Publications by authors named "Jean-Pierre Marie"

63 Publications

Survival Improvement over Time of 960 s-AML Patients Included in 13 EORTC-GIMEMA-HOVON Trials.

Cancers (Basel) 2020 Nov 11;12(11). Epub 2020 Nov 11.

GIGA-I3, Hematology, University of Liège, 4000 Liège, Belgium.

We report the outcomes of secondary acute myeloid leukemia (s-AML) patients included in one of 13 European Organisation for Research and Treatment of Cancer (EORTC) collaborative AML trials using intensive remission-induction chemotherapy. Among 8858 patients treated between May 1986 and January 2008, 960 were identified as having s-AML, either after MDS (cohort A; = 508), occurring after primary solid tumors or hematologic malignancies other than MDS (cohort B; = 361), or after non-malignant conditions or with a history of toxic exposure (cohort C; = 91). Median age was 64 years, 60 years and 61 years in cohort A, B and C, respectively. Among patients ≤60 years and classified in the cohorts A or B ( = 367), the 5-year overall survival (OS) rate was 28%. There was a systematic improvement in the 5-year OS rate over three time periods ( < 0.001): 7.7% (95% CI: 1.3-21.7%) for patients treated before 1990 (period 1: = 26), 23.3% (95% CI: 17.1-30.0%) for those treated between 1990 and 2000 (period 2: = 188) and 36.5% (95% CI: 28.7-44.3%) for those treated in 2000 or later (period 3: n = 153). In multivariate analysis, male gender (HR = 1.39; = 0.01), WBC ≥ 25 × 10/L (HR = 2.00; < 0.0001), age 46-60 years (HR = 1.65; < 0.001) and poor-risk cytogenetics (HR = 2.17; < 0.0001) were independently associated with shorter OS, while being treated during period 2 (HR = 0.50, = 0.003) or period 3 (HR = 0.43; = 0.0008). Having received high-dose cytarabine (HD-AraC) ( = 48) in the induction chemotherapy (HR = 0.54, = 0.012) was associated with a longer OS. In contrast, among patients >60 years of age ( = 502), the OS was dismal, and there was no improvement over time.
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http://dx.doi.org/10.3390/cancers12113334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697114PMC
November 2020

Impact of the type of anthracycline and of stem cell transplantation in younger patients with acute myeloid leukaemia: Long-term follow up of a phase III study.

Am J Hematol 2020 07 17;95(7):749-758. Epub 2020 Apr 17.

EORTC Headquarters, Brussels, Belgium.

We provide a long-term evaluation of patients enrolled in the EORTC/GIMEMA AML-10 trial which included a total of 2157 patients, 15-60 years old, randomized to receive either daunorubicin (DNR, 50 mg/m ), mitoxantrone (MXR, 12 mg/m ), or idarubicin (IDA, 10 mg/m ) in addition to standard-dose cytarabine and etoposide for induction chemotherapy and intermediate dose cytarabine for consolidation. Younger patients who reached complete remission with complete (CR) or incomplete (CRi) recovery were then scheduled to receive an allogeneic hematopoietic stem cell transplantation (HSCT). That was if they had a HLA-identical sibling donor; in all other cases, an autologous HSCT had to be administered. At an 11-year median follow-up, the 5-year, 10-year and 15-year overall survival (OS) rates were 33.2%, 30.1% and 28.0%, respectively. No significant difference between the three randomized groups regarding OS was observed (P = .38). In young patients, 15-45 years old, no treatment difference (P = .89) regarding OS was observed, while in patients 46-60 years old, MXR and IDA groups had a trend for a longer OS as compared to the DNR group (P = .029). Among younger patients without a favorable MRC cytogenetic risk subgroup who achieved a CR/CRi after induction chemotherapy, those with a HLA-identical sibling donor had higher 10-year and 15-year OS rates than those without. In older patients who reached CR/CRi, the long-term outcomes of those with or without a donor was similar. In conclusion, long-term outcomes of the study confirmed similar OS in the three randomized groups in the whole cohort of patients.
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http://dx.doi.org/10.1002/ajh.25795DOI Listing
July 2020

Impact of induction regimen and allogeneic hematopoietic cell transplantation on outcome in younger adults with acute myeloid leukemia with a monosomal karyotype.

