Publications by authors named "Selim Corm"

24 Publications

  • Page 1 of 1

Vasculitis associated with myelodysplastic syndrome and chronic myelomonocytic leukemia: French multicenter case-control study.

Semin Arthritis Rheum 2020 10 11;50(5):879-884. Epub 2020 Jul 11.

Department of Internal Medicine, Assistance Publique-Hôpitaux de Marseille, Hôpital La Timone, Marseille, France.

Introduction: Our objective was to evaluate characteristics, treatment and outcome of vasculitis associated with myelodysplastic syndrome (MDS) and chronic myelomonicytic leukemia (CMML) PATIENTS AND METHODS: Retrospective descriptive analysis of MDS/CMML-related vasculitis and comparison with MDS/CMML patients without dysimmune features.

Results: Seventy patients with vasculitis and MDS/CMML were included, with median age of 71.5 [21-90] years and male/female ratio of 2.3. Vasculitis was diagnosed prior to MDS/CMML in 31 patients (44%), and after in 20 patients. In comparison with MDS/CMML without autoimmune/inflammatory features, vasculitis with MDS/MPN showed no difference in MDS/CMML subtypes distribution nor International Prognostic Scoring System and CMML-specific prognostic (IPSS/CPSS) scores. Vasculitis subtypes included Giant cell arteritis in 24 patients (34%), Behçet's-like syndrome in 11 patients (20%) and polyarteritis nodosa in 6 patients (9%). Glucocorticoids (GCs) were used as first-line therapy for MDS/CMML vasculitis in 64/70 patients (91%) and 41 (59%) received combined immunosuppressive therapies during the follow-up. After a median follow-up of 33.2 months [1-162], 31 patients (44%) achieved sustained remission. At least one relapse occurred in 43 patients (61%). Relapse rates were higher in patients treated with conventional Disease Modifying Anti-Rheumatic Drug (DMARDs) (odds ratio 4.86 [95% CI 1.38 - 17.10]), but did not differ for biologics (odds ratio 0.59 [95% CI 0.11-3.20]) and azacytidine (odds ratio 1.44 [95% CI 0.21-9.76]) than under glucocorticoids. Overall survival in MDS/CMML vasculitis was not significantly different from MDS/CMML patients without autoimmune/inflammatory features (p = 0.5), but acute leukemia progression rates were decreased (log rank <0.05).

Conclusion: This study shows no correlation of vasculitis diagnoses with subtypes and severity of MDS/CMML, and no significant impact of vasculitis on overall survival. Whereas conventional DMARDs seem to be less effective, biologics or azacytidine therapy could be considered for even low-risk MDS/CMML vasculitis.
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http://dx.doi.org/10.1016/j.semarthrit.2020.07.002DOI Listing
October 2020

Pattern of Care and Outcomes of Adolescent and Young Adults with Lymphoma Treated in the Rhône-Alpes Region.

J Adolesc Young Adult Oncol 2019 12 14;8(6):684-696. Epub 2019 Aug 14.

EAM SIS 4128, Centre Léon Bérard, Lyon, France.

Management of adolescent and young adults (AYAs) cancer is very heterogeneous. In the case of lymphomas, outcomes are mostly favorable but there is still room for improvement. We retrospectively collected the pattern of care of all institutional 13- to 25-year-old AYAs patients with classical Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) diagnosed in the Rhône-Alpes region between the years 2000 and 2005. Management, including adherence to Clinical Practice Guidelines (CPGs), and long-term survival were analyzed by comparing adult units (AU) and pediatric units (PU). 278 patients were included: 198 treated for HL (median age of 19 years), 80 treated for NHL (median age of 20 years). Among them, 74% were managed in AU and 26% in PU. The median time between diagnosis and starting treatment was significantly lower in PU than in AU. Sixty-five patients (23%) were included in clinical trials, mostly in AU. Five-year overall survival was 96% for HL [14 deaths, median follow-up 91 months (9-180)] and 90% for NHL [nine deaths, median follow-up 80 months (3-180)]. Secondary cancers occurred for 2% ( = 3) of HL patients and for none in NHL. Other major late complications included cardiovascular accidents in two patients and fatal pulmonary fibrosis in one patient. Major differences in chemotherapy and radiotherapy use are emphasized. Global management conformed to CPGs by 56%. Important differences between adult and pediatric management were reported, without any impact on survival. A few patients can be included in clinical trials: Homogeneity in management could improve specific care for AYAs.
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http://dx.doi.org/10.1089/jayao.2019.0016DOI Listing
December 2019

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

A phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for first-line treatment of older patients with mantle cell lymphoma.

