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Factor XI deficiency is a rare coagulation disorder with variable bleeding manifestations.To evaluate the correlation between the degree of factorXI deficiency and the clinical expression of the disease.Retrospective study, spanning 10 years from January 1, 2010 to December 31, 2019, concerning patients followed at the Hemophilia Center at Aziza Othmana Hospital in Tunis. The data were collected from the medical records. The determination of PT, APTT, fibrinogen level and coagulation factors are performed by coagulometric technique on STA® compact / ACL TOP®. FactorXI deficiency was confirmed on two different samples. Statistical analysis of the clinical-biological correlation was performed using the chi-square test. The significance level was 0.05.Twenty patients were collected. The mean age of discovery was 25 years with a sex ratio (M/F) =0.33. The circumstances of discovery were incidental in 14 patients. A family history of bleeding was reported in 30% of cases. Eight patients underwent surgery, six of whom had a simple postoperative course. The APTT was prolonged and isolated in 75% of cases. The hemostasis test was normal in 5 cases. The average FactorXI level was 24%. The tendency to bleed did not seem to be correlated with FactorXI levels.Prospective multicenter studies including molecular study would be necessary to better elucidate this rare disorder.

Summary Background In the LYM-3002 study, the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were compared in transplant-ineligible patients with untreated, newly diagnosed, mantle cell lymphoma. We report the final overall survival and safety outcomes for patients in the long-term follow-up phase after the primary progression-free-survival endpoint was met. Methods LYM-3002 was a randomised, open-label, phase 3 study done at 128 clinical centres in 28 countries in Asia, Europe, North America, and South America. Adult patients with confirmed stage II–IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomisation was done according to a computer-generated randomisation schedule prepared by the sponsor; permuted blocks central randomisation was used (block size of 4), and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00722137 , and is closed to new participants with follow-up completed. Findings Between May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1–94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51–0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease. Interpretations Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma. Funding Janssen Research & Development.

Background: The Glanzmann’s thrombasthenia (GT) is a rare autosomal-recessive bleeding disorder with uncommon neonatal revelation. It is due to abnormalities of quantitative and/or qualitative α IIb β 3 integrin. This cell adhesion receptor is essential for platelet aggregation and allows the formation of a hemostatic plug if the vessel is damaged by injury. The clinical picture of GT is variable, with mucocutaneous bleeding due to non-functional platelets. Management requires a good expertise in bleeding disorders. We describe the clinical and the epidemiological data of GT in Aziza Othmana Hospital Hemophilia Center. Methods: This was a retrospective study of all patients with GT monitored and treated in our hemophilia center during the period of 2011 - 2015. Results: Twenty-seven patients among the 35 patients included in our hemophilia center registry were studied. The most common sign encountered is the gingival bleeding. In our women cohort, one completed her pregnancy. The consanguinity is present with a frequency of 62%. Treatments used depending on the case are tranexamic acid, platelet transfusion, packed red blood cells and rFVIIa, respectively. Conclusion: GT is relatively frequent in Tunisia and especially in the North of the country which can be explained by the high consanguinity in our population. J Hematol. 2017;6(2-3):44-48 doi: https://doi.org/10.14740/jh330e

International audience; Data are limited in developing countries regarding the clinicopathologic features and response to therapy of chronic myeloid leukemia (CML) in the era of imatinib (IM). The objective of this study is to report on the clinicoepidemiologic features of CML in Tunisia, to evaluate the long-term outcome of patients in chronic (CP) or accelerated phase (AP) treated with IM 400 mg daily as frontline therapy, and to determine imatinib's efficacy and safety. From October 2002 to December 2014, 410 CML patients were treated with IM in six Tunisian departments of hematology. Response (hematologic, cytogenetic, and molecular responses) and outcome-overall survival (OS), event-free survival (EFS), and progression-free survival (PFS)-were evaluated. The following prognostic factors were analyzed for their impact on the European leukemia net (ELN) response, OS, EFS, and PFS at 5 years: age, sex, leukocyte count, Sokal score, European Treatment and Outcome Study (EUTOS) score, CML phase, time to starting IM, and impact of adverse events. The median age was 45 years (3-85 years). Two hundred ten (51.2%) patients were male. Splenomegaly was present in 322 of the 410 (79%). Additional cytogenetic abnormalities were encountered in 25 (6.3%) patients. At diagnosis, 379 (92.4%) patients were in CP, 31 (7.6%) were in AP. The Sokal risk was low in 87 (22.5%), intermediate in 138 (35.7%), and high in 164 patients (41.9%). The EUTOS risk was low in 217 (74%), and high in 77 (26%) patients. The rates of cumulative complete cytogenetic response (CCyR), major molecular response (MMR), and molecular response 4/5 log (MR4.5) in CP/AP-CML patients were 72, 68.4, and 46.4%, respectively. The median time to reach CCyR, MMR, and MR4.5 was 6 months (3-51), 18 months (3-72), and 24 months (3-100), respectively. According to the ELN criteria, optimal, suboptimal response, and failure were noted in 206 (51.8%), 61 (15.3%), and 125 (31.4%) patients, respectively. Five-year event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) were 81, 90, and 90%, respectively. By multivariate analysis, AP, high EUTOS risk, and baseline WBC ≥ 150G/l remained independent predictive factors of non-optimal response to IM. The adverse events (AE) of IM were moderate and tolerable. With the caveats that the monitoring of the disease was not optimal, response rates were similar to those reported in previous studies. It is clear to us that improvements should be made in treatment of AP-CML and high Sokal risk group of CP-CML. The frontline use of second-generation tyrosine kinase inhibitor (TKI) is expected to improve the results of the first-line treatment of these high-risk Tunisian patients, but cost and accessibility of this therapy remain the problems in developing countries.

MABLE investigated the efficacy and safety of rituximab plus bendamustine or rituximab plus chlorambucil in fludarabine-ineligible patients with chronic lymphocytic leukemia. Patients received rituximab plus bendamustine or rituximab plus chlorambucil every four weeks for six cycles. Rituximab plus chlorambucil-treated patients without a complete response after Cycle 6 received chlorambucil monotherapy for at least six additional cycles or until complete response. The primary endpoint was complete response rate (confirmed by bone marrow biopsy) after Cycle 6 in first-line patients. Secondary endpoints included progression-free survival, overall survival, minimal residual disease, and safety. Overall, 357 patients were randomized (rituximab plus bendamustine, n=178; rituximab plus chlorambucil, n=179; intent-to-treat population), including 241 first-line patients (n=121 and n=120, respectively); 355 patients received treatment (n=177 and n=178, respectively; safety population). In first-line patients, complete response rate after Cycle 6 (rituximab plus bendamustine, 24%; rituximab plus chlorambucil, 9%; P=0.002) and median progression-free survival (rituximab plus bendamustine, 40 months; rituximab plus chlorambucil, 30 months; P=0.003) were higher with rituximab plus bendamustine than rituximab plus chlorambucil. Overall response rate and overall survival were not different. In first-line patients with a complete response, minimal residual disease-negativity was higher with rituximab plus bendamustine than rituximab plus chlorambucil (66% vs. 36%). Overall adverse event incidence was similar (rituximab plus bendamustine, 98%; rituximab plus chlorambucil, 97%). Rituximab plus bendamustine may be a valuable first-line option for fludarabine-ineligible patients with chronic lymphocytic leukemia. clinicaltrials.gov identifier: 01056510

Primary non-Hodgkin's lymphoma of the adrenal gland is rare. We report the case of a 56-year-old patient suffering from B symptoms. The CT scan showed a bilateral adrenal mass without any lymph nodes. Scan-guided biopsies led to the diagnosis of diffuse large B-cell lymphoma. The medullar biopsy eliminated a secondary lymphoma. The patient was treated by immunochemotherapy with a complete response before autologous stem cell transplantation.Adrenal bezin Hodgkin dışı lenfoması nadirdir. Burada B semptomları ile başvuran 56 yaşında bir olgu bildirilmektedir. Bilgisayarlı tomografide bilateral adrenal kütle saptandı. Eşlik eden patolojik büyüklükte lenfadenopati görülmedi. Görüntüleme eşliğinde yapılan biyopsiler ile diffüz büyük B hücreli lenfoma tanısı kondu. Kemik iliği biyopsisi sekonder lenfoma tanısını dışladı. Hastada immunokemoterapi uygulaması ile otolog kök hücre nakli öncesinde tam yanıt sağlandı.

Pseudomonas is a clinically significant and opportunist pathogen, usually associated in causing high mortality nosocomial infections. The aim of this study was to determine the risk factors associated with septic shock in patients diagnosed with hematologic malignancies and Pseudomonas infections. A total of 80 Pseudomonas isolates (77 Pseudomonas aeruginosa) were collected from 66 patients aged 2-64 years: 52 with acute leukemia (79%), 7 with lymphoma (10.5%), and 7 with other hematologic disorders (10.5%), between 2001 and 2009. The median age of the patients was 30 years. Isolates were collected mostly from bloodstreams (45%) and skin lesions (31.5%). The median time for microbiologic documentation was 8 days (range 0-35 days) from onset of neutropenia. At least 11 patients (16.6%) had recurrent (≥2) infections. The clinical symptoms observed were skin lesions (34%), diarrhea (20%), isolated fever (18%), and respiratory symptoms (14%). The isolates tested were found resistant to piperacillin/tazobactam (43%), ceftazidime (31%), imipenem-cilastatin (26%), ciprofloxacin (25%), and amikacin (26%). Septic shock occurred in 16.2% of episodes (13/80). Crude mortality due to septic shock occurred in 19.6% of patients (13/66). The median time for response to antibiotic therapy in the remaining 80.4% of patients (53/66) was 2.5 days. Univariate analysis revealed that factors associated with septic shock were: fever for ≥3 days in patients on antibiotic therapy (P = 0.019), serum lactate5 mmol (P = 0.05), hemoglobin level50 g/l (P = 0.042), hypoproteinemia50 g/l (P = 0.01), procalcitonin10 ng/ml (P = 0.031), and hypophosphatemia (P = 0.001). Multivariate analysis revealed that hypophosphatemia (P = 0.018), hypoproteinemia (P = 0.028), and high serum lactate (P = 0.012) are significant factors, independently associated with increased risk of septic shock in patients with hematologic malignancies and Pseudomonas infections.