Haematologica 2019 06 6;104(6):1168-1175. Epub 2018 Dec 6.

EORTC Headquarters, Brussels, Belgium.

Monosomal karyotype confers a poor prognosis in patients with acute myeloid leukemia. Here, we determined the impact of the type of remission-induction chemotherapy and the impact of having a donor in younger acute myeloid leukemia patients with a monosomal karyotype included in two phase III trials. In the first trial patients were randomized to receive either daunorubicin, mitoxantrone, or idarubicin in addition to standard-dose cytarabine and etoposide for induction chemotherapy. In the second trial patients were randomized to standard-dose cytarabine or high-dose cytarabine induction, both with daunorubicin and etoposide. In both trials, patients who achieved a complete remission with or without complete hematologic recovery underwent allogeneic hematopoietic stem cell transplantation if they had a donor; otherwise, they underwent autologous transplantation. In comparison to patients with intermediate-risk cytogenetics without a monosomal karyotype (n=1,584) and with adverse cytogenetics without a monosomal karyotype (n=218), patients with a monosomal karyotype (n=188) were more likely not to achieve a complete remission with or without count recovery [odds ratio=2.85, 95% confidence interval (95%, CI): 2.10-3.88] and had shorter overall survival [hazard ratio, (HR)=2.44, 95% CI: 2.08-2.88]. There was no impact of the type of anthracycline or of the dose of cytarabine on outcomes in patients with a monosomal karyotype. Among monosomal karyo type patients who achieved a complete remission with or without count recovery, HLA-identical related donor availability was associated with longer survival from complete remission with or without count recovery (HR=0.59, 95% CI: 0.37-0.95). ClinicalTrials.gov identifiers: AML-10: NCT00002549; AML-12: NCT00004128.
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http://dx.doi.org/10.3324/haematol.2018.204826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545848PMC
June 2019

Cytogenetic clonal heterogeneity is not an independent prognosis factor in 15-60-year-old AML patients: results on 1291 patients included in the EORTC/GIMEMA AML-10 and AML-12 trials.

Ann Hematol 2018 Oct 20;97(10):1785-1795. Epub 2018 Jun 20.

EORTC Headquarters, Brussels, Belgium.

The presence of cytogenetic clonal heterogeneity has been associated with poor prognosis in patients with acute myeloid leukemia (AML). Here, we reassessed this association. The study cohort consisted of all patients with an abnormal karyotype randomized in the EORTC/GIMEMA AML-10 and AML-12 trials. Abnormal karyotypes were classified as no subclones present (cytogenetic abnormality in a single clone), defined subclones present (presence of one to three subclones), and composite karyotypes (CP) (clonal heterogeneity not allowing enumeration of individual subclones). The main endpoints were overall survival (OS) and disease-free survival (DFS). Among 1291 patients with an abnormal karyotype, 1026 had no subclones, 226 at least 1 subclone, and 39 a CP. Patients with defined subclones had an OS similar to those with no subclones (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.88-1.26), but CP patients had a shorter OS (HR = 1.58, 95% CI 1.11-2.26). However, in a multivariate Cox model stratified by protocol and adjusted for age, cytogenetic risk group, secondary versus primary AML, and performance status, clonal heterogeneity lost its prognostic importance (HR = 1.10, 95% CI 0.91-1.32 for defined subclones versus no subclones; HR = 0.96, 95% CI 0.67-1.38 for CP versus no subclones). Also, the impact of having a donor on DFS was similar in the three clonal subgroups. In summary, in patients with cytogenetic abnormality, presence of subclones had no impact on OS. The dismal outcome in patients with a CP was explained by the known predictors of poor prognosis.

