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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.

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.

In Tunisia, the management of Adult Hodgkin's Lymphoma (HL) has been standardized since 1999. We propose in this study to report the therapeutic results of the national protocol of adult HL treatment (MDH2008).Our study is prospective multicenter interesting 444 patients followed for HL between July 2008 and June 2013 and treated according to the MDH2008 protocol. The median age of our patients was 30 years. B symptoms were present in 62.8 % of our patients. According to the Ann Arbor classification, our patients were in stages I, II, III and IV in 3 %, 42 %, 26 % and 29 %, respectively. The MDH2008 protocol is based on a strategy adapted to the therapeutic response to 2 cycles of chemotherapy.Response≥75 % to 2 courses of chemotherapy was achieved in 43 % of patients and the response rate at the end of treatment was 92.1 %. Forty-eight patients (11.4 %) had primary failure. In the multi-variant study, bulky mediastinal mass (IMT≥0.35) was an independent predictive factor of primary failure (P: 0.000). Nineteen toxic deaths (4.35 %) were reported. The relapse rate was 7.8 %. Event free survival, relapse-free survival and overall survival at 5years were 75 %, 89 % and 90 %, respectively. Adaptation of the treatment to the 2 cycles response was effective in unfavorable early stages and advanced stages.Compared to MDH2002 (second version of Tunisian prospective protocol), the MDH2008 reduced the primary failure rate, the rate of toxic deaths with escalated BEACOPP and the rate of relapse in Tunisian patients.

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

Hematologic toxicity is a severe complication of chemotherapy. The objective of our study is to evaluate the impact of early lymphopenia on the risk of occurrence of febrile neutropenia and hematological toxicity after aggressive chemotherapy for Hodgkin lymphoma or high grade non-Hodgkin lymphoma.This prospective study involved 42 patients who received 193 cycles of chemotherapy in 2009. We assessed the impact of lymphopenia on day 1 and 8 on the risk of occurrence of febrile neutropenia. We also investigated the relation between the occurrence of hematologic toxicity after the first cycle and the subsequent cycles.Febrile neutropenia was observed in 25% of cycles. Grade 3/4 hematologic toxicity occurred in 63% of cycles. Growth factors were used in 79% of cycles. Lymphopenia ≤ 700/mm3 on day1 and 8 was noted in 21% and 65% of cycles. If the lymphocyte count was ≤700/mm3 on day1, the risk of febrile neutropenia was significantly higher (p=0.042) and the mean duration of antibiotic therapy longer (p = 0.013). Lymphopenia ≤700/mm3 on day 8 was associated with a greater risk of febrile neutropenia in univariate analysis (OR=2.4; p=0.02). Moreover analyzes showed that this factor was significantly associated with increase in hematologic toxicity (p=0.02), duration of neutropenia (p=0.001) and duration of antibiotics (p=0.05). Hematologic toxicity during the first cycle was predictive of its occurrence in subsequent cycles of chemotherapy (p=0.028).Our results confirmed the impact of early lymphopenia on the occurrence of febrile neutropenia and hematologic toxicity after aggressive chemotherapy for Hodgkin lymphoma or high grade non Hodgkin lymphoma.

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.

Methotrexate (MTX) is a folic acid antagonist used at high-dose intravenously on 24 hours (24h) in the treatment of the acute lymphoblastic leukemia (ALL). To prevent potential toxicity, MTX is usually administered following the application of preventive measures. We report a case of an accidental shortening time for high dose MTX infusion and a literature review of accidental intoxications by the MTX. This case illustrates the importance of the respect of MTX high dose infusion time and the major role played by the therapeutic drug monitoring.

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.

Menstruations, by their abundance and their duration, can be a source of impaired quality of life. Women with inherited bleeding disorders appear to be, specially at risk.Assess the impact of menstrual blood loss on the quality of life for women with inherited bleeding disorders.31 women with various inherited bleeding disorders were interviewed. They completed a quality of life questionnaire.Von Willebrand disease was the most frequent inherited bleeding disorder in our population (38.7%). 54.8% of patients had a menstrual period more than 6 days 61.3% of them consider their menstrual flow to be normal. The general condition apart of the menstrual period was considered medium to poor in 35.5% of patients. The average score assessing the impact of menstruation on daily life was of 5.00 ± 3.47. Only 19.35% of patients felt that dysmenorrhea significantly affect their quality of life. Impaired quality of life was seen in 64.5% of patients according to score Aand in 41.9% of them according to score B. During menstruation 22.6% of the patients didn't do to work or to school because of the menstrual flow. On the other hand, 48.4% of patients were hospitalized at least once for a heavy menstrual flow.The quality of life during menstruation, in women with an inherited bleeding disorder, according to the different scores appear altered. Although because of the small size of our study population, we could not prove correlation between the importance of menstrual blood loss and the impairment of quality of life.