Acute promyelocytic leukemia (APL) has now become the most curable of all subtypes of acute myeloid leukemia. A cure rate of 75-80% can be anticipated with a combination of all-trans retinoic acid (ATRA) and anthracyclines. In Tunisia, the ATRA era began in 1998 with the use, consecutively, of two regimens of a combination of ATRA with anthracycline and cytarabine (APL93), and without cytarabine (LPA99). From 2004, 39 patients with confirmed APL either by t(15;17) or PML/RARA were treated by the PETHEMA LPA 99 trial. The rationale of this protocol by avoiding cytarabine is to reduce death in complete remission (CR) without increasing the incidence of relapse. Thirty-three patients achieved CR (84.6%). The remaining six patients were considered as failure due to early death: three caused by differentiation syndrome (DS) and three died from central nervous system hemorrhage. Baseline blood cell count (WBC) >10 x 10(9)/l (P=0.26) and creatinine >1.4 mg/dl (P=0.42) were not predictive of mortality. DS was observed in 11 patients (30.5%) with a median onset time of 12 days (range: 3-23 days) and median WBC of 29 x 10(9)/L (range: 1.2 x 10(9)-82.7 x 10(9)/l). DS was severe in seven cases, moderate in four, and fatal in three cases. Body mass index > or =30 (P=0.044) and baseline WBC > or =20 x 10(9)/l (P=0.025) are independent predictors of DS. The median follow-up of this study is 36 months. Thirty patients are alive in continuous complete remission; two patients died in CR from septic shock and secondary myelodysplastic syndrome respectively; one patient died 47 months after achieving two relapses. Event free survival from diagnosis was 80% and overall survival was 82%. Our results are quite acceptable and can be improved by reducing mortality rate.

Severe sepsis defined as infection-induced organ dysfunction or hypoperfusion abnormalities predispose to septic shock and increased mortality in neutropenic setting. We aimed at determining predictors of severe sepsis in neutropenic patients. Between 1 October and 31 December 2007, 41 patients (21 with acute myeloid leukemia, 19 with acute lymphoid leukemia and one with autologous stem cell transplantation for a mantle cell lymphoma) with chemotherapy-induced neutropenia (

The combination of all-trans-retinoic acid (ATRA) and chemotherapy has made acute promyelocytic leukemia (APL) a highly curable leukemia. However, several complications are reported with this treatment the most serious and life threatening being Retinoic Acid Syndrome (RAS). We aimed at identifying factors that could predict complications caused by ATRA during induction treatment of APL.Forty-two patients with confirmed APL (by t(15;17) and/or PML/RARA) treated at our institution (University hospital of Tunis) between January 1998 and June 2006 using two consecutive protocols: European APL93 trial (24 patients) until February 2004 and Spanish PETHEMA LPA99 trial (18 patients) more recently. Induction regimen consisted of ATRA 45 mg/m(2)/d until CR combined to DNR 60 mg/m(2)/d x 3+Cytarabine 200 mg/m(2)/d x 7 (APL93) and Idarubicin 12 mg/m(2) d2, 4, 6, 8 (LPA99). Prednisone (0.5 mg/kg d1-d15) was added if WBC10 x 10(9)/L to prevent RAS in LPA 99.Median age was 36 yr (7-64 yr), M/F=16/26 (0.61), median WBC was 2.4 x 10(9)/L (range 0.6-100 x 10(9)/L). WBC10 x 10(9)/L was noted in 14 patients (33%). Additional cytogenetic abnormalities were seen in 12/42 (28%). Median body mass index (BMI=weight/height(2):N 20-25) was 24 kg/m(2) (range 16-40 kg/m(2)), BMI30 was noted in nine patients (8F and 1M). Thirty-three patients achieved CR (78.57%):18/24 (75%) in APL93 versus 15/18 (83%) in LPA99. Nine patients (21.42%) had early death. Causes of early death were: RAS (6) and CNS hemorrhage (3). Complications due to ATRA were: RAS (10), Scrotal ulcerations (3), Sweet syndrome (2), Perineal ulcerations (1), and Pseudotumor cerebri (1). Prognostic factors for complications of ATRA (Fisher exact test) were: BMI35 (p=0.055), induction treatment without cytarabine (LPA99 trial) (p=0.047), whereas age (p=0.74), gender (p=0.51), initial WBC (p=0.47), and additional cytogenetic abnormalities (p=0.83) were not predictive. Retinoic Acid Syndrome was more reported in patients with initial WBC10 x 10(9)/L (p=0.08).We found high BMI (35) in female and treatment without Cytarabine to increase the risk of developing complications with ATRA.

Background: High dose Melphalan (HDM) and autologous stem cell transplantation (ASCT) is a standard care for Myeloma ≤ 65 years. Studies have demonstrated that depth of response prior to ASCT does not impact outcome post ASCT, e.g. solely depth of response post ASCT matters. However, with improving induction regimens, the questions remains whether patients achieving a deeper response at completion of induction would not perform better post ASCT. ASCT can only be performed in Tunisia if newly diagnosed Multiple Myeloma (NDMM) achieves at least PR; we therefore sought to report the national Tunisian experience. Patients and Methods: NDMM aged ≤65 years received three cycles of Thalidomide (200mg daily) and Dexamethasone, followed by HDM and ASCT.52% received maintenance therapy for 12 months with Thalidomide, from 3 months post transplantation. Non responders to TD induction were salvaged with Lenalidomide or Bortezomib-based regimen. The response was assessed based on IMWG response criteria. The study is performed in ITT. Results: 202 consecutive pts were included between April 2012 and December 2014. The median age was 56 yrs (range, 25-65), sex ratio was 1.R-ISS stage was 3 in 27.5%. 21% had high risk cytogenetic (by Conventional karyotyping and FISH). Renal failure was observed in 17%. ORR after induction was 71% with 12% CR, 17% VGPR. 22% failed to obtain PR following TD induction, and 51% of whom received salvage induction therapy (ST) with 72% that further reached ≥PR after ST. Overall, 141 pts (70%) underwent ASCT, 121 of whom had evidence of chemo-sensitive MM at completion of induction. 16% were transplanted in CR, 22% in VGPR and 62% in PR. At 3 months post-ASCT, the ORR in induction chemo-sensitive MM was 89%: 36% CR, 20% VGPR, and 33% PR. With a median follow-up post-ASCT of 27 months, the OS, PFS and EFS at 27 months were 82%, 60.5% and 56%, respectively. Maintenance treatment was significantly associated with longer PFS only in MM who did not achieve CR (29 versus 9 months, p=0.004). MM with improved response post-ASCT had a significantly longer PFS (39 versus 21 months, p=0.003) and EFS (39 versus 20 months, p=0.002). Importantly, achieving CR before (p=0.03) and after ASCT (p In multivariate analysis, ISS stage 3 was the sole independent predictor of induction failure (p=0.003). Importantly, predictive factors of achievement of CR post-ASCT comprised absence of delay farther to 4 months from completion of induction (p=0.006; OR = 4.54) and achievement of at least VGPR status before transplant (p=0,001; OR = 4.09). Conclusion: Achievement of at least VGPR at completion of induction improved response after ASCT and consequently influenced the post-ASCT outcome. Therefore, depth of response matters before and after ASCT, and validates in some extent the concept of induction salvage therapy prior to ASCT for patient not reaching response. Disclosures Leleu: TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

