Abstract: Introduction: Acute myeloid leukaemia (AML) is a group of heterogeneous malignant disorders. AML incidence rates in world populations generally ranged from 3.0 to 4.0 cases per 100,000 person-years in adult populations, while developing countries had about one-third the incidence of AML. In Algeria there are no large-scale studies regarding acute myeloid leukemia epidemiology. The objective of this study was to analyze the initial basic characteristics of patients diagnosed with AML in our population and the incidence rate. Patients and methods: A survey form was distributed to all departments of hematology at the 21 participating centers of the Algerian AML Study Group (A.AMLSG). In this multicenter, retrospective study, 2,231 patients were included between 2011 and 2017. We intended to register all patients aged 15 years or older with newly diagnosed AML. Data noted age at presentation, gender, medical history, physical examination, and blood and bone marrow investigations such as, hemoglobin levels, blood cell count, and AML subtype according to flow cytometry analysis. AML cases were classified according to the 2008 World Health Organization (WHO) proposal. Age-standardized incidence rates (ASR) of AML were calculated using Algerian population data in the years 2011-2017. SPSS 20 was used for data analysis. Results: Of the 2,231 patients, 1059 (47%) were females and 1172 (53%) males, with a mean of 318.7 cases per year for the whole country. The overall mean age was 46.7±18.2 years. The most common age group was 30-70 years with 1444 (64.7%) patients. Most frequent clinical features at presentation included fever 987/2120 (46.5%), weakness 532/2120 (25%) and bleeding tendency 1033/2120 (48.7%). A significant number of patients had presented with body aches, respiratory complaints and hepatosplenomegaly or other abdominal complaints. Median hemoglobin levels was 7.6 g/dl (IQR: 2.4 - 14,8), whereas median counts for white blood cells (WBC), platelets and blasts were 20 G/L (IQR: 0,2-260), 35,5 G/L (IQR: 1-425) and 58% (IQR: 28-100), respectively. AML subtypes were available for 1946 (87.2%) patients. The most common AML subtype according to latest WHO classification was "AML with maturation" (M2) having 499 (26%) patients, followed by acute monocytic leukemia (M4) with 378 (19.4%). APL was the fourth most frequent pathology with 283 (15%) cases, 147 (52%) were females and 136 (48%) males, with a mean age of 37±16,1years. According to the SANZ classification, patients were diagnosed with favorable risk (N = 31, 11%), intermediate risk (N = 107, 38%), and adverse risk (N = 145, 51%). Cytogenetic studies were performed in 21% of the patients, and molecular biology studies were performed in 12% of the patients. Mutated FLT3-ITD was present in 12 patients (16%) among 75 patients. The trend of continuous annual increase in cases of AML where 250 cases had been registered in 2011, 252 in 2012, 339 in 2013, 290 in 2014, 320 in 2015, 370 in 2016 and 410 in 2017. According to their place of care, the patient distribution shows that over 58% had been diagnosed in the seven oldest hematological centers in the country, while according to their place of residence, the city of Algiers had the highest frequency of 12.9%. Globally, 28% of AML were diagnosed in the whole western region of the country, 43% in the center and 29% in the east. The crude annual incidence per 100 000 of the population continued to rise from 0.94 in 2011 to 1.39 in 2017. The age-specific incidence varied from 0.72 for ages 15- 20 years, with a trend of a continuous increase in the rate, and a sharp increase to 2.44 after age 60 years reaching the highest 2.63 after age 80. Conclusion: The young population in Algeria was expected to result in a relatively lower AML incidence rate and median age since AML incidence usually occurs much later in life. An overall increase in the number of AML patients diagnosed nationwide over the last seven years indicates a need for additional health care resources including curative and therapy-intense strategies, such as stem cell transplant facilities to optimize outcome. Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction: Older patients with an age above 60 years with classical Hodgkin lymphoma (cHL) represent a proportion of 20% to 30% of all cHL. Older cHL patients are characterized by unfavorable prognostic factors with an aggressive disease, a poor tolerance to chemotherapy resulting to a significant reduced survival as compared to younger patients. In relapsed and refractory HL, prospective and retrospective studies showed that bendamustine in monotherapy provided interesting efficacy with 30% of complete response with an acceptable toxicity profile. We developed the PVAB (Prednisone, Vinblastine, Doxorubicin and Bendamustine) regimen in first line therapy to improve prognosis of older HL with advanced stage. Methods: In this prospective phase II, we recruited newly diagnosed classical HL patients age of 61 years or older with an advanced stage (Ann Arbor stage III, IV, IIB with risk factors). Inclusion criteria were: baseline 18-FDG PET scan performed before any treatment with at least one hypermetabolic lesion; ECOG performance status 0-2; adequate cardio-pulmonary function with LVEF ≥ 50%; adequate renal function with creatinine clearance ≥ 40 mL/min; HIV negative; For patients aged 70 years old and more, a Mini Nutritional Assessment (MNA) ≥ 17. Treatment consisted of 6 cycles of prednisone (40mg/m2 D1-5), vinblastine (6mg/m2, D1), doxorubicin (40mg/m2, D1) and bendamustine (120mg/m2, D1) every 21 days. A first evaluation was performed after 4 cycles by CT scan and a final evaluation by PET scan after 6 cycles. No radiotherapy was applied in this protocol. The primary endpoint was the complete metabolic response (CMR) rate after 6 cycles of study treatment or at premature treatment discontinuation according to Lugano Classification. The main analysis for the CMR rate was based on a Simon's phase II design. We selected P0 and P1 to be 70% and 85%, respectively for CMR rate. A total of 79 patients provided nominal power of 80% at the nominal one-sided 5% significance level. Using a drop-out rate of 10%, 90 patients should be included in this trial. Results: Between July 2015 and July 2018, 89 patients who signed the consent form and received at least one PVAB cycle corresponding to intention to treat (ITT) group were included in 34 LYSA centers. Among them, four patients did not respected major inclusion criteria (one patient had a nodular lymphocyte predominant subtype after histological review and three patients ≥ 70 years had no MNA evaluation at inclusion) corresponding to the modified ITT group (N=85). The median age of the 89 patients was 68 years (range, 61-88) with 35 patients ≥70 years old (39%) and 58 male (65%). According to the central review, the main histological subtype was nodular sclerosis cHL (66%). Ann Arbor stages were as follows: II (n=3, 3%), III (n=30, 34%), IV (n=56, 63%). B symptoms were present in 57% of patients and 70 patients (80%) had IPS≥3. 78 patients (88%) completed the 6 cycles of PVAB. In ITT, the CMR rate corresponding to the primary endpoint of the study was 77.5% (95%CI, 67-86) with 69 patients in CMR; 8 patients were in partial metabolic response; 2 and 5 patients had a stable and progressive disease, respectively and 5 were not evaluable. In the modified ITT group, the CMR rate at this end of treatment was 77.6% (95%CI, 67-86). With a median follow-up of 23 months (0.5-40.3), 25 patients relapsed or progressed (28%). The 2-year progression survival rate (PFS) rate was 61.3% (95%CI, 49-72). For the 69 patients achieving CMR, the 2-year disease free survival (DFS) rate was 73.3% (95%CI, 61-82). At the date of analysis (December 2018), 17 patients (19%) died: 7 cHL, 4 treatment toxicity, 3 second cancers, 3 other causes. The 2-year overall survival rate was 84.1% (95%CI, 73-91). For toxicity, 4 patients presented toxic death during treatment: one cardiogenic shock (71y, 〉 cycle 1) one septic shock (70y, 〉 cycle 1), one brain hematoma with grade 4 thrombocytopenia (76y, 〉 cycle 1), one fungal infection (86y, 〉 cycle 4). At least one serious adverse events (SAE) were presented by 28 patients (31.5%) mainly infections (13 patients, 15%), blood (11 patients, 12%) and cardiac disorders (4 patients, 4.5%). Conclusions: Six cycles of PVAB regimen provided high CMR (77.5%) with acceptable toxicity in older cHL patients with advanced stage. Patients with CMR at the end of treatment had a particular favorable outcome but long term follow-up is needed for a better evaluation of survival endpoints. Disclosures Morschhauser: Roche/Genentech: Consultancy; Celgene: Honoraria; Servier: Consultancy; Gilead: Consultancy; Janssen: Honoraria; BMS: Honoraria. André:Celgene: Other: Travel grants, Research Funding; Chugai: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding. Quittet:Novartis: Honoraria, Speakers Bureau. Brice:Takeda France: Consultancy, Honoraria; Millennium Takeda: Research Funding; BMS: Honoraria. OffLabel Disclosure: Bendamustine is off-label drug use in Hodgkin lymphoma

