisation is 12.2 g/dL (7.1 – 15.6). There rate of deaths during the treatment period is similar between arms (8% and 10%) and mainly related to treatment toxicity or lymphoma progression. The number of serious adverse events of any cause is lower in Arm 1 (96 events) compared to Arm 2 (153 events). Grade 3–4 Hb toxicity is higher in Arm 2 (39% versus 22%, p = NS). 18/63 (29%) patients received red blood cells transfusions in Arm 1 compared to 37/67 (55%) in Arm 2 (p=0.01). The number of patients with at least one episode of febrile neutropenia is lower in Arm 1 as compared to in Arm 2 (23% vs 36%, p = NS). There is no increase of cardiac and vascular events (respectively 9% and 9% in Arm 1 compared to 8% and 10% in Arm 2). The median level of Hb in Arm 1 during treatment is 12.05 g/dL and 10.65 g/dL in Arm 2. Sixteen percent of patients in Arm 1 have had at least one episode of Hb > 15 g/dL during treatment compared to 5% in Arm 2. The rate of thromboembolic events is similar in these patients (2/10) and in those who never have reached this Hb level (7/53). One year after completion of treatment, overall survival (OS) of the entire population is estimated at 74% and event free survival (EFS) at 67%. OS (78% in Arm 1 versus 70% in Arm 2 at 1 year) and EFS (73% in Arm 1 versus 64% in Arm 2 at 1 year) are similar between the two arms. Conclusions: these preliminary results provide encouraging results about the safety of a prophylactic use of Darbepoetin alfa and support the continuation of accrual to draw definite conclusions about safety and also efficacy.

We have shown (Haioun, JCO 2000) that consolidative HDC provides a better survival for patients (pts) with aggressive non-Hodgkin’s lymphoma presenting with 2 or 3 adverse age-adjusted International-Prognostic-Index (aa-IPI) factors in complete remission after induction treatment. In the same time, rituximab had been evaluated as a single therapeutic agent in aggressive lymphomas with promising efficacy (Coiffier, Blood 1998). More recently, rituximab maintenance therapy has been successfully used after chemotherapy or after ASCT to keep responding patients in remission. The primary objective of the present study was to evaluate the potential benefit, as randomly compared to observation, of rituximab - 375 mg/m2/week for 4 weeks - 2 months after HDC, in decreasing the relapse rate (second randomization: R2). A secondary objective was to improve the response rate before HDC treatment using the intensified ACE chemotherapy regimen (doxorubicin 75mg/m2 d1, cyclophosphamide 1g/m2 d1-d2, etoposide 150mg/m2 d1–d3) as compared to the standard GELA ACVBP induction regimen (first randomization: R1). Induction regimens were delivered every 15 days for 4 cycles. In responding pts, peripheral blood stem cell (PBSC) collection was performed after the third or fourth cycle. HDC (mitoxantrone 45 mg/m2, cyclophosphamide 1500 mg/m2 x 4d, etoposide 250 mg/m2 x 4d and carmustine 300 mg/m2) was started between d80 and d90 after one or two courses of high-dose methotrexate. From 10/99 to 05/03 (closing date), 476 pts younger than 60 years with diffuse large B-cell lymphoma and aa-IPI 2 or 3 (aa-IPI 3: 29%). were enrolled. We here present the results of the final analysis, performed in July 2005 with 235 pts assigned to receive ACE and 241 to ACVBP. Complete response (CR+CRu) rates to induction treatment did not significantly differ between the 2 regimens (65% and 63%, respectively, p=0.71) and toxic death rates were similar (2% and 3%, respectively) despite higher NCIC grade 3–4 infectious toxicity with the ACE regimen. Among the 331 pts who received HDC, 269 were randomized (R2) to receive either rituximab (n=139) or observation (n=130). 545 infusions of rituximab were administered with no clinically relevant infectious toxicity except two resolutive VZV infections. With a median follow-up of 3 years after R2, a trend toward a better 3y-EFS was observed in the rituximab group (80% vs 72%, p=0.10). Early and brief rituximab maintenance is feasible after HDC. We hypothesize that prolongation of treatment may improve the results as well as selection of patients more likely to respond to rituximab therapy.