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.

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.

Urinary infection is a frequent pathology in the community as well as at the hospital.To analyze the profile of bacteria isolated from urinary tract infectious in women and their antimicrobial resistance.During two year period (1 January 2005 to 31 December 2006), 4536 urinary specimens were analyzed at the Laboratory of Aziza Othmana Hospital. All bacteria isolated from urinary tract infection (UTI) at women were retrospectively reviewed.495 cases of UTI were collected during this period. They were recovered from out patients (67%) or from hospitalized patients in Gynecology and obstetrics (23%). Enterobacteriacae were the most frequently identified strains (90.4%) including Escherichia coli (71%). The identified strains presented natural resistance and a high frequency of acquired resistance to betalactams(60.3% of E.coli, 72% of P.mirabilis were resistant to amoxicillin)and cotrimoxazole(30.4% of E.coli, 19,1 of K.pneumoniae, 21.4% of P.mirabilis). 5.7% of K.pneumoniae and 1.8% of E.coli were producing extended spectrum betalactamase(ESBL). Aminoglycosides remained active on enterobacteriacae(resistance to amikacin14%,gentamicin5%).Ofloxacin was highly active against enterobacteriacae (resistance14%)Enterobacteriacae were the most frequent species in women urinary tract infection. Among these isolates, a high frequency of acquired resistance to betalactams and cotrimoxazole was shown. Aminoglysosides and fluoroquinolones remained the most active drugs. In every case antibiotherapy should have been prescribed after performing an antibiogram for each strain. These data were useful for the first line antibiotherapy, however the antimicrobial susceptibility testing is necessary for the rational use to limit the highly active drugs to multiresistant strains.

Congenital dysfibrinogenemia is a functional disorder of the fibrinogen that represents a rare cause of thrombophilia.To report a Tunisian case of the association dysfibrinogenemia and thrombosis.A woman with inherited dysfibrinogenemia associated with mild tendency to bleeding experienced a deep vein thrombosis of the lower-extremity at 26 years of age and a fatal pulmonary embolism a few years later. Paradoxically coagulation function of fibrinogen was markedly altered in vitro with a significantly prolonged prothrombin time, activated partial thromboplastin time and thrombin time, a functional fibrinogen level that was undetected and a severely impaired fibrin polymerisation. The thromboembolic events in the patient could be related to dysfibrinogenemia since the main causes of thrombophilia were excluded.Although it is rare, this cause of thrombophilia must not be misdiagnosed, systematic measuring of prothrombin time, activated partial thromboplastin time and functional fibrinogen might be helpful.

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.

Thalassemia intermedia empasses a mild clinical and biological spectrum. The aim is to report the clinical and biological features and treatment of this disease.It is a retrospective study about 36 thalassemia intermedia patients (17 males, 19 females). Epidemiological, haematological aspects and treatment were reportedThe diagnosis was carried out at a relatively old age 15 years (1-72).The thalassemia intermedia was characterized by mild facial deformities, splenomegaly and moderate anemia ( Hb = 9.1 g/dl). The mean serum ferritin was 518 ng/ml (25-1800). Three phenotypes are caracterised: heterozygosis beta thalassemia, beta degrees thalassemia and beta + thalassemia. Clinical complications were hypersplenism, extra medullary hematopoiesis, leg ulcers, thrombosis and pulmonary hypertension. Treatment was based on occasionally transfusion and splenectomy on event of hypersplenious (47%). Evolution of this disease was generally good with a long lifespan at 31 years (6-83).Thalassemia intermedia is well tolerated. Transfusions and splenectomy were indicated in case of hypersplenious.

International audience; Increased BMI has been correlated to an increased incidence of APL, but not to the occurrence of differentiation syndrome (DS) in APL. We consecutively treated 39 APL patients with ATRA and idarubicin ( according to PETHEMA regimen). Median age was 26 years. Forty-one percent patients were classified as intermediate risk, and 59% as high risk according to Sanz's score. Thirty-three patients (85%) reached CR. Eleven of the 36 patients evaluable for DS (30.5%) developed this syndrome (severe in 7 cases, moderate in 4, and fatal in 3 cases) within a median of 12 days (range 3-23) of ATRA onset. Six of the 9 (66.6%) patients with BMI >= 30 developed DS vs. 5 of 27 (18.5%) with BMI= 40 year (p = 0.033), baseline WBC >= 20 x 10(9)/l (p = 0.003), and creatinine > 1.4 mg/dl (p = 0.009). In multivariate analysis, BMI >= 30 remained an independent predictor of DS in addition to baseline WBC >= 20 x 10(9)/l. (C) 2009 Elsevier Ltd. All rights reserved.