Publications by authors named "Borhane Slama"

20 Publications

  • Page 1 of 1

Genomic analysis of primary and secondary myelofibrosis redefines the prognostic impact of ASXL1 mutations: a FIM study.

Blood Adv 2021 03;5(5):1442-1451

Service d'Hématologie, CH Perpignan, Perpignan, France.

We aimed to study the prognostic impact of the mutational landscape in primary and secondary myelofibrosis. The study included 479 patients with myelofibrosis recruited from 24 French Intergroup of Myeloproliferative Neoplasms (FIM) centers. The molecular landscape was studied by high-throughput sequencing of 77 genes. A Bayesian network allowed the identification of genomic groups whose prognostic impact was studied in a multistate model considering transitions from the 3 conditions: myelofibrosis, acute leukemia, and death. Results were validated using an independent, previously published cohort (n = 276). Four genomic groups were identified: patients with TP53 mutation; patients with ≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (high-risk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or high-risk genes); and other patients. A multistate model found that both TP53 and high-risk groups were associated with leukemic transformation (hazard ratios [HRs] [95% confidence interval], 8.68 [3.32-22.73] and 3.24 [1.58-6.64], respectively) and death from myelofibrosis (HRs, 3.03 [1.66-5.56] and 1.77 [1.18-2.67], respectively). ASXL1-only mutations had no prognostic value that was confirmed in the validation cohort. However, ASXL1 mutations conferred a worse prognosis when associated with a mutation in TP53 or high-risk genes. This study provides a new definition of adverse mutations in myelofibrosis with the addition of TP53, CBL, NRAS, KRAS, and U2AF1 to previously described genes. Furthermore, our results argue that ASXL1 mutations alone cannot be considered detrimental.
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http://dx.doi.org/10.1182/bloodadvances.2020003444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948260PMC
March 2021

Bortezomib, thalidomide, and dexamethasone with or without daratumumab for transplantation-eligible patients with newly diagnosed multiple myeloma (CASSIOPEIA): health-related quality of life outcomes of a randomised, open-label, phase 3 trial.

Lancet Haematol 2020 Dec;7(12):e874-e883

Erasmus MC Cancer Institute, Rotterdam, Netherlands. Electronic address:

Background: In part 1 of the two-part CASSIOPEIA study, treatment before and after autologous haematopoietic stem-cell transplantation (HSCT) with daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) significantly improved rates of stringent complete response and progression-free survival versus bortezomib, thalidomide, and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma.

Methods: CASSIOPEIA is an ongoing randomised, open-label, active-controlled, parallel-group, phase 3 trial done at 111 academic and community practice centres in Europe. Transplantation-eligible adults with newly diagnosed multiple myeloma were randomly assigned (1:1) to D-VTd or VTd. Treatment consisted of four 28-day cycles of induction therapy before autologous HSCT and two 28-day cycles of consolidation therapy after. In this prespecified secondary analysis, patient-reported outcomes were assessed using the European Organization for Research and Treatment of Cancer quality of life questionnaire-core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire at baseline, after induction (cycle 4, day 28), and after consolidation (day 100 after autologous HSCT). The analysis was done in all patients in the intention-to-treat population with a baseline and at least one post-baseline patient-reported outcome assessment. The trial is registered at ClinicalTrials.gov (NCT02541383).