Trial Registration: AML-10: ClinicalTrials.gov identifier: NCT00002549, retrospectively registered July 19, 2004; AML12: ClinicalTrials.gov identifier: NCT00004128, registered January 27, 2003.
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http://dx.doi.org/10.1007/s00277-018-3396-4DOI Listing
October 2018

Phase 2b study of 2 dosing regimens of quizartinib monotherapy in -ITD-mutated, relapsed or refractory AML.

Blood 2018 08 6;132(6):598-607. Epub 2018 Jun 6.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.

This randomized, open-label, phase 2b study (NCT01565668) evaluated the efficacy and safety of 2 dosing regimens of quizartinib monotherapy in patients with relapsed/refractory (R/R) -internal tandem duplication (ITD)-mutated acute myeloid leukemia (AML) who previously underwent transplant or 1 second-line salvage therapy. Patients (N = 76) were randomly assigned to 30- or 60-mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral quizartinib dihydrochloride. Allelic frequency of at least 10% was defined as -ITD-mutated disease. Coprimary endpoints were composite complete remission (CRc) rates and incidence of QT interval corrected by Fridericia's formula (QTcF) of more than 480 ms (grade 2 or greater). Secondary endpoints included overall survival (OS), duration of CRc, bridge to transplant, and safety. CRc rates were 47% in both groups, similar to earlier reports with higher quizartinib doses. Incidence of QTcF above 480 ms was 11% and 17%, and QTcF above 500 ms was 5% and 3% in the 30- and 60-mg groups, respectively, which is less than earlier reports with higher doses of quizartinib. Median OS (20.9 and 27.3 weeks), duration of CRc (4.2 and 9.1 weeks), and bridge to transplant rates (32% and 42%) were higher in the 60-mg groups than in the 30-mg group. Dose escalation occurred in 61% and 14% of patients in the 30- and 60-mg groups, respectively. This high clinical activity of quizartinib at the evaluated doses is consistent with previous reports with an improved safety profile. Need to dose-escalate more than half of patients who received quizartinib 30 mg also supports further investigation of treatment with quizartinib 60 mg/day.
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http://dx.doi.org/10.1182/blood-2018-01-821629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085992PMC
August 2018

Endothelial protein C receptor gene 6936A/G single-nucleotide polymorphism as a possible biomarker of thrombotic risk in acute myeloid leukemia.

Mol Clin Oncol 2015 Nov 8;3(6):1280-1284. Epub 2015 Sep 8.

UMR, Paris Diderot, Paris 7 University, Lariboisière Hospital, INSERM U965, 75010 Paris, France.

Protein C (PC) is a natural anticoagulant, which interacts with the endothelial PC receptor (EPCR). EPCR single-nucleotide polymorphism (SNP) 6936A/G results in high levels of a free soluble form of EPCR (sEPCR) and may affect the risk of coagulation. The objective of this study was to assess whether the 6936A/G SNP of the EPCR gene is involved in the procoagulant activity displayed by hematological malignancies. EPCR 6936A/G polymorphism analysis was performed in 205 patients with hematological malignancies and in 63 healthy controls. All the subjects were genotyped for the EPCR 6936A/G SNP (AA, AG and GG genotypes). The 6936A/G polymorphism distribution was similar between healthy donors and patients. The association between EPCR 6936A/G SNP and thrombosis was investigated in 110 patients. The disease-wise break-up revealed that 55 of the patients suffered from acute myeloid leukemia (AML). In AML patients, the incidence of thrombosis was 28.3% and significantly higher in the 6936AG compared with that in the 6936AA genotype (50 vs. 22%, respectively). In conclusion, this study revealed a significant association of the 6936AG genotype of EPCR with thrombotic events in AML. Therefore, the presence of the 6936AG genotype in AML patients may be considered as a risk indicator of thrombosis.
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http://dx.doi.org/10.3892/mco.2015.638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665720PMC
November 2015

Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group.

