ALBERT

Description: Key Points Pom-Dex is active and well tolerated in adverse cytogenetic patients with early RRMM, particularly in those with del(17p). Pom-Dex prolonged OS in adverse cytogenetic patients with early RRMM.

Description: The benefit of radiotherapy (RT) following chemotherapy in limited-stage DLBCL remains controversial. Before the Rituximab era, 4 randomized trials have been reported with conflicting results (ECOG 1484 and SWOG 8736, GELA 93-1 and 93-4 studies). More recently, the German Unfolder study prematurely closed the R-CHOP without RT arm in bulky limited-stage DLBCL due to an excess of relapse. In 2005, we conducted a randomized trial in patients with non-bulky (defined by a tumor size 50% but a persistent positive FDG-PET) after C4, 2 additional cycles of R-CHOP followed by RT (even if not initially allocated) were recommended. The primary objective was EFS at one year after the last randomization, and secondary objectives were the impact of interim FDG-PET on EFS and the toxicity of RT. From May 2005 to December 2013, 313 patients were randomized and 301 patients are currently evaluable. Median age was 56 yr (20-75). There were 181 males and 120 females: 106 patients (35%) were older than 60 yr. Most patients had normal LDH (82%), PS=0 (80%), and no B symptoms (96% of cases). Modified IPI score was as follows: IPI =0 (n=170), IPI=1 (n=113), IPI=2 (n=16), IPI=3 (n=2). Main tumor sites were cervical (n=159), Waldeyer’s ring and sinus (n=36), inguinal (n=29), axillary (n=25), mediastinum (n=21). Extra-nodal sites were observed in 121 patients (40%). One hundred and fifty patients were randomized in the R-CHOP arm and 151 in the R-CHOP + RT arm. After 4 cycles, 253 patients (84%) were in CR and 43 in PR (14%). Three patients had stable disease. Thirty-four patients (79%) out of the 43 partial responders received 2 additional cycles of R-CHOP followed by RT (including 12 patients not initially allocated to RT arm). At the end of treatment, CR and PR rate were 94% and 3%, respectively. Seven (4%) out of the 151 patients randomized in the RT arm declined radiation. With a median follow-up of 51 months (2-110), there were 20 relapses: 12 in the R-CHOP arm and 8 in the R-CHOP+RT arm (p=ns). Sixteen patients died. Causes of death were as follows: relapses (n=9), toxic (n=1), secondary malignancies (n=3), unknown (n=3). Median time of relapse was 21 months (2-110 months). EFS and OS are not statistically different between the two arms. In an intent to treat analysis, 5y-EFS is 87% n the R-CHOP arm versus 91% in the R-CHOP + RT arm (HR=0.55), p=0.13, and 5yr-OS is 90% in the R-CHOP arm versus 95% in the R-CHOP + RT arm (HR=0.60), p=0.32. For patients in complete response after the 4 cycles of R-CHOP (84% of the patients), 5yr-EFS is 89% in the R-CHOP arm versus 91% in the R-CHOP + RT arm (HR=0.59), p=0.24. In this prospective study, the results demonstrate that in non-bulky limited-stage DLBCL, R-CHOP alone (4 to 6 cycles) induces very high CR rate with a very good overall survival and a very low relapse rate. With the current follow-up, the addition of radiotherapy is not significantly superior to R-CHOP alone and should be reserved to the minority of patients who do not reach CR after R-CHOP. Disclosures Gyan: Roche: Research Funding.

