[Immunophenotyping in adult acute myeloid leukemia: which prognostic value?]. / Immunophénotypage des leucémies aiguës myeloïdes de l'adulte : quelle valeur pronostique ?

BACKGROUND: Immunophenotyping is an essential step in the diagnosis of acute myeloid leukemia. Its prognostic value remains controversial with contradictory results. AIM: To assess prognostic impact of the immunophenotyping in AML. METHODS: Our study is retrospective (October, 2005 - July, 2007) concerning 56 cases of AML (AML3 excluded) of the adult from 18 to 55 years old diagnosed and treated in Tunis Aziza Othmana Hospital. The immunophenotyping was performed by flow cytometry (Beckman Coulter EPICS XL MCL®). We studied clinical and biological characteristic, immunophenotypic expressions, and parameters of the response to the treatment: complete remission (CR), overall survival (OS), relapse free survival (RFS) and relapse in a delay of 1 year and 2 years. SPSS software was used to perform the statistical analysis. RESULTS: The median age of the patients is of 37,7±11.8 years. Sex ratio (M/F) is 1.33. Among individual antigenic expressions, only CD7 is associated to lower CR rates (p=0.044). We did not find any statistically significant association between immunophenotypic expressions and OS nor with relapse or RFS. CONCLUSION: The impact of immunophenotyping in AML remains controversial because of contradictory results. The research of molecular changes would be an interesting alternative in our context.

Cytogenetic profile of a large cohort of Tunisian de novo acute myeloid leukemia.

BACKGROUND: Cytogenetic data are essential not only for the diagnosis of acute myeloid leukemia but also for the evaluation of prognosis. Large systematic studies of cytogenetic aberrations in patients with acute myeloid leukaemia (AML) from Arab countries are not available. METHODS: We analysed 631 consecutive newly diagnosed AML patients by conventional cytogenetics and compared our results with reports from other regions of the world. There were 97 (15·4%) children and 534 (84·6%) adults. RESULTS: Abnormal karyotypes were found in 397 (62·9%) of all cases. T(15;17) and t(8;21) were the most frequent chromosomal abnormalities observed in 83 (13·2%) and in 78 (12·4%) patients, respectively. -5/del(5q) and -7/del(7q) were less frequent, seen in only 14 (2·2%) and 19 (3%) cases, respectively. Trisomy 8 was found in 44 (7%) of our patients followed by 11q23 rearrangements seen in 24 (3·8%) and then by inv(16) observed in only 22 (3·5%) of all cases. Unusual or novel cytogenetic abnormalities were found in 107 (17%) of our patients. DISCUSSION: Although we confirmed, as usually described, that some recurrent cytogenetic abnormalities are correlated with the FAB subtypes, we noted however that some of them vary in frequency among different geographical areas and ethnic groups. This finding suggests a geographic heterogeneity in the pathogenesis of AML but more extensive epidemiological studies are required to confirm this.

Treatment of Acute Promyelocytic Leukemia with AIDA Based Regimen. Update of a Tunisian Single Center Study.

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.

Risk factors of septic shock in patients with hematologic malignancies and Pseudomonas infections.

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 lactate >5 mmol (P = 0.05), hemoglobin level <50 g/l (P = 0.042), hypoproteinemia <50 g/l (P = 0.01), procalcitonin >10 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.

ATRA and anthracycline-based chemotherapy in the treatment of childhood acute promyelocytic leukemia (APL): A 10-year experience in Tunisia.

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.

Recurrent differentiation syndrome or septic shock? Unresolved dilemma in a patient with acute promyelocytic leukemia.

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.

Treatment of acute promyelocytic leukemia with PETHEMA LPA 99 protocol: a Tunisian single center experience.

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.

Factors associated with severe sepsis: prospective study of 94 neutropenic febrile episodes.

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 (<0.5 x 10(9)/l) lasting for more than 7 days were included in this study. The median age was 28 years (range: 3-58 years). All patients were on oral antibacterial (colistin and gentamicin) and anti-fungal (amphotericin B) prophylaxis. The first neutropenic febrile episode was treated with piperacillin/tazobactam and colistin IV; if the patient remains febrile at 48 h from the start of this first line of treatment, amphotericin B i.v. is added. Imipenem was introduced in the case of non-response and finally glycopeptides were introduced according to the IDSA criteria. Severe sepsis and septic shock are defined according to the criteria of the consensus conference of the ACCP/SCCM excluding the leukocyte count since all the patients were neutropenic. Ninety-four febrile episodes were observed: 27 microbiologically documented (28.7%), six clinically documented (6.3%) and 61 fever of unknown origin (65%). Microbiologically documented infections were: 13 Gram-negative organisms, 11 Gram-positive organisms and three combined (Gram+ and -). Clinically documented infections were pneumonia (two), neutropenic enterocolitis (one), sinuses infection (one) and cutaneous infection (two). Severe sepsis accounted for 22 febrile episodes. Factors associated with the occurrence of severe sepsis were: hypophosphatemia (<0.8 mmol/l; p=0.05, OR=3.9, 95% CI: 1.3-45.7), hypoproteinemia (<62 g/l; p=0.006, OR=4.1, 95% CI: 1.4-11.4) and non-adapted antibiotherapy at the onset of severe sepsis (p=0.019, OR=2.7, 95% CI: 1.02-7.39). However, heart rate/systolic blood pressure ratio <1.1 (p<0.001, OR=0.1, 95% CI: 0.03-0.31) and Creactive protein <80 mg (p=0.001, OR=0.14, 95% CI: 0.04-0.54) were not predictive.