Introduction: ITP, characterized by a reduction in platelets leading to thrombocytopenia, which persists for >12 months is considered chronic (cITP). Eltrombopag is an oral thrombopoietin receptor agonist approved for treatment of patients with cITP aged ≥1 year refractory to other treatments (eg corticosteroids, immunoglobulins). The recently completed Phase III EXTEND (Eltrombopag eXTENded Dosing) study was a global, open-label, extension study of patients with cITP, who received eltrombopag or placebo in prior eltrombopag clinical studies. The primary objective of EXTEND was to describe the long-term safety and tolerability of eltrombopag treatment in these patients. Here, we examine the occurrence of hepatobiliary and thromboembolic events (TEEs) as adverse events (AEs) of special interest in this study. Methods :Adult patients (≥18 years old) diagnosed with cITP according to ASH/BCSH guidelines were enrolled and received eltrombopag starting at 50 mg/day. Dose was titrated to 25-75 mg per day or less often as required, based on individual platelet count responses (targeted range ≥50-200x109/L). Patients who received 2 years of treatment and transitioned off eltrombopag due to commercial availability of eltrombopag were considered to have completed the study, whether or not they continued treatment with eltrombopag. The primary endpoint included detection and documentation of investigator-reported AEs, which included hepatobiliary AEs and TEEs. Analyses were conducted using the safety population, defined as all subjects who entered the study and had taken at least one dose of the study medication. Results:302 patients were enrolled and received at least one dose of eltrombopag: 67% were female; 38% splenectomized; 49% aged 18-49 years. Median duration of exposure was 2.4 years (range, 2 days to 8.8 years) and mean average daily dose was 50.2 (range, 1-75) mg/day. Overall, 259/302 (86%) achieved platelet counts of ≥50×109/L at least once during the study and 126/248 (51%) patients maintained continuous platelet counts ≥50×109/L for at least 31 weeks. Incidence of bleeding symptoms (WHO grades 1-4) generally decreased over time in patients with available data, from 57% (n=171/302) at baseline to 16% at 1 year (n=13/80), and 21% (12/58) at 2 years. 45 (15%) patients experienced at least one hepatobiliary AE, with the highest incidence within the first year of treatment (Figure A). AEs of increased ALT or AST led to the discontinuation of five and three patients, respectively and four patients discontinued due to an AE of increased blood bilirubin. Nine patients experienced ALT and/or AST >3 x upper limit of normal (ULN) and total bilirubin >1.5xULN. 19 (6.3%) patients experienced a total of 23 TEEs. Most events occurred in the first year (Figure B), and none after year 4. TEEs included deep vein thrombosis (n=6), cerebral infarction (stroke) [n=3], myocardial infarction (n=4), transient ischemic attack (n=2), others (n=8, 1 occurrence of each). A clear association with elevated platelet counts was not observed. Platelets >200x109/L at the time of the TEE were recorded in 8/19 patients; 6/19 experienced the TEE at or shortly after achieving their maximum platelet count. In total, 10 patients discontinued because of TEEs. Conclusions: Long-term treatment with eltrombopag in patients with cITP led to sustained platelet increases and reduced bleeding symptoms. The highest incidences of hepatobiliary AEs and TEEs occurred during the first year of treatment, though several events were recorded after 3 years of therapy. Long-term eltrombopag therapy was well-tolerated with a positive benefit-risk relationship in adults with cITP, with decreasing events after the first year of treatment. Disclosures Saleh: GSK: Consultancy, Research Funding, Speakers Bureau. Bussel:Amgen, Novartis & GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingleheim, Prophylix Pharma, Protalex, Rigel Pharmaceuticals: Research Funding; Momenta Pharmaceuticals, Novartis, Prophylix Pharma, Protalex, Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; UptoDate: Patents & Royalties; Physicians Education Resource: Speakers Bureau. Wong:Bayer, Biogen-Idec and Novartis: Consultancy; Bayer, Biogen-Idec, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, and Roche: Research Funding; Biogen-Idec and Novartis: Membership on an entity's Board of Directors or advisory committees. El-Ali:Novartis: Employment. Quebe-Fehling:Novartis: Employment.

Introduction: Eltrombopag is an oral thrombopoietin receptor agonist, approved for the treatment of patients with cITP (persisting >12 months) aged ≥1 year, who are refractory to other treatments (eg corticosteroids, immunoglobulins). Pharmacokinetic studies of eltrombopag have demonstrated that patients of East Asian origin (eg Japanese, Chinese, Taiwanese and Korean) experience increased plasma exposure to eltrombopag compared to non-East Asian patients (predominantly Caucasian). As such, the recommended starting dose is 25 mg/day for East Asian patients, compared with 50 mg/day in non-East Asians. In the EXTEND (Eltrombopag eXTENded Dosing) study, all patients, irrespective of ancestry, received 50 mg/day starting dose that was subsequently adjusted to the platelet response. Unpublished anecdotal reports of platelet responses in East Asian patients from EXTEND describe lower doses of eltrombopag. Here, we examine the responses to eltrombopag in East Asian and non-East Asian patients who completed the EXTEND study. Methods : Adult patients (≥18 years old) diagnosed with cITP who had completed a previous ITP study of eltrombopag were enrolled in EXTEND. All patients received eltrombopag starting at 50 mg/day, titrated to 25-75 mg/day or less often as required, based on individual platelet count responses (range ≥50-200x109/L). Maintenance dosing continued after minimization of concomitant ITP medication and optimization of eltrombopag dosing. Patients who received 2 years of treatment and transitioned off due to commercial availability of eltrombopag were considered to have completed the study. Patients could remain on study beyond 2 years until eltrombopag became commercially available. Here we describe the efficacy and durability of response in East Asian and non-East Asian patients. Analyses were conducted using the safety population, defined as all patients who had taken at least one dose of the study medication. Results: Of 302 patients enrolled and exposed to treatment (median duration 2.4 years [range, 2 days to 8.8 years]), 41 (14%) were of East Asian origin. Mean average eltrombopag dose in East Asian and non-East Asian patients was 48.9 (range 4.2-74.9) mg/day and 50.4 (range 1.0-74.6) mg/day, respectively. Maintenance of platelet counts ≥30×109/L for at least 25 weeks was seen in 25/35 (71%) East Asian and 158/222 (71%) non-East Asian patients. In total, 13/35 (37%) East Asian patients and 120/222 (54%) non-East Asian patients maintained continuous platelet counts ≥50×109/L for at least 25 weeks, without rescue therapy (Figure). At the start of response, mean daily dose in East Asian and non-East Asian patients was 45.2 and 45.4 mg/day, respectively. The number of patients receiving dose adjustments according to platelet response was similar in East Asian and non-East Asian patients (Table). Conclusions: Treatment with eltrombopag in East Asian and non-East Asian patients resulted in sustained platelet responses ≥30×109/L for at least 25 weeks in a similar proportion of patients. However, a higher proportion of non-East Asian patients achieved continuous platelet counts ≥50×109/L. Direct comparisons should be interpreted with caution because: a) of limited patient numbers in the East Asian group; b) the possible selection bias of patients entering the EXTEND study following completion of earlier eltrombopag studies, eg, primarily responders; and c) the absence of PK data from these patient groups. All patients received similar doses of eltrombopag irrespective of racial background, and dose modifications according to platelet responses were similar. Further investigations are ongoing to determine whether there were any differences in terms of safety and tolerability outcomes in East Asian and non-East Asian patients. Disclosures Wong: Bayer, Biogen-Idec, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, and Roche: Research Funding; Biogen-Idec and Novartis: Membership on an entity's Board of Directors or advisory committees; Bayer, Biogen-Idec and Novartis: Consultancy. Bussel:Amgen, Novartis & GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingleheim, Prophylix Pharma, Protalex, Rigel Pharmaceuticals: Research Funding; Momenta Pharmaceuticals, Novartis, Prophylix Pharma, Protalex, Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; UptoDate: Patents & Royalties; Physicians Education Resource: Speakers Bureau. Saleh:GSK: Consultancy, Research Funding, Speakers Bureau. El-Ali:Novartis: Employment. Quebe-Fehling:Novartis: Employment.

Introduction Hemophilia A is an X linked recessive hemorrhagic disorder caused by mutations in the F8 gene that lead to qualitative and/or quantitative deficiencies of coagulation factor VIII (FVIII). Molecular diagnosis of hemophilia A is challenging because of the high number of different causative mutations that are distributed throughout the large F8 gene. Molecular studies of these mutations are essential in order to reinforce our understanding of their pathogenic effect responsible for the disorder. Aim In this study we have performed molecular analysis of 28 Tunisian hemophilia A patients and analyzed the F8 mutation spectrum. Methods We screened the presence of intron 22 and intron 1 inversion in severe hemophilia A patients by southern blotting and polymerase chain reaction (PCR). Detection of point mutations was performed by dHPLC/sequencing of the coding F8 gene region. We predict the potential functional consequences of novel missense mutations with bioinformatics approaches and mapping of their spatial positions on the available FVIII 3D structure. Results We identified 23 different mutations in 28 Tunisian hemophilia A patients belonging to 22 unrelated families. The identified mutations included 5 intron 22 inversions, 7 insertions, 4 deletions and 7 substitutions. In total 18 point mutations were identified, of which 9 are located in exon 14, the most mutated exonic sequence in the F8 gene. Among the 23 mutations, 8 are novel and not deposited in the HAMSTeRS database nor described in recently published articles. Conclusion The mutation spectrum of Tunisian hemophilia A patients is heterogeneous with the presence of some characteristic features. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1693269827490715

Inherited factor VII (FVII) deficiency is a rare disorder characterized by a bleeding phenotype varying from mild to severe. To date, more than 200 mutations have been described along the F7 gene encoding for FVII. The aim of this study was the identification of genetic defects underlying FVII deficiency in 10 patients belonging to eight unrelated families of the North provinces from Tunisia. Mutation detection was performed by sequencing the whole F7 gene coding region, exon-intron boundaries and about 400 bp of the promoter region. We identified 5 mutations in five unrelated families; the novel p.F328Y mutation and the reported mutations: p.R304Q, p.M298I, IVS1aG > A and p.G-39G. For the remaining 5 patients we didn’t identified any mutations using PCR/Sequencing protocol. In conclusion, this study represents the first comprehensive molecular series of FVII deficiency affected patients in Tunisia from the North. We will try in the future to continue the molecular study for Tunisian patients from Center and South provinces in order to have a complete idea about the FVII deficiency mutational profile in our country. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1288044089753085

In Tunisia, the ATRA era began in 1998 with the use, consecutively, of two regimens combining ATRA and an anthracycline with cytarabine (APL93), and without cytarabine (LPA99). From 2004, 51 patients with confirmed APL either by t(15;17) or PML/RARA were treated according to the PETHEMA LPA 99 trial. Forty three patients achieved CR (86%). The remaining seven patients had early death (one died before treatment onset): four caused by differentiation syndrome (DS) and three died from central nervous system hemorrhage. Multivariate analysis revealed that female gender (P=0.045), baseline WBC> 10 G/L ( P=0.041) and serum creatinine > 1.4mg/dl ( P=0.021) were predictive of mortality during induction. DS was observed in 16 patients (32%) after a median onset time of 15 days from treatment onset (range, 2–29). Body mass index ≥ 30 (P=0.01) was the only independent predictor of DS. Occurrence of hypertensive peaks significantly predicted occurrence of DS (P=0.011) and was significantly associated with high BMI (p=0.003). With a median follow-up of 50 months, 5 year cumulative incidence of relapse, event free and overall survival were 4.7%, 74% and 78%, respectively.