Description: Twenty four patients (pts) with planned autologous stem cell transplantation for lymphoma diseases (Hodgkin’s disease=4; non-Hodgkin’s lymphoma=20) received chemotherapy (CT) (Induction CT=3 and salvage regimen= 21) followed by a fixed single dose (6 mg) administration of Pegfilgrastim (PF) after the last day of CT for peripheral blood stem cell collection (PBSC) (target cell dose of 3 2×106 CD34+/kg). Median age was 53 yrs (24–68) and median weight was 72, 5 kg (45–98). Among the 24 pts, 7 received more than 2 lines of CT regimens. The injection of PF was well tolerated. Median time interval between day 1(D1) of the cycle of CT mobilization and first leukapheresis session was 14 days (10–18) while the median time interval between injection of PF and first leukapheresis session was 9 days (6–13). Stem cell collection was started when the absolute number of circulating CD34+ cells was 〉10×106/L and performed with standard volume leukapheresis. Median CD34+ cells level at D1 of leukapheresis was 35, 5/mm3 (11–320) and interestingly, more than 35 % of pts could reach this median level of CD34+ early after PF injection (around D6). Notably, 22 pts reached the target cell dose in 2 sessions of leukapheresis or less (10 pts after 1 session, 10 other pts after 2 sessions, 2 pts after 3 and 4 sessions respectively). The median number of leukapheresis sessions was 2(1–4) and the median CD34+ cells harvested was 4×106/kg (0,8–26,6). Two pts (DLBCL = 1 and FL = 1) could not reach the level of CD34+ required to start leukapheresis and both became secondary refractory to CT. In univariate analysis, PBSC collection of 〉 4×106/kg was highly correlated with pts who started their collection at D9 of PF administration (P=0,01) and with those presenting a CD34+ cells level 〉 35.5/mm3 at D1 of leukapheresis (P=0,033). White blood cells level higher than 9 G/l was also predictive of circulating CD34+ cells 〉35,5/mm3 (P=0,033). These data suggest that PF may represent an attractive option for PBSC mobilization particularly for pts with lymphoma when optimal compliance of frequent sequential regimens of CT is required. We also emphasize that stem cell mobilization is effective even in pts in second or subsequent salvage CT regimen. Importantly, the circulating CD34+ count should be performed from D6 of PF administration. The presentation will include the updated data.

Description: Abstract 4023 Background: Treatment of CMML remains difficult, with no drug having shown a clear clinical benefit. AZA has demonstrated a survival benefit in higher risk MDS, in a study that included a small number of CMML (Lancet Oncol, 2009). Several small series of CMML treated by Decitabine (Wijermans, Leuk Res. 2008, Aribi A, Cancer. 2007 and Kantarjian H, Blood. 2007), and AZA (Scott, Br J Haematol. 2010) have been reported, but pts were often very heterogeneous in terms of risk factors and treatment, while in the AZA paper, patients also received etanercept in combination. Methods: The French health agency (AFSSAPS) designed, between 2004 and 2008, a pt named program (ATU) of AZA in higher risk MDS and poor risk AML. 38 pts with CMML or AML arising from CMML included in this program before April 08 and having completed ≥ 1 cycle of AZA (75 mg/m2/d during 7 days every 28 d) are analysed here. As CMML has features of both MDS and MPD, its risk factors are somewhat composite. Based on our previous experience (JCO 1988 6:1417, Blood 1996 88:2480) and on IPSS, pts with WBC 13 G/L, risk factors were based on: marrow blasts≥5%, Hb 5cm) and extramedullary disease (EMD). Response was evaluated according to IWG 2006 criteria in pts with WBC 13G/L, and IWG-AML 2003 criteria for AML. Results: median age was 71 y (range 50–87), M/F: 28/10. Median interval from diagnosis to treatment was 22 months (range 0.2–74 months). Previous treatment was low dose chemotherapy (CT) (n= 10, low dose Arac n=2, HU n=8), Intensive CT (n=12), allogeneic SCT (n=1), ATO (n=2). At inclusion, 9 pts had CMML-1, 17 CMML-2 and 12 AML secondary to CMML according to WHO. Karyotype was normal (n=16), isolated –7/7q- (n=2), +8 (n=1), del 20q (n=1), complex (n=2), -Y (n=2) and a failure (n=2). In the 14 CMML with WBC 13G/L, 10 had more than 3 risk factors defined in Blood 1996 88:2480. The median number of cycles of AZA administered was 4 (range 1–26). 