Search

Introduction: In 2010 the French Health Agency opened a compassionate patient named program of gemtuzumab ozogamicin (GO, Mylotarg®) in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML). Of note, since 2012, it was recommended to use GO at the dose of 3 or 6 mg/m 2 in addition to chemotherapy. We conducted a retrospective trial (NCT03287128) to evaluate the efficacy and the safety of GO-based regimen in R/R adult AML patients. Patients and methods: We retrospectively collected data of patients older than 18 years treated with GO-based regimen for AML in first relapse or for refractory AML, defined by failure after a prior standard intensive chemotherapy, in 18 French centers between December 15, 2011 and November 10, 2016. The primary objective was to assess the response to GO-based regimen. Patients were considered in response if reaching complete remission (CR), CR without platelet recovery (CRp) or CR with incomplete hematological recovery (CRi). Secondary objectives were the cumulative incidence of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the safety of the use of GO-based regimen. Results: Three hundred and thirty-five adult patients with R/R AML were included. Median age was 58 years (20 to 80 years). At diagnosis, cytogenetics was favorable in 50 (17%) patients, intermediate in 173 (59%) and adverse in 60 (20%). ELN distribution was favorable: 35%, intermediate: 42% and unfavorable: 23%. NPM1 mutation was present in 29% of patients and FLT3 mutation in 23%. Most patients had de novo AML (84%). Two hundred and thirty-eight patients (79%) were in first relapse and 65 (21%) had a refractory AML. The time between first diagnosis of AML and treatment with GO-based regimen was 4 to 16 months (median 9.4 months). Most patients (88%) received GO in combination with various intensive chemotherapy scheme including "7+3" with anthracycline/cytarabine (n=39 patients), intermediate and high-dose cytarabine (n=68), cytarabine in continuous intravenous infusion (n=78), mitoxantrone/cytarabine (n=49) and fludarabine/cytarabine and/or amsacrine and/or etoposide chemotherapy (n=35). Median follow-up time was 11 months. Among the 305 patients, 191 responded to GO-based regimen: 110 (36%) were in CR, 62 (20%) were in CRp and 19 (6%) in CRi for an overall response rate (CR+CRp+CRi, ORR) of 63%. In multivariate analysis, response was associated with age Regarding safety of GO-based regimen, early deaths occurred within Conclusion. Our study is the first to report efficacy data in the real-world setting of R/R AML adult patients treated with GO-based regimen. In our cohort of 305 patients, response rate was 63% and GO-based regimen appears as a valuable bridge-to-transplant option. Safety analysis showed toxicities consistent with the known safety profile of GO and chemotherapy. Figure 1 Figure 1. Disclosures Lambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy. Pautas: PFIZER: Consultancy; ABBVIE: Consultancy. Raffoux: ASTELLAS: Consultancy; PFIZER: Consultancy; ABBVIE: Consultancy; CELGENE/BMS: Consultancy. Legrand: Servier: Consultancy. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mathilde: SERVIER: Consultancy; ABBVIE: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Castaigne: PFIZER: Consultancy.

In spite of CR rates of 75-80% currently achieved with anthracycline-cytarabine regimens in younger patients with favorable and intermediate-risk AML, relapse remains a major issue. The French AML intergroup launched the BIG-1 trial in 2015 in order to test different strategies aiming at reducing relapse rate and improving survival. All patients with previously untreated non-APL and non-CBF AML aged 18-60 years are eligible for trial participation which is still ongoing. The trial design includes several randomizations (R): Idarubicin vs daunorubicin for induction (R1), HDAC vs IDAC for consolidation (R2), post-transplant GVHD prophylaxis modalities (R3). R4 consists of nested randomized phase 2-3 trials testing the addition of new drugs to the IDAC or HDAC backbones during the consolidation phase. The protocol was designed to allow the sequential evaluation of several new agents over the trial period. Vosaroxin (VOS) has shown antileukemic activity (Advani, Clin Cancer Res 2010). The combination of VOS and IDAC showed higher CR rate and a non-significant OS benefit as compared to a placebo-IDAC arm in a large phase 3 trial in patients with refractory/relapsed AML (Ravandi Lancet Oncol 2015). We hypothesized that the addition of VOS to IDAC would improve LFS as compared to IDAC alone when given during the consolidation phase. Methods. Eligibility criteria in the BIG-1 trial include: previously untreated AML according to WHO 2016 classification (AML secondary to an untreated myelodysplastic syndrome allowed), age 18-60, ECOG PS 0-2, no cardiac contra-indication to anthracyclines. Patients with APL and patients with CBF-AML are excluded. Eligibility criteria for R4 randomization were: Patients in first CR/CRp/CRi following 1 or 2 courses of induction chemotherapy according to the BIG-1 protocol; ELN2010 favorable- and intermediate-risk groups; ECOG PS ≤ 3; Absence of severe uncontrolled infection. Patients were scheduled to receive Cytarabine: 1.5 gr/m² twice daily on D1, 3, 5 with or without Vosaroxin: 70 mg/m² on D1 and D4 per cycle for a maximum of three cycles at 4-6 weeks intervals. Patients scheduled for allo-SCT or those who had reached CR after 2 induction cycles were to receive only 2 cycles of VOS-IDAC/IDAC. R4-VOS sub-trial was designed to detect an increase of the 18-month LFS from 55% to 75% using a two-step phase 2-3 study. With type I and II errors set at 20% and using a one-sided test, 70 patients had to be randomized. If the predefined statistical objectives were met, study would resume recruiting 130 additional patients in the phase 3 part for a total of 200 patients. Results. 70 patients (35 in each arm), median age 47, ELN 2010 favorable and intermediate risk groups, have been included. 