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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.

Resume Introduction En Tunisie, la prise en charge du lymphome de Hodgkin de l’adulte est standardisee depuis 1999. Nous rapportons les resultats du protocole national de traitement du lymphome de Hodgkin de l’adulte (MDH2008). Patients et methodes Notre etude prospective et multicentrique a interesse 444 patients pris en charge pour un lymphome de Hodgkin entre juillet 2008 et juin 2013 et traites selon le protocole MDH2008. L’âge median de nos patients etait de 30 ans et 62,8 % avaient des symptomes B. La repartition selon la classification d’Ann-Arbor etait la suivante : stade I (3 %), II (42 %), III (26 %) et stade IV (29 %). Le protocole MDH2008 est base sur une strategie therapeutique adaptee a la reponse a deux cycles de chimiotherapie. Resultats Une reponse ≥ 75 % a deux cycles a ete obtenue chez 43 % des patients et le taux de reponse en fin de traitement etait de 92,1 %. Le taux d’echec primaire etait a 11,4 %. L’existence d’un gros mediastin (IMT ≥ 0,35) etait le seul facteur predictif independant d’echec primaire (p = 0,000). Dix-neuf deces toxiques (4,35 %) ont ete constates. Le taux des rechutes etait a 7,8 %. Les taux de survie sans evenement, de survie sans rechute et de survie globale a cinq ans etaient respectivement de 75 %, 89 % et 90 %. L’adaptation du traitement a la reponse a deux cycles etait efficace dans les stades localises defavorables et les stades etendus. Conclusion Compare au MDH2002, ce protocole a permis de diminuer le taux d’echec primaire, le taux de deces toxique au BEACOPP renforce et le taux des rechutes chez nos patients.

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.

Summary. Combined factor V (FV) and factor VIII (FVIII) deficiency (F5F8D) is a rare autosomal recessive disorder caused by mutations in LMAN1 or MCFD2 genes which encode proteins that form a complex involved in the transport of FV and FVIII from the endoplasmic reticulum to Golgi apparatus. We report two novel mutations in MCFD2 gene and one recurrent mutation in LMAN1 gene that caused combined FV and FVIII deficiency in two unrelated Tunisian Muslim families. For the first family two patients were homozygous for a new missense mutation Asp81His in exon 3 of MCFD2 and heterozygous for a second new missense mutation Val100Asp in the same exon. Replacement respectively of the hydrophilic Asp residue with hydrophobic positively charged His and of the hydrophobic neutral Val residue with the Asp residue most likely disrupts the MCFD2–LMAN1 interaction, thus leading to the disease phenotype. For the second family a reported Arg202X mutation in exon 5 in the LMAN1 gene was identified in the homozygous state.

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.

The development of imatinib is a milestone in the treatment of chronic myeloid leukaemia (CML), and its therapeutic effect has been extensively investigated in patients with CML who carry M-bcr and m-bcrBCR–ABL fusion transcripts. However, knowledge about its therapeutic effect on patients with CML who have the rare BCR–ABL fusion transcript e19a2 (μ-bcr) remains sparse. This report describes a patient with Philadelphia-positive chronic myeloid leukaemia with e19a2 rearrangement, in whom E355G mutation had been acquired. The patient was resistant to imatinib treatment based on conventional cytogenetic and fluorescence in situ hybridisation analysis.

