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Purpose: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi). Experimental Design: In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort. Results: From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4–14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS. Conclusions: In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.

Rational: Patients with t-AML are those previously treated for primary malignancy and are categorized with poor prognosis. t-AML treatment options include intensive chemotherapy (IC), hypomethylating agents (HMA) or low dose cytarabine (LDC). However, survival remains poor and allogeneic hematopoietic cell transplantation (Allo-HCT) could lead to better outcomes. The aim of this analysis is to assess the outcome of all consecutive t-AML pts from two regional centers in France, based on treatment intensity, and to identify prognostic factors. Patients and Methods: between January 2006 and December 2019, 112 adult pts diagnosed with t-AML occurring after treatment of solid tumors (ST; n=72), hematologic malignancies (HM; n=34) or autoimmune diseases (AID; n=6). Pts received chemotherapy and/or radiotherapy or high dose chemotherapy followed by autologous hematopoietic cell transplantation (Auto-HCT) in some. All eligible t-AML pts received intensive chemotherapy (IC, n=55) with the combination of anthracycline and cytarabine in 48 pts and CPX-351 in 7 pts. Unfit pts received non-IC (9 LDC, 24 HMA). The third study group (24 pts) received best supportive care (BSC). Fifteen pts underwent HSCT in first CR. Statistical analysis: We performed a descriptive analysis of the baseline characteristics and each treatment group was compared with a Kruskal-Wallis test and a Pearson's Chi-square test. Survival curves (Kaplan-Meier method) were compared with a log-rank test. Univariate and multivariate analyses on survival, relapse and NRM were done using Cox regression, Gray test, Fine & Gray regression. The bilateral level of significance was set at 5%. All analyses and graphics were made under the R program (v3.5.1). A pair-matched control analysis with de novo AML was performed only on pts who received IC matched for age, cytogenetics and ELN 2010 classification. Results: A total of 112 t-AML pts were identified, 56 were males (50%) with a median age of 68 yrs (19-87) at t-AML diagnosis. Before t-AML, 72 pts had ST (64.5%), 34 HM (30.5%) and 6 AID (5%). Forty-six pts (41%) received chemotherapy alone for their primary cancer, 17 (15%) radiotherapy alone, 49 (44%) radio chemotherapy, 17 (15%) auto-HCT and 6 (5%) long-term methotrexate for AID. Median interval from treatment of previous ST or HM to t-AML diagnosis was 4.7 years in ST, 6.6 years in HM and 21 years in AID (p=0.03). At t-AML diagnosis, 42% of pts presented an unfavorable karyotype and 44% an unfavorable ELN 2010 classification. Regarding molecular alterations, FLT3-ITD, FLT3-TKD, NPM1 and IDH1/2 mutations were observed in 6.9, 2.3, 11.5 and 2.3% of pts respectively. MECOM1 was overexpressed in 25.5% of cases. Among treated pts (n=88), 43 pts (49%) achieved CR: 4 from 33 (12%) in non-IC pts (3 in HMA and 1 in LDC) and 39 from 55 (71%) in IC pts. Fifteen pts (17%) underwent Allo-HCT with a median interval between AML diagnosis and Allo-HCT of 4.7 mo (2.6-17.5). The best response after transplantation was CR in 10 pts; at the last follow up, 4 pts are alive (3 in CR and 1 in relapse) and 11 died (5 from relapse, 5 from TRM causes and 1 from another subsequent malignancy). Overall, with a median follow up of 5.5 mo (0-144), the median OS and DFS were 9 mo (5.9-13.5) and 6.3 mo (5.3-10.3) respectively (Figure). There was a significant difference between the 3 treatment groups concerning OS (p Conclusion: The prognosis of t-AML remains poor and our study showed the advantage of using intensive chemotherapy whenever possible and, in comparison with de-novo AML, a higher NRM and a lower incidence relapse. Figure 1 Figure 1. Disclosures Nicolini: Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria.