94% had de novo AML with NPM1 mutations in 46% and FLT3-ITD in 20%. As shown in the Table, patients and disease characteristics were not different between the 2 arms except for slightly more patients in CRi in the VOS-IDAC arm. Patients received a median of 4 chemotherapy cycle (including induction; range 3-4) without difference between the treatment arms. 13 patients (18.5%) received an alloSCT (VOS-IDAC: 5, IDAC: 8). Time between cycle 1 and cycle 2 was significantly longer in the VOS-IDAC arm (p= 0.017). Hematologic toxicity was higher in the VOS-IDAC group with a significantly longer neutropenia duration after each cycle, a greater number of RBC and Platelet transfusions, a significantly greater number of days with antibiotics and antifungal therapies and days with fever (during cycle 1). There were also significantly more cutaneous toxicity, mild nausea/vomiting and diarrhea in the VOS-IDAC arm. With a median follow-up of 19 months, 14 and 15 patients relapse in the VOS-IDAC vs IDAC arms respectively. The study primary endpoint has not been reached and LFS was not significantly higher in the VOS-IDAC arm (18-month LFS of 51% vs 46% for VOS-IDAC vs IDAC respectively; see Figure) even after accounting for allo-SCT as a time-dependent variable (p-value=.49). The 2-year CIR was 51% vs 46% (p=NS) and 2-year OS was 88% vs 68% (p=NS). Conclusion, the study's primary endpoint has not been met and results fail to show a significant improvement of 18-month LFS with the addition of VOS to IDAC consolidation of favorable/intermediate-risk AML in first CR. The phase 3 part of the trial will not open. The BIG-1 trial is still ongoing and uses the same design to tests addition of other drugs to the IDAC/HDAC consolidation backbone. Disclosures Guieze: abbvie: Honoraria, Other: advisory board, travel funds; janssen cilag: Honoraria, Other: advisory board, travel funds; roche: Other: travle funds; gilead: Honoraria, Other: travel funds; astrazanecka: Honoraria, Other: advisory board. Dombret:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Nova: Consultancy, Research Funding; Celgene: Consultancy; Jazz Pharma: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Servier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy. Hunault:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Introduction. Chronic lymphocytic leukemia (CLL) has typically an indolent course but can undergo transformation into a more aggressive lymphoma (mainly of diffuse large B-cell lymphoma histology) that is called Richter's syndrome. While the advent of novel therapies targeting the BCR signaling or the BCL-2 protein is transforming the management of patients with CLL, these drugs failed to prevent the risk of RS that is estimated to be 0.5-1% per year. RS is associated with a very poor outcome and is thus becoming the main obstacle to long term CLL cure. Allogeneic stem-cells transplantation (allo-SCT) has been recommended as the treatment of choice in eligible patients with clonally related RS (Rossi Blood 2018) but previous experience is still limited to less than 50 cases. We here aimed to investigate the safety and efficacy of allo-SCT for patients with RS. Methods. We report on a retrospective study of consecutive patients with RS who underwent allo-HSCT between 2005 and 2016 in 15 French and Belgian centers from the Société Francophone de Greffe de Moelle et de Transplantation Cellulaire (SFGM-TC). Inclusion criteria were: age >18, confirmed RS diagnosis, allo-HCST from either sibling or unrelated donor. Data quality was ensured using computerized discrepancy errors and on-site data verification. Results. A total of 24 patients (median age=59 years [19-69], M/F= 18/6) were included in the present study. Median time from CLL to RS diagnosis was 59 months [0-198]. The histology was DLBCL (86%) or HL (14%). The patients received a median of 1 [0-4] therapeutic line for CLL and 1 [0-3] for RS. Nine (38%) patients underwent auto-SCT prior to allo-HCT. At allo-HCT, 17 (71%) of patients were in complete and 7 (29%) in partial response. Most patients received reduced intensity conditioning (RIC) regimen (n= 18, 75%) and peripheral blood (76%) as source of stem-cells. Two (8%) patients received bone marrow stem cells and 4 (16%) cord blood stem cells. Donors were related (n=8) or unrelated (mismatched, n=8; matched, n=5; missing, n=3). A total of 15 patients (63%) received total body irradiation (TBI) within the conditioning. With a median follow-up of 27 months, 2-year OS was 44% (figure 1). The 100-day non-relapse mortality was 25%. Cause of death was relapse (n=3), treatment toxicity (n=10; GVHd, n=3; infectious complications, n=6; pulmonary toxicity, n=1), infection complications (n=1) and cerebral stroke (n=1). 2-year OS was significantly shorter for older patients (20% if >59 years old vs 64% if ≤59,P = 0.031). The 2-year OS was influenced by presence of cGVHD (73% vs 25%,P = 0.006). Neither donor type, prior auto-SCT, disease status prior to allo-HCT, use of antilymphocyte serum infusions nor the regimen conditioning significantly impact OS. Conclusion. Our study suggests that allo-HCT is a strategy achieving prolonged survival but should be performed in young patients to limit the risk of NRM. The favorable impact of GVHd suggests an anti-RS allogenic effect. Disclosures Guieze: abbvie: Honoraria; janssen: Honoraria; gilead: Honoraria.

Based on our previous demonstration that quinine could be used clinically to reverse P-glycoprotein–mediated resistance, we designed a multicenter, randomized trial aiming to determine whether quinine would improve the survival of adult patients (15-60 years old) with de novo acute myelogenous leukemia (AML). These patients randomly received (n = 213) or did not receive (n = 212) a 30 mg/kg/day continuous intravenous infusion of quinine in combination with induction chemotherapy combining idarubicine and cytarabine and, depending on bone marrow examination at day 20, an additional course of cytarabine and mitoxantrone. The mean steady-state quinine concentration was 7.8 mg/L and the mean multidrug resistance reversing activity of serum was 1.96. Complete remission (CR) was obtained in 344 patients (80.9%) without significant influence of quinine. Of the patients in complete remission, 82 were assigned to receive HLA-matched bone marrow transplants, whereas 262 were assigned to 2 courses of intensive consolidation chemotherapy, with or without quinine, depending on initial randomization. The 4-year actuarial overall survival (OS) of the 425 eligible patients was 42.0% ± 2.5%, without significant influence of quinine. Of 160 patients who could be studied, 54 demonstrated rhodamine 123 efflux. In these patients, quinine significantly improved the CR rate from 12 of 25 (48.0%) to 24 of 29 (82.8%) (P = .01). However, there was no significant difference in OS. Neither mdr1 gene nor P-glycoprotein expression influenced the outcome. We conclude that quinine does not improve the survival of adult patients with de novo AML, even though it improves CR rate in a small subgroup of patients defined by rhodamine 123 efflux.