From January 1997 to December 2005, 337 patients with aggressive non Hodgkin's lymphoma were treated with one of the two successive multicentric non randomized protocols established in Tunisia. The mean age was 53 years. Most patients had diffuse large cell lymphoma with B phenotype in 86% and T in 14%. The performance status was 2 or 3 in 34% of cases. The LDH were elevated in 74% of cases. Advanced disease (III or IV stage) was noted in 59% of cases and 10% had a tumoral mass greater than 10 cm. According to the international prognostic index (IPI) adjusted to age, we distinguish four groups: group 1 (0 factor and age 70 years). The patients of group 1 (N = 47) received 3 courses of CHOP regimen followed by irradiation. The patients of group 2 (N = 160) received 4 courses of ACVBP regimen (+ rituximab for 21 patients) followed by consolidation (N = 92) or peripheral blood progenitor cell transplantation (N = 20). The patients of group 3 (N = 61) received 8 courses of CHOP regimen (+ rituximab for 20 patients). The patients of group 4 (N = 69) received 6 courses of mini-CEOP regimen (N = 48) or 6 courses CVP regimen (N = 21). The 4-year overall survival was 56% and the 4-year event free survival was 49%.

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.

Von Willebrand's disease (VWD) is the most commonly inherited bleeding disorder. It is characterized by clinical, biological and molecular heterogeneity. In certain types of the disease, diagnosis can be difficult.We report the clinico-biological characteristics of VWD's patients and analyze diagnosis difficulties.33 cases were diagnosed in the laboratoryfrom February to May, 2011. Screening hemostasis included the measuring ofC, VWF: Ag and VWF: RCo. Blood cell count and blood group were performed in all cases.Mean age at diagnosis is 13 years [10 months -43 years]. The sex ratio M/F is 0.5. The patients are classified type 3 VWD in 52% of the cases, type 2 VWD in 30 % of the cases and type 1 VWD in 18 % of the cases. The diagnosis of type 2B VWD suspected in combination of the ratio VWF:RCo / VWF: Ag0,7 and thrombocytopenia in one case. Required tests for positive diagnosis and distinction between the primary categories of VWD are available. Specialized tests will allow a best characterization variants type 2 VWD for a better therapeutic approach.