Background The development of inhibitors against factor 8 (F8) is the most serious complication of replacement therapy with F8 in children with severe hemophilia. It was suggested that mismatched F8 replacement therapy may be a risk factor for the development of anti-factor F8 alloantibodies. Recently four single nucleotide polymorphisms (SNPs) encoding six distinct haplotypes, designated H1 through H6, were studied in different populations. Two SNPs are components of the A2 and C2 immunodominant-inhibitor epitopes. The aim of this study is to determine the different types of haplotypes in relation with inhibitors developments and their frequencies in our Tunisian hemophiliac population. Materials and methods 95/116 Tunisian patients with hemophilia A undergoing treatment at Hemophilia Treatment Center, Aziza Othmana hospital, participate in this study. Among them only six patients develop inhibitors. The four SNPs were amplified and sequenced. Results and Discussion In a total of 77 patients, we identified the H1, H2, H3 and the infrequent H5 haplotypes. The H1 and H2 haplotypes, which have the same amino acid sequence in the recombinant F8 molecules used clinically, are the most represented with the frequency of 0.763 and 0.157 respectively. This distribution is almost similar to that of Caucasians in which the frequencies are respectively 0.926 and 0.074, whereas it is 0.354 and 0.374 among Subsaharians. Four patients with inhibitors studied here have the H1 haplotype. For one patient who has a large deletion including the exon 10 we can't identify his haplotype. Theses frequencies may explain partially the low level of inhibitors in our patients.

Hereditary thrombotic thrombocytopenic purpura (TTP) is a rare disorder characterized by occlusive microvascular thrombosis, consumptive thrombocytopenia, and microangiopathic hemolytic anemia. Homozygous or compound heterozygous mutations in the ADAMTS13 gene result in a congenital severe ADAMTS13 deficiency and subsequent accumulation of ultra-large von Willebrand factor multimers, which tend to form platelet thrombi in the microcirculation. We report a first case of congenital TTP on the African continent with a new, homozygous mutation in the metalloprotease domain of ADAMTS13. An initially oligo-symptomatic presentation was followed by acute exacerbation with ischemic stroke and acute renal failure highlighting the severity of this syndrome.

Background: Hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and must be further improved. In addition, AZA yields only about 30% of marrow responses (including CR+PR+marrow CR). Intensive chemotherapy combining Idarubicin (IDA) and AraC yields 30 to 50 % CR in higher risk MDS (Beran and all, cancer 2001) and IDA, as single agent, induces about 30% CR in elderly AML patients (Carella, haematologica 1990). We designed a phase I/II study evaluating the safety and efficacy of the combination of AZA and IDA (1 day during each AZA cycle) in higher risk MDS patients (NCT01305135). Methods: Main Inclusion criteria were: (1) IPSS int-2 or high MDS, or CMML with WBC < 13 G/l and marrow blasts > 10%, or AML with 20-30% marrow blasts (2) Age ≥ 18 years (3) Performance Status (PS) Results: Between Dec 2010 and Jan 2014, 41 patients (from 13 centers) were enrolled, including 13 women and 28 men with a median age of 74 years [IQR 70; 76]. At inclusion, WHO classification was RCMD in 1 pt, CMML in 2 pts, RAEB-1 in 10 pts, RAEB-2 in 13 pts, AML in 12 pts and unclassified MDS in 3 pts. Median marrow blast % was 9.5 [IQR: 6-19.9] and karyotype according to IPSS was favorable in 12 (29%), intermediate in 9 (22%) and unfavorable in 18 pts (44%) (2 cytogenetic failures). IPSS was int-2 and high in 56% and 44%, respectively. PS was 0 in 39%, 1 in 55% and 2 in 6% pts. 10 patients received 5 mg/m2 of idarubicin (cohort 1) and 31 received 10 mg/m2 (cohort 2). 375 cycles of AZA were administered (219 of them with AZA+IDA, as IDA was used only for the first 9 cycles), with a median number of 6 cycles/patient (median 6 in the IDA 5 mg/m2 cohort and 4 in the 10 mg/m2 cohort (p=0.9). Of the 41 patients enrolled, 20(48.8%, 95%CI: 32.9-64.9) achieved response (6 CR, 7 PR, 4 mCR and 3 stable disease with HI) with no difference between the two cohorts (50% vs 48%) and a marrow response rate (CR + PR + mCR) of 41,5%. Thirteen of the 22 patients with abnormal karyotype were evaluable for cytogenetic response: 5 achieved cytogenetic response (4 complete, 1 partial), 1 in cohort 1 and 4 in cohort 2. With a median follow up of 14 months, 9 of the 20 responders had relapsed. Median response duration was 11 months [3.2-42.7], with no difference between the two cohorts. Median OS was 14.3 months [IC95%: 12.5; NA] and 2y OS was 24.8%, with no significant difference between the 2 cohorts (p=0.43). By univariate analysis no baseline parameter including gender, karyotype, marrow blast %, IPSS and IDA dosage (5 or 10 mg/m2), had any significant impact on response or survival. 45 SAEs were reported in 26 patients, including febrile neutropenia (n=25), bleeding (n=7) and 2 non-clinically significant reductions in left ventricular ejection fraction (1 transient, and 1 persisting without symptoms). The number of infections per cycle [9/85 (10%) in the IDA 5 mg/m2 arm and 38/281 (14%) in the IDA 10 mg/m2 arm] and the number of bleeding events (9% vs 17%) did not significantly differ between the two cohorts. Conclusion: In our experience, Idarubicin (on day 8 of each cycle) can be combined to Azacitidine without any additional toxicity. The marrow response rate obtained with the combination (41.5%) may be higher than with AZA alone. We are currently comparing in higher risk MDS patients this AZA-IDA combination versus AZA alone (and other combinations of AZA with other drugs) in a prospective randomized GFM trial. Disclosures Sebert: Celgene: Research Funding. Fenaux:Celgene: Research Funding.

We prospectively studied 478 patients with megaloblastic anemia living in Tunisia. Overall, 98% of patients had vitamin B12 deficiency. Pernicious anemia accounted for most of these cases, and median age at presentation was 45 years. Megaloblastic anemia occurred in 19 subjects under 15 years of age, and of these, nine had the Immerslund-Graesbeck syndrome.

Background The introduction of the first targeted tyrosine kinase inhibitor (TKI), imatinib mesylate (IM) revolutionized the therapeutic paradigm and dramatically improved outcomes of chronic myeloid leukemia(CML). Data are limited in developing countries regarding the clinicopathologic features and response to therapy in the era of IM. Aims To report on the clinicoepidemiologic features of CML in Tunisia, to evaluate the long-term outcome of patients in chronic (CP) or accelerated phase (AP) treated with IM 400mg daily as frontline therapy and to determine imatinib’s efficacy and safety. Methods From October 2002 to December 2011, two hundred and ninety two CML patients were treated with IM in 6 Tunisian departments of hematology. Monitoring response was defined as the ELN provided guidelines. Response (Hematologic, cytogenetic and molecular responses), adverse events and outcome (overall survival, event free survival and progression free survival) were evaluated. The factors associated with outcome of IM therapy were also analyzed. Results Two hundred ninety-two patients enrolled with a median follow-up duration of 56 (8 -290) months: The median age was 44 years (3-78 years). One hundred and fifty (51.3%) patients were male, 134 (49%) were asymptomatic at diagnosis. Splenomegaly was present in 237 of 292 (81%). Additional cytogenetic abnormalities were encountred in 24 (8.3%) patients. At diagnosis, 271 (92.8%) patients were in CP, 21 (7.2%) were in AP. The Sokal risk was low in 64 (23%), intermediate in 94 (33.5%), and high in 122 patients (43.5%). The Eutos risk was low in 179 (75%), and high in 60 (25%) patients.The rate of cumulative complete hematologic response (CHR), complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response 4/5 log (CMR) in CP/AP CML patients were 93.8%, 73%, 65% and 33.9%, respectively. According to the 2009 ELN criteria, optimal, suboptimal response and failure were noted in 132 (47%), 68 (24%) and 82 (29%) patients, respectively. Five year event free survival (EFS), progression free survival (PFS) and overall survival (OS) were 78%, 89% and 91%, respectively. By multivariate analyzis, AP, high Eutos risk and baseline WBC ≥ 150G/l remained independent predictive factors of non optimal response to IM. AP was an adverse independent prognostic factor for EFS, PFS and OS. Patients obtained CCyR at 12 months after the initiation of IM treatment were associated with longer PFS (P< 0.0001) and OS (P< 0.0001). ELN response was also significantly associated with EFS. The adverse events (AE) of IM were moderate and tolerable. Only 3 patients discontinued IM for intolerance. IM-related hematologic AE included neutropenia in 6.2%, anemia in 8.9%, and thrombocytopenia in 17.2%. Nonhematologic AE (21%), including mainly edema in 7.1%, digestive disorders in 5.5%, weight gain and skin rash in 3.1%. Conclusion We found that substantial number of patients in our series were in intermediate or high risk group. With the caveats that the monitoring of the disease was not optimal, response rates were similar to those reported in previous studies. It is clear to us that improvements should be made in treatment of AP-CML and high Sokal risk group of CP-CML. The front-line use of 2nd TKI are expected to improve the results of the first line treatment of these high risk Tunisian patients, but cost and accessibility of this therapy remain the problems in developing countries. Disclosures: No relevant conflicts of interest to declare.