We have developed a real-time quantitative polymerase chain reaction (PCR) assay using TaqMan technology (Applied Biosystems, Foster City, CA) for monitoring donor cell engraftment in allogenic hematopoietic stem cell transplant recipients. For this purpose, we selected 19 specific sequence polymorphisms belonging to 11 human biallelic loci located on 9 different chromosomes. Using a set of specially designed primers and fluorogenic probes, we evaluated the 19 markers' informativity on a panel of 126 DNA samples from 63 recipient/donor pairs. In more than 90% of these pairs, discrimination between recipient and donor genetic profile was possible. By using serial dilutions of mixed DNAs, we evaluated the linearity and sensitivity of the method. A linear correlation with rhigher than 0.98 and a sensitivity of 0.1% proved reproducible. Fluorescent-based PCR of short tandem repeats (STR-PCR) and real-time PCR chimerism assay were compared with a panel of artificial cell mixtures. The main advantage of the real-time PCR method over STR-PCR chimerism assays is the absence of PCR competition and plateau biases, and results evidenced greater sensitivity and linearity with the real-time PCR method. Furthermore, different samples can be tested in the same PCR run with a final result in fewer than 48 hours. Finally, we prospectively analyzed patients who received allografts and present 4 different clinical situations that illustrate the informativity level of our method. In conclusion, this new assay provides an accurate quantitative assessment of mixed chimerism that can be useful in guiding early implementation of additional treatments in hematopoietic stem cell transplantation.

In elderly pts, the prognosis of AML associated with poor risk cytogenetics or secondary to either MDS or previous cancer is so bad that only supportive care or investigational studies are usually recommended. Fit patients may achieve CR after conventional induction, but early relapse appears to be nearly inescapable whatever classical consolidation or maintenance therapy is used. Therefore, the GOELAMS investigated the impact of a maintenance using two agents mainly used in MDS, ie AZA and Len. Between March 2011 and February 2013, 117 pts from 27 centers (median age 69 yrs; 60-80) with previously untreated poor prognosis AML were included. Poor Risk factors were either preceding MDS (n=52), previous cancer (n=37) or centrally reviewed (IL) poor risk cytogenetics (n=83) defined as complex karyotype (≥3 abnormalities, n=65), monosomal karyotypes (n=54), del or - 5 (n=61) or 7 (n=44), 3q abnormality (n=9) or MLL rearrangement except for t(9;11) (n=5). Median WBC was 2.9 G/L (0.5-160), 7 pts had WBC ≥ 30 G/L. Induction chemotherapy included Lomustine 200 mg/m² po d1, Idarubicine 8 mg/m²/d (d1-5), Cytarabine 100mg/m²/d CI (d1-7). Patients in CR received 12 maintenance cycles alternating every 28 days AZA (sc 75 mg/m²/d1-7) and Len (10mg/d1-21), which started if PMN and platelets were >1 G/L and 100 G/L respectively. After d42, subsequent cycles were reduced to 50 mg/m²/d and 5 mg/d. GCSF was allowed in case of PMN < 0.5 G/L after 7 days or febrile neutropenia. At the end of induction, CR was achieved in 56% (65 pts) without any predictive factor, 9% died from infection (n=6), cerebral hemorrhage (n=1) or MOF (n=4) and 35% (41pts including 5 CRp) failed to achieve CR. The 12 planned maintenance courses could be given to 21 pts (32%) (median: 6). Few toxicities were observed. AZA courses were slightly more toxic than Len courses (table 1). Table 1.AZA courses %Len courses %Gr 3/4 neutropenia46.8/ 27.339.7 /17.6Antibiotics for fever at home6.97Hospitalization for febrile neutropenia0.52.7RBC transfusions55.4Gr 3 Thrombopenia2016Platelets transfusion8.67.9Interval between courses > 35 days26.118.4Median time interval between courses31 d28 dCourses with doses reductions9.621.6 Maintenance courses were interrupted because of relapse (n= 34, 77%), alloSCT (n=4 %), count error (n=1 %) or toxicities (n =5, 11%) occurring after Len (depression, vascular purpura and pseudomembranous diarrhea, sudden death, all during cycle 1) or after Aza (atrial fibrillation and cardiac dysfunction). Twenty Gr3/4 AE were reported among 441 cycles (0.56%/courses). Median follow-up for survivors was 38 mo (26-47). Median OS was 10 mo, with 21% 2y OS. Median CR duration was 7 mo (1-30). Impact of prognostic factors on DFS is shown table 2. Within poor risk factors, Cytogenetic abnormalities appeared as even poorer than previous MDS or cancer. Table 2.CR %CR NDFS median moP VALUE1y DFS %2y DFS %All patients56657.941.512.3Age ≥ 7058.3288.6 vs 7.746.417.9WBC ≥ 3.3 G/L48.1267.0 vs12.423.111.5Previous MDS51.92713.8 vs 6.4.0551.922.2MDS only68.41316.8 vs 6.4.00869.230.8Previous cancer54207.5 vs 7.9355Cancer only80812.4 vs 7.755012.5Poor cytogenetic53445.1 vs 15.3.0429.56.8Complex caryotype49.2324.8 vs 12.9.012259.4Monosomal caryotype50274.6 vs 12.9.00218.57.4Chromosome 5 abnormality52.5325 vs 13.8.00218.86.3Chromosome 7 abnormality54.5243.6 vs 12.00120.84.23q55.6510.4 vs 7.740017p deletion48.5165.0 vs 10.52512.5MLL8043.4 vs 8.4250poor cytogenetic + MDS42.997.7 vs 7.944.422poor cytogenetic + cancer46.774.8 vs 7.928.90poor cytogenetic + cancer + MDS71.453.4 vs 8.4200cancer + MDS00---Poor cytogenetic only rev aza57.5236.3 vs 12.9.05521.74.3Poor cytogenetic only SA255436.430.220.9 In the previous GOELAMS SA2 trial, 78 pts with poor risk cytogenetics without secondary leukemia received the same LIA induction followed in CR by maintenance therapy with 6 mini-reinductions (Ida 10mg/m² d1, cytarabine 50 mg/m²x2/d d1-5) and 6MP-MTX for 2years. In the present study, the DFS of the group of pts with poor risk cytogenetics without previous cancer or MDS is very similar. This alternating azacitidine/lenalidomide maintenance improved DFS and OS of pts without poor risk cytogenetics (median 15.7 and 24 mo). In this setting, it could be randomly compared to conventional chemotherapy maintenance. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Twenty percent of classical Hodgkin Lymphoma (cHL) patients are aged 60 years or older. Their survival rate is inferior to that of younger patients for several reasons including lower delivery of standard chemotherapy and toxicity excess. For relapsed or refractory (R/R) cHL young patients, autologous stem cell transplantation (ASCT) is a standard of care after salvage chemotherapy. However, little is known regarding the outcome of R/R cHL in elderly patients (≥60 years) receiving ASCT. Method: The current report retrospectively analyzed the outcome of all consecutive patients aged 60 years or older with the diagnosis of R/R cHL who were transplanted between 1992 and 2013 and who were reported to the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) registry. Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all SFGM-TC centers. This study was approved by the scientific committee of the SFGM-TC and is in accordance with Helsinki declaration for clinical research. Of note, specific study questionnaires were sent to transplant centers to obtain comprehensive, updated data. Results: One hundred and twenty patients met these criteria. Ninety-one patients (63M/28F) with documented data from 28 transplant centers were analyzed. Median age was 63 years at transplant (range 60-75). At diagnosis, 64 patients had advanced stage cHL, 46 had B symptoms and 6 had poor performance status (ECOG 2). Thirty-four patients had primary refractory disease, and 22 patients relapsed within the first year after first CR. The median number of salvage chemotherapy regimens was 2 (range 1-4). Most of the patients showed disease sensitivity to salvage treatment with 52 patients transplanted in CR, 5 patients in CRu, 30 patients in PR and 1 patient transplanted with progressive disease. The most frequently used conditioning regimen consisted of BEAM chemotherapy (93%) (Carmustine 300 mg/m2 d-6, Etoposide 100 mg/m2 Q12H d -5 to -2, Cytarabine 200 mg/m2 IV Q12H d-5 to -2, Melphalan 140 mg/m2 d -1). The median number of CD34 peripheral blood stem cells was 4.2 106 cells/kg (range 0.9-17.8). The median duration of hospitalization was 22 days (8-49). The median time to achieve neutrophil count >1x109/L and platelet count > 20x109/L were 11 days (range 8-104) and 13 days (range 7-115), respectively. Grade 3-4 toxicities occurred in 24 patients (mucositis: 13, sepsis: 3, interstitial pneumonia: 2, diarrhea: 2, heart failure: 2, multiorgan failure (MOF): 1, unspecified case: 1. With a median follow-up of 32 months (range 1-185), the 6-year estimate of OS was 64% (95% CI 51-75). In univariate analysis, none of the usual prognostic factors (gender, age ≥ 65, disease status before transplant, CD34+ cells count, time to relapse < 1 year, disease stage at relapse, Hb level) significantly influenced OS. At last follow-up, 13 patients died: 5 from toxicity (1 MOF, 2 interstitial pneumonia, 1 heart failure and 1 invasive pulmonary aspergillosis), 4 from disease progression, and 4 from unspecified causes. Conclusion: This retrospective study with long term follow-up, despite its limitations, suggests that in selected elderly patients ASCT is a valid treatment option for chemosensitive R/R cHL patients, with an acceptable rate of toxicity warranting further investigations in the era of novel agents such as brentuximab. Disclosures Brice: Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Roche: Honoraria.

Purpose: Pediatric-like protocols have yielded significant advances in younger adults with Ph-negative ALL. Nonetheless, the 5-year cumulative incidence of relapse was still estimated at 32% in the GRAALL-2003/2005 trials, approximately 25% of the relapses occurring after allogeneic stem cell transplantation (SCT). We report here on the outcome of these relapsing patients. Patients and Methods: Among 880 GRAALL-2003/2005 patients(18-60 years) with Ph-negative ALL in first complete remission (CR1), 264 relapsed. Data were available for 229 of them (151 B-cell precursor [BCP] ALL, 78 T-ALL; 45 standard-risk, 165 high-risk, and 19 unclassified ALL according to the risk classification used in these trials). Relapse site was bone marrow (BM), isolated CNS, combined BM/CNS and other in 181, 20, 17 and 11 patients, respectively. At relapse, median age was 35.7 years (range, 17-63). Median CR1 duration was 10 months (range, 0.5-74), 50 patients (22%) having CR1 > 18 months. Fifty-four patients (24%) had received allogeneic SCT during CR1. First salvage treatments were classified as follows: standard curative therapy, 194 (85%); low-intensity therapy, 21 (9%); allogeneic SCT, 6 (2.5%); and best supportive care (BSC), 8 (3.5%). Post-relapse allogeneic SCT was analyzed as a time-dependent event using Mantel-Byar estimations. Results: A total of 121 patients (53%) achieved CR2, including 100/194 patients after standard salvage, 7/21 patients after low-intensity salvage, and 14 patients after SCT (6 as first salvage, 8 as subsequent salvage after standard salvage failure). Thus, 107/215 patients (50%) treated with standard or low-intensity first salvage achieved CR2 and in multivariable analysis (including age, ALL lineage, ALL risk classification, CR1 duration, prior SCT, relapse site and salvage type), a younger age and a longer CR1 duration were associated with CR2 achievement in these patients. Of note, few patients with t(4;11) BCP-ALL reached CR2 (19%). A total of 77 patients received allogeneic SCT after relapse, including 55 patients in CR2 after standard salvage (52 in CR2 at SCT time), 4 patients in CR2 after low-intensity salvage (all in CR2 at SCT time), the 6 patients transplanted as first salvage (all reaching CR2), and 12 patients transplanted as subsequent salvage (8 reaching CR2). The median time between relapse and SCT was 111 days (range, 5-311). With a median post-relapse follow-up of 3.1 years, post-relapse overall survival (OS) was 19.3% (14-25%) at 2 years and 13.3% (9-19%) at 5 years (median OS, 6.7 months). In landmark analysis, OS was significantly longer in patients who achieved CR2 (HR, 0.19; p 18 months (HR, 0.43; p 18 months and SCT after relapse were associated with longer OS (HR, 0.49 and 0.39; p=0.001 and 18 months and SCT after relapse were the two factors that independently predicted longer DFS (HR, 0.36 and 0.44; p=0.001 and 0.003) and OS (HR, 0.39 and 0.57; p=0.004 and 0.043, respectively) in these patients. Conclusion: Adult patients relapsing after current ALL therapies still retain apoor outcome. Although a minority of them may be cured, especially if CR1 duration exceeds 18 months and if they may receive allogeneic SCT in CR2, new therapies are definitely needed for these patients. Disclosures No relevant conflicts of interest to declare.