Background: Rituximab, administered intravenously (IV), is the mainstay of treatment for CD20+ B-cell non-Hodgkin lymphoma (NHL). A subcutaneous (SC) formulation has been approved in Europe and other countries based on the SABRINA study, which showed non-inferior pharmacokinetics and comparable safety and efficacy for rituximab SC compared with IV in treatment-naïve patients with follicular lymphoma (FL) (Davies A, et al. Lancet Oncol 2014;15:343-52). Furthermore, rituximab SC reduces healthcare resource burden (De Cock et al. PLoS One 2016;11:eD157957) and improves patient satisfaction and convenience compared with IV (Rummel et al. Blood 2015;18:A469). MabRella is a global umbrella study comprising three local open-label, single-arm, Phase 3b studies evaluating the safety of first-line (1L) rituximab SC treatment in patients with FL or diffuse large B-cell lymphoma (DLBCL) with a focus on administration-related reactions (ARRs). The studies share a core protocol, study endpoints, and timepoints, but have flexibility for modifications at local level. Data from participating countries is pooled for pre-defined global analyses. Methods: Patients were aged 18-80 years with grade 1-3a FL or DLBCL, and ECOG PS of ≤3. All patients had received ≥1 full dose of rituximab IV as 1L induction or maintenance prior to study entry, and were eligible to receive at least 4 additional cycles of induction or 6 additional cycles of maintenance. Patients with FL or DLBCL receiving induction therapy were treated with rituximab SC 1400mg every cycle (14, 21, or 28 days) for 4-7 cycles, in combination with standard chemotherapy. FL patients undergoing maintenance treatment received single-agent rituximab SC 1400mg every 2 months for 6-12 cycles. The primary endpoint was incidence of ARRs following multiple doses of rituximab SC; ARRs were defined as all adverse events (AEs) occurring within 24 hours of rituximab administration and considered related to the study drug by the investigator. Secondary safety endpoints included grade ≥3 AEs and serious AEs (SAEs). The safety analysis included all patients who received ≥1 dose of study treatment. Safety data were not collected for rituximab IV, as patients entered the trial after they had switched to SC. Data are presented from a planned interim analysis of safety (cut-off March 31, 2016). Results: At the data cut-off, the safety population comprised 336 patients: 157 from Italy; 139 from Spain; and 40 from North Africa (Tunisia and Algeria). The median (range) age was 59 (19-80) years and 50% patients were male; 205 patients had FL and 131 had DLBCL. With respect to patients with FL, 84 completed ≥1 cycle of rituximab SC induction (37 completed all 7 cycles) and 190 completed ≥1 cycle of maintenance (169 completed 6 cycles and 26 completed all 12 cycles). Among DLBCL patients, 37 completed all 7 cycles of induction. Overall, 282 patients (84%) experienced an AE during treatment (Table 1). ARRs were observed in 75 patients (22%), the most common of which (≥2% incidence) were erythema (12%) and injection-site erythema (4%). Other AEs reported in ≥10% of patients were neutropenia, asthenia, erythema, pyrexia, and diarrhea (Table 1). Grade ≥3 AEs occurring in ≥5% of patients were neutropenia (24%) and febrile neutropenia (6%). Grade ≥3 ARRs were observed in 4 patients (1%). SAEs were reported in 29% of patients (8% drug-related). Of 11 deaths attributed to AEs, 2 were considered to be related to treatment (Klebsiella infection and sepsis). The safety profile of rituximab SC was generally comparable between FL and DLBCL patients, although neutropenia (any grade and grade ≥3) was more prevalent in DLBCL patients, while erythema (any grade) was more common in FL patients (Table 1). The profile of AEs was similar during induction and maintenance, but the intensity and seriousness of events was lower during maintenance (Table 2). Geographic location (Spain, Italy, North Africa) of study sites did not appear to impact on the safety profile of rituximab SC. Conclusions: In line with previous reports (Davies et al. 2014), rituximab SC is well tolerated during the 1L treatment of patients with NHL. The safety profile of 1L rituximab SC is similar to reports for IV administration, with the exception of an expected increase in ARRs, the majority of which are mild or moderate in intensity, and resolve spontaneously. Disclosures Panizo: Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche Pharmaceuticals: Speakers Bureau. Rigoroso Mendoza:F Hoffmann La Roche Ltd: Employment. Truman:Aurinia Pharmaceuticals: Consultancy; F Hoffmann La Roche Ltd: Consultancy, Equity Ownership. Smith:F. Hoffmann La Roche Ltd.: Employment.

International audience; Hypereosinophilic syndromes (HES) are a heterogenous group of rare disorders characterized by sustained and otherwise unexplained overproduction of eosinophils with organ involvement and consecutive dysfunction. Detection of the FIP1L1-PDGFRA fusion gene or the corresponding cryptic 4q12 deletion in HES supports the diagnosis of chronic eosinophilic leukemia (CEL) and provides a molecular explanation for the pathogenesis of this disorder. We screened seven Tunisian patients fulfilling the WHO criteria of HES for the presence of the FIP1L1-PDGFRA fusion gene using nested reverse transcription polymerase chain reaction on peripheral blood samples. Four of the seven patients were positive for this fusion gene. Sequence analysis revealed a substantial heterogeneity of the fusion transcripts due to the involvement of several FIP1L1 exons. All patients were male. The median age at diagnosis was 24 years (range, 18-50); one patient had a history of hypereosinophilia of more than 10 years. Two patients had clinically important and symptomatic eosinophilic endomyocardial disease with thrombotic events. Splenomegaly was constant in FIP1L1-PDGFRA positive CEL but not in the other HES patients (only 1/3).; Les hyperéosinophilies essentielles sont caractérisées par une hyperéosinophilie supérieure à 1500 éléments/mm 3 persistante au-delà de sixmois, après exclusion d ’ une éosinophilie réactionnelle. Différentes altérations viscérales peuvent s’y associer leur pronostic est souvent redou-table et jusqu’à une période récente, il n’existait pas de traitement spécifique ou réellement efficace. En 2003 un gène de fusion :FIP1L1-PDGFR alpha a été retrouvée de façon récurrente dans ces syndromes, ce gène de fusion est généré à la suite d’une délétion interstitielle en 4q12 qui est cryptique à l’ analyse cytogénétique standard, la protéine chimérique résultante a une activité tyrosine kinase constitutive qui répond au traitement par l’ imatinib utilisé par ailleurs pour le traitement de la leucémie myéloïde chronique. Nous rapportons quatre cas d’hyperéosinophilie associéesà ce remaniement génétique