Abstract 4297 Background: In Tunisia children with acute lymphoblastic leukemia (ALL) are treated according to the EORTC 58951 protocol with complete remission rate (CR) of 84% and long-term survivals reaching 80% at 5 years. Survivals of adult ALL remain disappointing mainly because of the high rate of early deaths, the limited number of allografted patients performed only for those aged < 40y, and lack of access to the international bone marrow donors registry. Are the improvements made in the last decades in developed countries in the treatment of adult ALL transposable for patients diagnosed in developing countries? The aim of the present study is to report the experience of a Tunisian hematology center in the management of adult ALL. Patients and methods: Fifty one adult ALL patients were treated with three consecutive trials in the hematology department of Aziza Othmana university hospital of Tunis between January 2005 and July 2011.18 patients were treated with Tunisian LALA03 protocol (pediatric –inspired induction) between 2005 and 2007: BFM-like HR induction (PND 60mg/m2x22d, VCRx4, DNR 30mg/m2x4, ASPx8). HR patients receive 6 consolidations blocs (GRAALL03 blocs) + CNS RT+ maintenance therapy. SR patients receive EORTC AR2 consolidations (IB, interval therapy, IIAIIB) +CNS RT +maintenance therapy. This protocol led to an inacceptable rate of induction death of 38.8%. 24 and 9 patients were respectively treated with Hyper-CVAD regimen from 2008 to 2010 and GRAALL05 since 2010. Results: Male/female ratio was is 2.6. Median age was 37.5 years (21–59). Immunophenotyping revealed B-cell precursor and T-lineage ALL in respectively 60% and 35% of patients. 1 patient had biphenotypic leukemia and the immunophenotype was not precised in one case. Median baseline WBC count was 18.2 × 109/L (0.3–265 ×109/L). Three patients presented with central nervous system (CNS) disease at diagnosis. 21.5% of patients have Philadelphia positive ALL. Only 14 patients had SCT from a matched sibling donor. Complete remission rate after induction was 74.5%. Eight patients (15.6%) had early death during induction from septic shock and pneumonia in 5 and 3 cases respectively. Median overall survival (OS) was 18 months. 3 years OS was 30%. By univariate analysis, age less than 32 years (p=0.01) and bone marrow transplantation (p=0.04) had positive impact on OS. For the whole study population 3 year relapse free survival (RFS) was 20%. Despite a lower RFS with Hyper CVAD there was no significant difference between the three trials but a trend to better outcome with pediatric inspired trials i.e. LALA03 and GRAALL05. Conclusion: Pediatric-inspired protocols are associated with increased early death but prolonged remission duration compared to Hyper-CVAD. Hyper-CVAD is well tolerated but is associated to a high rate of relapse in our patients mainly because of the small number of SCT. The outcome of adult ALL in Tunisia is still unsatisfactory and can be improved with pediatric-like regimens. Effective therapy for adult ALL is feasible in our country. Controlling death induction by supportive measures and better management of myelosuppression and offering a stem cell transplant to a greater number of patients could be an option to improve on the RFS and OS. Disclosures: No relevant conflicts of interest to declare.

2744 The current standard of care for fit patients (pts) with chronic lymphocytic leukemia (CLL) is rituximab (R) in combination with fludarabine and cyclophosphamide; however, many pts with CLL are elderly and have comorbidities that render them ineligible for fludarabine treatment. Two common treatment options for fludarabine-ineligible pts are bendamustine (B) or chlorambucil (Clb). A further promising treatment option, following the success of the combination of R with fludarabine and cyclophosphamide, might be to combine B or Clb with R. The following study aims to assess the responses of pts to a combination of R and either B or Clb in first-line (1L) or second-line (2L) pts with CLL, with the primary objective being to compare the confirmed complete response (CR) rate (assessed according to Hallek et al. Blood 2008) after 6 cycles of treatment between the two treatment arms for the pooled 1L and 2L pts. Pts (aged ≥ 18 years) who were ineligible for fludarabine treatment, as a result of age or a greater number of comorbidities, were randomized to either the R-B or R-Clb arm. Pts were 1L or 2L, where relapse had occurred no earlier than 12 months since their last dose of 1L treatment. Pts in the R-B arm were treated with six 28-day cycles of B (1L: 90 mg/m2 Days 1 and 2; 2L: 70 mg/m2 Days 1 and 2) with R administered on Day 1 of cycle 1 (375 mg/m2) and cycles 2–6 (500 mg/m2). Pts in the R-Clb arm received the same dose of R but in place of B they received Clb (10 mg/m2Days 1–7, cycles 1–6), and those pts in the R-Clb arm that had not achieved a CR after 6 cycles continued to receive Clb monotherapy for up to 6 further cycles. Tumor assessments were made after cycles 3, 6 and 12 and then 3-monthly for at least a year. Enrollment and randomization are ongoing and, at present, a total of 339 pts have been randomized between the two treatment arms, 126 of whom are included in this interim analysis with the remaining pts continuing on the study. Of these 126 pts, 58 were randomized into the R-B arm and 68 the R-Clb arm. Patient characteristics between the two treatment arms were well balanced (Table). The median age of pts was 74 years (75 years for the R-B arm and 73 years for the R-Clb arm) and the majority of pts were taking concomitant medication (57/58 pts [98%] in the R-B arm; 64/68 pts [94%] in the R-Clb arm). Compared with previous clinical trials in CLL where pts are usually younger and fitter, this patient population is closer in age and fitness to pts presenting in the clinic. A total of 85 pts were previously untreated, with the remaining 41 having received one line of previous treatment. 2L pts had received a median of 6 prior cycles of treatment. The safety population was made up of 124 pts (R-B: n = 57; R-Clb: n = 67) who had received at least one dose of the study medication; 104/124 pts completed all 6 cycles of rituximab treatment. After 6 cycles of treatment, 14/58 pts (24%) in the R-B arm had a confirmed CR compared with 7/68 pts (10%) in the R-Clb arm (p = 0.033). For 1L pts the corresponding CR rates were 30% in the R-B arm vs 13% in the R-Clb arm (p = 0.054) and 2L pts exhibited CR rates of 11% in the R-B arm vs 4% in the R-Clb arm (p = 0.413). At the end of treatment, the overall response rate (ORR) was not different between the R-B and the R-Clb arms (88% and 81%, respectively [p = 0.404]). ORRs for 1L pts were 88% in the R-B arm vs 80% in the R-Clb arm and for 2L pts were 89% in the R-B arm vs 83% in the R-Clb arm. Safety was similar between the two treatment arms with the most common adverse events (AEs) (any grade) being neutropenia (R-B: 42% vs R-Clb: 46%) followed by nausea (R-B: 26% vs R-Clb: 22%). The most common AE at ≥ grade 3 was neutropenia (R-B: 32% vs R-Clb: 34%). Serious AEs were experienced by 20 pts (35%) in the R-B arm and 23 pts (34%) in the R-Clb arm; the most frequent serious AE was pneumonia (R-B: 7% vs R-Clb: 2%). 5/57 pts (9%) in the R-B arm and 8/67 pts (12%) in the R-Clb arm withdrew from the study prematurely due to AEs. R-B or R-Clb could provide useful treatment options for pts with CLL who are ineligible for the current fludarabine-containing standard of care. Interim results from this study have indicated that R-B shows a trend towards higher CR rates compared with R-Clb. | Characteristic | R-bendamustine (n = 58) | R-chlorambucil (n = 68) | |:-------------------------:| ----------------------- | ----------------------- | | Median age, years (range) | 75 (49–87) | 73 (44–91) | | Sex, % | - | - | | Male | 60 | 65 | | Female | 40 | 35 | | Binet stage, % | - | - | | A | 5 | | | B | 55 | 59 | | C | 33 | 37 | | Not reported | 7 | 4 | | 17p/11q del, % | 12 | 4 | | IGVH status, % | - | - | | Mutated | 41 | 52 | | Unmutated | 53 | 38 | | Other | 5 | 10 | | Line of treatment, % | - | - | | 1L | 69 | 66 | | 2L | 31 | 34 | Table: Baseline patient characteristics Disclosures: Leblond: Roche: Advisory Board Other, Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Janssen-Cilag: Honoraria. Off Label Use: Rituximab in Combination with Bendamustine or Chlorambucil for Treating Patients with Chronic Lymphocytic Leukemia. Rassam: Johnson and Johnson: Unrestricted research grant Other; ROCHE: Honoraria; BMS: Honoraria. Raposo: Roche: Consultancy. Oertel: Roche: Employment, Equity Ownership.