Objectives Allogeneic hematopoietic stem cell transplantation (AHSCT) is an effective treatment modality for a number of hematological malignancies. Several retrospective studies demonstrate that the addition of antithymocyte globulin (ATG) to standard GvHD prophylaxis in myeloablative conditioned AHSCT resulted in a reduction of the incidence of acute and chronic GvHD. However the impact of rabbit ATG incorporated within a standard myeloablative conditioning regimen (MAC) prior to AHSCT on overall survival (OS) has never been clearly assessed. The purpose of this study is to evaluate retrospectively the long term influence of ATG on OS in a large cohort. Methods All AHSCT with matched sibling donor (MSD) and matched unrelated donor (MUD) performed between 2001-2010 in France and reported to Promise database were retrospectively studied. Patients fulfilling the requirements for this study had received a MAC such as total body irradiation (TBI)-cyclophosphamide or busulfan-cyclophosphamide (Bu-Cy) with or without ATG. Results 1980 AHSCT were reported in 32 transplant centers. One hundred and fifty (8%) patients received ATG (25 with MSD and 125 with MUD), whereas 1830 (92%) did not receive ATG (1441 with MSD and 389 with MUD). Diagnosis were 1452 acute leukemia (73%), 340 myelodysplasia (MDS) and/or myeloproliferative syndrome (MPS) (17%), 157 lymphoma (8%), 9 myeloma and 21 chronic lymphocytic leukemia (CLL) (2%). 1385 patients received a TBI 12 Gy based regimen with cyclophosphamide whereas 595 patients received Bu-Cy. Bone marrow (1468 patients) or peripheral blood stem cells (512 patients) were infused 24-48h after the last cyclophosphamide administration (day 0). Median age at transplantation was 37.5 years in the ATG group and 39.2 years in the non ATG group. Median follow-up was of 79.8 months [19.2-138.8]. Using multivariable analysis, OS was adversely significantly influenced by age of recipient older than 39.1 years, bone marrow stem cell source, MUD, non-complete remission status before HSCT, GvHD grade 2-4, age of donor older than 38.3 years and the use of GvHD prophylaxis other than cyclosporine and methotrexate. ATG was not an independent variable influencing OS. The use of different model of multivariate analyses including propensity score trends to demonstrate that the influence of ATG on OS remain strongly correlated to donor type (MSD vs MUD). According to our results, patient with MSD presented better OS (not reached) than patient with MUD (37 months) (p Conclusion The use of ATG does not influence OS. However, this use is strongly influenced by stem cell source with a negative impact of ATG for the group of patients who received BM. Its usefulness should be discussed. Disclosures: No relevant conflicts of interest to declare.

Abstract 1525 Trastuzumab (rhu-mAb-HER2, Herceptin®, F. Hoffmann-La Roche, Basel, Switzerland) is the humanized equivalent of the murine 4D5 monoclonal antibody targeted against the HER2 cell-surface receptor. In combination with chemotherapy, trastuzumab has significantly improved the outcome of women with HER2+ breast cancer. We have previously shown that HER2 surface antigen is up-regulated in around one third of adult B-ALL and is associated with chemoresistance in these patients (Chevallier et al, Haematologica, 2004). We report here for the first time the results of a Phase II study evaluating the safety and efficacy of trastuzumab in refractory/relapsed HER2 + adult B-ALL patients. Prior to patient inclusion, HER2 positivity was assessed using multicolor flow cytometry with the phycoerythrin-conjugated HER2 Neu 24.7 antibody (BD) and a CD19+ CD45+low blast cell gating strategy. The mean fluorescence intensity (MFI) ratio was obtained by dividing the MFI of HER2 with that of its isotypic control. HER2 positivity threshold was defined by a ratio intensity (RI) >= 2. Also, HER2 oncogene amplification was assessed by FISH analysis using the HER2 DNA probe kit (Vysis, Downers Grove, IL, USA). Relapsed/refractory B-ALL patients aged >=18 years and with a HER2+ expression for at least 30% of the leukemic blast population in peripheral blood (PB) and/or bone marrow (BM) were included. Left ventricular ejection fraction has to be > 50%. All patients gave informed consent and the protocol was approved by the required regulatory authorities. The trial was registered at http://clinicaltrials.gov/ct no.NCT00724360. Trastuzumab was administered according to the approved schedule in breast cancer patients at 4 mg/kg intravenous loading dose followed by 2 mg/kg weekly. There was no corticosteroid premedication. Trastuzumab was provided by Roche. Out of 50 patients screened for the HER2 expression, 15 patients (30%) (male n=8; female n=7), with a median age of 62 years (range: 24–80), have been included in the study between November 2006 and July 2011. This was considered as a very high-risk population: 2 patients had refractory disease after 2 induction courses, 2 patients were in first untreated relapse while 11 patients had a refractory first relapse or were beyond first relapse. Median percentage of HER2+ leukemic blast population was 94% (range: 0–100) in PB and 100% (range: 31–100) in BM. Surprisingly, no HER2 gene amplification was detected in samples assayed by FISH. Normal and complex karyotype were detected in 7 and 3 patients respectively. Three patients had a Phi+ B-ALL, and 1 patient a monosomy 7 (unknown karyotype n=1). Currently, 3 patients are still receiving therapy. Considering the 12 other patients, the median number of trastuzumab infusions was 4 (1 month of treatment) (range: 2–20). No grade 3–4 toxicities were observed, with no cardiotoxic events. The overall response rate (CR or PR (decrease >=50% of blast population) or blast clearance in BM or PB) was 33%. No CR was observed. Two patients achieved partial response in BM (92% vs 12% after 9 infusions with loss of HER2 expression on blast population, total number of infusions (TNI) n=18); 25% vs 11% after 4 injections, TNI n=13) while blast clearance was observed in 2 other patients (96% vs 57% of blasts in BM after 8 infusions with loss of HER2 blast expression, TNI n=20; 20.5% vs 2% of blasts in PB after 3 infusions, TNI n=3). In all, we conclude that trastuzumab in monotherapy can allow for some responses in this very high-risk refractory/relapsed HER2+ adult B-ALL population. Combination of trastuzumab with chemotherapy or other therapeutic monoclonal antibodies should be tested in the future. An updated follow-up of the study will be provided during the meeting. Disclosures: No relevant conflicts of interest to declare.