Summary Some progress has been made regarding availability of recombinant factor VIII concentrates and prophylaxis for haemophilia A in emerging countries, where plasma-derived concentrates were used in the vast majority. Clinical studies to document their introduction and effectiveness are so far not widely available in literature. This non-interventional study evaluates the real-life effectiveness and safety of prophylactic and on-demand treatment with recombinant factor VIII formulated with sucrose (rFVIII-FS) for bleed control and preservation of joints in emerging countries from Eastern Europe, North Africa and Middle East area. One hundred and eighty-six patients from 11 countries were enrolled, mean ± SD age 12.8 ± 12.7 years. At enrolment, majority (79.6%) had severe haemophilia A (

We report two cases of atypical defibrination syndromes in patients with respectively acute monoblastic leukemia (chronic myeloid leukemia initially) and acute lymphoblastic leukemia. Hemostasis studies show low fibrinogen level, elevated D-dimers, decreased alpha 2 antiplasmin and factor V, normal antithrombin III values. Plasminogen is below the normal range in one patient. Soluble complexes, which are an important argument for diagnosis of intravascular coagulation disease, are not detected in both patients. Primary or secondary hyperfibrinolysis seems also excluded since euglobulin clot lysis time was normal. Enzymatic proteolysis of fibrinogen (or fibrin) by the blast cells has been reported by some authors; this mechanism could account for the hemostasis abnormalities observed in these two patients.

Differentiation syndrome (DS) is a life-threatening complication observed in patients with acute promyelocytic leukemia (APL) receiving induction therapy with all-trans-retinoic acid (ATRA). A bimodal incidence of DS has been observed, with a majority of cases occurring during the first week of ATRA treatment ("early" DS), but a substantial number of cases occurring during the third or even fourth week of ATRA treatment ("late" DS). However, to our knowledge occurrence of both early and late DS in the same patient has not been reported. We report an APL patient treated with the AIDA regimen, who experienced both early and late DS, a situation where differential diagnosis was difficult.

Background. Gram-positive bacteremia (GPB) is an increasing infection after allogeneic bone marrow transplantation (BMT). Our purpose was to identify risk factors for GPB, to evaluate its impact on early mortality and morbidity, and to compare prophylactic with empirical intravenous vancomycin. Methods and Results. We studied 89 consecutive BMTs in adult patients. Early GPB occurred in 29% of posttransplantation episodes. T-cell depletion (odds ratio [OR]: 0.18) and vancomycin-prophylaxis (OR: 0.28) reduced the risk of GPB. Mortality at 6 weeks was not significantly different in patients with GPB (15% vs. 9.5%, P =0.669). GPB was associated with the development of major complications, the use of amphotericin B, and prolonged neutropenia. Vancomycin prophylaxis led to an increased risk of early renal dysfunction (OR: 18.7). Conclusion. GPB contributes to overall morbidity during the early post-BMT episode but has no impact on mortality. Vancomycin prophylaxis is effective to reduce GPB but has a negative effect on renal function.

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

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) remained 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.