Abstract: Abstract 4998 Purpose Prevalence of patients (pts) suffering of non-Hodgkin's lymphoma (NHL) and diabetes is increasing. Previous investigations were mainly focused on possible association with an increased risk of NHL in pts with type 2 diabetes. In another way, it is well known that NHL patients (pts) with co-morbidity are treated less intensively and have worse prognosis. We propose a retrospective analysis of a homogeneous aggressive lymphoma cohort based on a multicentric regional network database to assess the cross-impact of diabetes and NHL in term of pts management and survival. Patients and methods All pts with high-grade NHL cases, histologically proven, diagnosed between 2003 and 2008 in the Hematology Department of regional network HEMATOLIM, have been included. Diabetes of type 2 has been defined according to international criteria. Data about diabetes and lymphoma treatments, toxicity, relapse, progression or death, have been collected from the Database Structure Régionale de Référence sur les Lymphomes en Limousin. Statistical analysis had been done by StatView and SAS 9.1.2 softwares. Results We included 251 NHL pts with aggressive NHL concerning 69.3% Diffuse Large B Cell Lymphoma (DLBCL) (n=174), 7.6% Mantle cell (n=19), 5.2% Peripheral T-cell (n=13), 5.2% Burkitt (n=13) and 12.7% others (anaplastic (n=9), Follicular grade 3B (n=8),T angioimmunoblastic (n=8), primary mediastinal NHL (n=3), nasal NK-T (n=2), T-cell-rich BCL (n=1), centroblastic BCL (n=1)). Among these NHL, 16.7% had type 2 diabetes (n=42). Sex ratio was 1 for diabetic pts (dp) versus (vs) 1.4 for non-diabetic pts (ndp), the average age was 65.1±15.8, 71.3±8.4 for dp vs 63.8±16.6 for ndp (p=0.005). All received first-line chemotherapy mainly Cyclophosphamide/Oncovin/ Adriamycine/Prednisone ± Rituximab (54.6%, n=137), with no difference between dp and ndp (respectively 59.5% vs 57.0%). Chemo-resistance was reported for 22.7% of pts (28.6% dp (n=12) and 21.5% ndp (n=45)). Chemotherapy-related toxicities were more frequent in dp (71.4%, n=30, vs 47.8%, n=100 ndp) (p=0.005), mainly fever and/or bleeding and infectious complications or back to hospitalization. Dose reductions were more frequent in dp, 31.0%, (n=13) vs ndp 12.0%, n=25) (p=0.0017) and adjustements in time-interval (54.8%, n=23, vs 38.8%, n=81 ndp) (p=0.05) of chemotherapy course. A logistic regression analysis showed that dose reductions and treatment-related toxicities were associated to diabetes status (p=0.015 and p=0.026, respectively). Complete remission (CR) was achieved for 66% ndp (n=138) vs 40.5% dp (n=17) with significant difference (p=0.0019). Relapses: no significant difference between both groups with 13.9% ndp (n=29) vs 19% dp (n=8). Mortality rate was significantly increased: 41.6 % ndp vs 59.5% dp (p=0.033), mainly due to NHL complications, 41.6% ndp (n=87) vs 59.5% dp (n=25) (p=0.033). With a median follow-up of 17 months (m) (range 0-72), median overall survival (OS) was not reached for ndp vs 12±9 m for dp (p=0.006), median event-free survival (EFS) was 41±6.2 m for ndp vs 11±4.3 m for dp (p=0.002). In a multivariate analysis, the differences disappeared on OS and EFS after adjustment on age. A logistic regression analysis showed an important increasing of complications, adjustment of doses, and CR but these chemotherapy-related toxicities had no impact on dp survival. The impact of chemotherapy mainly including corticosteroids on the long term diabetes status has been assessed at the end of NHL treatment, 35.7% increased oral medication to oral insulin or received an intensified dose of the antidiabetic treatment (9.5%, n=4). Some dp with oral treatment improved their glycemia (7.1%, n=3), and used only hygiene-dietary measures. Long term insulin treatment was introduced after glycemia disorders for 3.8% ndp (n=8). Conclusion Aggressive NHL were more frequently associated with type 2 diabetes (16%) in our regional cohort probably due to the study population median age around 68 years. A real impact of incidence of the chemotherapy-related toxicities, back to hospitalization, a less dose-intensity chemotherapy on dp CR has been significantly demonstrated. EFS and OS were not significant in multivariate analysis especially with adjustment on age. These results claim for a cautious management of diabetes at the initial assessment and during chemotherapy for decreasing complications and by an intensive patient education. Disclosures No relevant conflicts of interest to declare.