Ann Hematol 2016 Jan 23;95(2):191-9. Epub 2015 Nov 23.

Department of Hematology, Haga Hospital, The Hague, The Netherlands.

In a study of elderly AML patients treated with the hypomethylating agent decitabine (DAC), we noted a surprisingly favorable outcome in the (usually very unfavorable) subgroup with two or more autosomal monosomies (MK2+) within a complex karyotype (Lübbert et al., Haematologica 97:393-401, 2012). We now analyzed 206 myelodysplastic syndrome (MDS) patients (88 % of 233 patients randomized in the EORTC/GMDSSG phase III trial 06011, 61 of them with RAEBt, i.e. AML by WHO) with cytogenetics informative for MK status.. Endpoints are the following: complete/partial (CR/PR) and overall response rate (ORR) and progression-free (PFS) and overall survival (OS). Cytogenetic subgroups are the following: 63 cytogenetically normal (CN) patients, 143 with cytogenetic abnormalities, 73 of them MK-negative (MK-), and 70 MK-positive (MK+). These MK+ patients could be divided into 17 with a single autosomal monosomy (MK1) and 53 with at least two monosomies (MK2+). ORR with DAC in CN patients: 36.1 %, in MK- patients: 16.7 %, in MK+ patients: 43.6 % (MK1: 44.4 %, MK2+ 43.3 %). PFS was prolonged by DAC compared to best supportive care (BSC) in the CN (hazard ratio (HR) 0.55, 99 % confidence interval (CI), 0.26; 1.15, p = 0.03) and MK2+ (HR 0.50; 99 % CI, 0.23; 1.06, p = 0.016) but not in the MK-, MK+, and MK1 subgroups. OS was not improved by DAC in any subgroup. In conclusion, we demonstrate for the first time in a randomized phase III trial that high-risk MDS patients with complex karyotypes harboring two or more autosomal monosomies attain encouraging responses and have improved PFS with DAC treatment compared to BSC.
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http://dx.doi.org/10.1007/s00277-015-2547-0DOI Listing
January 2016

Prognosis of body mass index and chemotherapy dose capping in acute myeloid leukaemia.

Leuk Res 2014 Dec 7;38(12):1425-9. Epub 2014 Oct 7.

Service d'hématologie clinique et de thérapie cellulaire, Hôpital Saint-Antoine, APHP, Paris, France; UPMC, Univ Paris 06, GRC n°7, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, Paris, France; INSERM, UMR_S 938, CDR Saint Antoine, F-75012 Paris, France. Electronic address:

Body Mass Index (BMI) prognosis in acute myeloid leukaemia (AML) is unknown. Capping chemotherapy dose at 2m(2) of body surface area (BSA) is used without any rationale. We assessed whether both of them could be correlated with outcome in 233 AML patients. Thirty three percent were overweight, 10% obese and BSA over 2m(2) was observed in 15%. BMI and BSA>2m(2) were not associated with OS (p=0.16; p=0.39), nor with DFS (p=0.18; p=0.42), nor with CR. OS-associated factors were age (p<0.001), cytogenetic (p=0.002), FLT3-ITD (p=0.01). BMI and chemotherapy dose capping are not pejorative factors on intensively treated AML patients.
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http://dx.doi.org/10.1016/j.leukres.2014.09.013DOI Listing
December 2014

Specific scoring systems to predict survival of patients with high-risk myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML) after intensive antileukemic treatment based on results of the EORTC-GIMEMA AML-10 and intergroup CRIANT studies.

Ann Hematol 2015 Jan 7;94(1):23-34. Epub 2014 Aug 7.

Department of Tumor Immunology, Nijmegen Center of Life Sciences, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, Netherlands.