Abstract 4271 Background: In Tunisia, before 1998, ATRA was not available in APL, and we reported CR rates of 37.5% (unpublished results). The ATRA era began in 1998 with the consecutive use of two regimens combining ATRA and an anthracycline with AraC (APL93 trial), and without AraC (LPA99 trial). We report outcome of those clinical trials in our country, whose yearly GDP is about 8000 USD/inhabitant (ranking n°55 in the world). Methods: Between 1998 and 2010, consecutive patients with genetically confirmed APL were treated, until 2004 (n= 27 patients, median age, 27 years) with the European APL93 trial induction treatment with ATRA 45 mg/m2 from day (D)1 and DNR (60mg/m2/d x3)+ AraC (200mg/m2/d x7) started from D1 if WBC ≥ 5G/L and D3 if WBC < 5G/L.Patients achieving CR received a first consolidation course with the same CT and a second with DNR at 45 mg/m2/dx3 and AraC 1g/m2/12h x8. Maintenance treatment consisted of a combination of ATRA 45 mg/m2 for 15 days every 3 months,6MP at 50 mg/m2/d and MTX 15mg/m2/week (Adès L.Blood 2010;115:1690). Between 2004 and 2010, 51 patients (median age,30 years) received the Spanish PETHEMA LPA 99 protocol (Induction with ATRA 45 mg/m2/day and idarubicin 12 mg/m2 on days 2, 4, 6, 8); 2 risk-adapted consolidation courses with IDA, with ATRA (only for Int- and high-risk patients) and for all patients one consolidation course with mitoxantrone 10mg/m2 for 5 days, followed by the same maintenance therapy as in the European APL trial. (Sanz MA, Blood 2008;112:3130). During induction therapy coagulopathy was treated with fresh-frozen plasma(FFP) and apheresis platelets with the objective of maintaining platelet counts above 30G/L, prothrombin time >50% and, fibrinogen >1 g/L. Heparin was not used. During maintenance treatment, all patients were monitored clinically every month and molecularly for PML-RARA every 3–4 months. Results: The two patient cohorts were comparable except for the incidence of M3v (1/27 in APL93 vs. 12/51 in LPA 99,P=0.023).34.6% (27/78) of patients were HR Sanz’ score.With the European trial (26 patients treated, one patient died before treatment), the CR rate was 77%, while 23 % patients (6/26) had early death: 4 from hemorrhage and 2 from DS (overall incidence of DS: 15%).4 year event free survival (EFS), cumulative incidence of relapse (CIR) and overall survival (OS) was 61.5%, 14.2%, 65% respectively. In high risk patients (n=9), 5 achieved CR,2 relapsed, and 3 were long term survivors. With LPA 99 trial, 43 (86%) pts achieved CR. The remaining 7 (14%) pts had early death (one died before treatment onset): 4 from DS (overall incidence of DS: 32%) and 3 from CNS hemorrhage. 2 pts relapsed at 35 and 36 months of CR. 2 pts developed secondary MDS and 2 died in CR,from sepsis during the third consolidation course and one from cardiac failure after 15 months of CR, respectively. With a median follow-up of 50 months, 5 year CIR, EFS and OS were 4.7%, 74% and 78%, respectively. In high risk patients (n=18), the CR rate,5 year CIR, EFS and OS were 70.5 %,0%,64.7 %,64.7%, respectively. The only prognostic factor of death during induction for the whole study population was high baseline WBC > 10G/L (P=0.003). Male gender (P=0.77), M3v (P=0.23),CD56 positivity (P=0.49), and WBC > 10G/L (P=0.71) were not predictive of relapse. Median transfusion requirement during induction treatment was: 8 PRBC in APL93 trial (range, 3–18) and 4 in LPA 99 trial (range, 3–11); 6 apheresis platelet concentrates in APL 93 trial (range, 3–11) and 4 in LPA 99 trial (range, 1–16); 11 FFP concentrates (range, 0–53) and 7 (range, 0–36), respectively. Conclusion: Despite more limited resources than in industrialized countries, and non availability of arsenic derivatives, our results are quite acceptable. The CR rate we observed is still inferior to what is reported in international trials but, our results improved over time especially with the less myelosuppressive Spanish trial, including in patients with WBC > 10 G/l. Our results suggest that there is probably no need to adapt protocols by reducing dose-intensity in APL trials in developing countries, at least if an adequate transfusion program and adequate management of DS can be implemented during induction treatment. Disclosures: Fenaux: Celgene: Honoraria, Research Funding.

Abstract 4852 Sickle Cell Disease (SCD) is a complex disease with various complications such as stroke, vaso-occlusive crisis (VOC), acute chest syndrome and leg ulcers. Sickle cell anemia (SCA; homozygous hemoglobin SS) is the most common form of SCD. Genetic variations and/or environmental modifiers may modulate clinical presentation of SCD. Few studies have examined hemoglobinopathies in Tunisia, North Africa. However, recently, frequencies of beta-thalassemia and sickle cell trait were estimated at 2.21% and 1.89%, respectively (Fattoum, 2006). In order to identify genetic factors that may predispose patients to SCD complications in this population, a pilot case control study was designed to assess polymorphisms in Human Platelet Antigen (HPA) Genes. HPA polymorphisms were recently associated with severe coronary artery disease in the general population in Tunisia (Abboud et al, 2010) and VOC presentation in SCA patients from Bahrain (Al-Subaie et al, 2009). We present here a study conducted in collaboration with the Department of Clinical Hematology at the Aziza Othmana Hospital in Tunis (Tunisia). The National Medical Ethics committee of Tunisia as well as the Institutional Review Board (IRB) of Morehouse School of Medicine (MSM) approved the study. Blood samples, clinical history and DNA samples were collected from SCD adult patients and healthy controls after informed consent. Previously validated questionnaires for genetic risks in patients with SCD (courtesy of Dr Telen, Duke University) were adapted to French. The Helena test kit was used to generate hemoglobin variant data in conjunction with cellulose acetate electrophoresis. Blood samples were collected in EDTA vacutainer tubes and genomic DNA was isolated,stored at −80°C and then shipped to MSM. Single nucleotide polymorphisms, SNPs (Table 1) were genotyped using PCR-RFLPs and compared with different clinical sub-phenotypes such as, onset age, strokes, cardiac problems, splenectomies, etc. as defined in the questionnaire. Pearson Chi-Square was used for comparison and a PCLeu33ProMspIHPA2rs606517GP1BA (2811)524 C>TMet145ThrSfaNIHPA3rs591117ITGA2B (3674)2622 T>GIle843SerFokITable 2:Tunisian cohort collection took place from January to December 2009. This table summarizes the number and genotypes of patients enrolled and questionnaires collectedSexMaleFemaleTotal (%)TOTAL455196 (100)SCD Patients403575 (78)Healthy Controls51621 (22)Hemoglobin Genotype of SCD patientsSS141529 (38.6)Sβ010919 (25.3)Sβ+112 (2.6)SC112 (2.6)SO101 (1.3)unknown13922 (29.3)Total (%)403575 (100)Questionnaires filled282654No questionnaires111021 Disclosures: No relevant conflicts of interest to declare.

Abstract 682 INTRODUCTION: Eltrombopag (PROMACTA; GlaxoSmithKline, Collegeville, PA) is the first oral, small molecule, thrombopoietin receptor agonist approved in the US for the treatment of chronic immune thrombocytopenic purpura (ITP). Eltrombopag is also being evaluated for the treatment of thrombocytopenia due to other causes (eg, hepatitis C, MDS). Chronic ITP is characterized by autoantibody-induced platelet destruction and reduced platelet production, leading to chronically low platelet counts. Eltrombopag has been shown to significantly increase platelet counts and reduce clinically relevant bleeding symptoms in 3 placebo-controlled ITP trials evaluating a total of 429 patients. EXTEND is an ongoing open-label, phase 3 extension study to assess the long-term safety and efficacy of eltrombopag in chronic ITP. METHODS: Patients with previously treated, chronic ITP who completed a prior eltrombopag study were eligible to participate in EXTEND. Eltrombopag treatment was initiated at 50 mg once daily and then adjusted to maintain platelet counts between ≥50,000/μL and RESULTS: At the time of this analysis, 299 patients (median age 50 years; 66% female) had received eltrombopag (240, 126, 48, and 17 patients exposed for ≥6, 12, 18, and 24 months, respectively). The median duration of eltrombopag treatment was 204 days and ranged from 2–861 days. At baseline, 33% were receiving concomitant ITP medication and 38% had been splenectomized. The majority of patients (70%) had baseline platelet counts 1.5x ULN, or alkaline phosphatase >1.5x ULN). Thirteen patients (4%) experienced 16 thromboembolic events (TEEs); 11/13 (85%) experienced the event at a platelet count lower than the maximum platelet count achieved during eltrombopag treatment. Platelet counts proximal to the TEEs ranged from 14,000–407,000/μL. Eighty-six BM biopsies were performed. No clinically relevant effects of eltrombopag on BM were detected. CONCLUSION: Oral eltrombopag treatment for up to 2 years effectively raised platelet counts, decreased bleeding symptoms, and was generally well-tolerated in chronic ITP. Disclosures: Saleh: GlaxoSmithKline: Speakers Bureau; Amgen: Speakers Bureau. Bussel:Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Research Funding; Sysmex: Research Funding; Scienta: Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees. Cheng:GlaxoSmithKline: Research Funding. Mayer:GlaxoSmithKline: Employment. Bailey:GlaxoSmithKline: Employment. Aivado:GlaxoSmithKline: Employment.