Findings: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled and randomly assigned D-VTd (n=543) or VTd (n=542). Questionnaire completion rates were high at baseline (511 [94%] of 543 in the D-VTd group vs 510 [94%] of 542 in the VTd group). Compliance rates (calculated from the number of completed surveys as a proportion of the predicted number of participants still on study treatment) were high at post-induction (431 [84%] of 513 vs 405 [80%] of 509) and post-consolidation (414 [90%] of 460 vs 386 [88%] of 438) assessments and were similar between treatment groups. Mean changes in global health status scores from baseline to post-induction were not different between the D-VTd group (3·8 [95% CI 1·6 to 6·0]) and VTd group (2·9 [0·7 to 5·1]; p=0·43), or from baseline to post-consolidation between the two groups (D-VTd group, 9·7 (95% CI 7·4 to 11·9) vs VTd group, 8·7 (6·5 to 11·0; p=0·45). Improvements from baseline in EORTC QLQ-C30 global health status and EQ-5D-5L visual analogue scale scores were observed in post-consolidation scores in both groups. Post-consolidation scores showed significantly greater mean decreases in pain (-23·3 [95% CI -26·6 to -20·0] in the D-VTd group vs -19·7 [-23·0 to -16·3] in the VTd group; p=0·042), significantly smaller reductions in cognitive functioning (-5·0 [-7·6 to -2·4] vs -7·9 [-10·6 to -5·3]; p=0·036), and significantly greater improvements in emotional functioning (13·0 [10·4 to 15·5] vs 9·5 [6·9 to 12·1]; p=0·013) and in constipation (-3·2 [-7·3 to 0·9] vs 1·8 [-2·4 to 6·0]; p=0·025) with D-VTd versus VTd. Between-group differences in change from baseline for all other scales were not significant.

Interpretation: D-VTd and VTd were associated with on-treatment health-related quality of life improvements from baseline in transplantation-eligible patients with newly diagnosed multiple myeloma. The significantly greater reductions in pain, less deterioration of cognitive functioning, and greater emotional functioning improvements complement the clinical benefits observed with D-VTd versus VTd, and support the addition of daratumumab to standard regimens in patients with newly diagnosed multiple myeloma.

Funding: Intergroupe Francophone du Myélome, The Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research and Development.
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http://dx.doi.org/10.1016/S2352-3026(20)30356-2DOI Listing
December 2020

Long-term safety and efficacy of rituximab in 248 adults with immune thrombocytopenia: Results at 5 years from the French prospective registry ITP-ritux.

Am J Hematol 2019 12 8;94(12):1314-1324. Epub 2019 Oct 8.

Service de Médecine Interne, Centre National de Référence des Cytopénies Auto-Immunes de l'Adulte, Centre Hospitalier Universitaire Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.

Rituximab is a second-line option in adults with immune thrombocytopenia (ITP), but the estimated 5-year response rate, only based on pooled retrospective data, is about 20%, and no studies have focused on long-term safety. We conducted a prospective multicenter registry of 248 adults with ITP treated with rituximab with 5 years of follow-up to assess its long-term safety and efficacy. The median follow-up was 68.4 [53.7-78.5] months. The incidence of severe infections was only 2/100 patient-years. Profound hypogammaglobulinemia (<5 g/L) developed in five patients at 15 to 31 months after the last rituximab infusion. In total, 25 patients died at a median age of 80 [69.5-83.9] years, corresponding to a mortality rate of 2.3/100 patient-years. Only three deaths related to infection that occurred 12 to 14 months after rituximab infusions could be due in part to rituximab. At 60 months of follow-up, 73 (29.4%) patients had a sustained response. On univariate and multivariate analysis, the only factor significantly associated with sustained response was a previous transient response to corticosteroids (P = .022). Overall, 24 patients with an initial response and then relapse received retreatment with rituximab, which gave a response in 92%, with a higher duration of response in 54%. As a result of its safety profile and its sustained response rate, rituximab remains an important option in the current therapeutic armamentarium for adult ITP. Retreatment could be an effective and safe option.
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http://dx.doi.org/10.1002/ajh.25632DOI Listing
December 2019

Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry.

Haematologica 2020 03 5;105(3):640-651. Epub 2019 Jul 5.

St. James's Institute of Oncology, Leeds Teaching Hospitals, Leeds, UK.

