ALBERT

Description: Abstract 2786 Background: LEN is currently the reference treatment of low/int 1 (lower) risk MDS with del 5q, yielding RBC transfusion independence (TI) in two thirds of the cases, with a median RBC-TI duration of 2.2 years. (MDS 003 trial, List, NEJM, 2006). In case of primary or secondary failure of LEN, however combined analysis of MDS 003 and MDS 004 trial showed prognosis to be unfavorable and treatment approaches uncertain. We report results of treatment with AZA in 13 lower risk MDS with del 5q with primary or secondary failure of LEN. Methods: The 13 cases were treated between November 2005 and June 2011 in 10 centers of the Groupe Francophone des Myelodysplasies (GFM). At onset of LEN, median age was 71 years, M/F 0.43, 7 patients (pts) had RAEB 1 and 6 RA, 11 had isolated del 5q and 2 had 1 additional chromosomal abnormality. IPSS was low in 6 and int 1 in 7 patients. The LEN dose was 5mg/d, 10mg/d 3 weeks/4weeks, 10mg/d in 8, 3 and 2 patients, respectively. 11 (85%) patients had achieved RBC-TI, for a median duration of 26.3m (range 5.8–57.3)(secondary failures), while 2 patients had not achieved RBC-TI (primary failures). At onset of AZA, 11 patients had progressed with a change in WHO category (RA to RAEB1, or RAEB 1 to RAEB2) in 8 patients, and/or acquisition of additional chromosomal abnormalities in 9 patients, 5 eventually having complex karyotype, of whom 2 had chromosome 17 abnormality leading to TP53 gene deletion (TP53 mutation analysis is in progress); IPSS was low (n=0), int 1 (n= 3), int 2 (n=2), high (n=8). Prior to onset of AZA, attempts had been made to increase the LEN dose from 5 to 10 mg/d in 2 patients, without success. Results: AZA was administered at the FDA/EMEA approved schedule (75mg/m2/dx7) in 12 pts, and reduced (5 day schedule) in 1 pt. The median number of cycles administered was 6 (range 1–23). Five patients (46%) achieved a response according to IWG 2006 criteria, including CR, PR, HI in 1, 0 and 4 pts respectively. All 5 responders achieved RBC –TI. 4 patients received less than 4 cycles of AZA: 2 stopped AZA after 1 cycle for hematological toxicity, 1 stopped after 3 cycles for progression, 1 pt died from septic shock after 3 cycles. Response duration was 2.9+, 4.4+, 6.2+, 13.8, and 24.6 months, respectively. No responder was allografted, but the age of responders was 68, 70, 78, 78 and 86 years, respectively. Median survival from onset of AZA was 8.8 m (range 0.8–24.9). The 5 responders were still alive 3+, 4.4+, 6.2+, 13.9+ and 24.8+ m after onset of AZA, while median survival in non-responders was 8.7 months. Among the 5 patients who responded to AZA, 4 had at onset of AZA a high IPSS, 3 had complex karyotype and 2 one additional chromosomal abn, while 4/5 had previously achieved RBC-TI with LEN (with a median duration of 26.1 months). Neither of the 2 patients with TP53 deletion responded to AZA. Finally, among the 2 primary failures to Lenalidomide, one achieved HI with AZA (of 4.4+ months duration) and the other died within 2 months. Conclusion: In this relatively small series almost 40% of the patients with lower risk MDS and del 5q who progressed under LEN could be salvaged by AZA, and might expect survival prolongation. The appearance of novel chromosomal abnormalities or complex karyotype at progression did not predict poor response to AZA, while we are currently analyzing the prognostic value of TP 53 mutations, which occur frequently at th at disease stage (Jadersten, JCO 2011), on response to AZA. Disclosures: Fenaux: Celgene: Honoraria, Research Funding.

Description: Abstract 189 In frail elderly patients, the low warfarin maintenance dose requirements and high risk of thrombosis and bleeding raise specific challenges, especially at treatment initiation. Because of a narrow therapeutic index and a marked interindividual variability in dosage requirements, warfarin induction doses must be tailored to individual and disease-specific factors. The aim of our multicenter study was to investigate whether VKORC1 and CYP2C9 genotypes helped to predict the warfarin maintenance dose when added to demographic, clinical data and INR values prospectively collected at baseline and during warfarin induction. In a cohort of elderly inpatients, we developed clinical and pharmacogenetic models and evaluated their accuracy in predicting the warfarin maintenance dose comparatively to the accuracy of a dosing algorithm based solely on INR values. The derivation sample consisted in 115 Caucasian inpatients (mean age, 86 years), all initiated using the same warfarin induction protocol designed for the elderly (Siguret, Am J Med 2005, Gouin-Thibault J Am Geriatr Soc 2010): INR was measured at baseline, the day after three 4-mg warfarin intake (Day 3) (INR3) and on Day 6±1: their values allowed to adjust the dose according to the algorithm. The actual daily warfarin maintenance dose was defined as the amount of warfarin required to achieve a stable INR in the 2.0–3.0 range in two consecutive samples at least 48–72 h apart, in the absence of dosage changes within the previous 4 days. At baseline, the clinical model failed to accurately predict the maintenance dose (R2

