Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study.

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.

Chronic myeloid leukemia patients in Tunisia: epidemiology and outcome in the imatinib era (a multicentric experience).

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.

Tunisian adult's Hodgkin lymphoma Study Group.

The Tunisian adult's Hodgkin lymphoma (HL) Study Group was created in 1999. It aimed to improve the management of this curable hematologic malignancy by standardizing the diagnosis, assessment of disease, treatment management and therapeutic evaluation in different Tunisian centers (Hematology, oncology and radiotherapy).Since 1998, four versions of the prospective national protocol for treating adult Hodgkin lymphoma have succeeded (MDH99, MDH2002, MDH2008, MDH2015). Each version was based on the results of the previous version and analyzed according to new data from the literature. Due to this national study group, the number of patients lost to follow decreased significantly (30% before the creation of the group and only 3% for patients treated with MDH2008), the complete and uncertain response rates have improved (75% before the creation of the group and 92% in patients treated with MDH2008) with dramatically improved rates of overall survival from 57% to 90%. On the other hand there was an improvement of toxic death rate (13% of toxic deaths in MDH2002 to 4.37% in the MDH2008) with a decrease of the respective rate of primary failure and relapse by 17% and 12.5% in MDH2002 against the 11.4% and 7.8% in the MDH2008. This resulted in an improvement in overall survival (90%) and event-free survival at 5 years (75%). Now with the introduction of positron emission tomography in Tunisia, we hope yet to finalize the assessment of response and thus better adapt the treatment of this disease. Our objective remains the improvement of event-free survival rate to reach 80%.

Monocentric study of Willebrand's disease in Tunisia: assets and difficulties.

BACKGROUND: 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. AIM: We report the clinico-biological characteristics of VWD's patients and analyze diagnosis difficulties. METHODS: 33 cases were diagnosed in the laboratoryfrom February to May, 2011. Screening hemostasis included the measuring of FVIII: C, VWF: Ag and VWF: RCo. Blood cell count and blood group were performed in all cases. RESULTS: 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: Ag <0,7 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.

[Impact of early lymphopenia on the risk of febrile neutropenia and hematological toxicity]. / Impact de la lymphopénie précoce sur la survenue de neutropenia fébrile et de toxicité hématologique.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Primary adrenal lymphoma.

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.

[Quality of life during menstruation in women with an inherited bleeding disorder: report of 31 cases]. / Qualité de vie pendant les menstruations chez les patientes portueses d'un troble héréditaire de l'hémostase: a propos de 31 patientes.

BACKGROUND: 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. AIM: Assess the impact of menstrual blood loss on the quality of life for women with inherited bleeding disorders. METHODS: 31 women with various inherited bleeding disorders were interviewed. They completed a quality of life questionnaire. RESULTS: 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. CONCLUSION: 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.

Factor XI deficiency: About 20 cases and literature review.

INTRODUCTION: Factor XI deficiency is a rare coagulation disorder with variable bleeding manifestations. AIM: To evaluate the correlation between the degree of factorXI deficiency and the clinical expression of the disease. METHODS: 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. RESULTS: 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. CONCLUSION: Prospective multicenter studies including molecular study would be necessary to better elucidate this rare disorder.

Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Eltrombopag increased platelet counts in a dose-dependent manner in patients with relapsed or refractory ITP. (ClinicalTrials.gov number, NCT00102739.)

[Dysfibrinogenemia and thrombosis. A case report]. / Association dysfibrinogénémie et thrombose. A propos d'un cas.

BACKGROUND: Congenital dysfibrinogenemia is a functional disorder of the fibrinogen that represents a rare cause of thrombophilia. AIM: To report a Tunisian case of the association dysfibrinogenemia and thrombosis. CASE: 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. CONCLUSION: 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.

[Bacteriological profile of urinary tract infections in women in Aziza Othmana Hospital: 495 cases]. / Profil bactériologique des infections urinaires chez la femme à l'Hôpital Aziza Othmana: étude à propos de 495 cas.

BACKGROUND: Urinary infection is a frequent pathology in the community as well as at the hospital. AIM: To analyze the profile of bacteria isolated from urinary tract infectious in women and their antimicrobial resistance. METHODS: 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. RESULTS: 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 amikacin<14%,gentamicin<5%).Ofloxacin was highly active against enterobacteriacae (resistance<14%) CONCLUSION: 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.

[Thalassemia intermedia: 36 cases]. / La bêta thalassémie intermédiaire: a propos de 36 cas.

BACKGROUND: Thalassemia intermedia empasses a mild clinical and biological spectrum. The aim is to report the clinical and biological features and treatment of this disease. METHODS: It is a retrospective study about 36 thalassemia intermedia patients (17 males, 19 females). Epidemiological, haematological aspects and treatment were reported RESULTS: The 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). CONCLUSION: Thalassemia intermedia is well tolerated. Transfusions and splenectomy were indicated in case of hypersplenious.

A first case of congenital TTP on the African continent due to a new homozygous mutation in the catalytic domain of ADAMTS13.