Iron overload due to red blood cell (RBC) transfusions is associated with morbidity and mortality in lower-risk myelodysplastic syndrome (MDS) patients. Many studies have suggested improved survival after iron chelation therapy (ICT), but valid data are limited. The aim of this study was to assess the effect of ICT on overall survival and hematologic improvement in lower-risk MDS patients in the European MDS registry. We compared chelated patients with a contemporary, non-chelated control group within the European MDS registry, that met the eligibility criteria for starting iron chelation. A Cox proportional hazards model was used to assess overall survival (OS), treating receipt of chelation as a time-varying variable. Additionally, chelated and non-chelated patients were compared using a propensity-score matched model. Of 2,200 patients, 224 received iron chelation. The hazard ratio and 95% confidence interval for OS for chelated patients, adjusted for age, sex, comorbidity, performance status, cumulative RBC transfusions, Revised-International Prognostic Scoring System (IPSS-R), and presence of ringed sideroblasts was 0.50 (0.34-0.74). The propensity-score analysis, matched for age, sex, country, RBC transfusion intensity, ferritin level, comorbidity, performance status, and IPSS-R, and, in addition, corrected for cumulative RBC transfusions and presence of ringed sideroblasts, demonstrated a significantly improved OS for chelated patients with a hazard ratio of 0.42 (0.27-0.63) compared to non-chelated patients. Up to 39% of chelated patients reached an erythroid response. In conclusion, our results suggest that iron chelation may improve OS and hematopoiesis in transfused lower-risk MDS patients. This trial was registered at
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http://dx.doi.org/10.3324/haematol.2018.212332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049356PMC
March 2020

Dyserythropoiesis evaluated by the RED score and hepcidin:ferritin ratio predicts response to erythropoietin in lower-risk myelodysplastic syndromes.

Haematologica 2019 03 4;104(3):497-504. Epub 2018 Oct 4.

Department of Hematology, CHU Grenoble-Alpes, Grenoble.

Erythropoiesis-stimulating agents are generally the first line of treatment of anemia in patients with lower-risk myelodysplastic syndrome. We prospectively investigated the predictive value of somatic mutations, and biomarkers of ineffective erythropoiesis including the flow cytometry RED score, serum growth-differentiation factor-15, and hepcidin levels. Inclusion criteria were no prior treatment with erythropoiesis-stimulating agents, low- or intermediate-1-risk myelodysplastic syndrome according to the International Prognostic Scoring System, and a hemoglobin level <10 g/dL. Patients could be red blood cell transfusion-dependent or not and were given epoetin zeta 40 000 IU/week. Serum erythropoietin level, iron parameters, hepcidin, flow cytometry Ogata and RED scores, and growth-differentiation factor-15 levels were determined at baseline, and molecular analysis by next-generation sequencing was also conducted. Erythroid response (defined according to the International Working Group 2006 criteria) was assessed at week 12. Seventy patients, with a median age of 78 years, were included in the study. There were 22 patients with refractory cytopenia with multilineage dysplasia, 19 with refractory cytopenia with unilineage dysplasia, 14 with refractory anemia with ring sideroblasts, four with refractory anemia with excess blasts-1, six with chronic myelomonocytic leukemia, two with del5q-and three with unclassifiable myelodysplastic syndrome. According to the revised International Prognostic Scoring System, 13 had very low risk, 47 had low risk, nine intermediate risk and one had high-risk disease. Twenty patients were transfusion dependent. Forty-eight percent had an erythroid response and the median duration of the response was 26 months. At baseline, non-responders had significantly higher RED scores and lower hepcidin:ferritin ratios. In multivariate analysis, only a RED score >4 (=0.05) and a hepcidin:ferritin ratio <9 (=0.02) were statistically significantly associated with worse erythroid response. The median response duration was shorter in patients with growth-differentiation factor-15 >2000 pg/mL and a hepcidin:ferritin ratio <9 (=0.0008 and =0.01, respectively). In multivariate analysis, both variables were associated with shorter response duration. Erythroid response to epoetin zeta was similar to that obtained with other erythropoiesis-stimulating agents and was correlated with higher baseline hepcidin:ferritin ratio and lower RED score. .
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http://dx.doi.org/10.3324/haematol.2018.203158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395339PMC
March 2019

Efficacy and Safety of IQYMUNE®, a Ten Percent Intravenous Immunoglobulin in Adult Patients With Chronic, Primary Immune Thrombocytopenia.

J Hematol 2018 Sep 1;7(3):87-95. Epub 2018 Sep 1.