On behalf of the GRAALL group. Introduction. Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients diagnosed with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). In a previous randomized trial (GRAAPH-2005; Chalandon Y., Blood 2015), our group demonstrated that anthracycline and cyclophosphamide could be safely omitted during the first Hyper-CVAD chemotherapy cycle when combined to imatinib. In the present GRAAPH-2014 trial, we investigated whether the use of nilotinib, a 2 nd generation TKI, would allow further decreasing chemotherapy intensity through the omission of high-dose cytarabine (HD-AraC) during consolidation cycles 2 and 4. Methods. From March 2016, patients aged 18-60 years old were randomized frontline to receive 4 cycles (1=3, 2=4) of chemotherapy combined with continuous nilotinib 400 mg bid. Cycle 1 and 3 were similar in both arms, identical to the less-intensive first cycle of the previous GRAAPH-2005 trial with weekly vincristine and dexamethasone and nilotinib instead of imatinib. Cycle 2 and 4 differed between control arm A (MTX 1 g/sqm over 24h, HD-AraC 3 g/sqm/12h for 2 days) and experimental arm B (MTX 1 g/sqm over 24h only). Marrow minimal residual disease (MRD) was assessed by both BCR-ABL1 and IG-TCR qPCR after each cycle (MRD1-4). Patients in complete remission (CR) after cycle 4 were eligible to receive allogeneic stem cell transplant (alloSCT). Non allografted patients had the option to receive autologous SCT (autoSCT) if a major molecular response (MMolR) (MRD4 BCR-ABL1 40y) and BCR-ABL1 breakpoint region (M/m-bcr). MMolR rate at MRD4 was the primary endpoint of this non-inferiority study, with a margin set at 0.15. In February 2019, the study DSMB decided to stop the randomizations after an unplanned analysis demonstrating a significant excess of relapse in arm B (without HD-AraC). An intention-to-treat analysis is provided. All patients gave informed consent. The study is registered at EudraCT under the number: 2014-002146-44. Results. A total of 156 patients were randomized (77 in arm A, and 79 in arm B). Median age was 47.1 years old (range 18.1-59.9). One-hundred and ten patients had the m-bcr (70.5%) and 46 (29.5%) the M-bcr. An IKZF1 intragenic deletion was found in 87/153 (56.9%). Median follow-up was 2.8 years (95%CI 2.6-3.1). All evaluable patients reached CR after a maximum of two cycles. Three patients died during cycle 1 (2 in arm A, 1 in arm B), and 2 during cycle 2 (1 per arm). Most patients received the 4 scheduled cycles (n=143, 91,7%). AlloSCT was performed in 91 patients (58.3%), whereas 41 patients received an autoSCT (26.3%) with no difference in allo/autoSCT rates between arms. A non-inferiority in late MRD response (MRD4) between the two arms was observed (primary endpoint). MMolR was reached in 55/75 (73.3%) and 61/78 (78.2%) of CR patients in arm A and B, respectively, with an estimated 95% CI of difference of -11% to +16% (-9.2% to +20.8% in the ITT analysis treating missing data as failures). At 3 years, overall survival (OS) was 86.0% in arm A versus 74.2% in arm B (p=.08, Figure A). Progression-free survival (PFS) was 79.6% in arm A versus 57.2% in arm B (p=.008, Figure B). Thirty-one patients experienced hematological relapse (8 in arm A and 23 in arm B). Twenty-height out of 31 relapsed patients were tested for the acquisition of BCR-ABL1 mutations, 20/28 (71%) had at least one mutation and 10/28 (36%) had a T315I mutation. At 3 years, the cumulative incidence of relapse (CIR) was 21.3%, significantly higher in arm B than in arm A (30.8% vs 10.6%, p=.007). When analyzing the CIR considering alloSCT as a competing event for relapse, a significant higher CIR was still observed in arm B as compared to arm A (Figure C). Conclusion. Four cycles of the combined administration of nilotinib and chemotherapy is very efficient for bridging younger adults with Ph-positive ALL to SCT. However, omitting HD-AraC is associated with a higher relapse incidence despite non-inferior levels of BCR-ABL1 MRD4. Figure 1 Figure 1. Disclosures Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Vincent: Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy; ABBVIE: Consultancy. Boissel: Amgen: Consultancy, Honoraria, Research Funding; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding. 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. OffLabel Disclosure: Nilotinib as a therapy for PH-positive acute lymphoblastic leukemia

Introduction Clonal selection is one of the mechanisms leading to therapy-related myeloid neoplasms (TRMN). A preexisting somatic mutation in hematopoietic stem cell (defined as clonal hematopoiesis [CH]) emerges under pressure of chemotherapy or radiotherapy, leading to TRMN development. Most of these mutations belong to the DNA damage response (DDR) pathway as TP53 or PPM1D mutations and are known to confer a dismal prognosis. Recently authorized for the treatment of ovarian cancers (OC), the poly (ADP-ribose) polymerase inhibitors (PARPi) represent a promising targeted therapy. However, by inducing DNA damage and altering DNA repair process, PARP inhibition could represent a challenge for the genetic stability of the healthy tissues. Thus, we assessed the effect of PARP inhibition on the development of CH and TRMN after PARPi treatment for OC (TRMN-PARPi) in combination with chemotherapies. Methods Firstly, we performed a targeted 77 genes mutational analysis using Next Generation Sequencing (NGS) in 13 patients exposed to PARPi without TRMN. Secondly, we retrospectively identified, with the help of the UNIHEM group of Unicancer, 17 patients who experienced TRMN-PARPi. Clinical, biological and survival data were collected and compared to 23 OC patients with TRMN not treated with PARPi (Gustave Roussy institutional database). Lastly, NGS was performed for 3 patients with TRMN-PARPi with sequential sampling. Patient's samples were obtained with informed consent. Results Thirteen OC patients during maintenance treatment with PARPi without TRMN were explored by NGS. Median age at NGS was 64.5 years old (yo) (40.5-75.3). 4/13 (31%) patients harbored BRCA1/2 germline mutation. Time between OC diagnosis and NGS was 4.3 y (1-11.6). The median number of chemotherapy line at PARPi initiation was 2 (1-3). 7 received Olaparib, 5 Niraparib and 1 Rucaparib. The median duration of PARPi treatment before NGS was 4.7 months (1.1-25.1). 12/13 patients experienced hematological toxicities during the PARPi treatment. CH was found in 10/13 (77%) patients (Figure 1a), including mutations of DDR genes in 8/10 (80%). 6/8 (75%) patients had 2 or more gene mutations. Next we identified 17 cases of TRMN occurring during or after PARPi administration for OC (6/17 [35%] t-AML and 11/17 [65%] t-MDS). 12/17 (71%) patients had BRCA germline mutations (7 BRCA1 and 5 BRCA2). All received Olaparib with a median dose of 600mg/d (400-1200). Median duration of Olaparib treatment was 1.7 years (0.2-4.6). TRMN-PARPi were described 1.4 months (0-10.9) after the end of PARPi administration. We compared these patients to a cohort of TRMN post OC not treated by PARPi. Number of therapy lines for OC, time between TRMN and OC diagnosis, median age at TRMN, were, for TRMN-PARPi, 2 (1-8), 5.9 y (0.9-20.8), 64.4 yo (46-74); respectively, compared to 3 (1-8), 4.9 y (1.7-36.9), 59.3 yo (35.7-85.7); (p=ns). TRMN-PARPi cytogenetic was unfavorable for 16/17 (94%) (including 11/17 [65%] complex karyotype) compared to 16/23 (70%) (11/23 [48%] complex karyotype). C Median survival was significantly lower in the TRMN-PARPi group 3.9 months 95%CI [2.0-9.7] and 6.1 months 95%CI [4.1-15.8] respectively, p=0.046, Fig 1b). However, median survival from OC diagnosis was not different between the two groups 6.2 y 95%CI [5.6-NA] for TRMN-PARPi vs 5.6 y 95%CI [5.0-11.6]. NGS was available for 8/17 TRMN-PARPi and revealed mutations in DDR genes in 7/8 patients (6 patients with TP53 mutation, 2 with PPM1D mutation). For 3 patients, we had samples from OC stage, before PARPi administration. We found that mutations from TRMN stage were present at lower frequency, confirming clonal selection by PARPi treatment (Figure 1c). Conclusions Here we described, for the first time, a cohort of TRMN patients previously treated with PARPi for an OC. Intriguingly, most of these TRMN occurred with a short latency at the end of PARPi treatment, with unfavorable cytogenetic and very short OS. Moreover, we found a very high percentage of CH involved in the DDR pathway (62%) in patients under PARPi treatment without TRMN suggesting a potential clonal selection which could lead ultimately to TRMN. PARPi are now indicated in 1rst line high grade OC regardless of BRCA status, which should expand indications. Benefit for OC patients is not questionable; however, caution will be warranted for patients with CH before PARPi treatment, especially implicating DDR mutations. Disclosures Etienne: Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.