Haematologica 2019 01 31;104(1):138-146. Epub 2018 Aug 31.

Hematology Department, Catherine de Sienne Clinic, Nantes.

We present results of a prospective, multicenter, phase II study evaluating rituximab, bendamustine, bortezomib and dexamethasone as first-line treatment for patients with mantle cell lymphoma aged 65 years or older. A total of 74 patients were enrolled (median age, 73 years). Patients received a maximum of six cycles of treatment at 28-day intervals. The primary objective was to achieve an 18-month progression-free survival rate of 65% or higher. Secondary objectives were to evaluate toxicity and the prognostic impact of mantle cell lymphoma prognostic index, Ki67 expression, [F]fluorodeoxyglucose-positron emission tomography and molecular minimal residual disease, in peripheral blood or bone marrow. With a median follow-up of 52 months, the 24-month progression-free survival rate was 70%, hence the primary objective was reached. After six cycles of treatment, 91% (54/59) of responding patients were analyzed for peripheral blood residual disease and 87% of these (47/54) were negative. Four-year overall survival rates of the patients who did not have or had detectable molecular residual disease in the blood at completion of treatment were 86.6% and 28.6%, respectively (<0.0001). Neither the mantle cell lymphoma index, nor fluorodeoxyglucose-positron emission tomography nor Ki67 positivity (cut off of ≥30%) showed a prognostic impact for survival. Hematologic grade 3-4 toxicities were mainly neutropenia (51%), thrombocytopenia (35%) and lymphopenia (65%). Grade 3-4 non-hematologic toxicities were mainly fatigue (18.5%), neuropathy (15%) and infections. In conclusion, the tested treatment regimen is active as frontline therapy in older patients with mantle cell lymphoma, with manageable toxicity. Minimal residual disease status after induction could serve as an early predictor of survival in mantle cell lymphoma. .
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http://dx.doi.org/10.3324/haematol.2018.191429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312036PMC
January 2019

Nationwide survey on the use of eltrombopag in patients with severe aplastic anemia: a report on behalf of the French Reference Center for Aplastic Anemia.

Haematologica 2018 02 23;103(2):212-220. Epub 2017 Nov 23.

Department of Hematology, CRNMR Aplasie Médullaire, Saint-Louis University Hospital - AP-HP, Paris, France.

Few therapeutic options are available for patients with aplastic anemia who are ineligible for transplantation or refractory to immunosuppressive therapy. Eltrombopag was recently shown to produce trilineage responses in refractory patients. However, the effects of real-life use of this drug remain unknown. This retrospective study (2012-2016) was conducted by the French Reference Center for Aplastic Anemia on patients with relapsed/refractory aplastic anemia, and patients ineligible for antithymocyte globulin or transplantation, who received eltrombopag for at least 2 months. Forty-six patients with aplastic anemia were given eltrombopag without prior antithymocyte globulin treatment (n=11) or after antithymocyte globulin administration (n=35) in a relapsed/refractory setting. Eltrombopag (median daily dose 150 mg) was introduced 17 months (range, 8-50) after the diagnosis of aplastic anemia. At last followup, 49% were still receiving treatment, 9% had stopped due to a robust response, 2% due to toxicity and 40% due to eltrombopag failure. Before eltrombopag treatment, all patients received regular transfusions. The overall rates of red blood cell and platelet transfusion independence were 7%, 33%, 46% and 46% at 1, 3, 6 months and last follow-up. Responses were slower to develop in antithymocyte treatment-naïve patients. In patients achieving transfusion independence, hemoglobin concentration and platelet counts improved by 3 g/dL (interquartile range, 1.4-4.5) and 42×10/L (interquartile range, 11-100), respectively. Response in at least one lineage (according to National Institutes of Health criteria) was observed in 64% of antithymocyte treatment-naïve and 74% of relapsed/refractory patients, while trilineage improvement was observed in 27% and 34%, respectively. We found high rates of hematologic improvement and transfusion independence in refractory aplastic anemia patients but also in patients ineligible for antithymocyte globulin receiving first-line treatment. In conclusion, elderly patients unfit for antithymocyte globulin therapy may benefit from eltrombopag.
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http://dx.doi.org/10.3324/haematol.2017.176339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792265PMC
February 2018

Paroxysmal nocturnal hemoglobinuria (PNH) and T cell large granular lymphocyte (LGL) leukemia--an unusual association: another cause of cytopenia in PNH.