Description: Laboratory workup of the cause of anemia requires clinical staff to develop a differential diagnosis based on routine CBC parameters and to subsequently order confirmatory tests. The number of parameters to be reviewed and the complexity of calculations which are performed by individuals on a routine basis is necessarily limited. The wealth of information in the many novel parameters and the complex patterns provided by modern hematology analyzers are frequently not utilized in routine clinical care. The use of computers for pre-classification of common RBC disorders would provide immediate information to order reflex confirmatory tests on the first sample, thereby improving patient care and allowing significant cost savings. Eleven European sites collected 2,303 data files from hematologically normal patients and individuals diagnosed with at least one of 36 RBC disorders. Samples were run on the ADVIA 120 Hematology System (Bayer HealthCare LLC, Diagnostics Division, Tarrytown, NY), an automated cell counter used in routine clinical hematology laboratories worldwide. Based on their representation within this database, a subset of 5 diseases (β-thalassemia heterozygote, β-thalassemia homozygote, Hb S homozygote, Hb SC, and hereditary spherocytosis; n=779 samples) and 123 normal cases were selected and used to develop a neural-network based computer program, the Computer Assisted RBC Disorder (CARD) Classification tool. The CARD utilizes hundreds of routine and novel CBC, differential and reticulocyte parameters available from the ADVIA 120 and 2120 Hematology Systems to determine possible causes of a patient’s anemia. We evaluated the CARD by using it to classify 273 new cases from 9 worldwide centers. The program correctly identified 93% of the cases. The majority of misidentifications were due to normal cases being classified as abnormal. 2 Hb S homozygote and one β-thalassemia heterozygote samples were misidentified as Hb SC. Only 2 of 137 abnormal cases, which were β-thalassemia heterozygote, were misclassified as normal. The performance of the tool for the presence of any hemoglobinopathy/thalassemia investigated was: sensitivity: 99%; specificity: 90%; PPV: 90%, NPV: 98%. This neural network-based computer program has demonstrated excellent performance with a validation set of samples and demonstrates the potential for using information from automated hematology analyzers to screen for the presence of certain hemoglobinopathies and to provide real-time information to direct an anemia workup. CARD TOOL ACCURACY # Correct # Incorrect Normal 122 14 β-Thalassemia Heterozygote 99 3 β-Thalassemia Homozygote 18 0 Hb S Homozygote 11 2 Hb SC 2 0 Hereditary Spherocytosis 2 0 TOTAL 254 (93%) 19 (7%)

Description: Abstract 2814 Purpose: ESA are generally the first line treatment of anemia of IPSS low and int1 (lower) risk MDS. While endogenous EPO level and RBC transfusion requirement are well defined prognostic factors of response to ESA (Hellstrom, BJH 2003), many patients (pts) are treated before they require RBC transfusions and, in a GFM large cohort of lower risk MDS with anemia, baseline EPO level was below 500U/l in 88% of the cases (Kelaidi, Haematologica 2010). In non transfusion dependent (non TD) lower risk MDS, it is therefore important to find additional simple prognostic factors of response to ESA. In a joint study of the French (GFM) and Italian (FISM) MDS groups, we retrospectively assessed prognostic factors of response to ESA in non TD lower risk MDS. Particular emphasis was put on the prognostic value of marrow dysplastic features on ESA response, suggested in a previous work (Howe, Blood, 2004). Methods: We are performing a cooperative (GFM and FISM) retrospective study in IPSS low and int 1 (lower risk) MDS diagnosed between 1994 and 2010. The present analysis focused on lower risk MDS with Hb level