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.

Background:Therapy related acute myeloid leukemia (t-AML) is a late complication following cytotoxic therapy for a primary neoplasm or a non-neoplastic disorder as autoimmune diseases and a highly fatal complication in patients treated for first primary malignancy. Therapy related AML are considered to have a worse prognosis and inferior outcome compared with de novo AML. The aim of this retrospective analysis is to describe clinical and biological characteristics and outcomes of these poor prognosis patients. Methods:This retrospective analysis include 116 adult patients in 2 institutions (Leon Berard cancer center and Lyon Sud university hospital) between January 2006 and June 2019 treated with chemotherapy and/or radiation for different previous malignancies and who subsequently developed AML. We analyzed demographic characteristics, parameters related to previous malignancies (type, delay until occurrence of AML and treatment), to AML (cytogenetic and mutational profile, treatment and outcome). Event for overall survival (OS) was death and patients were censored at the date of last contact if alive or at the date of allogeneic HSCT. Event for disease free survival were death and first relapse. Results:We analyzed retrospectively, 116 adult patients (57 male and 59 female) with median age of 67.5 [19 to 87] years diagnosed with t-AML according to 2016 revised WHO criteria and caused by exposure to chemotherapy and/or radiotherapy for previous solid tumors in 81 pts (70%) or hematologic malignancies in 35 pts (30%). Median time between diagnosis of previous neoplasm and AML was 5.4 [0.4-34.3] years. For the treatment of previous cancer, 48 pts (41%) received chemotherapy alone, 17 pts (15%) radiotherapy and 51 pts (44%) received both modalities. T-AML occurred after exposure to alkylating agents in 12 pts (12%), to agents targeting topoisomerase II in 7 pts (7%), to both agents in 65 pts (66%) and other treatment in 15 pts (15%). Cytogenetic profile was performed in 108 pts and was favorable in 4 pts (3.7%), intermediate in 46 pts (42.8%), unfavorable in 47 pts (43.5%) and assessment failed in 11 pts (10%). Eighty eight available leukemia samples were analyzed using molecular RT-PCR and, more recently, NGS profiling. Gene mutations concern 8 pts for FLT-3, 20 pts for Evi1, 1 pt for IDH1, 1 pt for IDH2 and 8 pts were TP53 mutated. Treatment of t-AML consisted in intensive chemotherapy (IC) in 59 pts (51%), hypomethylating agents (HMA) or low dose cytarabine in 29 pts (25%), best supportive care (BSC) in 28 pts (24%). Only 15 pts underwent allogeneic hematopoietic stem cell transplantation. Median overall survival (OS) [95% CI] was 7.75 months [5.55-12.32] and median progression free survival (PFS) [95% CI] was 6.14 months [5.22-9.07] in whole cohort. According to cytogenetic risk group and as expected, the median survival is significantly longer in favorable than in intermediate and unfavorable risk group (45.3 vs 15.2 vs 5.4 mths for OS with p = 0.005 and 45.3 vs 10.3 vs 5.3 mths for PFS with p = 0.007). Conclusion:This descriptive analysis confirm data of literature with poor prognosis and worse survival in unfavorable and intermediate risk groups of t-AML. However, pts with no comorbidities and candidate to IC had a significant better survival than those receiving HMA or BSC and should be considered for allogeneic transplantation Figure Disclosures No relevant conflicts of interest to declare.