Abstract 4552 Background Pseudomonas aeruginosa is a leading cause of nosocomial infections usually associated with high mortality. The aim of this study was to determine the predictive factors of severe sepsis or septic shock in patients with hematological malignancies and pseudomonas infections. Methods This study was conducted in a teaching hospital (Aziza Othmana University Hospital, Tunis, Tunisia) to evaluate the clinical profile of infections due to Pseudomonas species and to determine risk factors for severe sepsis or septic shock defined according to the criteria of the ACCP/SCCM. Pearson test was used for univariate analysis, and logistic regression for multivariate analysis. Results Between 2004 and 2009,a total of 73 pseudomonas isolates (70 P, aeruginosa) was collected in 60 patients : 47 with acute leukemia (78%), 7 with lymphoma (12%), and 6 with others hematological disorders (10%).The median age was 29 yrs (range, 2-64). Most common sites of the isolates were from bloodstream (45%), and skin lesions (31.5%). At least 11 patients (18%) had 2 or more infections due to Pseudomonas. The most common clinical signs observed were isolated fever (18%), respiratory symptoms (15%), diarrhea (21%), and skin lesions (29%).Susceptibility to major anti-pseudomonas antibiotics revealed that isolates tested were resistant to:piperacillin/tazobactam (40%), cefatazidim (28%), ciprofloxacin (20.5%), imipenem (22%), and amikacin (22%).Severe sepsis or septic shock occurred in 49% of episodes. Crude mortality was (18%, 11 of the 60 patients) all caused by septic shock. In univariate analysis factors associated with severe sepsis or septic shock were: Isolates from more than one site (p=0.04), Absolute neutrophil count < 0.1 × 109/l (p=0.003), concomitant infection with other microorganism (p=0.019), fever lasting for more than 3 days in patients with antibiotherapy (p=0.003), C-reactive protein > 100 mg/l (p 2.2 mmol/l (p< 0.0001), serum bicarbonate < 19 mmol/l (p=0.002), hemoglobin level < 70g/l (p 50 μmol/l (p=0.03), and hypoproteinemia 100 (p=0.04,OR=15,95%CI: 1,1-219,8), hemoglobin level Conclusions This study revealed that several factors such as level of neutrophil count, C-reactive protein, hemoglobin level, severe hypophosphatemia, and antibiotherapy > 72 h before microbiological documentation may play a significant and independent role for the development of severe sepsis/septic shock and increase mortality of Pseudomonas infections in patients with hematological malignancies. Disclosures: No relevant conflicts of interest to declare.

INTRODUCTION: Eltrombopag (PROMACTA®/REVOLADE®; GlaxoSmithKline, Collegeville, PA) is the first oral small molecule, non-peptide thrombopoietin receptor agonist shown to increase platelets and reduce bleeding symptoms during placebo-controlled trials in chronic ITP patients. EXTEND is an ongoing, open-label study designed to assess the long-term safety and clinical benefit of eltrombopag in patients with chronic ITP. While eltrombopag has been shown to raise platelet counts above the recognized goal of ≥50,000/μL in the majority of patients, it unknown whether patients who do not achieve this level of elevation derive other clinical benefit from eltrombopag therapy. METHODS: For this analysis, patients who were enrolled in EXTEND for at least 6 weeks were evaluated to determine what percentage achieved platelet counts ≥50,000/μL from baseline platelet counts ≤30,000/μL. Furthermore, clinical benefit, in terms of doubled platelet counts, reduced bleeding symptoms, or reduced concomitant ITP medication use, was evaluated in the subgroup of patients who did not achieve platelet counts ≥50,000/μL during the study. Bleeding symptoms were prospectively evaluated using the WHO Bleeding Scale: Grade 0 = no bleeding, Grade 1 = mild bleeding, Grade 2 = moderate bleeding, Grade 3 = gross bleeding, and Grade 4 = debilitating blood loss. RESULTS: Of the 117 patients with baseline platelet counts ≤30,000/μL evaluated, 91 patients (78%) achieved platelet counts ≥50,000/μL at least once during the study; whereas, 26 patients (22%) did not achieve platelet counts ≥50,000/μL. The majority of patients not achieving platelet counts ≥50,000/μL had baseline platelet counts ≤15,000/μL (96%, n = 24/26); however, 69% of all patients with baseline platelet counts ≤15,000/μL on study for at least 6 weeks achieved platelet counts ≥50,000/μL. The majority of patients not achieving platelet counts ≥50,000/μL during the study doubled their platelet count from baseline at least once (62%, n = 16/26). Among patients whose platelet counts doubled, the median baseline platelet count was 4,000/μL, compared to the median maximum platelet count of 29,000/μL achieved during treatment with eltrombopag. Nineteen of the 26 patients not achieving platelet counts ≥50,000/μL had bleeding symptoms at baseline (WHO Grades 1–4). The majority of the 19 patients with bleeding symptoms at baseline reduced their bleeding symptoms during treatment with eltrombopag (68%, n = 13/19). Eleven of the 26 patients not achieving platelet counts ≥50,000/μL were receiving concomitant ITP medications at baseline. Five of the 11 (45%) were able to reduce or discontinue at least 1 baseline concomitant ITP medication while receiving eltrombopag. A total of 24 of the 26 patients (92%) not achieving platelet counts ≥50,000/μL during the study derived clinical benefit (doubling of platelet count, reduction in bleeding, and/or reduction in use of concomitant ITP medications) following treatment with eltrombopag. CONCLUSION: Approximately 80% of evaluated patients with baseline platelet counts ≤30,000/μL achieved platelet counts ≥50,000/μL during the study. In the subgroup of patients who did not achieve platelet counts ≥50,000/μL, clinical benefit was achieved by 92% of patients and consisted of doubled platelet counts, reduced bleeding symptoms, and/or reduced concomitant medication use.

INTRODUCTION: Refractory ITP patients have an unmet medical need for new treatment options. It is unknown how novel therapeutic agents such as eltrombopag (PROMACTA®/REVOLADE®; GlaxoSmithKline), the first oral, small-molecule, non-peptide thrombopoietin receptor agonist, may help ITP patients refractory to standard therapies. Eltrombopag was shown to substantially increase platelet counts during 2 placebo-controlled trials including >200 previously treated chronic ITP patients. EXTEND is an ongoing, open-label study designed to assess the long-term safety and clinical benefit of eltrombopag in patients with chronic ITP. METHODS: A post hoc analysis of EXTEND data assessed the efficacy of eltrombopag treatment in 165 chronic ITP patients, by refractoriness to prior therapy. Patients included had to have been on study ≥6 weeks. Refractory patients were defined as those with no response to a prior therapy (corticosteroids, IVIg, anti-D, or rituximab), and non-refractory patients were those previously treated patients who had either relapsed or become intolerant to their prior therapy. Specifically, corticosteroid-refractory patients had to have either no prior response to corticosteroids, or if there had been at least 1 documented response, there was subsequently nonresponse to all corticosteroids attempted. To determine whether outcome of prior therapy impacts a patient’s response to eltrombopag, refractory ITP patients were compared to non-refractory ITP patients with regard to 3 measures of clinical benefit: 1) the proportion of patients who achieved platelet counts ≥50,000/μL and 2X baseline, 2) median weekly platelet counts on therapy through 39 weeks (9 mo.), and 3) the proportion of patients with clinically significant bleeding symptoms (WHO Grades 2–4) at each week on therapy through 39 weeks (9 mo.). Bleeding symptoms were prospectively evaluated using the WHO Bleeding Scale: Grade 0 = no bleeding, Grade 1 = mild bleeding, Grade 2 = moderate bleeding, Grade 3 = gross bleeding, and Grade 4 = debilitating blood loss. RESULTS: Of the 165 patients included, 68 were refractory to at least 1 of the following medications: corticosteroids (no response, n = 36; no response following prior response, n = 7), IVIg (n = 20), anti-D (n = 12), or rituximab (n = 23). The median baseline platelet count was 17,000/μL in both the refractory and non-refractory patients. Overall, 75% (n = 51/68) of refractory patients achieved platelet counts ≥50,000/μL and 2X baseline, compared to 84% (n = 81/97) of non-refractory patients. A logistic regression model, adjusted for baseline splenectomy status, ITP medication use, and baseline platelet count showed no significant difference in this response between refractory and non-refractory patients (p = 0.1425). In addition, weekly median platelet counts in both refractory and non-refractory patients generally remained at or above 50,000/μL from week 1 through week 39 (9 mo.). While refractory patients had more clinically significant bleeding at baseline than non-refractory patients: 32% (n = 22/68) and 14% (n = 14/97), respectively, the proportion of patients with clinically significant bleeding in both groups was lower than baseline at any point from weeks 1 to 39. The proportion of patients with clinically significant bleeding in both groups was generally reduced 50% from baseline throughout this period. CONCLUSION: Eltrombopag induces long lasting platelet count increases and reduces clinically significant bleeding symptoms in refractory and non-refractory chronic ITP patients. We hypothesize that eltrombopag’s novel mechanism of action, stimulation of platelet production, underlies its ability to successfully treat patients refractory to treatments which impede platelet destruction.