6 pts received also HU during the first cycles to reduce WBC count. 9 pts received less than 4 cycles due to early death (n=4), progression (n=3) and haematological toxicity (n=2). 20 pts (53%) responded including 9 CR, 3 marrow CR,8 HI-E and 1 partial remission. 19 (68%) of the 28 pts who received more than 4 cycles responded, including 9 CR, 3 mCR, 1 PR and 6 HI. Of the 26 CMML without AML progression, 15 (58%) responded (7 CR, 2 marrow CR and 6 HI-E). Of the 12 AML arising from CMML, 5 (42%) responded (2 CR, 1 marrow CR, 1 PR and 1 HI-E). Median number of cycles of AZA to achieve best response was 4 (range 3–12). Age (p=0.38), WBC count (p=0.76), Hb level (p=0.987), platelet count (p=0.07), blood monocytes (p=0.4823), Sex (p=0.28), CMML 1 vs 2 (p=0.48), splenomegaly (p=0.7), normal karyotype (p=1), -7/del7q(p=0.65), concomitant treatment with HU (p=0.6), 〉3 risk factors in CMML with WBC〉13 G/l, and previous treatment (p=0.506) had no impact on response. 9 of the 20 responders relapsed after a median of 10.6 months (range 3–23), including 4/9 (44%), 1/3 (33%), 0/1, 4/8 (50%) of the pts who had achieved CR, mCR, PR and HI respectively, 10 remained responders after a median of 26 months (16-35) and 1 pt with HI died without relapse. Median overall survival (OS) was 24 months in CMML compared to 7 months in AML arising from CMML (p= 0.0081). Presence of splenomegaly, WBC〉13 G/l, previous treatment (excluding ESA), Sex, -7/del7q and normal karyotype had no impact on OS. Conclusion: In this series of CMML which had on average more unfavourable prognostic factors than in previous series of CMML treated with Decitabine or AZA (10/14 with WBC 13 G/L had at least 3 risk factors, and 12 had progressed to AML), AZA showed clear efficacy, but mainly in pts who had not progressed to AML. Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Description: Abstract 2796 Background: Diffuse large B-cell lymphoma (DLBCL) relapse prognosis is poor, and the optimal salvage treatment is not known. In a previous pilot study, vinorelbine, ifosfamide, mitoxantrone, and prednisone (NIMP) without rituximab has shown a promising efficacy in the setting of relapsed DLBCL. Aims: To evaluate the efficacy and tolerability of the combination of rituximab and NIMP in the treatment of DLBCL in first relapse. Methods: This multicentric, single-arm phase II study included patients 18 to 75 years old, with CD20-positive DLBCL in first relapse (defined as having obtained at least a PR of more than 50% to an anthracycline-based front-line regimen) occurring more than 30 days after the last chemotherapy cycle or more than one year after an autologous stem cell transplantation (ASCT) in first line. Other inclusion criteria were a performance status ≤ 2, absence of CNS involvement, and having signed an informed consent form. Patients with evidence of transformation from indolent lymphoma, primary refractory disease, or positive HIV tests were excluded. Initial and relapse biopsies were centrally reviewed. Patients received intravenous (IV) rituximab 375 mg/m2 D1, ifosfamide 1000 mg/m2 as a continuous infusion from D1 to D5, IV vinorelbine 25 mg/m2 D1 and D15, IV mitoxantrone 10 mg/m2 D1, and oral prednisone 1 mg/kg D1 to D5, repeated every 28 days for three cycles. Pegfilgrastim support (6 mg at D7) was recommended. The primary endpoint was CR/CRu after 3 cycles, and was assessed by computed tomography according to the IWG criteria. Mobilization, consolidation or subsequent salvage therapy was decided at the discretion of the investigator. All the monitoring and data management were performed by the GOELAMS clinical research assistants, with a database lock on July 27, 2010. Results: Fifty patients (21[42%] women and 29[58%] men) were included in 18 centers between December 2004 and accrual closure in April 2010. All patients received at least 1 cycle of R-NIMP. Forty-five patients were available for central pathology review, toxicity and response. The central review of all patient samples confirmed DLBCL histology. Median