Ann Hematol 2015 Oct 9;94(10):1759-60. Epub 2015 Jul 9.

Laboratoire d'Hématologie, Centre de Biologie Pathologie, CHRU Lille, 2 Boulevard du Pr Jules Leclercq, 59037, Lille Cedex 1, France,

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http://dx.doi.org/10.1007/s00277-015-2439-3DOI Listing
October 2015

Administration of alemtuzumab and G-CSF to adults with relapsed or refractory acute lymphoblastic leukemia: results of a phase II study.

Eur J Haematol 2013 Oct 28;91(4):315-21. Epub 2013 Aug 28.

Department of Hematology and Cell Therapy, Hopital Saint-Antoine, Assistance Publique-Hopitaux de Paris, and University UPMC, Paris, France.

The outlook for adults with refractory and relapsed acute lymphocytic leukemia (ALL) is poor. CD52 is expressed in most patients with ALL. Alemtuzumab is an anti-CD52 humanized monoclonal antibody. This phase II study assessed the efficacy of alemtuzumab combined with granulocyte-colony stimulating factor (G-CSF) to boost antibody-dependent cell cytotoxicity mediated by neutrophils. Twelve patients with relapsed (n = 11) or refractory (n = 1) ALL, including four relapses postallogeneic stem cell transplantation, were treated and monitored between October 2006 and January 2011. Patients received 1 wk of alemtuzumab every other day at increasing doses of 3, 10, and 30 mg to test tolerance and 30 mg three times a week for 12-18 infusions. If in complete remission (CR), patients received maintenance therapy for 1 wk, every 2 months. G-CSF was administered at 5 μg/kg per day during alemtuzumab administration. The primary endpoint was disappearance of blast cells on a marrow aspirate. CD52 was expressed in all patients. Four patients reached CR. In one additional patient, clearance of blast cells was observed in peripheral blood but not in the marrow. The most frequent adverse events during course 1 of treatment were fever and chills (n = 3), skin rash (n = 3), and bronchospasm (n = 2). Tumor lysis syndrome was observed at treatment initiation in one patient who reached CR. All patients progressed within a few months and all but one died. The surviving patient is still alive after relapse and a second allogeneic stem cell transplantation. This study shows that in relapse/refractory ALL, alemtuzumab with G-CSF can produce good responses of short duration.
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http://dx.doi.org/10.1111/ejh.12154DOI Listing
October 2013

Metabolites of tryptophan catabolism are elevated in sera of patients with myelodysplastic syndromes and inhibit hematopoietic progenitor amplification.

Leuk Res 2013 May 28;37(5):573-9. Epub 2013 Feb 28.

INSERM, unité 837, Institut pour la Recherche sur le Cancer de Lille, Lille, France.

Tryptophan catabolism, which is mediated by the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), produces kynurenine. Kynurenine itself is converted by downstream enzymes into secondary catabolites. We evaluated the serum levels of primary and secondary tryptophan catabolites in a cohort of patients with myelodysplastic syndromes (MDS). The MDS patients showed significantly higher levels tryptophan catabolites which correlated with cytopenia. The tryptophan catabolites inhibited progenitor expansion during the in vitro culture of hematopoietic cells. Thus, MDS patients are characterized by high tryptophan catabolism resulting in elevated primary and secondary metabolites, which both have inhibitory effects on hematopoiesis.
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http://dx.doi.org/10.1016/j.leukres.2013.02.001DOI Listing
May 2013

Lenalidomide in lower-risk myelodysplastic syndromes with karyotypes other than deletion 5q and refractory to erythropoiesis-stimulating agents.

Br J Haematol 2012 Mar 23;156(5):619-25. Epub 2011 Dec 23.

Hématologie, Centre Hospitalier Lyon Sud, Pierre Bénite, France.