Introduction In France, cancer incidence is increasing, reaching approximately 400,000 new cases in 2017. Thanks to diagnostic and therapeutic advances, net survival at 5 years is improving, with a corollary increase in the number of survivors. Among survivors, 44% have a poor quality of life due to the more or less late onset of treatment-related complications. Despite the objectives of the 2014-2019 national cancer plan considering the latest therapeutic advances, very few initiatives integrating systematic, early detection and management of complications exist in France. Methods and analysis PASCA (Care pathways through cancer) is a single-arm, interdisciplinary, prospective, interventional, cohort study. During a period of 24 months, it is intended to include 858 adults aged 18 to 65 years with non-Hodgkin and Hodgkin lymphoma, acute myeloid leukemia, testicular germ cell tumor, non-metastatic invasive breast cancer, soft tissue sarcoma, osteosarcoma or Ewing's sarcoma at Centre Leon Berard (Lyon, France). The program consists on exhaustive identification of 22 complications at 1 month, 6 months, 24 months and 60 months after the end of first line treatment: social precariousness, return-to-work issues, cognitive problems, anxiety and depression disorders, chronic fatigue, physical deconditioning, overweight/obesity, chronic pain, dermatological disorders, gastrointestinal disorders, sexual disorders, hypogonadism, premature ovarian failure, osteoporosis, chronic kidney failure, heart failure, coronary heart disease, respiratory failure, hypothyroidism, lymphedema, modifiable risk factors associated with the occurrence of secondary cancers. Each identification will give rise to management, which consists of referring the patient to a healthcare professional belonging to the network of dedicated healthcare professionals at the regional level. The course of action to be followed will be defined using decision trees based on international, national or learned society recommendations. Referral outside Centre Leon Berard will be made to a specialist doctor, a health professional from the paramedical field or the patient's general practitioner who will confirm the diagnosis and initiate patient management and follow-up. These patients will also benefit from their usual follow-up in the context of their initial malignancy. Each study visit will include a search for clinical signs using questionnaires, an assay of 12 biological parameters, a urine test strip, 5 tests evaluating physical deconditioning and an electrocardiogram. The weight, height, waist circumference, blood pressure will also be measured. Primary outcome will be the incidence of the 22 complications, measured at 1 month, 6 months, 24 months and 60 months after the end of intensive chemotherapy treatment. Ethics and dissemination The study protocol was approved by the French ethics committee (Comité de protection des personnes Ile de France IV), the study database is currently being declared and registered to the Commission Nationale de l'Informatique et des Libertés (CNIL) and the study on ClinicalTrials.gov. The results will be disseminated to patients and in peer-reviewed journals and academic conferences. Strengths and limitations of this study This study is based on a previous feasibility study with 52 patients recruited in onco-hematology, which demonstrated the feasibility of the intervention and the existence of patient management needs.(1) The study design does not include a comparator arm, as the objective of the study is to provide a comprehensive picture of treatment-related complications, especially those that appear over the long term. Due to the lack of recent data concerning some complications, sample size was calculated empirically on the basis of the active queue of patients at the Centre Leon Berard. References Michallet M, Sobh M, Buono R, Poirey S, Pascu I, Nicolas-Virelizier E, et al. Personalised Follow-up Program after Acute Phase of Treatment in Oncology/Hematology Patients Towards Early Intervention, Better Care and Quality of Life Improvement: Results from Pasca Pilot Study. Blood. 13 nov 2019;134(Supplement_1):5817-5817. Disclosures Nicolini: Sun Pharma Ltd: Consultancy; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

In a significant number of cases cancer therapy is followed by a resurgence of more aggressive tumors derived from immature cells. One example is acute myeloid leukemia (AML), where an accumulation of immature cells is responsible for relapse following treatment. We previously demonstrated in chronic myeloid leukemia that the bone morphogenetic proteins (BMP) pathway is involved in stem cell fate and contributes to transformation, expansion, and persistence of leukemic stem cells. Here, we have identified intrinsic and extrinsic dysregulations of the BMP pathway in AML patients at diagnosis. BMP2 and BMP4 protein concentrations are elevated within patients’ bone marrow with a BMP4-dominant availability. This overproduction likely depends on the bone marrow microenvironment, since MNCs do not overexpress BMP4 transcripts. Intrinsically, the receptor BMPR1A transcript is increased in leukemic samples with more cells presenting this receptor at the membrane. This high expression of BMPR1A is further increased upon BMP4 exposure, specifically in AML cells. Downstream analysis demonstrated that BMP4 controls the expression of the survival factor ΔNp73 through its binding to BMPR1A. At the functional level, this results in the direct induction of NANOG expression and an increase of stem-like features in leukemic cells, as shown by ALDH and functional assays. In addition, we identified for the first time a strong correlation between ΔNp73, BMPR1A and NANOG expression with patient outcome. These results highlight a new signaling cascade initiated by tumor environment alterations leading to stem-cell features and poor patients’ outcome.