age at study entry was 62.9 years (range: 34.8–75.6). Median time between first diagnosis of DLBCL and relapse was 18.0 months (range: 2.4–208). The following tumor responses were observed: 67.9 % overall response rate with 20 CR/CRu (43.5%), 11 PR (24.4%), 2 SD (4.4%), and 12 (26.7%) progressed under therapy. Toxicity information was available for 109/120 (91 %) of the first 3 cycles of R-NIMP administered. The following toxicities were observed (all grades, ≥ grade 3 for all cycles): anemia (87%, 8%), neutropenia (66%; 46%), thrombopenia (65%, 14%), elevated liver tests (39%, 0%), constipation (25%, 0%), kidney failure (7%, 0%), nausea (14%, 0%), vomiting (6%, 0%), allergic reactions (5%, 0%), and mucositis (5%, 0%). Twenty-nine infectious events (27%) were observed needing hospitalization in 9 cases. Twenty-nine patients received consolidation therapy at the discretion of the investigator. Of the 11 patients who received 3 additional cycles of R-NIMP, 3 remained in CR/CRu, 1 remained in PR, 4 converted from PR to CR/CRu, and 3 progressed. Among the 11 patients who underwent ASCT, 9 were in CR at the end of the procedure, one patient died of toxicity and 1 progressed. For the 12 patients mobilized after a R-NIMP cycle, a median of 1 apheresis (range 1–4) was necessary to harvest a median of 3.85 × 106 CD34+ cells/kg. The median time to second progression or relapse (TTP2) was 11.4 months, and the median survival of 55.5 months. On multivariate analysis, the variable associated with a longer TTP2 was the achievement of CR/Cru (RR: 0,12; CI95%: 0.03–0,39; p=0.0006). Within the subgroup of patients having received a consolidation treatment, having received an ASCT was associated with a longer TTP2 (RR: 0.20; CI95%: 0.04–0.98; p=0.047). Time to first relapse or previous rituximab exposure did not affect TTP2 nor OS, whereas relapse-IPI (as a continuous variable, by 1 additional risk factor) was associated with a poor survival (RR: 2.59; CI95%: 1.25–4.45; p=0.008). Conclusions: R-NIMP is a well-tolerated regimen, yields a high complete response rate, and allows for successful mobilization of CD34+ cells. This regimen is a suitable salvage treatment for relapsed DLBCL prior to appropriate consolidation. Further investigation is warranted. ClinicalTrials.gov number: NCT00842595 Disclosures: Off Label Use: Vinorelbine in Non-Hodgkin's Lymphoma (Off-label in France).

Description: Background. Bortezomib-melphalan-prednisone (VMP) and melphalan-prednisone-Thalidomide (MPT) are the 2 standards of care upfront in Multiple Myeloma (MM) ineligible for transplantation, along with Bendamustine-prednisone in a very limited indication in Europe. These regimens are based on an alkylator plarform, to which cyclophosphamide might replace melphalan in some countries. For patients initially exposed to Thalidomide several options are offered at first relapse with bortezomib or lenalidomide-based therapy and vive versa at subsequent relapses. For patients initially exposed to bortezomib, either they are retreated with a bortezomib-based regimen or receive a lenalidomide-based therapy, but these patients often have never been exposed to thalidomide throughout their myeloma disease history. We hypothesized that patients that will receive the 3 agents, thalidomide first followed by bortezomib and lenalidomide at subsequent relapses, will have a prolonged survival compared to patients that had bortezomib-based first followed by lenalidomide at subsequent relapses but never been exposed to thalidomide upfront. We sought to understand the prognostic impact of receiving versus being spared from Thalidomide in elderly MM newly diagnosed. Method. A total of 76 patients were recruited, 37% had receive thalidomide and 63% never been exposed to thalidomide. Patients were required to be aged ≥65 years, NDMM treated with either thalidomide upfront or never been exposed to thalidomide upfront or later in the myeloma disease course. Response rate was determined according to IMWG. All survival endpoints were evaluated using Kaplan-Meier estimates and compared with the log-rank test. Results. Overall, the median age was 73 years (range, 65 - 85), with 46% aged 〉75. The m:f