Lenalidomide (LEN) has been shown to yield red blood cell (RBC) transfusion independence in about 25% of lower risk myelodysplastic syndromes (MDS) without del(5q), but its efficacy in patients clearly refractory to erythropoiesis-stimulating agents (ESA) is not known. We report on 31 consecutive lower-risk non-del(5q) MDS patients with anaemia refractory to ESA and treated with LEN in a compassionate programme, 20 of whom also received an ESA. An erythroid response was obtained in 15 patients (48%), including 10 of the 27 (37%) previously transfusion-dependent (RBC-TD) patients, who became transfusion-independent (RBC-TI). Nine of the responders relapsed, whereas 6 (40%) were still responding and transfusion-free after 11(+)-31(+) months. Median response duration was 24 months. The erythroid response rate was lower in refractory cytopenia with multilineage dysplasia (27% vs. 60%) and tended to be higher in patients treated with LEN + ESA (55% vs. 36%). Response duration was significantly longer in responders who obtained RBC-TI and in patients treated with LEN after primary resistance to ESA. The main toxicity of LEN was cytopenias. We confirm that, in a patient population of lower risk MDS without del 5q clearly resistant to ESA, LEN is an interesting second line therapeutic option. Its combination with ESAs in this context warrants prospective studies.
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http://dx.doi.org/10.1111/j.1365-2141.2011.08979.xDOI Listing
March 2012

Changes in the dynamics of the excess mortality rate in chronic phase-chronic myeloid leukemia over 1990-2007: a population study.

Blood 2011 Oct 17;118(16):4331-7. Epub 2011 Aug 17.

Hôpital Claude Huriez, Service des Maladies du Sang, Lille, France.

Imatinib has transformed the prognosis and the management of chronic myeloid leukemia (CML) and has probably changed the patterns of mortality rates. We explored this change at each disease severity level (Sokal score) through a flexible statistical modeling of the effect of the year of diagnosis on the excess mortality rate. The study included 691 chronic-phase patients from Nord-Pas-de-Calais French CML registry diagnosed from 1990 to 2007. Imatinib was given to 93% of the patients diagnosed after 2000. Comparing the 1990-1994, 1995-1999, and 2000-2007 periods of diagnosis, the 5-year relative survival improved from 64% to 66% and 88%. The year of diagnosis was associated with a significant reduction of the excess mortality, but only in patients with intermediate to high Sokal scores. In high-risk patients diagnosed in the early 1990s, a peak of excess mortality was observed during the second year of follow-up. That peak decreased progressively over the years of diagnosis until disappearing in patients diagnosed after 2000. This study showed different effects according to Sokal scores of the use of imatinib on mortality in patients with chronic-phase CML and showed that since 2000 the pattern of mortality of high-risk patients became similar to that of intermediate-risk ones.
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http://dx.doi.org/10.1182/blood-2011-01-330332DOI Listing
October 2011

l-asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: results of the GRASPALL 2005-01 randomized trial.

Br J Haematol 2011 Apr 20;153(1):58-65. Epub 2011 Feb 20.

Institut d'Hemato-Oncologie pédiatrique, Hospices civils de Lyon, Université Claude Bernard, France.

l-asparaginase encapsulated within erythrocytes (GRASPA(®) ) should allow serum asparagine depletion over a longer period than the native form of the enzyme, using lower doses and allowing better tolerance. The GRASPALL 2005-01 study, a multicentre randomized controlled trial, investigated three doses of GRASPA(®) for the duration of asparagine depletion in a phase I/II study in adults and children with acute lymphoblastic leukaemia (ALL) in first relapse. Between February 2006 and April 2008, 18 patients received GRASPA(®) (50 iu/kg: n = 6,100 iu/kg: n = 6, 150 iu/kg: n = 6) after randomization, and six patients were assigned to the Escherichia coli native l-asparaginase (E. colil-ASNase) control group. GRASPA(®) was effective at depleting l-asparagine. One single injection of 150 iu/kg of GRASPA(®) provided similar results to 8 × 10,000 iu/m(2) intravenous injections of E. colil-ASNase. The safety profile of GRASPA(®) showed a reduction in the number and severity of allergic reactions and a trend towards less coagulation disorders. Other expected adverse events were comparable to those observed with E. colil-ASNase and there was also no difference between the three doses of GRASPA(®) .
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http://dx.doi.org/10.1111/j.1365-2141.2011.08588.xDOI Listing
April 2011

Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia.

N Engl J Med 2010 Dec;363(26):2511-21

Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Lille, and INSERM Unité 837, Lille, France.

Background: Imatinib (400 mg daily) is considered the best initial therapy for patients with newly diagnosed chronic myeloid leukemia (CML) in the chronic phase. However, only a minority of patients treated with imatinib have a complete molecular remission.