Abstract 2359 Background: The role of allogenic stem cell transplantation (SCT) for the treatment of relapsed/refractory Hodgkin Lymphoma (HL) remains controversial. Patients and Methods: we retrospectively analyzed 227 patients who underwent alloSCT between April 1998 and December 2008 for relapsed HL and whose data were reported in the French Society of Marrow Transplantation and Cellular Therapy registry. Thirty-six patients underwent alloSCT with Myeloabaltive Conditioning (MAC) and 191 with Reduced Intensity Conditioning (RIC). Median age was 31 years (13-63 years). Median number of previous therapy regimens was 4. Eighty-nine percent of patients had received a previous Autologous Stem Cell Transplantation (ASCT). Results: Median follow up was 36 months (2-103 months). The 1-year cumulative incidence of non-relapse mortality (NRM) was 17%. Estimated 3 years Overall Survival (OS), Progression free Survival (PFS) and cumulative incidence of relapse (CIR) were 55%, 36%, 47%, respectively for the entire cohort. In multivariate analysis, there was no difference in outcome between patients in CR and PR at time of transplantation for OS (67% vs 68% at 3 years) and PFS (50% vs 40% at 3 years, p=ns). However, patients with chemoresistant disease (stable or progressive) at time of transplantation had a significantly shorter PFS (13% at 3 years p Conclusion: This study shows that Allogenic SCT especially following reduced intensity conditioning is a feasible option for relapsed HL. Disease status at transplantation remains the major risk factor for outcome. In addition our data suggest that allogenic SCT should be performed as early as possible after ASCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 4874 Introduction Monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM) are two asymptomatic early stages of multiple myeloma, and are characterized by the absence of bone involvement. In contrast, bone lytic lesions are common complications of multiple myeloma. Magnetic resonance imaging (MRI) has improved the evaluation of bone involvement in multiple myeloma. Moreover MRI allows visualization of the medullary cavity and a direct assessment of the degree of myeloma cell infiltration before bone destruction becomes visible on plain radiographs. Diffusion weighted magnetic resonance imaging (DWI) probes the diffusion of water in the body. This sequence yields qualitative and quantitative information that reflects the tissue cellularity and cell membrane intregrity and thus complements morphological information obtained by conventional MRI. It shows considerable promise for detecting and characterizing tumors and evaluating treatment response. Objective Our objective was to study the potential interest of diffusion weighted MRI for the evaluation of bone marrow infiltration in multiple myeloma, SMM and MGUS. Diagnostic criteria used were those defined by the International Myeloma Working Group. Patients and methods This retrospective study was conducted over a period of 8 months (November 2008 - June 2009) in Internal Medicine and Hematology departments of our institution. All patients who had a whole body MRI for evaluation of multiple myeloma, SMM or MGUS were included. We choose to study simultaneously 3 complementary sequences: T1 weighted, short time inversion recovery (STIR) and diffusion weighted. Results Seventy patients were included in this study: 9 MGUS, 19 SMM and 42 symptomatic multiple myeloma (16 at diagnosis and 27 at relapse). They were 30 men and 40 women. The median age was 64 years (36 - 89 years). Thirty one of the 42 multiple myeloma patients have focal bone lesions. Focal lesions were observed in the 3 MRI sequences and diffusion did not detect new lesions. Regarding bone marrow infiltration assessment by MRI, four groups of patients could be identified: - Group 1 (20 patients – 28.6%): normal signal in T1, STIR, and diffusion. - Group 2 (19 patients – 27.1%): abnormal signal involving the whole spine on the STIR or diffusion weighted sequences and with a normal signal of the spine on T1.- Group 3 (25 patients – 35.7%): abnormal signal involving the whole spine on the STIR and diffusion weighted sequences and with a normal signal of the spine on T1.- Group 4 (6 patients – 8.6%): abnormal signal involving the whole spine on the 3 sequences. For the 28 patients with either MGUS or SMM, the distribution in the 4 groups was respectively 13 patients (46.4%), 7 patients (25.0%), 7 patients (25.0%) and 1 patient (3.6%) for group 1,2 3 and 4. Regarding the 42 cases of symptomatic multiple myeloma, 7 patients (16.7%) were classified in group 1, 12 (28.6%) in group 2, 18 (42.9%) in group 3 and 5 (11.9%) in group 4. There was no correlation between number of focal lesions and degree of diffuse infiltration. The degree of bone marrow infiltration evaluated by MRI was not correlated with Durie and Salmon stage, ISS, monoclonal component concentration or bone marrow plasmocytosis. Discussion Diffusion weighted magnetic resonance imaging combined with conventional sequences (T1 and STIR) can distinguish 4 groups of patients with different aspects of bone marrow infiltration. Fifteen patients (53.6%) with either MGUS or SMM had various degree of bone marrow infiltration without any focal lesions. A prospective study on a large population of MGUS and SMM is needed to assess the impact of these asymptomatic infiltrations on the risk of malignant transformation. The degree of bone marrow infiltration evaluated by MRI is very heterogeneous between patients with multiple myeloma and not correlated with classical prognostic factors. Further prospective studies are necessary to investigate the possible prognostic impact of these different groups on the evolution of myeloma. Disclosures No relevant conflicts of interest to declare.