ratio was 1.2, 49% of the patients were ISS 3, the median b2m was 4.5mg/L, 33% had an ECOG score ≥ 2, 47% renal insufficiency, 11% had elevated LDH, 8% presence of plasmacytoma, and 11% had adverse FISH (del17p, t(4;14) and or t(14;16)). There was no difference between the 2 studied groups, according to exposure or not to thalidomide. In the thalidomide group, all patients had MPT initially for a median of 8 cycles (range 3 – 12), at a median dose of thalidomide of 100mg/day (50-200), 11% dose reduction, an ORR of 79%, a median PFS of 30 months (CI95% 27;32). In the bortezomib group upfront, patients received Vd, VCd or VMP upfront. The median dose administered of bortezomib was 1.3mg/m², for a median of 5 cycles (2-9). The ORR was 67%, a median PFS of 17 months (CI95% 13;20) with 44% at 2-years PFS. With a median follow-up of 5 years, 93% had relapse, 47% have died. We then sought to compare the OS according to whether the patients were exposed to thalidomide. Interestingly, the median OS of the thalidomide group was 4 years (CI95% 3;5) versus 5 years for the group with no exposition to thalidomide (3.5;6), p=ns. The estimated 6-years OS was 32% and 44% for the 2 groups, respectively. Conclusion. The sequence of bortezomib-based regimen upfront followed by lenalidomide with no exposure to thalidomide in transplant ineligible patients appeared to be slightly superior to the sequence including-based regimen upfront followed by bortezomib and lenalidomide at subsequent relapses. This data needs to be confirmed in a larger study, but it seems that thalidomide could be spared for elderly NDMM that receive bortezomib-based and lenalidomide-based regimens with possibly an improvement of OS in this latter group with a prolonged follow up. Disclosures Gay: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Karyotype is one of the most important prognosis factor in acute myeloid leukemia. The MLL gene, located at 11q23, is fused to a variety of partner genes through chromosomal translocations and generates the critical leukemogenic fusion proteins. We performed a large retrospective study in 146 adults and children with 11q23/MLL + rearrangement enrolled in 6 clinical trials conducted in France between 1987 and 1998. Prognosis studies were performed in the 110 patients (47 adults and 63 children) who achieved a complete remission. Individual data were registred, including age, blood and marrow count, extramedullary disease and cytogenetics. The kaplan-Meier method was used in survival analysis and the cox proportinal-hazards model was used to analyse the effect of potential prognosis factors on survival. Among 47 adults, 43 % (20/47) carried t(9 ;11), 19% (9/47) carried t(6 ;11), 23% (11/47) carried t(11 ;19), 6% (3/47) carried t(10 ;11) and 8% (4/47) carried another abnormalities involved 11q23/MLL. Estimated 5-year disease-free survival (DFS), overall survival (OS) and relapse rate (RR) were respectively 17%, 21% and 77%. We analysed separately all translocations involved MLL and we found that the only translocation indicating a favorable prognosis was the translocation t(11 ;19). Compared with other translocations involving MLL, the estimated 5-year DFS, OS and RR of patients with a t(11 ;19) were respectively 45 vs 8% (p=.02), 54 vs 11% (p=.006) and 48 vs 84% (p=.04). Relative risk of relapse was 0,29 (95% confidence interval, 0.09 to 0,9 ;p=.03). Among 63 children, 63% (40/63) carried t(9 ;11), 3% (2/63) carried t(6 ;11), 8% (5/63) carried t(11 ;19), 14% (9/63) carried t(10 ;11) and 11% (7/63) carried another MLL rearrangement. Estimated 5-year DFS, OS and RR were respectively 59%, 72% and 36%. Compared with other translocations involving MLL, we found no difference in outcome between patients with t(9 ;11) and those with other rearrangement of MLL. In conclusion, the most common recurrent abnormality in this large study was translocation t(9 ;11) in adults and children. We found that adults patients whose leukemic cells contained the t(11 ;19) have a better outcome compared with those whose leukemic cells contain other 11q23 /MLL alterations. In children, we do not confirm the favorable impact of t(9 ;11) suggested in previous reports.