Description: Background: Anemia of MDS is common in elderly patients. Recombinant Erythopoietin (EPO) alfa or beta, when used alone, improves anemia in 20 to 30 % of MDS in general population. In older patients with MDS, anemia is usually treated by transfusion supportive regimens. We report the results of a prospective study we conducted on the use of Epoetin Beta in anemic elderly patients with MDS. Patients and Treatment: Inclusion criteria were patient aged 75 years and over with MDS chronic anemia requiring transfusion or Hb 〈 10g/dl exclusion of other causes of anemia. Patients were treated with Epoetin beta 150 IU/ kg x 3/week during at least 8 weeks. In the absence of response, Epoetin beta dose was increased to 300 IU/ kg x 3/week and a new evaluation made after 8 weeks. Response was evaluated based on IWG criteria. In patients responding to Epoetin Beta, intervals between injections were adjusted to maintain Hb levels between 11 and 13g/dl. Seventy five patients (25 men, 50 women), median age 87.7 years (75 – 103), median creatinine clearance (CrCl) 36 ml/min (15 – 86) were included. They were classified as follows, 1 RARS, 54 RCMD, 17 RAEB1, 2 RAEB2, 1 5q- syndrome. There was not statistically significant correlation between pretreatment serum epo level and CrCl. Anemia was associated with neutropenia and/or thrombopenia in 19 patients and required transfusion in 44 patients. Karyotype was not performed in most of the patients. The median interval between onset of anemia and study treatment was 9 months (range 4 – 48). None of the patients had previously received EPO alfa or beta or Darbopoetin. Results: Sixty one of the 75 patients (81 %), including the patient with 5q- syndrome, had major erythroid haematological improvement (EHI) (transfusion independence in formerly transfused patients or rise of at least 2 g/dl of haemoglobin level in formerly non transfused patients). EHI was obtained with Epoetin beta lowest dose in 50/61 patients. No effect was seen on granulocytes and platelets. No side effects were observed. The response rates were 85 %, 68.5 % for RCMD and RAEB, respectively (p=NS). Pretreatment serum epo level was lower in responding patients than in non responding patients (median level 34 and 104 UI/l respectively, p〈 0.05). Response rate was lower in transfused than in non transfused patients (72 and 93 % respectively, p or 〈 to 40 ml/min (88 and 78 % respectively). Median response duration was not reached with a median follow up of 13 months (4 – 36). In responding patients, median adjusted Epoetin Beta dose was 190 IU/kg /week Conclusion: In elderly patients with MDS, EPO appears to be an effective treatment to correct anemia. Our results may be superior to those obtained in general population because of lowest pretreatment serum EPO levels and more frequent low risk MDS in elderly patients. In studies evaluating the effect of EPO on the anemia of MDS patients, response rates should be analyzed according to age especially if old and very old patients are included.

Description: Abstract 172 The “Innohep® in Renal Insufficiency Study” (IRIS) was an international, multicentre, open, randomized, parallel group clinical trial with a primary objective to compare the safety of tinzaparin and unfractionated heparin in terms of clinically relevant bleeding (CRB) in elderly patients with impaired renal function for initial treatment of acute deep vein thrombosis. In the elderly, concerns have been raised about the risk of an accumulation effect and/or overdose due to the renal elimination of low molecular weight heparins (LMWH). In a subset of centres participating in the IRIS study, we conducted a substudy in order to assess whether there was an accumulation of anti-Xa activity and whether there was any relationship between anti-Xa activity and age, weight, creatinine clearance or clinical outcomes in patients treated with tinzaparin (175 IU/kg/24h) for venous thromboembolism. Plasma anti-Xa activity was to be analysed at peak level (4–6 hours after injection) on Day 2 or Day 3 and on Day 5 or at visit S (VS: day of visit at end of SC treatment) using a chromogenic assay (Rotachrom® heparin, Diagnostica Stago®). Of the complete IRIS study population who received tinzaparin (n=268), data from 87 patients (32%) were analysed. The patient characteristics (mean age 83±5 years [75–99 years], mean creatinine clearance (Cockcroft-Gault) 40.8 mL/min (SD 11.7, range 14–59) were consistent with those of the overall population of IRIS study. Of note, 24.1% had severe renal impairment (creatinine clearance 〈 30 mL/min). The mean peak anti-Xa activities, which were 0.86 (SD 0.34) and 0.87 (SD 0.31) IU/mL on Day2/3 and Day5/VS, respectively, were found close to the mean 0.85 IU/mL reported in the literature in patients receiving tinzaparin at therapeutic dose. There was no correlation between the anti-Xa activity and age, weight, or creatinine clearance. There was no significant difference in the anti-Xa levels between patients with, versus those without, severe renal impairment. The mean accumulation ratio (defined as anti-Xa activity on Day5/VS divided by the anti-Xa activity on Day2/3) was 1.06 (SD 0.30, 90% CI:1.01–1.11): as the 90% CI of the accumulation did not exceed the pre-defined upper limit of 1.25, no significant accumulation was detected. The mean anti-Xa activity did not differ significantly between the 8 patients experiencing a CRB during tinzaparin treatment and the 79 who did not experience a CRB during tinzaparin treatment. Among the 8 patients who had a CRB, one had an anti-Xa activity 〉 2.0 IU/mL (considered above therapeutic level) whereas the seven others had anti-Xa 〈 1.5 IU/mL. Interestingly, we found that the mean anti-Xa activities were significantly lower in the 12 patients with infectious disease at baseline compared to the patients without infectious disease: 0.66 (SD 0.18) vs 0.8 (SD 0.35) IU/mL on Day2/3, p=0.007; 0.62 (SD 0.23) vs 0.91 (SD 0.30) IU/mL on Day5/VS, p=0.002). These numbers are small but may require further investigation. There was no statistically significant difference in anti-Xa levels when comparing patients with versus those without ongoing malignancy. In conclusion, an IRIS substudy demonstrated no accumulation of anti-Xa activity in elderly patients with moderate to severe renal impairment receiving unadjusted recommended full dose of tinzaparin and confirms previous pharmacokinetic studies in similar populations. The high proportion of higher molecular weight moieties in tinzaparin may account for reduced dependence on renal elimination of the anti-Xa activity seen in elderly patients with renal impairment. Disclosures: Siguret: Leo-Pharma: this work was supported by a grant from Leo-Pharma. Leizorovicz:GSK: Consultancy. Gouin-Thibault:Leo-Pharma: this work was supported by a grant from Leo-Pharma.