Methods: We randomly assigned 636 patients with untreated chronic-phase CML to receive imatinib alone at a dose of 400 mg daily, imatinib (400 mg daily) plus cytarabine (20 mg per square meter of body-surface area per day on days 15 through 28 of each 28-day cycle) or pegylated interferon (peginterferon) alfa-2a (90 μg weekly), or imatinib alone at a dose of 600 mg daily. Molecular and cytogenetic responses, time to treatment failure, overall and event-free survival, and adverse events were assessed. An analysis of molecular response at 12 months was planned. A superior molecular response was defined as a decrease in the ratio of transcripts of the tyrosine kinase gene BCR-ABL to transcripts of ABL of 0.01% or less, corresponding to a reduction of 4 log(10) units or more from the baseline level, as assessed by means of a real-time quantitative polymerase-chain-reaction assay.

Results: At 12 months, the rates of cytogenetic response were similar among the four groups. The rate of a superior molecular response was significantly higher among patients receiving imatinib and peginterferon alfa-2a (30%) than among patients receiving 400 mg of imatinib alone (14%) (P=0.001). The rate was significantly higher among patients treated for more than 12 months than among those treated for 12 months or less. Gastrointestinal events were more frequent among patients receiving cytarabine, whereas rash and depression were more frequent among patients receiving peginterferon alfa-2a.

Conclusions: As compared with other treatments, the addition of peginterferon alfa-2a to imatinib therapy resulted in significantly higher rates of molecular response in patients with chronic-phase CML. (Funded by the French Ministry of Health and others; ClinicalTrials.gov number, NCT00219739.).
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http://dx.doi.org/10.1056/NEJMoa1004095DOI Listing
December 2010

Genomic characterization of Imatinib resistance in CD34+ cell populations from chronic myeloid leukaemia patients.

Leuk Res 2011 Apr 3;35(4):448-58. Epub 2010 Aug 3.

Institut de Recherche sur le Cancer de Lille (IRCL), Centre JP Aubert, Unité Inserm 837, Lille, France.

To ascertain genomic alterations associated with Imatinib resistance in chronic myeloid leukaemia, we performed high resolution genomic analysis of CD34(+) cells from 25 Imatinib (IM) resistant and 11 responders CML patients. Using patients' T-cells as reference, we found significant association between number of acquired cryptic copy number alterations (CNA) and disease phase (p=0.036) or loss of IM response for patients diagnosed in chronic phase (CP) (p=0.04). Recurrent cryptic losses were identified on chromosomes 7, 12 and 13. On chromosome 7, recurrent deletions of the IKZF1 locus were detected, for the first time, in 4 patients in CP.
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http://dx.doi.org/10.1016/j.leukres.2010.07.012DOI Listing
April 2011

Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study.

J Clin Oncol 2010 Feb 4;28(5):808-14. Epub 2010 Jan 4.

Centre Hospitalier de Versailles, Hôpital André Mignot, Service Hématologie et Oncologie, 177 rue de Versailles, 78150 Le Chesnay, France.

PURPOSE In patients with acute myeloid leukemia (AML), induction chemotherapy is based on standard doses of anthracyclines and cytarabine. High doses of cytarabine have been reported as being too toxic for patients older than age 50 years, but few studies have evaluated intensified doses of anthracyclines. PATIENTS AND METHODS In this randomized Acute Leukemia French Association 9801 (ALFA-9801) study, high doses of daunorubicin (DNR; 80 mg/m(2)/d x 3 days) or idarubicin (IDA4; 12 mg/m(2)/d x 4 days) were compared with standard doses of idarubicin (IDA3; 12 mg/m(2)/d x 3 days) for remission induction in patients age 50 to 70 years, with an event-free survival (EFS) end point. After two consolidation courses based on intermediate doses of cytarabine, patients in continuous remission were randomly assigned to receive or not receive maintenance therapy with recombinant interleukin-2 (rIL-2; 5 x 10(6) U/m(2) x 5 days each month) for a total duration of 12 months. A total of 468 patients entered the study (median age, 60 years). Results Overall complete remission rate was 77% with significant differences among the three randomization arms (83%, 78%, and 70% in the IDA3, IDA4, and DNR arms, respectively; P = .04). However, no significant differences were observed in relapse incidence, EFS, or overall survival among the three arms. In the 161 patients randomly assigned for maintenance therapy, no difference in outcome was observed between the rIL-2 and the no further treatment arms. CONCLUSION Neither intensification of anthracycline doses nor maintenance with rIL-2 showed a significant impact on AML course, at least as scheduled in this trial.
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http://dx.doi.org/10.1200/JCO.2009.23.2652DOI Listing
February 2010

Management of chronic myeloid leukaemia in clinical practice in France: results of the French subset of patients from the UNIC study.

Curr Med Res Opin 2010 Feb;26(2):307-17

Hospices Civils de Lyon, 5 pl Arsonval, Lyon 69437, France.