High-risk myelodysplastic syndrome (MDS) patients have usually a less favorable outcome after intensive treatment compared with de novo acute myeloid leukemia (AML) patients. This may reflect different disease-related and patient-related factors. The purpose of this analysis is to identify disease-specific prognostic factors and to develop prognostic scores for both patient groups. A total of 692 patients in the EORTC/GIMEMA AML-10 study and 289 patients in the CRIANT study received identical remission-induction and consolidation treatment. Estimated 5-year survival rate was 34 % in the AML-10 versus 27 % in the CRIANT study, and estimated disease-free survival was 40 % versus 28 %, respectively. In multivariate analysis, cytogenetic characteristics, white blood count, and age appeared prognostic for survival in both studies. French-American-British (FAB) subtype and performance status were prognostic in the AML-10 study only, whereas number of cytopenias and duration of antecedent hematologic disorder >6 months were prognostic in the CRIANT study only. The prognostic scores distinguish three groups with a 5-year survival rate of 54, 38, and 19 % in the AML-10 study versus 69, 37, and 5 % in the CRIANT study. The prognostic value of these scores has been validated on two external series. The new scoring systems form a practical tool to predict the outcome of individual MDS and AML patients treated with intensive antileukemic therapy.
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http://dx.doi.org/10.1007/s00277-014-2177-yDOI Listing
January 2015

A subset of bone marrow stromal cells regulate ATP-binding cassette gene expression via insulin-like growth factor-I in a leukemia cell line.

Int J Oncol 2014 Oct 29;45(4):1372-80. Epub 2014 Jul 29.

UMR, Paris Diderot, Paris 7 University, Lariboisiere Hospital, INSERM U965, Paris, France.

The importance of the insulin-like growth factor, IGF, as a signaling axis in cancer development, progression and metastasis is highlighted by its effects on cancer cells, notably proliferation and acquired resistance. The role of the microenvironment within which cancer cells evolve and which mediates this effect is far from clear. Here, the involvement of IGF-I in inducing multidrug resistance in a myeloid leukemia cell line, grown in the presence of bone marrow-derived stromal cells called 'Hospicells' (BMH), is demonstrated. We found that i) drug sensitive as well as resistant leukemia cells express IGF-I and its receptor IGF-IR. However, the resistant cells were found to secrete high levels of IGF-I. ii) Presence of exogenous IGF-I promoted cell proliferation, which decreased when an inhibitor of IGF-IR (picropodophyllin, PPP) was added. iii) BMH and IGF-I are both involved in the regulation of genes of the ATP binding cassette (ABC) related to resistance development (MDR1, MRP1, MRP2, MRP3 and BCRP). iv) The levels of ABC gene expression by leukemia cells were found to increase in the presence of increasing numbers of BMH. However, these levels decreased when IGF-IR was inhibited by addition of PPP. v) Co-culture of the drug-sensitive leukemia cells with BMH induced protection against the action of daunorubicin. This chemoresistance was amplified by the presence of IGF-I whereas it decreased when IGF-IR was inhibited. Our results underline the role of microenvironment in concert with the IGF-1 pathway in conferring drug resistance to leukemia cells.
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http://dx.doi.org/10.3892/ijo.2014.2569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151812PMC
October 2014

Clinical and biological impact of TET2 mutations and expression in younger adult AML patients treated within the EORTC/GIMEMA AML-12 clinical trial.

Ann Hematol 2014 Aug 29;93(8):1401-12. Epub 2014 Mar 29.

Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Nijmegen Medical Center, Geert Grooteplein zuid 8, 6525 GA, Nijmegen, The Netherlands.