Description: Introduction The utility of D-dimer testing as a screening tool for venous thromboembolism (VTE) exclusion is uncertain in cancer patients, due to low specificity. A new fibrin assay independent of inflammation and hypercoagulability has been recently developed. Methods Non-anticoagulated patients with clinically suspected VTE from the FSET study (NCT02523937) had VTE diagnosed using the standard diagnostic algorithms, including a 3-month clinical follow-up. In all patients, the fibrin assay prototype (Diagnostica Stago) was performed at the time of admission. We divided the patients included in the FSET study in 3 groups: (i) history of cancer, (ii) active cancer (known or unequivocal evidence), and (iii) no cancer. We sought to evaluate the performances of the fibrin assay compared with the D-Dimer or age-adjusted D-Dimer test to exclude VTE in cancer patients. Results Of the 863 included patients, 83 (9.6%) had either a history of cancer (n=30) or an active cancer (known or unequivocal evidence) (n=53). The prevalence of VTE was of 3.3% and 20.7%, respectively, vs 7.6% in non-cancer patients. Patients with a history of cancer had most frequently breast cancer (40%) and genito-urinary cancer (23.3%).Of the 53 patients with active cancer (known or unequivocal evidence), 9.4% had a recurrence, and most patients had metastatic cancers (52.8%). Those patients had most frequently lung cancer (26.4 %) and breast cancer (15.1 %). Overall, 18.9% of patients with known cancer were treated with chemotherapy, 3.7% with immunotherapy and 13.2% with hormonotherapy. In the present study, 9.4% of patients with known active cancer had a high VTE probability vs 2.8% in patients without cancer. Overall, given a high VTE clinical probability score in a substantial number of cancer patients on one hand, and the DDi level most likely above the cut-off value for VTE exclusion in those with a low-to-moderate probability on the other hand, cancer patients required more often imaging to confirm or exclude VTE diagnosis, 68.7% in patients with a history of cancer or with active cancer versus 42.6% in patients without cancer, respectively. The fibrin assay specificity for VTE was highly increased compared to D-Dimer test, associated with a 100% negative predictive value [95% CI 89-100%] and [95% CI 83-100%] respectively in patients with a history of cancer or with active cancer. Fibrin assay allowed ruling out VTE in a much higher proportion of patients compared to the 500 μg/L D-Dimer cut-off / or age-adjusted D-Dimer cut-off strategy, irrespectively of clinical probability assessment: 76.7% vs 40%/60% in patients with a history of cancer, 39.6% vs 17.0%/22.6% in patients with active cancer, 76.7% vs 54.5%/60.9% in non-cancer patients. Conclusion The new fibrin assay demonstrated an increased specificity compared to DDi or age-adjusted cut-off strategy with excellent negative predictive value, resulting in safely excluding more than 25% VTE compared to DDi or more than 15% VTE compared to age-adjusted cut-off in patients with a history or an active cancer; thus reducing imaging testing in these patients, irrespectively of the clinical probability. These promising results require further confirmation in future trials. Disclosures Mahe: Leo Pharma: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Bayer: Speakers Bureau; Pfizer: Speakers Bureau. Meyer:BMS-Pfizer: Other: travel support, Research Funding; Boehringer Ingelheim: Research Funding; LEO pharma: Other: travel support, Research Funding; SANOFI: Other: travel support, Research Funding; Bayer: Other: travel support. Contant:Diagnostica Stago: Employment. Depasse:Diagnostica Stago: Employment.