Actually, the prognosis of localized Hodgkin’s lymphoma (HL) patients may be assessed by different scoring systems. Although many similar characteristics have been identified, these scoring systems are not easy to relate to advanced stage HL. The aim of the present study was to refine the assessment of risk using the published scoring systems and to construct a statistical model for predicting risk of death. We report here the results of the EORTC, GHSG and Canadian-ECOG scoring systems obtained in 1156 patients for whom hematological data were available among the 1390 patients with localized HL prospectively treated within GELA centres in H8 (518 pts) and H9 (638 pts) trials. The International prognostic score (IPS) was available only for the H9 subset. All patients have been treated with radio-chemotherapy of different intensity or duration according to their prognostic factors. Median age was 30 yr [14–69] and age≥45yr.: 18%, female 50%; stage 1: 25%; stage 2: 75%; B symptoms with elevated ESR: 40%; number of nodal sites 1–2: 52%; ≥3: 48%; extra nodal involvement: 8%, bulky mediastinum> 0.35, 28%; elevated ESR> 50:33%; Hb< 10.5 g/dl: 7%; Lymphocytes < 600/μl: 6%; WBC > 15000/μl:11 %; albumin< 40g/l: 37%. With the EORTC scoring system 36% of patients had favourable HL, with GHSG 35% and with Canadian-ECOG 38%. The IPS was 0 in 19% and 1 in 45%. With a median follow up of 42 months, 54 patients died. Survival curves according to the different scoring systems significantly discriminated favourable and unfavourable patients outcomes (5 yrs OS 95% vs 92%, p=0.01). By multivariate Cox analysis, age > 45yr (RR=2.0), sex male (RR=2.5), haemoglobin Figure Figure

The anti-apoptotic protein bcl2 expression is associated with treatment failure in elderly patients (pts) with DLBCL (Blood 101:4279,2003). The ACVBP regimen with conventional consolidation therapy (JCO 18:3025,2000) yield a 2-year (yr) EFS at 71% in DLBCL pts aged 60 yrs or less with only 1 adverse age-adjusted International-Prognostic-Index factor (LI risk pts). To assess if ASCT reduces treatment failure in these pts, we initiated a trial stratified by bcl2 expression. Centralized staining for bcl2 was prospectively performed within 6 weeks after inclusion. Induction regimen consisted of 4 courses of ACVBP given every 2 weeks. In case of response, bcl2 negative pts received the conventional consolidation regimen, whereas bcl2 positive pts underwent peripheral blood stem cell collection after the 4th cycle, and ASCT (mitoxantrone 45 mg/m2, cyclophosphamide 1.5 g/m2 x 4d, etoposide 250 mg/m2 x 4d and carmustine 300 mg/m2) between d80 and d90. From 1999 to 2002, 272 LI-risk pts aged 18 to 59 (median 46, M/F=1.4) presented with bcl2 overexpression (151) or without (121). There was no difference in initial characteristics, toxicity of induction and complete response (CR+CRu) rates between bcl2 positive and bcl2 negative pts (78% and 82%, respectively, p = 0.38). ASCT was not performed in 35 pts, mainly because of early failure (37%). Although bcl2 negative pts retained a better 2-yr survival than bcl2 positive pts (95% vs. 86%, p=0.01) with a median follow-up of 21 months, 2-yr EFS and 2-yr DFS did not differ significantly (84% vs. 79%, p=0.33, and 89% vs. 87%, p=0.94 respectively). This analysis demonstrates the feasibility of taking bcl2 expression into account for the design of multicentre protocol. The lack of difference in EFS and DFS between bcl2 positive pts who received ASCT and bcl2 negative pts treated with conventional consolidation suggested that ASCT may overcome the adverse prognostic value of bcl2 expression in LI-risk pts who achieve CR or Cru.