Advances in diagnosis and treatment have helped increase cure rates for many cancers. However, the disease and its treatments are often accompanied by short-, mid- and long-term organic and psychosocial sequelae and increased risk of second cancer, adding to that, all pre-existing comorbidities, lifestyle risks and hereditary factors. At the Centre Leon Berard Cancer center, we launched a project named PASCA (Parcours de Sante au cours du Cancer) that aims at structuring and optimizing a follow-up schedule for patients suffering from breast cancer, testicular germ tumor, acute leukemia, lymphoma or myeloma, as well as patients who received hematopoietic stem cell transplantations (HSCT). The main objective of the program is the early detection and specific management of risk factors for second cancer as well as sequelae management after the acute treatment phase with the final objective of quality of life improvement. Follow-up and evaluation are done through the establishment of a multidisciplinary organic assessment, anthropometric and physical fitness, psychic and socio-professional evaluation, the aim is to establish a score for each assessment, complementary to the specific oncology and hematology monitoring, that allows later to establish a personalized and adapted sequelae management and prevention of complications that could significantly impact the patient quality of life but also compromise the optimal management of the malignant disease. Patients were referred to PASCA by the oncologist/hematologist after being discharged from the acute phase of treatment, an information sheet about the program was given as well as a package containing different questionnaires to capture information about risk factors, general health, social status, quality of life and others. At the same time a series of medical laboratory requests were ordered to get a full medical assessment. Based on the questionnaires/medical evaluation a score was given for each type of assessment. Score 0 means the patients needs only a simple follow-up, score 1 means the patient needs to be followed by the family doctor for the specific issue, and score 2 means there is a need for specialist intervention. We put together a network of internal medicine or organ specific doctors in addition to fitness-physiotherapy specialist as well as many other specialists available to intervene for patients with score 2. We started in Hematology a pilot phase that included non-Hodgkin lymphomas (NHL, N=27) and multiple myelomas (MM, N=27) patients, 15 (28%) females and 39 (72%) males. Median age at evaluation was 60 years (range: 56-65), all patients except 8 (all NHL) received autologous HSCT. Here we present some of the most relevant PASCA assessments with the different scores: nephrology (0: 94%, 1:6%), cardiology (0:27%, 1:63%, 2:10%), hepatology (0:49%, 1:42%, 2:9%), pneumology (0:41%, 1:39%, 2:20%), sexual (0:67%, 1:14%, 2:9%), dermatology (0:78%, 1:13%, 2:9%), pain (0:43%, 1:31%, 2:26%), gynecology (0:56%, 2:44%), endocrinology (0:67%, 1:31%, 2:2%), malnutrition (0:75%, 1:8%, 2:17%), obesity (0:54%, 1:20%, 2:26%), flexibility (0:46%, 1:27%, 2:27%), employment (0:76%, 2:24%), fatigue (0:24%, 1:2%, 2:73%), anxiety (0:56%, 1:22%, 2:22%), and depression (0:80%, 1:10%, 2:10%). In addition, a list of FACT questionnaires was collected for all patients as baseline evaluation and will be compared later during follow-up. During the PASCA consult visit, patient was informed about his different assessment results and in case of any score 1 or 2, a referral to the family doctor or a specialist was requested. Planned 6- and 12-months evaluation are ongoing to evaluate the potential improvement after PASCA program. Our results from this pilot study showed a real need for specific follow-up on the medical level but also on social/well being level that is in most of the cases given less priority when the patient is seen in oncology/hematology clinic. We noticed a significant positive feedback from patients included in this program and we expect to see a drastic improvement on the medical, psychological and social level as well as on quality of life. We are starting the full PASCA program that will include also patients with breast cancers, germ cells cancers and sarcoma. A protocol for a randomized multicentric study is in preparation and will allow to evaluate the impact and the importance of such program in patients with malignant diseases. Disclosures No relevant conflicts of interest to declare.

Introduction: Pneumocystis jirovecii (Pj) is an opportunistic fungus and a common cause of pneumonia (PCP) in immunocompromised patient. The gold standard for the diagnosis is the direct exam by microscopy. Patients with hematological malignancies may have a small burden of Pj with a negative direct exam. A polymerase chain reaction assay (PCR) can be used for the diagnosis. Real-time qPCR methods have a good sensitivity (97-100%) and specificity (90-94%) for the PCP detection whereas direct examination has lower sensitivity. Currently, the diagnostic impact of a positive PCR with a negative direct examination for patients with lymphoid malignancies suspected of PCP is not well known. Methods: We retrospectively analysed in this study all patients followed in the Department of Hematology of the Leon Berard Cancer Center (Lyon, France) between January 2003 and March 2014 who developed PCP. In at risk patients, PCP was considered when clinical signs and typical radiological features (e.g. ground glass opacities). Diagnosis was confirmed by the microscopic observation of Pj cysts and/or trophic forms on the bronchoalveolar lavage fluid (Group 1, gold standard) or a positive PCR with negative direct examination (Group 2). Results: PCP was diagnosed in 68 patients with lymphoid malignancies (76% non-Hodgkin lymphoma, 15% Hodgkin lymphoma, 7% chronic lymphocytic leukemia and 2% myeloma). PCP was diagnosed during first-line therapy for 42 patients (62%). Seven breakthrough infections (10%) under sulfamethoxazole and trimethoprim (S/T) prophylaxis were observed. PCP was confirmed in 27 patients (40%) by a positive direct exam (Group 1) and 41 patients (60%) by PCR only (Group 2). The clinical and biological characteristics at diagnosis of PCP were not significantly different between Group 1 and 2 (fever, cough, lymphocyte count, neutrophil count, hemoglobin level, C-reactive protein level, lactate deshydogenase level). However, Group 1 presented more frequently an oxygen saturation of less than 92% (88.9% vs. 56.1%, P=0.007) and dyspnea (88.9% vs. 65.9%, P=0.045) as compared to Group 2. The CT-scan showed bilateral ground-glass opacities in 74% and 71% of Group 1 and 2, respectively. Median time between the hematological diagnosis (3.02 months vs. 4.7 months, P=0.54) or the last chemotherapy (20.5 days vs. 21 days, P=0.62) and PCP diagnosis were similar in both groups. The median time between the first day of hospitalization and the initiation of curative treatment by S/T was similar in the two groups (6 days [0-30] vs. 7 days [0-33], P=0.71) but Group 1 received corticosteroids more frequently as compared to Group 2 (74% vs. 49%, P=0.047). We observed a similar rate of co-infections between the two groups (Group 1, 44% vs. Group 2, 39%, P=0.80). After the initiation of S/T, the median time to fever resolution (2 days [1-21] vs. 1 days [0-8], P=0.006) and to normal oxygen saturation (6 days [2-28] vs. 3 days [0-11], P=0.002) was longer for Group 1 as compared to Group 2. Hence, the median time between S/T initiation and hospital discharge was longer for Group 1 (16 days [4-53] vs. 10 days [2-44], P=0.02). The rate of hospitalization in intensive care unit was higher for Group 1 than for Group 2 (59% vs. 24%, P=0.005). In Group 1 and 2, 5 (18.5%) and 3 (7.3%) patients died from PCP, respectively (P=0.25). Conclusions: In our series, 60% of immunocompromised patients with lymphoid malignancies were diagnosed with PCP on the basis of a positive PCR and a negative direct examination. The presentation and clinical course of these patients are less severe than patients with a positive direct exam, possibly in relation with a lower fungal load. Quick improvement of clinical parameters was observed after curative S/T. These results suggest to promptly initiate a specific treatment for PCP in patients with a positive PCR and a negative direct examination. Disclosures Blay: MDS: Research Funding; Lilly: Research Funding; Bayer: Consultancy, Research Funding; Pharmamar: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; F. Hoffmann-La Roche: Consultancy, Research Funding.