Objective: To assess real-life treatment practices with imatinib for chronic-phase chronic myeloid leukaemia (CP-CML) in France.

Research Design And Methods: In the observational 'Unmet Needs in CML' (UNIC) study of CML management in Europe, case report forms were completed retrospectively for eligible patients (> or =18 years of age, currently treated for CML) during enrolment (September 2006-March 2007). Results from the subset of patients from France are presented.

Main Outcome Measures: Primary objectives were to estimate from the collected data the proportions of patients ever treated with imatinib and those experiencing imatinib resistance and/or intolerance as determined by physicians' diagnoses of resistance/intolerance leading to a change in imatinib use. Collected data were analysed descriptively. Secondary descriptive measures included imatinib dose modifications and methods for treatment response monitoring.

Results: Of the 654 French CP-CML patients, 95.9% had received imatinib. Of these, 15% were judged by physicians as imatinib-resistant and 31% as imatinib-intolerant (not mutually exclusive) during treatment, 44% required dose modification and 23% discontinued imatinib. In the 12 months preceding the last observation, 65% had a cytogenetic features analysis and 93% had a polymerase chain reaction (PCR) assessment of molecular response. Importantly, and contrasting with European recommendations, 46% of imatinib-resistant patients had never been assessed for BCR-ABL mutations.

Limitations: The observational study design limits data collection and interpretation. The findings are specific to the French healthcare system and may not apply to other countries.

Conclusion: This observational study of CP-CML management in France confirmed that most patients are treated with imatinib, a treatment widely recognised as efficacious. The study highlights opportunities for optimising CML management, as a proportion of patients may require alternative treatment strategies due to imatinib resistance/intolerance. Response monitoring rates differ from recommendations, representing another opportunity for improving care for CP-CML patients through early identification of patients failing current therapy.
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http://dx.doi.org/10.1185/03007990903479299DOI Listing
February 2010

[Guidelines for the management of dasatinib (Sprycel)-induced side effects in chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemias].

Bull Cancer 2008 Sep;95(9):805-11

Service d'onco-hématologie, CH d'Annecy, 1, avenue de l'Hôpital Metz-Tezzy 74374 Pringy, France.

Dasatinib (Sprycel) is a new-targeted therapy used since 2005 in the treatment of chronic myelogenous leukemia and de novo Philadelphia positive acute lymphoblastic leukaemia patients, intolerant or resistant to imatinib. Despite its high efficacy in such patients in terms of hematologic, cytogenetic and molecular responses, the onset of frequent and sometimes serious side effects particularly in advanced phase patients, especially myelosuppressions and pleural effusions, may impair optimal administration of the drug. Recently, dasatinib dose optimisation in chronic-phase has reduced the incidence of such adverse events without modification of the efficacy, however, their optimal overall management can efficiently reduce their severity and minimize their impact on disease response. Hereby, we attempted to propose a series of guidelines that might be of help in daily practice, in order to control properly these side effects.
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http://dx.doi.org/10.1684/bdc.2008.0703DOI Listing
September 2008

Cryptic and partial deletions of PRDM16 and RUNX1 without t(1;21)(p36;q22) and/or RUNX1-PRDM16 fusion in a case of progressive chronic myeloid leukemia: a complex chromosomal rearrangement of underestimated frequency in disease progression?

Genes Chromosomes Cancer 2008 Dec;47(12):1110-7

Cancer Research Institute of Lille, JP Aubert Center, Inserm Unit 837, Lille, France.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence in leukemic stem cells of the Philadelphia chromosome (Ph) and the formation of the BCR-ABL1 fusion. Untreated, the disease progresses to accelerate phase and blast crisis in which hematopoietic differentiation has become arrested. CML progression is frequently associated with cytogenetic evidence of clonal evolution, defined as additional chromosomal aberrations. We here report a CML resistant to tyrosine kinase inhibitors that rapidly progressed to blastic phase. At this time, array CGH performed on CD34(+) cells revealed cryptic partial deletions of both PRDM16 and RUNX1 and duplication of the der(21) chromosome. These genomic rearrangements were confirmed by FISH with probes targeting the deletion on chromosome 21 (24 kb), and with BAC probes flanking the deletion on 1p36 (220 kb). However, no cryptic t(1;21)(p36;q22) and/or RUNX1-PRDM16 were detected, suggesting that these deletions are the residual hallmarks of a more complex mechanism of chromosomal rearrangement, as indicated by the additional inversion of the region bounded by 1p36.32 and 1p36.12 breaks. At the molecular level, these abnormalities lead to the overexpression of the PR-domain negative oncogenic isoform of PRDM16, associated with two deleted copies within the runt domain of C-teminal aberrant RUNX1. These events are not detectable by conventional cytogenetic and molecular strategies, and may be of underestimated frequency in disease progression.
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http://dx.doi.org/10.1002/gcc.20611DOI Listing
December 2008

Indoleamine 2,3-dioxygenase activity of acute myeloid leukemia cells can be measured from patients' sera by HPLC and is inducible by IFN-gamma.