Institute for Transfusion Medicine, Charite Campus Virchow-Klinikum, Berlin, Germany.

Background: Intravenous immunoglobulin (IVIG) IQYMUNE® is a highly purified 10% IVIG that was assessed using the new stringent definition of response described in the revised guideline on the clinical investigation of IVIG. The efficacy and the safety of IQYMUNE® were investigated in adult patients with chronic primary immune thrombocytopenia (ITP).

Methods: In this phase III multinational, multicentre, prospective, uncontrolled, open-label, single-arm study, adult patients with a baseline platelet count < 30 × 10/L were treated with IVIG 10% at a dose of 2 g/kg body weight administered over 2 consecutive days. The primary endpoint was Response over the study period and was defined according to the recent and most stringent European Medicines Agency guidelines (platelet count ≥ 30 × 10/L and a ≥ 2-fold increase from baseline, no new bleeding, and no concomitant treatment with drugs that affect platelet count and/or induce bleeding cessation).

Results: Thirty-eight patients were enrolled; 73 infusions were administered (38 on Day 1 and 35 on Day 2). Response was reached by 24 patients corresponding to 63.2% of patients in the full analysis set (95% CI: 46.0; 78.2) and 68.6% of patients in the per-protocol set (95% CI: 50.7; 83.1). The median time to Response was 1 day. The median duration of Response was 13.5 days. Reasons for non-response were failure to reach the required platelet count (n = 12), a new bleeding event (n = 1), and forbidden medication use (n = 1). Among the 23 patients with a baseline platelet count ≤ 20 × 10/L, 19 patients (82.6%) achieved a platelet count ≥ 50 × 10/L at least once before Day 5 (previous European Medicines Agency definition of response). Treatment was well tolerated even in patients with a high flow rate (≥ 6 mL/kg/h in 40% of patients). Headache (34.2%), pyrexia (15.8%), and creatinine renal clearance decrease, including one case of decrease in glomerular filtration rate (10.5%) were the most frequently reported drug-related adverse events.

Conclusions: Administration of IQYMUNE® for 2 consecutive days at a dose of 2 g/kg was safe and efficacious. These results support the treatment of adult patients with chronic ITP with IQYMUNE®.
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http://dx.doi.org/10.14740/jh385wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155829PMC
September 2018

Erratum: Efficacy and safety of ClairYg®, a ready-to-use intravenous immunoglobulin, in adult patients with primary immune thrombocytopenia.

Am J Blood Res 2017 15;7(3):29. Epub 2017 Jun 15.

Department of Internal Medicine, University Hospital Henri MondorFrance.

[This corrects the article on p. 1 in vol. 7, PMID: 28203488.].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498821PMC
June 2017

Efficacy and safety of ClairYg, a ready-to-use intravenous immunoglobulin, in adult patients with primary immune thrombocytopenia.

Am J Blood Res 2017 15;7(1):1-9. Epub 2017 Jan 15.

Department of Internal Medicine, University Hospital Henri Mondor France.

Purpose: The present study was designed to assess the efficacy and safety of IGNG that is a new liquid, saccharose and maltose-free highly purified ready-to-use 5% intravenous immunoglobulin (IVIg), in primary immune thrombocytopenic patients with severe thrombocytopenia.

Methods: Nineteen adults with a platelet count ≤ 25 × 10/L received a single dose of IGNG (1 g/kg) on Day 1, with a second identical dose on Day 3 if needed. Patients were followed for 30 days. Primary endpoint was the response rate, defined as the proportion of patients with a platelet count ≥ 50 × 10/L within 96 hours after the first IGNG dose.

Results: All but one of the 17 evaluable patients for efficacy responded with an overall response rate of 94.1% (95% CI 71.3%-99.9%). Response was observed after only one infusion (1 g/kg boby weight) in 11 patients (59%) and the others required a second dose. Mean time to response was 2.2 days. Maximum platelet count was reached within 1 week after the first dose and lasted for approximately 2 weeks. Patients requiring a second dose had lower platelet counts at baseline than patients requiring a single dose. In the 19 evaluable patients for safety, IGNG demonstrated good safety, good hepatic and renal tolerance, and did not induce hemolysis. This trial was registered at the French Medical Agency (AFSSAPS) as #DI n°060735.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306448PMC
January 2017

VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial.