Description: Background: The treatment of Acute Myeloid Leukemia (AML) in elderly patients remains unsatisfactory, with an expected survival time of about 1 year post diagnosis. In an attempt to improve outcome for these patients, the prospective open-label phase 3 LAMSA-2007 trial (Clinicaltrial.gov ID, NCT00590837) repeated, at decreasing doses in consolidation and reinduction courses, a standard induction regimen with cytarabine and idarubicin (IC), with or without the randomized addition of lomustine (ICL). This alkylating agent with significant anti-leukemic activity is widely used in France for AML therapy. This study was performed as a confirmatory trial, following our previous report of the French experience in which this compound stood out as a favorable factor of improved outcome for patients with non-unfavorable cytogenetics (Pigneux, JCO 2010). Methods: Eligible patients were adults 60 years old or more, with previously untreated AML, fit to receive intensive chemotherapy (ECOG and SORROR

Description: Background Bortezomib (B) is an effective drug alone or in combination in naive and pretreated WM patients. The interest of high dose of dexamethasone (D) with bortezomib (B) has not been evaluated in WM patients and D is systematically added to bortezomib combination with or without Rituximab (R) (BD, BDR). However, D is responsible for side effects in elderly population. We tested in a phase II trial the efficacy and safety of the addition of D to B after 2 B cycles in patients with a stable or progressive disease (SD, PD). Patients and Methods Bortezomib was used at 1.3mg/m2 IV D1, 4, 8 and 11 every 21 days for 6 cycles. In no responding patients, D (20mg) was added at D1,2, 4, 5, 8, 9, 11 and 12 at Cycles 3 to 6. The main endpoint was the overall response rate (ORR) at two months before D adjunction; secondary outcomes were ORR at 4 and 6 months, response duration, overall survival (OS) and progression-free survival (PFS). Two interim analyses were scheduled and performed after the inclusion of 17 and 27 patients, respectively, using Bayesian estimation of ORR with stopping rules. Results Interim analyses did not allow stopping the trial, with probability of ORR above 35% below 0.9. Thus, a total of 34 patients (pts) were enrolled in the study in two years (2009-2011) in 17 centers. The median age was 70.2 (64.2-79.6).ECOG was ≥1 in 53% of the pts. The median of previous lines, hemoglobin, beta 2 microglobulin, IgM, and albumin was 1, 9.8g/dL, 4.35mg/L, 29g/L, 35 g/L respectively. At 2 cycles, there were 6 partial responses and 10 minor responses(group I), with estimated ORR at 44.1% (95%CI: 27.6-61.9%). D was added in 16/18 pts with stable or progressive disease (group 2). At 4 and 6 cycles, 22/28 and 20/26 pts were in response (12 and 8 in group 1, 10 and 12 in group 2), with resulting 4 and 6 cycles ORR estimated at 75% (95%CI: 47.4-91.7) and 50% (95%CI: 28.0-72.0) in group I and 62.5% (95%CI: 35.9-83.7) and 75% (95%CI: 47.4-91.7) in group 2. A total of 62 adverse events grade 〉 2 (first course: 11, second course: 18, subsequent courses: group 1: 14, group 2: 19) were observed in 38 courses. Of these 62 events (49 grade 3 and 13 grade 4), 52 (84%) consisted in hematological adverse events (18: platelets, 15: hemoglobin, 8: leucocytes, 1 lymphocytes, and 10 neutrophils); 3 neurological toxicities grade 〉2 were observed, 1 after the second course and 2 after the third course in group 1. Otherwise, there were 26 peripheral neurological toxicities grade ≤2, namely 5 for the first 2 courses, 11 in group 1 and 10 in group 2. With a median follow up of 36 months, 23 pts experienced disease progression or died (18 had disease progression and 5 died in response). For patients who achieved at least a minor response, the 18-month progression rates were 31.9% in group 1 and 52.1% in group 2 (p=0.43) and WM unrelated death rates were 6.3% in group I and 16.7% in group 2 (p=0.79). The 2-year survival rate was 79.8% [IC95%: 64.7; 98.3]. The median progression free survival time was 16.8 months [IC95%: 13.0-23.6]. Conclusion We showed that addition of D to B in the elderly population was well tolerated and allowed reaching 6-month response in patients who did not respond to two courses of isolated B. Dexamethasone must be associated to bortezomib-based regimen. Disclosures: Leblond: Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Bortezomib in Waldenstrom macroglobulinemi. Dilhuydy:Roche: Honoraria. Leleu:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; LeoPharma: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Amgen: Honoraria; Novartis: Honoraria. Tournilhac:MUNDIPHARMA: Consultancy, travel funding Other; GSK: Consultancy, travel funding, travel funding Other; Celgene: Consultancy, teaching, teaching Other.