INTRODUCTION: Eltrombopag (PROMACTA®/REVOLADE®; GlaxoSmithKline, Collegeville, PA) is the first oral, small molecule, non-peptide thrombopoietin receptor agonist under investigation for the treatment of thrombocytopenia due to various causes, including idiopathic thrombocytopenic purpura (ITP). Chronic ITP is characterized by autoantibody-induced platelet destruction and reduced platelet production, leading to chronically low peripheral platelet counts. Eltrombopag treatment has previously demonstrated a significant increase in platelet counts and a reduction in clinically relevant bleeding symptoms in 2 placebo-controlled trials evaluating a total of >200 patients with chronic ITP after up to 6 weeks of treatment. EXTEND is an ongoing open-label, phase III extension study to assess the long-term safety and efficacy of oral eltrombopag in ITP patients that have previously completed an eltrombopag trial. METHODS: Patients with previously treated, chronic ITP who completed a prior eltrombopag study were eligible to participate in EXTEND. Eltrombopag treatment was initiated at 50 mg once daily and then adjusted in order to maintain platelet counts ≥ 50,000/μL and RESULTS: At the time of this analysis, 207 patients (median age, 50 years; 67% female) had received eltrombopag on this study. At baseline, 33% were receiving concomitant ITP medication and 40% were splenectomized. The majority of patients (70%) enrolled with baseline platelet counts 50,000/μL, respectively. The duration of eltrombopag treatment ranged from 3 to 523 days. Seventy-nine percent (159/201) of patients achieved a platelet count ≥ 50,000/μL, and 24% (18/75) of patients who had received eltrombopag for at least 25 weeks maintained platelet counts ≥ 50,000/μL continuously for ≥ 25 weeks. Patients responded to eltrombopag regardless of splenectomy status (non-splenectomized: 78%, splenectomized: 81%) and use of baseline concomitant ITP medications (no baseline ITP medications: 79%, baseline ITP medications: 80%). Median platelet counts remained ≥ 50,000/μL throughout the observation period of the study (Figure 1) with only 3 exceptions, when the median platelet counts remained >40,000/μL. At baseline, 59% of patients reported bleeding symptoms (WHO Grades 1–4) compared with approximately 30% at months 1, 3, and 6. Adverse events (AEs) were reported in 150 patients (72%) while on therapy, the majority of which were mild to moderate. Headache (15%) was the most commonly reported on-therapy AE, followed by upper respiratory tract infection (13%), diarrhea (10%), and nasopharyngitis (9%). Six thromboembolic events were reported during the study. No clinically relevant effects of eltrombopag on patient bone marrow were detected. Thirty-nine serious AEs were reported by 17 patients (8%) while on therapy +1 day. Four deaths were reported in the study (2 deaths on therapy and 2 deaths >30 days after the last dose of eltrombopag); none were considered related to study medication. CONCLUSION: Oral eltrombopag is effective at raising platelet counts and decreasing bleeding symptoms during long-term treatment, regardless of splenectomy status or the use of baseline ITP medications. Eltrombopag is well tolerated during long-term treatment in patients with previously treated chronic ITP. Figure 1. Median platelet counts.a BL, median baseline value. aDotted line indicates 50,000 platelets/μL. Figure 1. Median platelet counts.a BL, median baseline value. aDotted line indicates 50,000 platelets/μL.

Background: HL, independently of socio economic conditions, is often intrinsically more aggressive in developing countries, including in Tunisia (Tunis Med.1999 77:614). We evaluated clinical characteristics and outcome of HL pts included in a prospective multicenter Tunisian adult HL trial. Methods: Between 2002 and 2006, 251 consecutive eligible pts from 6 Tunisian departments with newly diagnosed HL were enrolled in a prospective trial (MDH 2002). Pts were staged using EORTC prognostic factors in early stages and the international prognostic scoring (IPS) in advanced stages. ABVD was used at 3 cycles for favorable (fav) early stages (G1), 6 cycles for unfavorable (unfav) early stages (G2) and stage IIIA (G3) and 8 cycles for fav advanced stages (IPS Results: Median age at presentation was 31 years (range 15–70), with 140 M and 111 F. 50% patients had advanced disease (28% with stage IV) and 44% had unfav early stage (G2). 25% pts had Bulky mediastinal disease and 69% had B symptoms. 40% pts were treated in G2, 29% in G4, 17% in G5 and only 9% in G1. Eleven (4.3%) toxic deaths were observed during treatment, including 10 deaths in the 72 pts treated with escalated BEACOPP. Of the remaining pts, 83% had CR and 17% had primary failure at the end of the planned treatment (including 14 % with response 50 % to 75% response and with Conclusions: This study confirms the high incidence of aggressive forms of HD in Tunisia, therefore frequently requiring intensive treatment, sometimes difficult to apply in pts with relatively low socio economic condition Apart from escalated BEACOPP (which resulted in high toxicity that will have in the future to be better prevented), treatments could however generally be administered completely, which possibly contributed to the relatively few relapses. Bulky mediastinal disease and absence of CR at the end of treatment were, as in other countries, major issues requiring treatment intensification

INTRODUCTION: Eltrombopag (PROMACTA®/REVOLADE®; GlaxoSmithKline, Collegeville, PA) is the first oral, small molecule, non-peptide thrombopoietin receptor agonist developed as a treatment for thrombocytopenia of various etiologies, including chronic idiopathic thrombocytopenic purpura (ITP). In 2 placebo-controlled studies totaling over 200 patients with chronic ITP, eltrombopag has demonstrated a significant increase in platelet counts and a reduction in clinically relevant bleeding after up to 6 weeks of treatment. EXTEND is an ongoing open-label, phase III extension study to assess the long-term safety and efficacy of oral eltrombopag. Although the primary objective of this study was to raise platelet counts to a safe level (≥50,000/μL), the ability of eltrombopag treatment to allow patients to reduce concomitant ITP medications and avoid the adverse events associated with those therapies was also of interest. METHODS: Adult patients with previously treated chronic ITP who completed a prior eltrombopag study were eligible to participate in EXTEND. Eltrombopag treatment was initiated at 50 mg once daily and then adjusted to maintain platelet counts ≥50,000/μL and RESULTS: As of the clinical cut-off date (January 7, 2008), 207 patients (median age, 50 years; 67% female) had received eltrombopag. At baseline, 69 (33%) patients reported the use of ITP medications; of these, 65 patients had at least 1 post-baseline visit by the clinical cut-off date and were evaluable for response status. Eighty percent (52/65) of these patients responded to eltrombopag with a platelet count of ≥50,000/μL during the study. Forty-eight percent (33/69) of patients attempted to reduce or discontinue their concomitant ITP medications during the study. Seventy percent (23/33) of these patients discontinued or had a sustained reduction of their baseline ITP medication and did not require any subsequent rescue treatment as of the clinical cut-off date; of these, 65% (15/23) had maintained the discontinuation or reduction for at least 24 weeks as of the clinical cut-off date. Sixty-one percent (20/33) of patients discontinued at least 1 baseline ITP medication, and 55% (18/33) discontinued all baseline ITP medications, without subsequent rescue treatment. Discontinued or reduced medications included prednisone (n = 11); prednisolone (n = 8); danazol (n = 5); and azathioprine, dexamethasone, mycophenolic acid, and oxymetholone (n = 1 each). Only 12% (8/69) of patients increased the dose of concomitant ITP medication from baseline. CONCLUSION: In this study, long-term therapy with oral eltrombopag allowed 80% of patients with chronic ITP who were also receiving a concomitant ITP medication at baseline to maintain elevated platelet counts sufficient to permit a reduction in the use of concomitant ITP medications without the need for rescue therapy.

Idiopathic thrombocytopenic purpura (ITP) is a disease caused by inadequate platelet production as well as increased platelet destruction. Eltrombopag is a first-in-class, oral, non-peptide platelet growth factor that increases platelet counts by interacting with the thrombopoietin receptor on megakaryocytes and their precursors. Accordingly, in two completed 6-week, randomized, double-blind, placebo-controlled studies of adult subjects with chronic ITP, eltrombopag produced a substantial dose-dependent increase in platelet counts. EXTEND is an ongoing, open-label extension study designed to assess the long-term safety and efficacy of oral eltrombopag. Subjects previously enrolled in an eltrombopag study are eligible to enroll in EXTEND after an intervening washout period of at least 4 weeks. Subjects are administered a starting dose of 50 mg/day (which could be increased to 75 mg/day at any time after 3 weeks) in order to reach a platelet count of ≥50,000/uL (stage 1). Then, concomitant ITP medications, if taken at study entry, are tapered to a minimal dose or discontinued entirely (stage 2), whilst maintaining a platelet count of ≥50,000/uL. Eltrombopag is then titrated to a minimal effective dose (25–75 mg/day) required to maintain platelet counts of 50,000/uL-200,000/uL (stage 3). Eltrombopag is continued for as long as the subject continues to benefit (stage 4). Bleeding incidence and severity is assessed using the WHO bleeding scale (Grade 0–4). As of August 6, 2007, data were available on 96 subjects. Ninety-four subjects were administered eltrombopag. Evaluable subjects (n=89) had a median treatment duration of 151 days (2–333 days). At baseline, 42 (44%) subjects had a platelet count ≤15,000/uL, 60 (63%) had evidence of bleeding (WHO Grade 1-4), 44 (46%) were splenectomized, and 35 (36%) were receiving concomitant ITP treatment. Of the sixty-one subjects who entered into the study with a platelet count Stage Description Subjects entering Median Platelet counts (/uL) WHO Grade 2–4 Bleeding n (%) Stage 1 eltrombopag administered 94 16,000 25 (27%) Stage 2 tapering ITP con meds 17 143,500 4 (24%) Stage 3 titrating eltrombpag to maintain platelet counts 46 108,500 3 (7%) Stage 4 treating with eltrombopag long-term 27 104,000 1 (4%)