Leuk Res 2009 Mar 18;33(3):490-4. Epub 2008 Jul 18.

INSERM, unité 837, Equipe 3, Institut de Recherche sur le Cancer de Lille, Lille, France.

The enzyme indoleamine 2,3-dioxygenase (IDO) converts tryptophan to kynurenine, blocking T-cell activation and inducing immunosuppression. In patients with acute myeloid leukemia (AML), the serum kynurenine/tryptophan ratio (Kyn/Trp) was raised, suggesting a higher IDO activity than in healthy people. Patients with higher Kyn/Trp ratios showed lower survival. IDO activity was also detected in AML cells after exposure to IFN-gammain vitro, suggesting that the higher Kyn/Trp ratio in serum of AML patients might have resulted from stimulated leukemic blast cells. Thus, in AML, the activity of IDO can be easily monitored, providing a tool for future clinical testing of IDO-blocking drugs.
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http://dx.doi.org/10.1016/j.leukres.2008.06.014DOI Listing
March 2009

Mechanisms of genesis of variant translocation in chronic myeloid leukemia are not correlated with ABL1 or BCR deletion status or response to imatinib therapy.

Cancer Genet Cytogenet 2008 Apr;182(2):95-102

Laboratory of Medical Genetics, Hospital Jeanne de Flandre, University Hospital Regional Center-CHRU, Avenue Eugène Avinée, 59037 Lille cedex, France.

Many published studies have indicated that various mechanisms could be involved in the genesis of variant chronic myelogeneous leukemia (CML) translocations. These are mainly one-step or two-step mechanisms, associated or not with deletions adjacent to the translocation junction on der(9) or der(22) chromosomes (or both). Based on the mechanism of genesis, it has been suggested that the complexity may affect the occurrence of ABL1 and BCR deletions (either or both), or may be associated with the CML disease course, and thus could determine the response to imatinib therapy. Through a retrospective molecular cytogenetic study of 41 CML patients with variant Philadelphia chromosome (Ph), we explored the genesis of these variant rearrangements and analyzed the correlation with deletion status and imatinib efficiency. Our results confirmed that the one-step mechanism is the most frequent, evidenced in 30 of 41 patients (73%); 3 patients demonstrated other more complex multistep events and 8 patients (19.5%) harbored ABL1 or BCR deletions that are not significantly associated with the complexity of translocation genesis. We also found no association between one-step, two-step, or multistep mechanisms and the response to imatinib therapy.
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http://dx.doi.org/10.1016/j.cancergencyto.2008.01.005DOI Listing
April 2008

RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance.

Blood 2008 Apr 17;111(7):3735-41. Epub 2008 Jan 17.

Cancer Research Institute of Lille, JP Aubert Center, Inserm Unit 837, France.

Acquired molecular abnormalities (mutations or chromosomal translocations) of the RUNX1 transcription factor gene are frequent in acute myeloblastic leukemias (AMLs) and in therapy-related myelodysplastic syndromes, but rarely in acute lymphoblastic leukemias (ALLs) and chronic myelogenous leukemias (CMLs). Among 18 BCR-ABL+ leukemias presenting acquired trisomy of chromosome 21, we report a high frequency (33%) of recurrent point mutations (4 in myeloid blast crisis [BC] CML and one in chronic phase CML) within the DNA-binding region of RUNX1. We did not found any mutation in de novo BCR-ABL+ ALLs or lymphoid BC CML. Emergence of the RUNX1 mutations was detected at diagnosis or before the acquisition of trisomy 21 during disease progression. In addition, we also report a high frequency of cryptic chromosomal RUNX1 translocation to a novel recently described gene partner, PRDM16 on chromosome 1p36, for 3 (21.4%) of 14 investigated patients: 2 myeloid BC CMLs and, for the first time, 1 therapy-related BCR-ABL+ ALL. Two patients presented both RUNX1 mutations and RUNX1-PRDM16 fusion. These events are associated with a short survival and support the concept of a cooperative effect of BCR-ABL with molecular RUNX1 abnormalities on the differentiation arrest phenotype observed during progression of CML and in BCR-ABL+ ALL.
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http://dx.doi.org/10.1182/blood-2007-07-102533DOI Listing
April 2008

Clinical outcome of 27 imatinib mesylate-resistant chronic myelogenous leukemia patients harboring a T315I BCR-ABL mutation.