Description: Background: The prognostic value of COO classification by immunohistochemistry (IHC) for de novo untreated advanced DLBCL remains controversial after Rituximab-based frontline therapy. Other biomarkers such as BCL2 or MYC protein expression have been proposed to predict survival. IHC characteristics were investigated in a large multicenter randomized study. Methods: Three hundred twenty-three patients (pts) younger than 60 years with de novo untreated advanced DLBCL were randomized in the french prospective multicenter trial GOELAMS-075 to receive either 8 courses of RCHOP14 (n=161) or 2 courses of RCEEP (Rituximab, Cyclophosphamide, Eldisine, Epirubicine, Prednisone) and 1 course of Rituximab-Methotrexate-Cytarabine (RMC) followed by intensive BEAM conditionning with autologous transplant (ASCT) (n=162) upon negative interim PET-CT (visual analysis). In case of positivity, salvage regimen followed by ASCT was applied. Three years Event-free-survival (3y-EFS) was the primary endpoint. Event was defined by interim PET-CT positivity, progression or relapse, or death from any cause. Central pathology review confirmed de novo DLBCL diagnosis for 300 pts (93%). COO determination using Hans algorithm, BCL2 protein expression (clone 124, Dako) and MYC protein expression (clone Y69, Abcam) were recorded. Cut-off values were 70% for BCL2, and 40% for MYC. Results: COO analysis could be performed for 125/161 pts in RCHOP arm and 134/162 pts in intensive regimen arm including 36 and 34 Primary-Mediastinal-B-Cell subtype (PMBL) respectively. Repartition of non-PMBL was: 33/89 (37%) Germinal-Center subtype (GC), 56/89 (63%) Non-Germinal-Center subtype (NGC) in R-CHOP arm; 48/100 (48%) GC, 52/100 (52%) NGC in intensive regimen arm. Of 70 PMBL there were 50 NGC, 4 GC and 16 NE equally distributed in both arms. Clinical characteristics were similar in both GC and NGC subtypes, whereas PMBL presented with more frequent bulky disease and predominantly female gender. BCL2 ≥70% and MYC ≥40% were found in 147/285 (55%) and 85/185 (46%) of available samples, without difference between two arms. No correlation was found between BCL2 or MYC protein expression and GC or NGC subtype, however there were seen in a significantly lower proportion of PMBL (34% and 17% respectively). Coexpression of BCL2≥70% and MYC≥40% (MYC+/BCL2+) occurred in 52/184 (28%) cases, without difference between two arms or COO subtypes. By contrast, PMBL subtype displayed an extremely low rate of MYC+/BCL2+ cases (1/49, 2%). 3y-EFS rates were 52% ± 6% for GC, 58% ± 5% for NGC and 49% ± 6% for PMBL (p= 0,42) with no significant difference according to treatment arm. Of note, in PMBL, the majority of events was positive interim PET-CT. Worse EFS was seen in BCL2≥70% cases (3y-EFS: 47% ± 4% vs 60% ± 4%, p= 0,05) but this difference was erased in RCHOP arm (3y-EFS: 52% ± 6% vs 58% ± 6%). 3y-Progression Free Survival (PFS) rates were 73% ± 6% for GC, 76% ± 6% for NGC and 94% ± 4% for PMBL (p=0,03) with no difference between the two arms (Fig 1). There was no PFS difference in BCL2≥70% vs