Diffuse large cell lymphoma is the most common non-Hodgkin Lymphoma (NHL) that ranks among the most curable diffuse intermediate grade lymphomas. Most investigators have recognized that practically all patients with this cell type who are able to attain and maintain a complete response for 24 consecutive months are cured because late relapses seldom occur after this period of follow-up. However, relapses do occur late after the remission and the characteristics of patients who experience these relapses rarely have been studied especially for localized disease. From 1984 to 1996, three hundred and five patients aged more than 18 years were enrolled in a prospective multicenter study for primary treatment of localized stage I/II nodal and extra nodal high-grade NHL. The initial therapy consisted in three cycles of high dose CHOP regimen followed by involved field radiotherapy (40Gy). Of the 283 (93%) patients who obtained complete remission (CR), 36 (12.7%) patients relapsed more than 2 years after CR and 28 (9.8%) of them experienced relapse more than three years after CR. Clinical characteristics of patients at diagnosis are summarized in table 1. For the 28 patients who relapsed more than 3 years after diagnosis (group A), the median age was 55 years. There were 17 men and 11 women with predominant histology of diffuse large B cell lymphoma (n=15) and mixed small and large B-cell (n=6). Stage I disease was predominant (n=16) with normal LDH level (n=14). Extranodal disease was present in 11 patients. Most of the patients had no or one IPI risk factor at diagnosis (n=18). Relapses occurred after median CR duration of 84 (36–156) months. Seven patients (7/28; 25%) relapsed as a disseminated lymphoma and 17 of 21 patients who relapsed as a localized disease, relapsed at sites other than those of diagnosis. Only 4 patients relapsed at the same initial site of lymphoma. Nodal relapses remained the most frequent type of relapse (n=18; 64%). However, it is important to note that 10 patients experienced extranodal relapses especially in the central nervous system, the Waldeyer’s ring and the gastrointestinal tract. Three patients had multiple extranodal localisations. All relapsed patients received chemotherapy alone (n=20) or followed by autologous stem cell transplantation (n=8). CR was obtained in 13 patients (13/23; 56%), and partial response in 1 patients. Chemotherapy failed in 5 patients and 4 patients deceased from toxicities. At the last follow-up, only 8 (8/24; 33%) patients are still alive and disease free (n=5) or in relapse (n=3). Sixteen patients deceased and lymphoma was the most frequent cause of death (13/24; 54%). In conclusion, late relapses in the setting of localized high grade NHL treated with short course of chemotherapy and involved field radiotherapy are frequent. Relapses occurred frequently at different sites from the initial presentation mostly nodal and extranodal localisations are frequent. The rate of cure for relapsed patients is low and death from lymphoma remains high. The role of novel therapeutic approaches with the addition of rituximab to chemotherapy with or without radiotherapy in preventing late relapses is awaited. More data will be presented at the meeting Table 1: clinical characteristics at diagnosis

Despite a high response rate to 1st line chemotherapy, the probability of cure is very low in MCL. Secondary drug resistance invariably develops and the identification of mechanisms involved in this secondary drug resistance is a major challenge. We choose to track at a tumor level which genes are associated to the appearance of secondary drug resistance. The strategy was based on the use of paired samples from the same patient in order to control inter-patients variability. Five MCL patients had tumor samples collected from the same tissue before therapy and after failure. Two patients had refractory disease (non responders) and three achieved an objective response to therapy (responders). For each patient, pairs of samples from the same patient were co-hybridized on Agilent dual color DNA chips. Four DNA-chips were processed per patient (dye swap + replicate). The statistical analysis concentrated on variations in gene expression between the two samples from each patient. Each gene was analysed independently from the others. A multiple regression model (GLM procedure, SAS 8.2, Cary, NC, USA) was used to analyse the relation between the fold change in expression between the two samples of the same patient and several parameters including the response to treatment. Genes were selected on the basis of the absolute value of the coefficient associated to response to treatment. This absolute value was then expressed as a fold-change ratio (FCR), or ratio between the mean fold changes in responders and in non responders. Nineteen genes with a FCR greater than 2 and a P value < 10–6 were selected. FCR values larger than 5 were observed for CD69 (FCR=7.7) and BMP7 (FCR=7.0). Seventeen of the selected genes (89%) had a decreased expression at relapse in responders and an increased expression in non responders. The variation in expression according to response to therapy was in the reverse direction for the two remaining genes (BMP7 and TRAF5). The expression of TRAF5 decreased in non responders and remained unchanged in responders. In responders, the expression of BMP7, which was very low before treatment, was multiplied by about 8 after relapse, and did not vary in non responders. Because of this increase in expression, observed only in responders, BMP7 was considered as a major gene probably involved in secondary drug resistance. The possibility to interfere with its activity using miRNA was tested on JEKO cell line. JEKO cell line (EBV - MCL cell line) spontaneously express BMP7 and do not show growth inhibition when exposed in vitro to high concentration of BMP7. BMP7 RNA interference markedly increased necrosis (from 8.3% to 31.5%; P In conclusion, the patient oriented strategy is extremely powerful and permits relevant gene selection with a limited number of samples. Biologic validation with RNA interference confirms the relevance of this approach. Further investigations concerning the role of BMP7 and its possible use as a target for therapy are under investigation.