Haematologica 2007 Sep;92(9):1238-41

Hematology Department, Hôpital E. Herriot, Lyon, France.

We analyzed 27 CML patients treated with imatinib (IM) who developed a BCR-ABLT315I mutation. These patients had poor prognostic features: High or intermediate Sokal index (82%), and lack of CCyR under IM (59%). At T315I discovery, patients were in advanced phase (59%), with clonal evolution (84%). Median time since diagnosis was 39 months, and progression occurred 13 months after IM initiation, regardless of disease phase. Overall survival since IM initiation was 42.5 months for chronic, and 17.5 months for advanced phases, and all patients progressed. This mutation seems related to or (partially?) responsible for progression and poor survival.
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http://dx.doi.org/10.3324/haematol.11369DOI Listing
September 2007

Induction of leukemia-specific CD8+ cytotoxic T cells with autologous myeloid leukemic cells maturated with a fiber-modified adenovirus encoding TNF-alpha.

Mol Ther 2005 Jun 20;11(6):950-9. Epub 2005 Jan 20.

Unité INSERM 524, Institut de Recherche sur le Cancer de Lille, 59037 Lille, France.

Acute myeloid leukemia (AML) cells can be differentiated into dendritic cells (DCs) using appropriate combinations of cytokines but generation of autologous antileukemic cytotoxic T cells using leukemic DCs remains difficult. Transduction by adenoviral vectors has been reported to induce efficient maturation of monocyte-derived DCs but AML cells are generally resistant to adenoviral gene transfer. In this study we tested the effects of adenoviral TNF-alpha gene transfer on maturation of AML cells using the fiber-modified AdTNF.F(pK7) adenovirus. All samples expressed high and sustained levels of TNF-alpha following transduction. AdTNF.F(pK7) induced significantly greater maturation of AML cells into antigen-presenting cells (APC) than did recombinant TNF-alpha or control adenoviral vector. Maturation of leukemic cells into APCs was mediated at least partially via a PI3K/mTOR pathway, as the inhibitors LY294002, wortmannin, and rapamycin inhibited the maturation effect induced by the AdTNF.F(pK7) adenovirus. In addition, CD8+ T cells expanded with AdTNF.F(pK7)-transduced AML cells showed greater expansion and specific CD8+ CTL activity against autologous AML cells than T cells expanded by other means. Thus, fiber-modified adenoviral vectors encoding TNF-alpha are able to maturate AML cells into APCs with high efficacy and reproducibility, providing a useful tool to generate efficiently specific CD8+ CTLs against leukemic disease.
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http://dx.doi.org/10.1016/j.ymthe.2004.12.016DOI Listing
June 2005

Efficient generation of antileukemic autologous T cells by short-term culture and gamma-irradiation of myeloid leukemic cells.

Cancer Immunol Immunother 2004 Sep 20;53(9):793-8. Epub 2004 Apr 20.

Unité INSERM 524, Institut de Recherche sur le Cancer de Lille, Lille, France.

Blasts from patients with acute myeloid leukemia (AML) can be differentiated in dendritic cells (DCs) using appropriate combinations of cytokines. However, generation of autologous antileukemic cytotoxic T cells using leukemic DCs remains difficult. We have previously reported that expression of costimulatory molecules in cultured AML cells could be induced by gamma-irradiation. In the present study, blasts from 21 patients with AML were cultured in vitro for 2 days, then cells were gamma-irradiated and antigen-presenting cell (APC) characteristics were assessed. gamma-Irradiation induced expression of several characteristics of APCs in AML blasts, including expression of CD80, CD86, and BDCA-4, and were stimulators of allogeneic mixed lymphocyte reactions. Autologous antileukemic cytotoxicity was induced in seven out of ten cases. This study shows that cells with APC characteristics and able to induce ex vivo stimulation of autologous antileukemic T cells can be generated from AML cells using the simple and rapid method of gamma-irradiation of cultured leukemic cells.
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http://dx.doi.org/10.1007/s00262-004-0528-6DOI Listing
September 2004
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