Blood 2016 05 21;127(21):2569-74. Epub 2016 Mar 21.

University Hospital, Metz, France;

The Intergroupe Francophone du Myélome conducted a randomized trial to compare bortezomib-thalidomide-dexamethasone (VTD) with bortezomib-cyclophosphamide-dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma. Overall, a total of 340 patients were centrally randomly assigned to receive VTD or VCD. After 4 cycles, on an intent-to-treat basis, 66.3% of the patients in the VTD arm achieved at least a very good partial response (primary end point) vs 56.2% in the VCD arm (P = .05). In addition, the overall response rate was significantly higher in the VTD arm (92.3% vs 83.4% in the VCD arm; P = .01). Hematologic toxicity was higher in the VCD arm, with significantly increased rates of grade 3 and 4 anemia, thrombocytopenia, and neutropenia. On the other hand, the rate of peripheral neuropathy (PN) was significantly higher in the VTD arm. With the exception of hematologic adverse events and PN, other grade 3 or 4 toxicities were rare, with no significant differences between the VTD and VCD arms. Our data support the preferential use of VTD rather than VCD in preparation for ASCT. This trial was registered at www.clinicaltrials.gov as #NCT01564537 and at EudraCT as #2013-003174-27.
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http://dx.doi.org/10.1182/blood-2016-01-693580DOI Listing
May 2016

[Methods of development of recommendations for clinical practice (RCP) and of setting-up of a platform cancer heart vessels (PTF-CHV) in the inter3C Vaucluse-Arles].

Bull Cancer 2015 Nov 16;102(11):932-9. Epub 2015 Sep 16.

Institut Sainte-Catherine, 250, chemin de Baigne-Pieds CS 80005, 84918 Avignon cedex 9, France.

Monitoring and prevention of cardiovascular complications of anti-neoplastic treatment are currently well known for anthracyclines and trastuzumab but remain poorly implemented. The management of cardiac and vascular side effects of targeted therapies is not codified. The purpose of the platform heart-vessel cancer is to optimize the management of such complications within a small area (Vaucluse region of Arles). The platform will offer prescribers an easily accessible database, doctors performing exams standardized monitoring forms and patients a uniform follow-up. We report here the methodology of the elaboration of recommendations for clinical practice and the ways to develop the platform. After a year of active process, an analysis of the will be performed to see opportunities for improvement and dissemination on a larger scale.
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http://dx.doi.org/10.1016/j.bulcan.2015.08.002DOI Listing
November 2015

Validation of the revised international prognostic scoring system (IPSS-R) in patients with lower-risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry.

Br J Haematol 2015 Aug 24;170(3):372-83. Epub 2015 Apr 24.

Department of Tumor Immunology - Nijmegen, Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands.

Baseline characteristics, disease-management and outcome of 1000 lower-risk myelodysplastic syndrome (MDS) patients within the European LeukaemiaNet MDS (EUMDS) Registry are described in conjunction with the validation of the revised International Prognostic Scoring System (IPSS-R). The EUMDS registry confirmed established prognostic factors, such as age, gender and World Health Organization 2001 classification. Low quality of life (EQ-5D visual analogue scale score) was significantly associated with reduced survival. A high co-morbidity index predicted poor outcome in univariate analyses. The IPSS-R identified a large group of 247 patients with Low (43%) and Very low (23%) risk score within the IPSS intermediate-1 patients. The IPSS-R also identified 32 High or Very high risk patients within the IPSS intermediate-1 patients. IPSS-R was superior to the IPSS for predicting both disease progression and survival. Seventy percent of patients received MDS-specific treatment or supportive care, including red blood cell transfusions (51%), haematopoietic growth factors (58%) and iron chelation therapy (8%), within 2 years of diagnosis; while 30% of the patients only required active monitoring. The IPSS-R proved its utility as a more refined risk stratification tool for the identification of patients with a very good or poor prognosis and in this lower-risk MDS population.
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http://dx.doi.org/10.1111/bjh.13450DOI Listing
August 2015

Safety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients.