High body mass index is an independent predictor of differentiation syndrome in patients with acute promyelocytic leukemia.

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>or=30 developed DS vs. 5 of 27 (18.5%) with BMI<30 (p=0.012). Other predictors of DS in univariate analysis were: age>or=40 year (p=0.033), baseline WBC>or=20 x 10(9)/l (p=0.003), and creatinine>1.4 mg/dl (p=0.009). In multivariate analysis, BMI>or=30 remained an independent predictor of DS in addition to baseline WBC>or=20 x 10(9)/l.

Predictive factors of all-trans-retinoic acid related complications during induction therapy for acute promyelocytic leukemia.

BACKGROUND: 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. PATIENTS: 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 WBC >10 x 10(9)/L to prevent RAS in LPA 99. RESULTS: 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). WBC >10 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)), BMI >30 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: BMI >35 (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 WBC >10 x 10(9)/L (p=0.08). CONCLUSION: We found high BMI (>35) in female and treatment without Cytarabine to increase the risk of developing complications with ATRA.

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.

Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial.

From April 2003 to December 2006, 195 patients with de novo symptomatic myeloma and younger than 60 years of age were randomly assigned to receive either tandem transplantation up front (arm A, n = 97) or one autologous stem-cell transplantation followed by a maintenance therapy with thalidomide (day + 90, 100 mg per day during 6 months) (arm B, n = 98). Patients included in arm B received a second transplant at disease progression. In both arms, autologous stem-cell transplantation was preceded by first-line therapy with thalidomide-dexamethasone and subsequent collection of peripheral blood stem cells with high-dose cyclophosphamide (4 g/m(2)) and granulocyte colony stimulating factor. Data were analyzed on an intent-to-treat basis. With a median follow-up of 33 months (range, 6-46 months), the 3-year overall survival was 65% in arm A and 85% in arm B (P = .04). The 3-year progression-free survival was 57% in arm A and 85% in arm B (P = .02). Up-front single autologous transplantation followed by 6 months of maintenance therapy with thalidomide (with second transplant in reserve for relapse or progression) is an effective therapeutic strategy to treat multiple myeloma patients and appears superior to tandem transplant in this setting. This study was registered at www.ClinicalTrials.gov as (NCT 00207805).

[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.

[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.

Isolated extramedullary relapse in the breast of a patient with acute myeloid leukemia following allogeneic stem cell transplantation: case report and review of the literature.

We report an unsual case of a woman with acute myeloid leukemia who showed an isolated extramedullary relapse (IEMR) in the breast following allogeneic stem cell transplantation and review the related literature. Eighty cases of IEMR following allogeneic stem cell transplantation, including our case, were identified. The review suggests that an M2 or M4 phenotype in the French-American-British classification and a favorable cytogenetic risk group are more frequently associated with the occurrence of IEMR. Combined treatment with radiation and high-dose chemotherapy may be effective.

[Therapeutic results with apl 93 protocol in acute promyelocytic leukemia (34 cases)]. / Resultats therapeutiques dans les leucemies aigues promyelocytaires (34 cas).

BACKGROUND: Acute promyelocytic leukaemia (APL) account for approximately 10% to 15% of all AML in most reports. Clinical features includes the presence in 80% to 90% of patients of a severe hemorrhagic syndrome, a specific balanced translocation between chromosomes 15 and 17 with a fusion of a large pert of the retinoic acid receptor a gene (RARa) on chromosome 17 to a part of the promyelocytic leukaemia (PML) gene on chromosome 15. More than 75% of patients (under 65 years of age) can be cured, with the application of a combination of anthracyclines and all-trans retinoic acid (ATRA), followed by maintenance therapy. AIM: of the study was to assess of the therapeutic management of APL 93 protocol in acute promyelocytic leukemia. METHODS: We present here the results of a retrospective study concerning 34 patients with APL included between 1998 and 2004 in the APL 93 protocol : 20 in group B and 14 in group C. CR was 82 %. RESULTS: Failure is only due to toxic death (18%) Event free survival at 4 years is 63,47% with relapse rate at 14.25%. Overall survival at 4 years is 69,72%. Our results are acceptable and can be improved with reduction of failure due to toxic death, probably with omission of cytarabine from induction and consolidation adapted by the Spanish PETHEMA Group.

[Pseudotumor cerebri with all-trans retinoic acid. A case report]. / Pseudotumeur cerebrale secondaire au traitement par l'acide transretinoïque. A propos d'un cas.

The diagnosis of pseudotumor cerebri (PC) is based on the triad of: (1) papilledema, (2) elevated intracranial pressure with a normal cerebrospinal constituency and (3) normal central nervous system imaging studies. It is an uncommon complication of all-trans-retinoic acid (ATRA) therapy in children treated for acute promyelocytic leukaemia (APL). Its occurrence is rare among adult patients with APL and treated with ATRA . We report a case of an adult with APL who developed PC during induction therapy with ATRA-PC was managed with repeated lumbar punctures and corticotherapy.