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

Abstract: Abstract 4283 Introduction In recent area, management of CML has benefited from important changes with the development of targeted therapies and monitoring therapeutic response. Respect of good practices in rural countries, geographically isolated as the Limousin, requires patient's (pts) care in an health network like HEMATOLIM that includes 13 private or public health care facilities. The outcome of all new pts suffering CML, treated or not according a clinical trial and included in a regional database was analysed for estimate the impact of these new practices in real world. Patients and methods we conducted a retrospective observational, descriptive and analytical study of epidemiological data of consecutive pts with CML and in care into the regional network HEMATOLIM. Included criteria were cytogenetic or molecular proved CML, in regional pluridisciplinary staff and cytogenetic results and molecular response. Clinical data, biological data, therapeutic response, survival were collected in the database and statistically analysed by StatView. Results 176 pts diagnosed between 1978 and 2009, resident in Limousin for 75% (n=132), in limit departments 25% (n=44), sex ratio 1.2 and median age 59 years [22-84]. Between 2001 and 2007, regional incidence is 1.084/100000 pop per year versus 1 in France. At diagnosis, pts were in chronic phase 92% (n=162), accelerated phase 5.7% (n=10), blast crisis 0.6% (n=1), missing (ND) 1.7% for n=3 pts. Sokal was 〈 0.8 for 61% (n=108), 0.8-1.2 24% (n=42), 〉 1.2 11% (n=19), ND 4% (n=7). Cytogenetic t(9,22) or BCR-ABL expressing in initial molecular biology was 100% with another cytogenetic abnormality in 8%. Treatment was done by inclusion in a clinical trial (n=36) for 20% of pts. Treatment was Imatinib (IMB) for 72% (127/176) of pts with CML: 54% (n=68) in 1st line, 20% (n=26) 2nd line and 26% (n=33) 3rd line or more. RCC at 6, 12 and 24 months were respectively 57% (75 pts evaluable), 66% (71), 83% (58). RMC at 6, 12 and 24 months were respectively 14% (59), 23% (66), 37% (73). During treatment, 12% pts had resistance to IMB (n=15): 2 of them had a mutation of resistance to the IMB (2/15). Toxicity to IMB was observed in 12% (n=15). Pts have developed another malignancy during or after tyrosine kinase inhibitor (TKI) treatment for 9.5% (n=12) localized to prostate 3, colon 2, breast 1, pancreas 1, lung 1, parotid 1, melanoma 1, kidney 1 and bladder 1. Median survival of pts receiving TKI in 1st line is not reached, receiving TKI in 2nd line or more: 18 years and for pts never receiving TKI (1978-) 4 years (p 〈 0.0001). Conclusion In real life, impact of TKI and monitoring of molecular response on the survival of pts with CML is strongly illustrated by this retrospective cohort network study. The better survival since the XXI century included elderly patients CML, having already received several lines of treatment and often excluded of clinical research due to comorbidity. A long term follow-up of these cohorts of pts will be interesting in term of incidence of ITK resistance, emergence of second malignancies and medico-economic impacts. Disclosures: No relevant conflicts of interest to declare.

Abstract: Background. Cardiac iron overload is the major cause for death in regularly transfused thalassemic (Thal) patients. Its impact in myelodysplastic syndrome (MDS) patients is debated. Heart seems to be spared in regularly transfused patients with sickle cell anemia (SCA), which is supposed to be related to a later onset on transfusions and to the use of erythrocytapheresis rather than simple transfusion. Our aim was to assess the prevalence of cardiac iron overload, defined as a T2*cardiovascular magnetic resonance (MR) 〈 20ms, and to look for predisposing factors. Patients and methods. Patients were enrolled if they were regularly followed in a center where the exact number of erythrocyte concentrates (EC) could be obtained, had received in the previous year more than 8 EC, were older than 6 years (limit for MRI without sedation), had no known heart disease related to another pathology, and had given informed consent. All patients underwent 1.5T myocardial T2*MR imaging after validation of the procedures in the different sites. Assessment of Liver Iron Content (LIC) used two signal intensity ratio of gradient echo imaging (R2*) MRI protocols. Serum Non-Transferrin Bound Iron (NTBI) was measured by the FeROSTM eLPI kit, and serum hepcidin by LC-MSMS. Results. 