Blood 2014 Nov 7;124(22):3228-36. Epub 2014 Oct 7.

Service de Médecine Interne, Centre de Référence Labellisé des Cytopénies Auto-Immunes de l'Adulte and.

We conducted a prospective multicenter registry of 248 adult patients with immune thrombocytopenia (ITP) treated with rituximab to assess safety. We also assessed response and predictive factors of sustained response. In total, 173 patients received 4 infusions of 375 mg/m(2) and 72 received 2 fixed 1-g infusions 2 weeks apart. The choice of the rituximab regimen was based on the physician's preference and not patient characteristics. Overall, 38 patients showed minor intolerance to rituximab infusions; infusions had to be stopped for only 3 patients. Seven showed infection (n = 11 cases), with an incidence of 2.3 infections/100 patient-years. Three patients died of infection 12 to 14 months after rituximab infusions, but the role of rituximab was questionable. In total, 152 patients (61%) showed an overall initial response (platelet count ≥30 × 10(9)/L and ≥2 baseline value). At a median follow-up of 24 months, 96 patients (39%) showed a lasting response. On multivariate analysis, the probability of sustained response at 1 year was significantly associated with ITP duration <1 year (P = .02) and previous transient complete response to corticosteroids (P = .05). The pattern of response was similar with the 2 rituximab regimens. With its benefit/risk ratio, rituximab used off-label may remain a valid option for treating persistent or chronic ITP in adults. This trial was registered at www.clinicaltrials.gov as #NC1101295.
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http://dx.doi.org/10.1182/blood-2014-06-582346DOI Listing
November 2014

MELISSE, a large multicentric observational study to determine risk factors of venous thromboembolism in patients with multiple myeloma treated with immunomodulatory drugs.

Thromb Haemost 2013 Oct 1;110(4):844-51. Epub 2013 Aug 1.

Xavier Leleu, MD, PhD, Service des Maladies du Sang, Hôpital Huriez, CHRU Lille, Rue Michel Polonovski, 59037 Lille cedex, France, Tel : + 33 3 20 44 68 83, Fax: + 33 3 20 44 40 94, E-mail:

Immunomodulatory drugs (IMiDs) are associated with an increased risk of venous thromboembolism (VTE) in multiple myeloma (MM) patients. We designed MELISSE, a multicentre prospective observational study, to evaluate VTE incidence and identify risk factors in IMiDs-treated MM. Our objective was to determine the real-life practice of VTE prophylaxis strategy. A total of 524 MM patients were included, and we planned to collect information at baseline, at four and at 12 months, on MM therapy, on VTE risk factors and management. VTE incidence was 7% (n=31), including 2.5% pulmonary embolism (PE) (n=11), similar at four or 12 months. VTE was observed at all risk assessment levels, although the increased risk assessment level correlated to a lower rate of VTE, maybe due to the implemented thromboprophylaxis strategy. VTE occurred in 7% on aspirin vs 3% on low-molecular-weight heparin (LMWH) prophylaxis, and none on vitamin K antagonists (VKA). New risk factors for VTE in IMiDs-treated MM were identified. In conclusion, VTE prophylaxis is compulsory in IMiDs-treated MM, based on individualised VTE risk assessment. Anticoagulation prophylaxis with LMWH should clearly be prioritised in MM patients with high VTE risk, along with VKA. Further prospective studies will identify most relevant VTE risk factors in IMiDs-treated MM to select accurately which MM patients should receive LMWH prophylaxis and for which duration to optimise VTE risk reduction.
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http://dx.doi.org/10.1160/TH13-02-0140DOI Listing
October 2013

Mutation analysis of ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 in myeloproliferative neoplasms.

Genes Chromosomes Cancer 2012 Aug 9;51(8):743-55. Epub 2012 Apr 9.

Laboratoire d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille, UMR1068 Inserm, Institut Paoli-Calmettes, Marseille, France.