The aims of this study are to investigate the frequency of derivative chromosome 9 (der (9)) deletion in Tunisian patients with chronic myeloid leukemia (CML) and to assess the correlation between this deletion and the cytogenetic response for patients treated with hydroxyurea (HU) or imatinib (IM). Karyotype analysis of 336 patients with CML was performed with R-banding technique. Fluorescence in situ hybridization (FISH) was carried using home-brew probes 17L7 and 248J22 for detecting, respectively, adjacent 5′ABL and 3′BCR deletions on der(9). Cytogenetic study demonstrated typical t(9;22)(q34;q11) translocation in 89.6% and variant translocation in 10.4% of patients. Interphase FISH studies showed deletion of der(9) in 59 (17.6%) of the 336 patients, 23 (39%) of them had variant rearrangements. There are 19 patients with solely 5′ABL deletion and 40 with concomitant 5′ABL and 3′BCR deletions. Cytogenetic response was evaluated during 18 months with HU or IM therapy. Our results demonstrate that (a) 3′BCR deletion is associated with 5′ABL deletion in all patients with der(9) deletions, (b) the 5′ABL and 3′BCR deletions arise simultaneously with t(9;22), (c) deletions on der(9) chromosome were frequently encountered in older patients and in patients presenting variant rearrangements, (d) both 5′ABL and 3′BCR deletions were associated with cytogenetic response failure in patients treated with HU, however, patients treated with IM and carrying der(9) deletions presented better cytogenetic response.

Reports on childhood APL from developing countries are scarce. We treated 65 APL with two consecutive trials combining ATRA and chemotherapy. Twenty (30.7%) were aged less than 20 years including 11 girls and 9 boys, with a median age of 12 years. Fever at presentation (P = 0.002) and variant APL (P = 0.044) were more frequent in children, while there were no significant difference between children and adults for WBC count, Sanz’s score distribution and additional cytogenetic abnormalities. The CR rate was 95% (19/20) in children and 80% (36/45) in adults (P = 0.13). Differentiation syndrome (DS) was less often observed in children (1/20) than in adults (13/45) (P = 0.031). Two children relapsed and died during salvage therapy, and 2 died in CR from infection and from cardiac failure attributed to anthracyclines, while other children remained alive in CR. With a median follow-up of 4 years, 4-year EFS was 75% in children and 71.1% in adults (P = 0.57), while 4-year OS was 75% in children vs. 73.3% in adults (P = 0.72). Our results suggest that, even in the absence of optimal socio-economic condition, ATRA combined with anthracycline-based chemotherapy gives adequate results in childhood APL, as in adults.

Transfusion-related acute lung injury (TRALI) is a clinical syndrome characterized by sudden onset of respiratory distress due to pulmonary edema during or following transfusion. Two proposed pathophysiologic mechanisms for TRALI were proposed: the antibody hypothesis and the two-event hypothesis. The two-event hypothesis postulates that a pathway to neutrophil activation and aggregation can occur without leukocyte antibodies. We report a case of TRALI occurring during remission induction course of acute myeloid leukemia in a 27-year-old woman who received All-transretinoic-acid (ATRA). We postulate that ATRA may have played a role in this life-threatening complication by priming neutrophil and enhancing their adherence and their activation in the pulmonary endothelium. TRALI improved with non-invasive ventilation support and use of high dose corticosteroids.

The pathogenesis of chronic idiopathic thrombocytopenic purpura (ITP) involves antibody-mediated platelet destruction and reduced platelet production. Stimulation of platelet production may be an effective treatment for this disorder.We conducted a trial in which 118 adults with chronic ITP and platelet counts of less than 30,000 per cubic millimeter who had had relapses or whose platelet count was refractory to at least one standard treatment for ITP were randomly assigned to receive the oral thrombopoietin-receptor agonist eltrombopag (30, 50, or 75 mg daily) or placebo. The primary end point was a platelet count of 50,000 or more per cubic millimeter on day 43.In the eltrombopag groups receiving 30, 50, and 75 mg per day, the primary end point was achieved in 28%, 70%, and 81% of patients, respectively. In the placebo group, the end point was achieved in 11% of patients. The median platelet counts on day 43 for the groups receiving 30, 50, and 75 mg of eltrombopag were 26,000, 128,000, and 183,000 per cubic millimeter, respectively; for the placebo group the count was 16,000 per cubic millimeter. By day 15, more than 80% of patients receiving 50 or 75 mg of eltrombopag daily had an increased platelet count. Bleeding also decreased during treatment in these two groups. The incidence and severity of adverse events were similar in the placebo and eltrombopag groups.Eltrombopag increased platelet counts in a dose-dependent manner in patients with relapsed or refractory ITP. (ClinicalTrials.gov number, NCT00102739.)