20 Thal, 41 SCA and 25 MDS patients were evaluable. We divided SCA in 2 groups, according to the procedure recorded at the time of the study, manual exchange transfusion (G1, N = 30 patients), or erythrocytapheresis (G2, N=11 patients). We found cardiac overload in 0, 3 (15%), and 4 (16%) of SCA, Thal, and MDS patients respectively. Serum ferritins at beginning of chelation were not statistically different in all categories of patients, as well as Ferritin and LIC at the time of the study. Increased LIC and abnormal T2* were associated in Thal and MDS patients (p=0.04), with no correlation between abnormal T2* and parameters of transfusion and chelation. Plasmatic iron level was increased in Thal and MDS patients but remained at normal range in SCA patients. NTBI level was high in Thal and MDS but completely absent in SCA groups. The major discrepancy was in the values of hepcidin, which were collapsed in Thal, at normal range in SCA, and highly elevated in MDS patients. Discussion and conclusion. We confirm that SCA patients are relatively protected from cardiac iron overload. This results probably from massive consummation of iron through effective erythropoiesis, making toxic free iron (NTBI) less available in the circulation. In addition, since iron overload in SCA results from a massive outflow of hemoglobin (Hb) due to intravascular hemolysis and transfusion, the heme/Hb-bound iron must be efficiently handled in liver macrophages, limiting its release in the bloodstream. In Thal patients, underlying defects in erythropoietic processes, together with low hepcidin that stimulates intestinal iron absorption and increases NTBI, must provoke more organ damages. Hepcidin levels were high in MDS patients, suggesting that transfusion-dependent iron overload was a more effective regulator of hepcidin production than dyserythropoiesis. The % of T2* 〈 20 ms we observed in MDS patients (16%) was quite comparable with previous publications. Finally, we observe that, in opposition with previous reports, SCA patients undergoing eythrocytapheresis may experience severe iron overload and need iron chelation. Table 1. Thal SCA G1 SCA G2 MDS p Age at beginning of transfusion (yrs) 8.5[0-45] 7[0-45] 16.5[1-55] 66[38-83] 〈 0.001 Duration of transfusion (yrs) 10[1-39] 7[1-22] 10.5[0-25] 3[1-10] 〈 0.001 N EC since diagnosis 359[21-1360] 139[24-791] 201[14-888] 77[16-544] 0.0005 N CE/yr 24[8-67] 21[4-62] 35[17-58] 27[7-65] 0.09G1vsG2=0.03 % patientschelated 95 90 72.7 72 0.12 Age at beginning of chelation (yrs) 11[1-48] 9[2-47] 18[6-31] 68[38-84] 〈 0.0005 Ferritin at beginning of chelation (ng/ml) 1148[713-2400] 2075[448-3670] 1500[905-2804] 2398[482-5140] 0.22 N T2* 〈 20 ms 3(15%) 0 0 4(16%) 0.01 LIC (mg/g d.w.) 10.4[0.8-20.2] 10.7[0.8-37.1] 14[0.8-19.7] 15.2[3.0-45.3] 0.29 Plasmatic iron(μmol/l) 36.9[31-57] 22.5[6-42.2] 21[13-46] 38.2[11.9-72] 〈 0.001 NTBI (mg/ml) 7.1[0-31.1] 0[0-18.3] 0[0-12.4] 4.45[0-25.5] 0.0005 Ferritin (ng/ml) 870[169-4339] 2739[393-5596] 2404[33-20030] 1611[223-6813] 0.08 Hepcidin (ng/ml) 1.35[0-12.3] 9.95[0-67.9] 2.10[0-52.4] 36.35[3-143.2] 〈 0.001 Deferasirox dosage 〈 0.5 μg/ml 3/8(38%) 3/10(29%) 3/5(60%) 0/11(0%) 0.03 Disclosures De Montalembert: Addmedica: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau. Guerci-Bresler:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau.

Abstract: Abstract 3632 Introduction: Although Hodgkin Lymphoma (HL) is highly curable, about 15% of patients (pts) are refractory or relapsed after first line treatment. Classic prognostic scores (e.g. IPS) are useful for identifying high risk pts, who need intensive treatment, and low risk pts, who beneficiate de-escalation to minimize side effects. However, they are not enough suitable to predict outcomes. Consequently, finding new complementary tools for detecting refractory or relapsing pts, remains a challenge. Fluorodeoxyglucose (FDG)-PET/CT involvement in initial staging has been widely studied. Although clinical or CT tumor volume is an important prognostic factor, metabolic tumor volume (MTV) is not enough explored. We performed a study to 1) determine whether MTV and maximum standardized uptake value (SUV) max could be new prognostic markers and 2) compare metabolic tissue heterogeneity with CD68 expression, a promising new prognostic factor linked with inflammatory microenvironment. Patients and methods: Among 456 histologically proven HL pts registered in the Regional Lymphoma database of Limousin (SRRLL, France) since 1990's, 158 have an available sample for CD68 staining. Among the 106 pts who have undergone FDG-PET, 43 pts have available quantitative initial and early response (post-C2) SUV FDG-PET/CT data. The median follow-up was 21 months (6–72.5). Pts were classified following Ann Arbor stages I: 4 pts, II: 17 pts, III: 9 pts, IV: 13 pts. FDG-PET/CT exams were performed with a biograph6 Siemens® device and analyzed with Siemens MI® application. MTV was computed for all pts with a 2D delineation technique and using a thresholding method. The threshold (T) corresponds to mean liver SUV (+3 sd) calculated into 50 cm3 of normal liver. All the tumor voxels (3D pixels) equal or greater than the T belong to MTV. MTV per pathological area (MTVa) was also analyzed. Pts with spleen lesions have an increased volume compared to the others. To minimize spleen's impact, MTV was calculated without spleen (MTVws). Quantitative FDG uptake is routinely measured by SUVmax. The mean SUVmax was also worked out into 1 cm3 around the tumor