Background: JAK2 constitutive activation/overexpression is frequent in classical HL tumor cells and many autocrine/paracrine cytokines stimulate HL cells by recognizing JAK1- or JAK2-bound receptors. Thus, JAKs blockade may be of therapeutic value in HL. Methods: A phase II study (HIJAK study)was conducted to evaluate safety and efficacy of ruxolitinib, an oral JAK1/2 inhibitor, in R/R HL, given at 20 mg bid for 6 cycles of 28 days. Dosage at 15 mg bid was planned for patients with platelets comprised between 75 and 200 x 109/L at inclusion. Patients with platelets < 75 x 109/L, neutrophils < 1000 x 109/L were excluded. Maintenance beyond 6 cycles was permitted if disease control. The primary objective was overall response rate (ORR, Cheson 2007) at 6 cycles. Secondary objectives were safety, B symptoms relief, best ORR, response duration, PFS and OS. To be evaluable for response and survivals, patients had to receive at least one cycle of the study drug. The safety set included all patients who received at least one dose of ruxolitinib. Median follow-up was 27.1 months (95% CI: 14.4-27.1). Results: 33 patients were included between Jul 2013 and Dec 2014 in 10 LYSA centers in France and Belgium: M/F, 21/12; median age 37 (range 19-80) years; stage III/IV, 75.8%; B symptoms, 51.5%; median number of prior lines, 5 (range 1-16); prior transplantation, 60.6%; prior radiotherapy, 54,5%; prior brentuximab vedotin (BV), 82%; refractory to last therapy, 81.8%. Overall, median number of ruxolitinib cycles was 4. Nine (27.3%) patients received at least 6 cycles and 6 (18.2%) maintenance. ORR at the end of induction was 3/32 (9.4%) patients, all PRs. Best ORR at any time during study was 18.8% (6/32) with five PRs and 1 patient who converted into CR beyond 6 cycles. Transient stable disease was noted in 11 patients. Rapid and durable alleviation of B-symptoms (pruritus, fever, sweating) was frequently noted, especially pruritus which was present in 35.5% of patients before treatment and 6.6% of them after one cycle of ruxolitinib. Median duration of response was 7.7 months (95% CI: 1.8-NA). Two patients remain on therapy. Median PFS was 3.5 months (95%CI: 1.9-4.6) and median OS was 27.1 months (95%CI: 14.4-27.1). Using bead-based immunoassays, plasma levels of 27 cytokines related to the immune system were measured at baseline and after cycle 1. Before ruxolitinib, there was no difference in cytokine levels between responders and non-responders. In responders, the only cytokine that significantly decreased was CX-CL10 (P.01). In patients presenting with pruritus (n=11), PDGF-BB, IL-5, IL-10, IL-12, IL-13, IL-17, eotaxin, FGF basic, MIP1b, rantes, and VEGF were significantly increased. In the latter patients, ruxolitinib treatment significanlty decreased PDGF-BB, IL-10, IL-12, IL-13, IL-17, FGF basic and VEGF. Among patients who were analyzable for JAK2 amplification in RS cells (n=12), polysomy was detected in all of them and specific JAK2 amplification in one. Further analysis of Jak2 targets by IHC will be performed. 40 adverse events (AEs) were reported in 14/33 patients (42.4%), of which 18 were related to ruxolitinib and 18 were grade ≥ 3. One AE led to permanent treatment discontinuation. No AE leading to death was reported. 87.5% of AEs recovered without sequelae. Eight SAEs (infection, 3; anemia, 1; diarrhea, 1; subdural hematoma, 1; bone pain, 1; pulmonary embolism, 1) were reported in 4 patients (12.1%), of which 2 were related to ruxolitinib. No grade 4 neutropenia and 1 grade 3/4 thrombocytopenia was observed. Five patients had grade 3 anemia. Twelve patients died due to lymphoma (83.3%) or toxicity of additional treatment (8.3%) or other reason (8.3%). Among 30 patients who progressed (initial site in 97% and/or new site in 60%), 25 (83.3%) were retreated: with chemotherapy in 19 (comprising bendamustine in 10) and/or immunotherapy in 9 (rituximab, n=4; BV, n=3; nivolumab, n=2). Transplantation was eventually performed in 5/25 (4 allogenic, 1 autologous). In the 25 patients who were retreated, CR/PR rates were 10/15%, respectively. Conclusions: Ruxolitinib shows hints of activity beyond simple anti-inflammatory action in highly advanced, mostly refractory, HL patients, although most responses are short-lived. Toxicity was limited suggesting potential to be combined with other modalities. Further treatment, beyond ruxolitinib, was possible in most patients, even with chemotherapy. Disclosures Haioun: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Casasnovas:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; ROCHE: Consultancy, Honoraria, Research Funding. Ghesquieres:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; Roche France: Research Funding. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria.