Current APL chemotherapy protocols usually include high-dose anthracyclines, mitoxantrone, and epipodophillotoxins, which are topoisomerase II inhibitors of high leukemogenic potential. In the last years, several case reports of myelodysplastic syndrome (MDS) or AML (different from APL), occurring during the course of APL have been made. We report herein a first case of CMML with monosomy 7 occurring after treatment of APL.

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.

e126 relapse of 23,8 months [6-69]. One patient had CNS MM at diagnosis and 4 patients in first relapse. Three patients presented intraparenchymal focal lesions, 1 CNC myelomatosis and 1 intraparenchymal focal lesion associated with leptomenigeal infiltration. The patient, who presented CNS MM at diagnosis, received VCD followed by ASCT and he is in CR with a follow up of 19 months. Four patients presented CNS MM in relapse: 2 were treated with Lenalidomide and dexamethasone (Len+Dex) with an overall survival of 1 and 2 months since the diagnosis of CNS MM and 2 were treated with VCD (1 patient had an overall survival of 12 months and 1 is in VGPR with a follow up of 14 months since the diagnosis of CNS MM). Conclusion: There are no treatment guidelines for CNS MM and few new drugs cross the blood-brain barrier. The median overall survival from the time of diagnosis of SNC MM ranges from 2 to 6 months. Clinical results seem better when CNS involvement occurs at diagnosis compared to relapse setting. Clinical trials involving these patients are essential to improve outcomes.

The optimal management of malignant haematological disorders depend on the degree of tumor load reduction after therapy. Chronic myeloid leukemia constitutes a clinical model for molecular detection and therapy surveillance of malignant disease since this entity was the first leukemia shown to be associated with a specific bcr-abl fusion gene in the patient's leukemia cells. Molecular monitoring of bcr-abl transcript levels by real-time quantitative PCR is increasingly used to assess treatment response in patients with chronic myeloid leukemia (CML). This has become particularly relevant in the era of imatinib therapy when residual levels of leukaemia usually fall below the level of detection by bone marrow cytogenetic analysis. We monitored bcr-abl transcript levels by quantitative real time PCR in 50 tunisian patients treated with imatinib for chronic myeloid leukemia in chronic phase for a median of 29 months (3-60) after they started imatinib.

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.