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

[Surveillance of multidrug resistant bacteria in a Tunisian hospital]. / Surveillance des bactéries multirésistantes dans un hôpital Tunisien.

BACKGROUND: Controlling antibiotic resistance of bacteria is a priority for public healthcare. AIM: This study concerned the frequency of multidrug resistant bacteria (MDRB) in a Tunisian Hospital with the aim of establishing guidelines for MDRB prevention. METHODS: The study was conducted during two years (1 January 2005-31 December 2006). Samples collected for the clinical diagnostic were included. The MDRB concerned were: methicillin resistant Staphylococcus aureus(MRSA), Enterobacteriacae resistant to of third generation cephalosporin (ER3GC), Acinetobacter baumannii resistant to both imipenem and ceftazidime, Pseudomonas aeruginosa resistant to both imipenem and ceftazidime. RESULTS: During the study period, 2475 bacteria were tested by disk diffusion. 597 MDRB were collected, the rate of MBR was 24.1%. These MDRB were mainly recovered in burn unit (82.6%). ER3GC (47%) and MRSA (29,2%) were the most frequent MDRB. A. baumannii and P. aeruginosa multiresistant concerned 14,8% and 9% of MDRB. MDRB were isolated mainly from blood cultures (45%). The rate of MRSA was 46.4% among 375 strains of S. aureus. ER3GC represented 25,6% among 1096 isolates. Concerning A. baumannii and P. aeruginosa, 51.7% and 20.5% were resistant to both imipenem and ceftazidime among 170 and 264 isolates. Antibiotic resistance evolution showed a decrease of resistance in 2006 versus 2005. This decrease should be explained by the improvement of hygiene measure especially hand washing with the introduction of hydro- alcoholic solutions, a better targeted antibiotherapy promoted by a close cooperation between microbiologists and clinicians. CONCLUSION: The MDRB were frequent in our hospital. They were mainly isolated from the burn department. The measures of prevention already implemented are effective and must be strengthened with the continuous surveillance of MDRB.

[Tunisian National Protocol for Adult Hodgkin's Lymphoma Treatment: Results of a therapeutic regimen adapted to the 2-cycle CT response, about 444 patients]. / Protocole national Tunisien prospectif de traitement du Lymphome de Hodgkin de l'adulte : résultats d'un schéma thérapeutique adapté à la réponse par tomodensitométrie à 2 cycles, à propos de 444 patients.

OBJECTIVE: 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). PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

[Cytology and immunophenotype feautures of 80 acute myeloid leukemia]. / Caracteristiques cytologiques et immunophenotypiques de 80 leucemies aigues myeloides.

Acute myeloid leukemia (AML)'s diagnosis is clinical and biological. We report here 80 AML with cytology and immunophenotype features to establish correlations. 21 AML1, 23 AML2, 12 AML3, 2 AML4, 18 AML5 and 3 AML6 were diagnosed by cytology. Only one case of AML0 was diagnosed by immunophenotype. Myelogysplasia is present in 29.8% cases. CD19 and CD56 expression was significantly associated to AML +t(8;21). Additionally, concomitant negativity of CD34 and HLA-DR was discrimininatif to AML3 diagnosis. Prognostic value to expression some CD needs time backwards.

[Tumor lysis syndrome]. / Syndrome de lyse tumorale.

Tumor lysis syndrome is a potentially life threatening oncologic emergency that requires immediate medical intervention. The syndrome results from the destruction (or lysis) of a large number of rapidly dividing malignant cells spontaneously or during chemotherapy. The resulting metabolic abnormalities include hyperkaliemia, hyperuricemia, and hyperphosphatemia with secondary hypocalcemia, all of which put patients at risk for renal failure and alteration in cardiac function. The tumor lysis syndrome occurs most often in patients with large tumor burdens that are very sensitive to chemotherapy and radiotherapy, such as acute or chronic leukaemias with high leukocyte counts and high-grade lymphoma. The current standard management for tumor lysis syndrome consists of allopurinol or recombinant urate oxidase for high risk patient in conjunction with i.v. hydratation with or without alkalinization.

[Hemoglobin C disease: report of 16 Tunisian cases]. / L'hemoglobinose C: a propos de 16 cas Tunisiens.

AIM: was to provide the clinical and biological patterns hemoglobine disease in Tunisia. METHODS: This retrospective study collected to 16 cases of hemoglobin C disease : 6 homozygotic Hb C and 10 heterozygotic Hb C/beta-thalassemia. RESULTS: The clinical profile is characterized by mild hemolytic anemia (Hb = 11.7 g/dl) associated with splenomegaly and hypersplenism. Contrary to homozygous state, the Hb C/beta-thalassemia is associated with microcytosis and pseudopolycythemia. The diagnosis is based on target cells, specific intraerythrocytic Hb C crystals in blood smear and Hb C level at 100%. CONCLUSION: The Hb C disease must be considered as a benign hemoglobinopathy which is associated with a long survival without major complications.