Impact of 18 F-fluoro-deoxyglucose positron emission tomography (PET) imaging has become increasingly important in recent years in the management of patients with malignant lymphomas and is recommended for the staging and response to treatment assessment of both diffuse large B-cell and Hodgkin's lymphoma. Few data on the relevance of PET in the management of patients with mantle cell lymphoma (MCL) are available so far. Then, we retrospectively investigated the PET value for initial staging, interim response and predicting outcome in patients with MCL treated in two French institutions (Dijon University Hospital and the Centre Leon Berard, Lyon). From 2004 to 2013, a total of 61 de novo MCL patients assessed by PET were included. For each patient, were collected at baseline, the whole body SUVmax site, the presence of a bone marrow (BM) uptake, total metabolic tumour volume (TMTV) and total tumour glycolysis (TLG). The interim PET response after 3 or 4 cycles of induction treatment was assessed using the Deauville score and the quantitative variation of SUV between the baseline PET and the PET performed after 4 cycles of immunochemotherapy (ΔSUV). Patient's median age was 64 years [38 - 84]. At diagnosis, 92% presented a disseminated disease (stage III-IV). Mean MCL International Prognostic Index (MIPI) was 6.09 [5.89 - 6.29]. All patients received a first-line induction treatment. Twenty-eight (46%) received an autologous stem cell transplantation as consolidation treatment and 10 (16%) a rituximab maintenance. The baseline FDG uptake intensity was low (median SUVmax: 6.93 [2.5 - 25]) leading to consider that baseline PET was informative and suitable for a further PET reassessment in 40 (93%) patients. 72% of the patients with an informative baseline PET, had a SUVmax < 10 making the metabolic quantitative analyses (TMTV, TLG, ΔSUV) uninformative. Among the 46 (75%) patients with histologically proven BM involvement, only 14% of them had BM FDG uptake. After 3 to 4 cycles of induction treatment, 27 (75%) patients achieved a negative PET. With a median follow up of 27 months, a shorter PFS was related to a disseminated disease (stage III-IV) on the basis of baseline PET (2y-PFS: 47% vs 80% p = 0.03) and an insufficient interim metabolic response according to the Deauville score (score ≥ 4) (16% vs 64% p=6 (p = 0.04, HR = 7.1 IC 95% [1.1 - 46]) retained an independent negative impact on PFS. FDG avidity of LCM is usually low. PET underestimates BM involvement at diagnosis in 86 % of patients, compared with cytological and histological techniques, and has no independent prognostic value. The interim metabolic response assessed using the Deauville criteria is a prognosis factor independent from MIPI in patients with MCL. Disclosures Salles: Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau. Casasnovas:Gilead: Consultancy; Takeda: Consultancy; Roche: Consultancy, Research Funding.

In order to potentially mobilize and harvest the Ph cells observed in most patients with chronic myeloid leukaemia (CML) during interferon-alpha (IF-alpha) therapy, G-CSF (filgrastim), 5 microg/kg/d, was administered subcutaneously together with IF-alpha to 30 CML patients in haematological remission but with various degrees of cytogenetic remission, after IF-alpha therapy. Peripheral blood stem cells (PBSC) were harvested using standard aphereses from day 5 of G-CSF Patients underwent one to four (median three) aphereses. Median total yields/kg were 7.6 (range 3.8-25) x 10(8) MNC, 3.4 (0-140) x 10(6) CD34+ cells, and 17 (1.1-107) x 10(4) CFU-GM. No patient had a significant increase in the percentage of Ph+ cells in the bone marrow under G-CSF therapy. The percentage of Ph+ cells in apheresis products tended to decrease between the first and the last apheresis (P = 0.05). 14 patients who were not responsive to IF-alpha were transplanted after conditioning with busulphan 16 mg/kg and melphalan 140 mg/m2. Median time to neutrophils > 0.5 x 10(9)/l was 20 d (16-114 d) and to platelets > 50 x 10(9)/l 18 d (12-149 d). Nine patients had a major cytogenetic response post graft, which correlated with the amount of Ph+ cells reinfused with the graft (P = 0.02). We conclude that this procedure is feasible, allowing the harvest of enough PBSC, some of them Ph- in patients who responded to IF-alpha, to allow autologous transplantation.

In order to determine whether granulocyte colony-stimulating factor (G-CSF) alone was capable of mobilizing peripheral blood stem cells (PBSC) in myeloid as well in lymphoid malignancies, G-CSF (filgrastim), 5 μg/kg/day, SC, was administered to 48 patients with myeloid or lymphoid malignancies at various stages, after hematopoietic recovery from last chemotherapy. PBSC were harvested using daily aphereses from day 5 of G-CSF therapy. An adequate PBSC graft could be harvested in 43 patients (90%) after 2 to 5 (median 3) aphereses. Predictive factors for a good PBSC yield in a multivariate analysis included a high WBC count on day 5 of G-CSF therapy, and a diagnosis of myeloid malignancy. Thirty patients were transplanted after various conditioning regimens. Median times to neutrophil > 0.5 x 109/1 and platelet > 50 x 109/1 were 15 and 32 days respectively. The harvest of > 10 x 104 CFU-GM/kg and the absence of busulfan in the conditioning regimen were predictive of early platelet recovery. We conclude that G-CSF therapy initiated during stable hematopoiesis is efficient to allow PBSC harvest for autografting in myeloid as well as lymphoid malignancies.

The treatment of older adults with acute myeloid leukemia (AML) is associated with unsatisfactory rates of complete responses and long-term overall survival. Therefore, a clinically usefull prognostic index can facilitate therapeutic decision making and evaluation of investigational treatment strategies in this patient population. Overall, 243 of the 432 patients (56%, 95% CI: 51–60%) achieved CR (229 of them after the first induction course and 14 after salvage therapy). The median disease-free survival (DFS) and the median overall survival (OS) of the entire cohort were 8.4 months (95% CI: 7.2–10.1 months) and 8.3 months (95% CI: 7.2–10 months) respectively. A prognostic score is presented based on the multivariate analysis of 432 newly diagnosed non-M3 AML patients aged more than 60 years, selected on the base of their initial performance status and the absence of severe co-morbidity factors, for entering onto five successive clinical trials combining an anthracycline and cytarabine. Four clinically relevant parameters are included in this index: cytogenetics at diagnosis, history of previous hematologic disorder, hematologic features at diagnosis, and LDH level at diagnosis. Using this stratification system, three risk groups were defined: a favorable-risk group A (OS of 39% at 2 years and 21% at 5 years), an intermediate-risk group B (OS of 19% at 2 years and 8% at 5 years), and a poor-risk group (OS of 5% at 2 years and 0% at 5 years). The prognostic index estimates the outcome of elderly AML patients usually selected for intensive chemotherapy trials using four easily determined parameters and might identify patients who are really candidates for this treatment strategy from those for whom investigational therapy or palliation may be most appropriate.