Since the discovery of the JAK2V617F tyrosine kinase-activating mutation several genes have been found mutated in nonchronic myeloid leukemia (CML) myeloproliferative neoplasms (MPNs), which mainly comprise three subtypes of "classic" MPNs; polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). We searched for mutations in ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 genes in 149 non-CML MPNs, including 127 "classic" MPNs cases. JAK2 was mutated in 100% PV, 66% ET and 68% MF. We found a high incidence of ASXL1 mutation in MF patients (20%) and a low incidence in PV (7%) and ET (4%) patients. Mutations in the other genes were rare (CBL, DNMT3A, IDH2, MPL, SF3B1, SUZ12, NF1) or absent (IDH1).
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http://dx.doi.org/10.1002/gcc.21960DOI Listing
August 2012

Low-dose vs. high-dose thalidomide for advanced multiple myeloma: a prospective trial from the Intergroupe Francophone du Myélome.

Eur J Haematol 2012 Mar 4;88(3):249-59. Epub 2012 Jan 4.

Service des Maladies du Sang, CHU, Lille, France.

This multicentre prospective randomised trial compared the efficacy and safety of two doses of thalidomide in patients with relapsed or refractory myeloma. The study was designed to test the non-inferior efficacy and to confirm the better tolerability of low-dose thalidomide as compared to a higher dose. Four hundred patients were randomly assigned to receive either 100 or 400 mg/day of thalidomide. Dexamethasone treatment was added in both arms for patients with stable disease or treatment failure at 12 weeks. The primary endpoint was 1-year overall survival (OS). Thalidomide 100 mg/day was better tolerated than 400 mg/day with less high-grade somnolence, constipation, nausea/vomiting and peripheral neuropathy (P < 0.001, P = 0.007, P = 0.03 and P = 0.007, respectively). In the per-protocol population (PP), the estimated 1-year OS rates were of 74.5% (n = 149) and 67.3% (n = 156) in the 400 and 100 groups, respectively. The upper limit of the difference between these rates was of 15.6% higher than the non-inferiority acceptable limit of 12.75%, and the hypothesis of non-inferiority of 100 could not be established (P = 0.14). On the other hand, when intent-to-treat (ITT) population was analysed, the non-inferiority was demonstrated because the 1-year OS rates were of 72.8% (n = 195) and 68.8% (n = 205) in the same groups, leading to an upper limit of the difference of 11.49% lower than the non-inferiority acceptable limit. In addition, in patients alive 12 weeks postrandomisation and those who received thalidomide plus dexamethasone, there were no significant differences in response rates, time to progression, progression-free survival and OS between the two groups. Collectively, low-dose thalidomide 100 mg/day has significant activity in advanced myeloma with an improved safety profile and can be a good salvage therapy in combination with dexamethasone.
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http://dx.doi.org/10.1111/j.1600-0609.2011.01729.xDOI Listing
March 2012

Romiplostim safety and efficacy for immune thrombocytopenia in clinical practice: 2-year results of 72 adults in a romiplostim compassionate-use program.

Blood 2011 Oct 10;118(16):4338-45. Epub 2011 Aug 10.

Department of Internal Medicine, Centre Hospitalier Universitaire Henri-Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.

Romiplostim, a thrombopoietic agent with demonstrated efficacy against immune thrombocytopenia (ITP) in prospective controlled studies, was recently licensed for adults with chronic ITP. Only France has allowed romiplostim compassionate use since January 2008. ITP patients could receive romiplostim when they failed to respond to successive corticosteroids, intravenous immunoglobulins, rituximab, and splenectomy, or when splenectomy was not indicated. We included the first 80 patients enrolled in this program with at least 2 years of follow-up. Primary platelet response (platelet count ≥ 50 × 10(9)/L and double baseline) was observed in 74% of all patients. Long-term responses (2 years) were observed in 47 (65%) patients, 37 (79%) had sustained platelet responses with a median platelet count of 106 × 10(9)/L (interquartile range, 75-167 × 10(9)/L), and 10 (21%) were still taking romiplostim, despite a median platelet count of 38 × 10(9)/L (interquartile range, 35-44 × 10(9)/L), but with clinical benefit (lower dose and/or fewer concomitant treatment(s) and/or diminished bleeding signs). A high bleeding score and use of concomitant ITP therapy were baseline factors predicting romiplostim failure. The most frequently reported adverse events were: arthralgias (26%), fatigue (13%), and nausea (7%). Our results confirmed that romiplostim use in clinical practice is effective and safe for severe chronic ITP. This trial was registered at www.clinicaltrials.gov as #NCT01013181.
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http://dx.doi.org/10.1182/blood-2011-03-340166DOI Listing
October 2011