Haemophilia B disease is a recessively inherited X-linked bleeding disorder which results from deficiency of factor IX (F9). Haemophilia B has a frequency of approximately 1 in 25 000 men worldwide [1]. Haemophilia B results from heterogeneous mutations spread throughout the F9 gene [2]. According to the World Federation of Hemophilia Report on the annual global survey 2007, 51 haemophilia B in Tunisia have been reported [3]. In this first study on Tunisian haemophilia B, we report the molecular analysis of 16 unrelated haemophilia B families. Patients involved in this study were from the Hemophilia Treatment Center, Aziza Othmana hospital, Tunisia. Informed consent was obtained from all patients. Molecular analysis was performed using the following strategy: polymerase chain reactions for the entire coding sequence of the F9 gene were prepared as described previously [4]. The mutation detection protocol was performed by dHPLC on a WAVE DNA Fragment Analysis System (Transgenomics, San Jose, USA). Altered profiles detected by dHPLC were sequenced using ABI Dye Terminator Cycle Sequencing (Perkin-Elmer Applied Biosystems, Foster City, CA, USA) and analysed using a capillary sequencer Genetic Analyser ABI PRISM310 (Perkin-Elmer Applied Biosystems, Foster City, CA, USA [4]. Results were analysed using BLAST (http://www.ncbi.nlm. nih.gov/blast) program against the normal F9 gene sequence (GenBank Accession No. K02402) and the mutations were compared with the haemophilia B mutation database (http://www.umds.ac.uk/molgen). To evaluate the nature of missense mutations, we used PolyPhen (Polymorphism Phenotyping) (http://genetics.bwh.harvard.edu/pph). Our cohort is composed of 30 patients belonging to 16 unrelated families who represent 60% of total haemophilia B Tunisian population. A total of 15 different mutations were detected (Table 1), except for one family that did not show any mutations. In addition, the polymorphism g.20421A>G in exon 6 was also identified in five families. Five novel mutations were identified in five patients including 2 missense mutations, 1 nonsense mutation, 1 splice site mutation and one small deletion. For patient Hb 2, a deletion of CAG sequence from the 17795 to 17797 position inducing the loss of the last acid Ala173 in exon 5 (The numbering of the amino acids is according to the Swiss-Prot PZES (P00740)). For patient Hb10, a T to A substitution at nucleotide position 113 which changes a Cys acid in a codon stop (Cys27X) in exon 1, which will result in nonsense-mediated RNA decay and produce a severe phenotype as no protein will be translated, has been revealed. Patient Hb12 shows an acceptor splice substitution at the position 10507 in intron 4 (+2T > C). For Patient Hb14, a substitution of T to A at the position 31286 in exon 8, change the Cys 435 to Ser. Patient Hb16 present a substitution of G to A at the position 30932 in exon 8, which change Ala 317 to Thr. Replacement of a non-polar amino acid residue by a polar one is likely to affect the function, secretion or stability of the protein. Using PolyPhen these two mutations are predicted to be probably damaging with a score of 1.000 and 0.995 respectively. The question of whether these two candidate mutations Cys435Ser and Ala317Thr are pathogenic and alter the three-dimensional structure and function of F9 protein needs further investigation. However, as the latter mutations along with, Ala173Del, Ala317Thr and Cys435Ser occurred at amino acid residues highly conserved among different species, they may be involved in the F9 destabilization. Compared with previously published reports [5], we found that the two deletions identified in our patients bearing a severe disease. However, in our patient cohort the two nonsense mutations were associated with different phenotypes, severe and moderate disease respectively in patient Hb17(FIX:C level of 4) which is at variance with the majority of entries on the haemophilia B database for this mutation (which cite FIX:C and antigen levels of

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.

Background: Hemophilia is a hereditary bleeding disorder characterized by a deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B). It is established that hemophilia is a ubiquitous condition that affects one birth in 10,000, regardless of race or geographic region. We propose in this work to assess the incidence of hemophilia in the North of Tunisia with a literature review. The hemophilia treatment center at the hospital Aziza Othmana supports patients in northern Tunisia, which represents 60% of all tunisians cases. The estimated number of inhabitants is 5.19 million (50% of the country population). Methods: Assays of factors VIII and IX are performed by STA Compact, Stago®. Confirmation of the diagnosis ismade on two different samples. Results: Twenty cases of hemophilia were diagnosed between January 2010 and December 2011 in our center. The average of age was 3.37 years (2 months-28 years). The most frequent circumstances of diagnosis are hematomas and hemarthrosis following minor trauma (12 cases). Family history of hemophilia is found in 6 cases. For all patients, an isolated prolonged APTT with a correction to the mixture test was found. We note 15 cases of hemophilia A and 5 cases of hemophilia B. The distribution of cases according to severity is: severe (9 cases), moderate (8 cases) and minor (3 cases). Comment: The incidence of hemophilia on the north of Tunisia is 1.1cases per 10 000 births per year. The incidence found in our series corresponds to the incidence reported in the literature. However, the prevalence of hemophilia diagnosed in Tunisia remains low only 50% of the theoretical number of hemophilia is diagnosed.