Introduction: Treatment of first-line therapy of primary CNS lymphoma (PCNSL) is based on high-dose methotrexate and cytarabine combination chemotherapy. Consolidation radiotherapy is mainly withdrawal for patients older than 60 years old regarding the excessive rate of neurological toxicity. Rituximab improved outcome of systemic diffuse large B-cell lymphoma but no data from randomized phase III trial is available to prove such outcome improvement for PCNSL. We introduced in daily practice intravenous rituximab in combination with chemotherapy for B-cell PCNSL in first-line therapy in 2004. The goal of this study is to determine whether such therapeutic modification improves PCNSL patient's outcome. Methods: Patients were from consecutive PCNSL cases (N=209) included in Leon Berard Cancer Centre registry (Lyon, France), from 1987 to 2011 (date of diagnosis). Median age of patients was 63 years (range, 26-87), 56% were male, 51% had a performance status (PS) >1, 63% had an involvement of deep structures of brain, 66% a high CSF protein level, 12% a meningeal involvement and 42% a high LDH level. Of the 171 available patients, 16% had 0-1, 60% had 2-3, and 24% had 4-5 adverse IELSG prognostic scores, respectively. Patients were all treated by chemotherapy, 92% and 63% of them by high-dose methotrexate and cytarabine containing chemotherapy, respectively followed by brain radiotherapy for 108 patients (58%). Intravenous rituximab was used in combination with chemotherapy in 61 patients (29%) between 2004 and 2011. Results: No difference in term of clinical characteristics (median age, PS, tumor site, CSF protein level, meningeal involvement, LDH level) was observed between patients treated with or without rituximab in combination with chemotherapy. With the median of 86.3 months (18.2-259), the median progression free survival (PFS) and overall survival (OS) for whole series were 17.3 months (95%CI, 10.7-25.9) and 35.6 months (95%CI, 22.7-50.0), respectively. The 3-year PFS were 55.5% (95%CI, 43-67) and 31.1% (95%CI, 24-39) for patients treated or not with rituximab, respectively (P=0.001). The 3-year OS were 73.6% (95%CI, 61-83) and 39.9% (95%CI, 32-48) for patients treated or not with rituximab, respectively (P60 years (HR=1.74; 95%CI, 1.22-2.46; P=0.002), meningeal involvement (HR=2.33; 95%CI 1.42-3.85; P=0.0009) and used of rituximab (HR=0.50; 95%CI, 0.32-0.78; P=0.002) were identified as independent predictors of PFS. OS was significantly influenced by age>60 years (HR=1.94; 95%CI, 1.36-2.77; P=0.0002), PS (HR=1.76; 95%CI, 1.26-2.46; P=0.001), meningeal involvement (HR=2.17; 95%CI, 1.30-3.61; P=0.003) and used of rituximab (HR=0.39; 95%CI, 0.24-0.62; P=0.0001) in multivariate analysis. In a prognostic model integrating the IELSG score (0-1 vs. 2-3 vs. 4-5) (P=0.0002 for PFS and P Conclusion: In this retrospective analysis, we showed that PCNSL patients treated with intravenous rituximab in combination with first-line chemotherapy had a better outcome. The frequency of consolidation radiotherapy was reduced for these patients treated at rituximab era. In multivariate analysis, CSF involvement was an independent adverse prognostic factor that inclines to improve meningeal explorations and propose new therapeutic options for CSF positive PCNSL patients. Disclosures No relevant conflicts of interest to declare.

Abstract 3698 Background: Randomized trials had demonstrated that rituximab improved outcome in newly diagnosed follicular lymphoma (FL) and this anti-CD20 monoclonal antibody was approved in France since 2004 in combination of chemotherapy (CT) for LF in first line therapy. As these results were obtained in selected patients with strict inclusion and exclusion criteria used in clinical trials, whether the improvement of patient's outcome is valuable in unselected population of FL patients with various medical history, different CT regimens is questionable. We performed a retrospective analysis to evaluate if the management and the outcome of FL have significantly changed in our institution before and after rituximab approval in 2004. Patients and Methods: all adult patients referred for first line LF were included and separated into cohort 1 diagnosis between 1996 and 2003 (103 patients) and cohort 2 between 2004 and 2010 (144 patients). Baseline clinical and biological datas, Follicular Lymphoma International prognostic Index (FLIPI), type of therapy, treatment response, progression free survival (PFS) and overall survival (OS) were compared. Results: There were no statistical differences in patients' characteristics between the 2 cohorts, including FLIPI score. In cohort 2, 71% received in first line therapy a rituximab based regimen (19% in monotherapy and 52% with CT). In cohort 1, 58% of patients were treated with CT and 10% with rituximab, 2% in monotherapy and 8% in combination with CT. Response rate were significantly improved in cohort 2 compared to cohort 1: complete response rate was 74.3% versus 57.8%, P Conclusions: These datas confirms the improvement of FL patients' outcome observed in clinical trials after the approval of rituximab in first line therapy prescript in a context of daily practice whatever age, medical history, and type of CT. Disclosures: No relevant conflicts of interest to declare.