SUVmax. ROC curves were plotted for continuous variables such as age, erythrocyte sedimentation rate (ESR), MTV, SUVmax and mean SUVmax. CD68, tumor associated macrophage expression, was tested with a 25% threshold for positivity. Significant factors allowed dividing pts into favorable and unfavorable groups. Event free survival (EFS) studies were carried out for all binary variables using COX model. A univariate regression analysis was performed. Variables with a p 〈 0.20 were included in multivariate analysis. Results: Median age and sex ratio (n=43) were respectively 29 y-o (16–77) and 0.87. ROC and univariate analysis showed that MTV, MTVa and MTVws were significant predictors for absence of complete remission (CR) at post-C2 and EFS. Cut-off values for prognosis (Cp) were 310 cm3 for MTV or MTVws and 53 cm3 for MTVa (p 〈 0.001). Cut-off values for post-C2 were 244 cm3 for MTV or MTVws and 62 cm3 for MTVa (p 〈 0.007). For pts with a large tumor volume (MTV, MTVws or MTVa 〉 Cp), 1 and 2 years EFS were shorter (figure1). Two years EFS for MTV, MTVa and MTVws are respectively: 40%, 50% and 21% for large tumor volume and 87%, 86% and 89% for small tumor volume (p= 0.004, p=0.01 and p=0.0003). The mean SUVmax and heterogeneity were significant in univariate analysis (p=0.01 and p=0.04) but not in ROC analysis. Heterogeneity level was not correlated with CD68 expression. Each new parameter was compared, in multivariate analysis, to ESR, stages, B symptoms, bulky, age. MTV was an independent factor for predicting outcomes and post-C2 results (p 〈 0.01) and better than mean SUV max. Similar results were found for MTVa and MTVws (p 〈 0.02 and p 〈 0.01). Discussion: In spite of limited number of pts and short follow-up, prognostic value of MTV is very significant. Those data are in accordance with the few results previously reported (Hutchings et al. Int J Radiat Oncol Biol Phys, 2005). Song et al. (Cancer Science, 2012) also highlighted that MTV was better predictor than SUVmax in DLBCL. Conclusion: Large MTV seems to be a potential predictive marker for adverse post-C2 results and EFS. These data need further studies to confirm, in larger cohort, these first promising results to establish a better initial risk stratification of pts, leading to optimal adaptive therapy strategy. Disclosures: No relevant conflicts of interest to declare.

Abstract: Abstract 1558 Background: The tumor microenvironment is an important factor in the development and progression of classic Hodgkin's Lymphoma (HL). A recent study (Steidl et al 2010) demonstrated that increased number of CD68+ tumor-associated macrophages was correlated with adverse survival in HL. Moreover the result of the early FDG-PET assessment after the first 2 courses of chemotherapy (early PET) is a major prognostic criterion in treatment of HL. The purpose of this study was to evaluate the relationship between CD68 expression and: 1) The clinical outcome in general practice for all patients treated for HL, 2) The results of initial and early PET. Patients and methods: Our retrospective study included 151 patients (pts) initially diagnosed and treated at our center from February 1995 to March 2011 and who had a formalin-fixed paraffin-embedded lymph node biopsy available. The slides were stained for CD68 by a single pathologist (MDC) using the PG-M1 antibody (Dako®) and analyzed by immunochemistry. CD68 staining was scored 1: CD68+ cells & lt; 5%, 2: CD68+ cells from 5% to 25% and 3: CD68+ cells & gt;25% relative to overall cellularity. FDG-PET is available in our center since 1999. A total of 100 pts (66%) had initial evaluation and follow up by FDG-PET. Clinical and laboratory data available on presentation and follow-up were recorded. Sex ratio was 1.16, median age was 39 years [18–85], histological subtypes in WHO classification were nodular sclerosis in 123 pts (81.46%), mixed cellularity in 21 (13.91%), lymphocyte-rich in 6 (3.97%), lymphocyte-depleted in 1 (0.66%). The Ann Arbor Stage was I-II in 78 pts (52%), and III-IV in 73 (48%). B symptoms were present in 68 pts (45%). Treatment protocols were as follows: ABVD in 100 pts (66.22%), MOPP/ABV in 26 (17.22%), BEACOPP in 8 (5.30%), ABVD-like in 8 (5.30%), other in 9 (6%). Additional radiotherapy was performed in 76 pts (50%). Mean follow-up was 75.6 months [1.87–194.5] . Results: The CD68 percentage was: group 1: & lt;5% in 49 pts (32.45%); group 2: 5 to 25% in 67 (44.37%); group 3: & gt;25% in 35 (23.17%). We found like Steidl a correlation between progression free survival (PFS) and initial tumor CD68 expression in accordance with the 3 groups. Group 1: Median PFS not reached, PFS at 5 years=79.8%, group 2: median PFS not reached, PFS at 5 years=69.4%, group 3: median PFS=52.5 month, PFS at 5 years=39.5 % (p & lt;0.0068). Overall survival (OS) was not statistically different (p= 0.77) using these 3 groups, but it was the case when we mixed groups 1 and 2 (0 to 25% CD68+cells) compared to group 3 ( & gt;25%) for OS (p=0.0247) and for PFS (p=0.0026). Thus, these 2 groups with CD68 low (CD68≤25%) and CD68 high (CD68 & gt;25%) were used for the other statistical analysis. There was a correlation between B symptoms and CD68 expression (63% in the CD68 high group versus 40% in the CD68 low group) (p=0.016). We also found a correlation between the Ann Arbor stage and CD68 expression. Indeed, CD68 was high in 71% of pts in the stage III-IV versus 29% in the stage I-II (p=0.0016). FDG-TEP SUV-max and SUV-mean calculation is available since September 2007 (n=58). We did not find any correlation between CD68 and initial pre-therapeutic SUV-max or SUV-mean (Anova test). Furthermore, no correlation exists between CD68 and erythrocyte sedimentation rate (ESR). Since 2004, pts have an early PET. In the 62 pts assessed to date, the rate of FDG-PET positive was significantly higher after two treatments in pts CD 68 high (9 PET+/14=64%) compared to pts CD68 low (13PET+/48=27%) (p & lt;0.012). Combining CD68 low and early negative PET (35 pts/62=56%) allowed us to define a very good prognosis group with a 100% OS and an 80% PFS with a median follow up of 31.12 months whatever the initial stage was. Conclusion: We found a strong correlation between initial Ann Arbor stages and CD68 expression. We also observe a correlation between CD68 expression and B symptoms at diagnosis. We confirm the experience of Steidl with adverse outcomes (PFS) when number of CD68 is increased. In our experience there are a worse PFS and OS when CD68 cells are & gt;25% independently from initial clinical presentation. Our results show a strong correlation between CD68 expression and the results of early PET with an excellent PFS for the CD68 low/early PET negative group. The prognostic relevance of CD 68+ tumor-associated macrophages in HL should be validated prospectively to contribute in combination with FDG-PET to a better risk stratification of pts to adapted treatment in classical HL. Disclosures: No relevant conflicts of interest to declare.

Abstract: Background: About 15-20% of patients with early-stage unfavorable Hodgkin lymphoma (HL) relapse or are refractory to first-line treatment with combined modality therapies. Early assessment of metabolic response after 2 cycles of ABVD has been shown to be an accurate predictor of progression-free survival and overall survival. Brentuximab vedotin (BV) in combination with AVD chemotherapy (BV-AVD) has demonstrated a promising efficacy with a favorable safety profile in a phase I trial for treatment-naive patients (Younes A. et al, Lancet Oncol 2013). Based on these results, we conducted a randomized, multicentric, phase II trial in order to improve the PET response rate after 2 cycles with BV-AVD regimen for previously untreated, early-stage unfavorable Hodgkin lymphoma. Methods: Patients with previously untreated, stage I/II, HL and unfavorable EORTC/LYSA criteria (defined with at least one of the following: age ≥ 50 y, bulky mediastinal mass with mediastinum / thorax ratio ≥ 0.35, number of involved nodal areas ≥ 4, ESR ≥ 50mm/h or ≥ 30mm/h with B symptoms) were enrolled at the time of diagnosis. Patients were randomly assigned in a 2:1 ratio to receive 4 cycles of BV-AVD (experimental arm) or ABVD (standard arm), followed by 30Gy involved node radiation therapy (INRT). The primary objective was to evaluate the efficacy of the BV-AVD regimen, as measured by negative-PET rate after 2 cycles based on central review. PET was interpreted according to the Deauville 5-point scale with negative PET defined as Deauville 1-3. Patients with missing PET evaluation, whatever the reason, were considered as non-responders. The statistical hypothesis was based on an increase of 10% (from 75% to 85%) of the PET negativity rate after 2 cycles in the experimental arm. The standard arm was added in order to ensure that the hypothesis taken in the sample size evaluation (negative-PET rate after 2 cycles of ABVD ≤ 75%) was verified. If ≥ 93 patients out of 113 evaluable patients had negative-PET, the hypothesis that the negative-PET rate ≤ 75% in the experimental arm would be rejected. This planned analysis of the primary endpoint was performed by intention to treat (ClinicalTrials.gov registration: NCT02292979). Results: From March 2015 to October 2016, 170 patients were included, 113 were randomized in the BV-AVD arm and 57 in the ABVD arm. Median age at randomization was 29 y (range 18-60) and 51% were female. The median number of involved nodal areas was 3 and 92% of the patients were Ann Arbor stage II, 57% had a bulky disease and 40% had B symptoms. After 2 cycles of treatment, 93/113 patients (82.3%, 95% CI 75.3-88.0) and 43/57 (75.4%, 95% CI 64.3-84.5) achieved a negative-PET based on central review in the experimental and standard arms, respectively. With the lower bound of the 95% confidence interval superior to 75% in the experimental arm, the primary objective can be considered to be met. During the first 2 cycles, grade 3-4 adverse events (AEs) were documented in 74% of the