Thalidomide versus placebo in myeloid metaplasia with myelofibrosis: a prospective, randomized, double-blind, multicenter study.

Haematologica 2006 Aug;91(8):1027-32

Groupe Ouest-Est Leucémies et Maladies du Sang.

Background And Objectives: In non-randomized studies, thalidomide appeared to be effective in myeloid metaplasia with myelofibrosis (MMM). We compared thalidomide to placebo for treatment of anemia in MMM.

Design And Methods: A prospective phase II B, randomized double-blind multicenter trial comparing thalidomide 400 mg/d with placebo for 180 days was conducted in 52 anemic patients (hemoglobin pounds Sterling 9 g/dL or transfused). The main outcome measure was a 2 g/L increase in hemoglobin or 20% reduction in transfusions.

Results: In the thalidomide group only 10 patients completed 6 months of treatment. At 180 days, in an intention-to-treat analysis, no difference was observed between the thalidomide and placebo groups as regards improvement of hemoglobin levels (one patient in each group) or reduction of red blood cell transfusions (three vs five patients, respectively). The spleen size, determined by ultrasonography, increased significantly less in the thalidomide group than in the placebo group (p < 0.05). Thalidomide had no apparent benefit on the Dupriez score, the severity score, survival, death, or any other clinical or biological parameter. Somnolence, gastro-intestinal signs, weight gain, and edema were significantly more frequent in the thalidomide group. Outpatient discontinuation of thalidomide was significantly correlated with a high severity score > 4 (odds ratio, OR = 16; p < 0.01), and g-glutamyl transferase levels > 40 IU/L (OR = 12; p < 0.05).

Interpretation And Conclusions: Thalidomide (200-400 mg/d) does not demonstrate substantial efficacy in anemic MMM patients. The natural history of disease in the placebo group revealed spontaneous periods of remission of anemia. Tolerance of thalidomide was significantly correlated wih the severity and liver involvement of the disease.
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August 2006

Dual lympho-myeloproliferative disorder in a patient with t(8;22) with BCR-FGFR1 gene fusion.

Int J Oncol 2005 Jun;26(6):1485-92

Department of Molecular Oncology, Marseille Cancer Institute, UMR599 Inserm and Paoli-Calmettes Institute, Marseille, France.

The case of a patient presenting with a myeloproliferative disorder (MPD) characterized by a t(8;22) (p12;q11) translocation was investigated. The rearrangement resulted in the production of BCR-FGFR1 and FGFR1-BCR chimeric transcripts after in-frame fusions of BCR exon 4 with FGFR1 exon 9 and FGFR1 exon 8 with BCR exon 5, respectively. The four previously reported patients with such translocation presented with an atypical chronic myeloid leukemia (CML) without Philadelphia chromosome. In addition to a myeloproliferation, the patient had a B cell proliferation. The phenotypic characterization of the lymphoid cells in the bone marrow showed a continuum of maturation from blast B cells to polyclonal lymphocytes. In the blood, B cells showed a complete polyclonal maturation. The BCR-FGFR1 gene fusion was detected by dual-color fluorescence in situ hybridization in both CD19- and CD19+ populations. In contrast to the other FGFR1-MPDs that show myeloid and T cell proliferation, we propose that this t(8;22) MPD is a myeloid and B cell disease, and potentially a novel type of hematological disease. Although the FGFR1-MPD is rare, its study provides interesting clues to the understanding of hematopoietic stem cell biology and oncogene activation.
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June 2005
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