The incidence of AT and Fg deficiency and of thrombotic and bleeding events after Asp has been well evaluated in children with ALL, but little is known in adults. In this study, the incidence of these events and the use of coagulation supportive treatments was evaluated in 214 adult patients with ALL (n= 191) or LBL (n=23) included in the GOELAL02 trial (Blood 2004, in press). The induction therapy included steroids (40 mg/m2/d d1-21), vincristine (2 mg d1, 8, 15, 22), idarubicine (5 mg/m2 d1, 8,15, 22) and Asp (7500 UI/m2 d10, 13, 16, 19, 22, 25) delivered through a central venous access. Fresh frozen plasma (FFP), Fg (Clottagen®) and AT (Aclotine®) concentrates were recommended to maintain their levels > 1 g/l and 60%, respectively. If no transfusion, Asp infusion was delayed for 48 hours. Platelets were transfused when < 20 x 109/l. Heparin prophylaxis was left to institutional guidelines. Symptomatic thromboses and significant bleedings were systematically recorded. Active DIC was present in 10.3% of patients on d1. Fg and AT levels were measured 4098 times (20/patient, von Clauss assay) and 1718 times (8/patient, chromogenic assay) respectively, and evolved between d1 and d35 as shown below (mean ± sd). AT nadir was < 60% in 71% of patients with values < 40% in 26% of cases. Fg levels were < 1g/l in 73% of patients with values < 0.5g/l in 9%.Twenty-one thromboses occurred two to 35d after the first Asp infusion (median = 14d) in 20 patients (9.3%), with cerebral vein thrombosis (5), pulmonary embolism (3), upper (5) or lower (8) limb deep vein thrombosis. At the time of event, the median AT level was 48% (mean 60.7) with 12 of 21 thromboses (57%) occurring with AT < 60%. Fourty-two bleedings occurred one to 45d after the first Asp infusion (median = 8d) in 31 patients, with CNS hemorrhage (1), epistaxis (24), central venous access bleeding (8), GI bleeding (1), and large ecchymoses (8). At the time of event, median Fg level was 1.3 g/l. Asp infusions were reduced or delayed in 64% of all patients due to low Fg and/or AT levels. FFP, AT and Fg were infused in 31%, 41% and 52% of patients at mean doses of 5.3 ml/kg/infusion, 31UI/kg/infusion and 7.9 g respectively. AT level increased from 58%±16 (n=79) to 86%±23.2 (n=57) after the first AT infusion but was unchanged after FFP. Fg level increased from 0.9g/l ± 0.3 (n=85) to 1.4g/l ±0.5 (n=69) after Fg infusion but was unmodified after FFP. In conclusion, Fg and AT levels are frequently decreased in adults treated by Asp, with often a less than optimal chemotherapy. Bleeding events were not associated with severe Fg deficiency, but thrombotic events could be favored in some patients by acquired AT deficiency. The benefit of AT concentrates to prevent thrombosis and to reduce delay in Asp infusions could therefore be prospectively assessed in adults treated by Asp. d1 (n) d10-Asp 1 (n) d13-Asp2 (n) d19-Asp 4 (n) d25-Asp 6 (n) AT % - 121±16 (79) 83±16 (125) 65±20 (111) 65±22 (77) Fg g/l 3.2±1.7 (142) 1.9±1.0 (159) 1.4±0.7 (195) 1.1±0.4 (169) 1.4±0.6 (118)

Between March 1986 and May 1998, 28 patients (pts) (60,7% M, 39.3% F) with localized high-grade PBL were enrolled in the 02 (< 60 years, 20 pts) or 03 (≥ 60 years, 8 pts) GOELAMS trial. The aim of the study was to evaluate the OS, DFS and FFR after 3 VCAP courses (eldisine 3 mg/m² d1, doxorubicin 60 mg/m² d1, cyclophosphamide 1500 mg/m² d1, prednisone 80 mg/m² d1–5 every 3 weeks) in younger pts and after 3 VCEP-Bleo courses (eldisine 3 mg/m² d1, cyclophosphamide 750 mg/m² d2, farmorubicin 80 mg/m² d1, prednisone 50 mg/m²/d d1–7, bleomycine 10 mg d1 and 5, every 3 weeks) in older pts. Involved field radiotherapy (40 Gy) was performed for every patient. The median age was 46 years (17–69) and 70 years (65–75) respectively. Four patients between 60 and 69 with a good performance status (PS) were included in the 02 trial. In contrary to previous reports, the main localization were axial skeleton (20, 71%) including vertebrae (13), pelvis (5) and ribs (2) while skull and extremities were involved in both 4 patients (mandible 3, occiput 1, tibia 1, finger 1, humerus 2, one of them with including scapula involvement). Histological subtype included diffuse large cell lymphoma (68%), diffuse mixed cell lymphoma (14%), immunoblastic (10%), anaplastic Ki1+ (3%) and unclassified (3%). Immunophenotype were B (53.6%), T (3.6%), anaplastic (3.6%) or undone (39.3%). Ann Arbor classification included 23 stage I (82%) and 5 stage 2 (18%). Skin and subcutaneous tissues were involved by extension in 2 pts. Spinal compression, epidural involvement and paraplegia were observed in 8 pts. B symptoms were present in 5 pts (including 2 stage I). LDH were elevated in 5/23 pts. The IPI score was 0 for 18%, 1 for 39%, 2 for 14%, 3 for 10% and undetermined for 18%. PS >2 and bulk (≥ 5 cms) were observed in 43% and 39% of pts respectively. Besides age, VCAP and VCEP-Bleo groups were comparable for histological type, localization, Ann Arbor classification, B symptoms and LDH. All but one patient (96%) achieved CR. A 63 years old patient with costal localization, resistant to chemotherapy, died of progression after 15 months. Relapses occurred in 9/27 pts (33%, 3/8 for older pts, 6/20 for younger pts) at a median time of 2.3 years (0.4–6.5) from CR. Four of these relapses occurred before 2 years of CR, 4 between 2.1 and 5 years and 1 occurred 6.5 years after CR. Amongst 8 pts with spinal compression, 1 died in CR, 4 relapsed (1 alive in CR2) and 3 are in continuous CR. The relapse rate of pts without epidural involvement was 25% (5/20). With a median follow up of 8 years (1.2–17), OS, EFS and FFR were 62% (±12), 56% (±10) and 60% (±10), respectively. OS, EFS and FFR were 66%, 54%, 63% and 56%, 62%, 62% in VACP group and VCEP-Bleo group respectively. In univariate analysis, PS >2 significantly decreases OS, EFS and FFR (P = .036, .013 and .064). Epidural extension significantly decreases EFS (P = .009) but not OS. In multivariate analysis, poor PS but not epidural extension significantly decrease EFS and OS (P=.02 and P = .03 respectively for PS). The survival results of PBL are very similar to survival of 325 localized aggressive NHL treated in the 02-GOELAMS trial reported previously (Desablens ASH 2002). The poor prognostic value of PS and epidural extension of PBL should be underlined.