patients in the BV-AVD arm and 56% in the ABVD arm. The most frequent grade 3-4 AEs in the experimental arm were neutropenia (64%), leucopenia (31%), gastro-intestinal disorders (8%), febrile neutropenia (7%), transaminases increased (4%) and infections (4%). Only 2 patients (2%) have developed a grade 3-4 peripheral neuropathy after the first 2 cycles of BV-AVD. No pulmonary toxicity has been observed. Grade 3-4 serious AEs (SAEs) were documented in 19% of the patients in the experimental arm (treatment-related SAEs in 17%) and 7% in the standard arm. SAEs have led to permanent BV discontinuation in 7/113 (6%) patients during the first 2 cycles. Reasons for permanent BV discontinuation were loss of weight, hyponatremia, febrile neutropenia, epileptic seizure, peripheral neuropathy, hepatitis and cutaneous rash. Conclusion: This randomized, multicentric, open-label phase II trial aimed to evaluate the efficacy of BV in combination with AVD chemotherapy based on PET response after 2 cycles for previously untreated, unfavorable early-stage HL. The primary objective was met with an improvement of the negative-PET rate with BV-AVD regimen. This first analysis highlighted an increased toxicity with BV-AVD regimen compared to ABVD, with a higher rate of grade 3-4 AEs and SAEs during the first 2 cycles of treatment. Disclosures Fornecker: BMS: Honoraria; Servier: Honoraria; Gilead: Honoraria; Roche: Honoraria; Takeda: Honoraria. Aurer: takeda: Honoraria, Research Funding. Bonnet: Takeda: Other: advisory board. Perrot: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Amgen: Honoraria. Specht: Takeda: Other: advisory board. Touati: Takeda: Honoraria. Stamatoullas: Takeda: Consultancy; Celgene Corporation: Honoraria. Lugtenburg: Takeda: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Servier: Honoraria; Celgene: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Federico: takeda: Honoraria, Research Funding. Andre: Takeda: Honoraria, Other: Advisory board, Research Funding.

Abstract: Introduction: X-linked sideroblastic anemia (XLSA), a rare disease characterized by an inherited microcytic and hypochromic anemia with high ferritin serum level and dyserythropoiesis with ring sideroblasts in bone marrow (BM), caused by mutations in the erythroid-specific 5-aminolevulinic acid synthase (ALAS2) gene located in the X chromosome is usually diagnosed in the early age. Anemia is often mild and well tolerated with variable response to pyridoxine treatment. The evolution can be dominated by iron overload due to hyperabsorption of iron and transfusional uptake. We report 3 adult cases, diagnosed after 30 years old, of XLSA transfusion free with iron overload. Case 1: A 34 y-old man, was seen in 2005 for a microcytic anemia and high ferritin serum, hemoglobin (Hb) 10.4 g/dl, MCV 70 fl and MCH 20.9 pg, dyserythropoiesis with 36% of ring sideroblasts (RS) on BM, ferritin serum level 2284 ng/ml (N: 30–300), transferrin sat 93% (N: 17–40). The hepatic MRI revealed a major iron overload at 350 μmol/g (N 〈 36) confirmed by biopsy showing a slight liver fibrosis. Molecular analysis of ALAS2 gene demonstrates a p.Arg452Gly mutation. Pyridoxine treatment and phlebotomy allowed a correction of anemia and reduction of the S-ferritin (371 ng/ml). Case 2: The family investigation of case 1 detect an affected first cousin, a 38 y-old man with Hb 12.9 g/dl, MCV 77 fl and MCH 25 pg, S-ferritin 559 ng/ml and transferrin saturation 91%. BM aspirate showed a dyserythropoiesis with 20% of ring sideroblasts. The molecular analysis of ALAS2 gene found the same mutation. The MRI indicates a marked liver iron overload (150 μmol/g) and elastography measurement (Fibroscan®) no fibrosis. Treatment by pyridoxine and phlebotomy every 2 weeks allowed a favourable outcome. Case 3: a 46 y-old man presented in 1994 a microcytosis without anemia Hb 13,2 g/dl, MCV 68 fl and MCH 22,5 pg, S-ferritin 1000 ng/ml transferrin saturation 63% and dyserythropoiesis with 66% of ring sideroblasts on BM. Treatment by pyridoxine was not efficient and iterative phlebotomies because of asthenia with arthralgies attributed to iron overload, with benefit for the patient. The molecular analysis of ALAS2 gene revealed a p.Arg572His mutation. Comments: Hereditary etiology due to ALAS2 gene mutations is a diagnostic rarely performed in adults, because of his rarity far behind primary acquired myelodysplastic syndromes (RARS) and secondary causes induced by drugs or toxics. The XLSA is the main cause of hereditary SA. More than 30 mutations have been identified. The 3 cases reported are XLSA due to 2 new ALAS2 gene mutations, never reported in the Human Gene Mutation Database. Conclusion: In XLSA with ALAS2 gene mutation, anemia often moderate, well tolerate and often unrecognized. Iron overload appears in this disease without any transfusion. Early diagnosis allows preventing the complications of the iron overload by iterative phlebotomies or by chelators. Pyridoxine treatment is indicated with variable response.