We assessed the prognostic impact of TET2 mutations and mRNA expression in a prospective cohort of 357 adult AML patients < 60 years of age enrolled in the European Organization For Research and Treatment of Cancer (EORTC)/Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) AML-12 06991 clinical trial. In addition the co-occurrence with other genetic defects and the functional consequences of TET2 mutations were investigated. TET2 mutations occurred in 7.6 % of the patients and were an independent marker of poor prognosis (p = 0.024). TET2 and IDH1/2 mutations strongly associated with aberrations in the DNA methyltransferase DNMT3A. Functional studies confirmed previous work that neither nonsense truncations, nor missense TET2 mutations, induced 5-hydroxymethylcytosine formation. In addition, we now show that mutant TET2 forms did not act in a dominant negative manner when co-expressed with the wild-type protein. Finally, as loss-of-function TET2 mutations predicted poor outcome, we questioned whether low TET2 mRNA expression in cases of AML without TET2 mutations would affect overall survival. Notably, also AML patients with low TET2 mRNA expression levels showed inferior overall survival.
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http://dx.doi.org/10.1007/s00277-014-2055-7DOI Listing
August 2014

Characterization of acute myeloid leukemia based on levels of global hydroxymethylation.

Blood 2014 Aug 1;124(7):1110-8. Epub 2014 Jul 1.

Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands;

Patients with acute myeloid leukemia (AML) frequently harbor mutations in genes involved in the DNA (hydroxy)methylation pathway (DNMT3A, TET2, IDH1, and IDH2). In this study, we measured 5-hydroxymethylcytosine (5hmC) levels in 206 clinically and molecularly well-characterized younger adult AML patients (≤60 years) included in the European Organization for Research and Treatment of Cancer/Gruppo Italiano Malattie Ematologiche dell'Adulto (EORTC/GIMEMA) AML-12 06991 clinical trial and correlated the 5hmC levels with mutational status and overall survival (OS). In healthy control cells, 5hmC levels were confined to a narrow range (1.5-fold difference), whereas in AML cells, a much wider range was detected (15-fold difference). We identified 3 5hmC subpopulations in our patient cohort (low, intermediate, and high). The low 5hmC group consisted almost entirely of patients with TET2 or IDH mutations. As expected, TET2 and IDH mutated patients had significantly lower levels of 5hmC compared with patients without mutated TET2 and IDH1/2 (both P < .001). Interestingly, high 5hmC levels correlated with inferior OS (high vs intermediate 5hmC: P = .047, hazard ratio [HR] = 1.81). Multivariate analysis revealed that high 5hmC is an independent poor prognostic indicator for OS (high vs intermediate 5hmC: P = .01, HR = 2.10). This trial was registered at www.clinicaltrials.gov as NCT00004128.
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http://dx.doi.org/10.1182/blood-2013-08-518514DOI Listing
August 2014

Interest of cytogenetic and FISH evaluation for prognosis evaluation in 198 patients with acute myeloid leukemia in first complete remission in a single institution.

Leuk Res 2014 Aug 4;38(8):907-12. Epub 2014 Jun 4.

Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint-Antoine, APHP, Paris, France; UPMC, Univ Paris 06, GRC n°7, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MYPAC, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France; INSERM, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.

The prognostic interest of cytogenetic remission and fluorescent in situ hybridization (FISH) evaluation in patients with abnormal karyotype acute myeloid leukemia (AML) has been poorly studied. Among 198 patients that reached complete remission (CR), 24 did not reach cytogenetic remission (CyCR). CyCR had no prognosis impact, especially in patients with intermediate or unfavorable cytogenetic. Twenty of 52 evaluated patients in CyCR did not reach FISH CR. FISH CR was associated with better OS (p=0.004) and tended to be associated with better disease-free survival (DFS) (p=0.08). FISH evaluation may be a useful tool for prognosis evaluation and minimal residual disease (MRD) assessment in patients with abnormal cytogenetic AML.
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http://dx.doi.org/10.1016/j.leukres.2014.05.021DOI Listing
August 2014

Acute myeloid leukemia in patients older than 75: prognostic impact of FLT3-ITD and NPM1 mutations.

Leuk Lymphoma 2015 Jan 16;56(1):147-50. Epub 2014 Jun 16.

Service d'hématologie clinique et de thérapie cellulaire, Hôpital Saint-Antoine, APHP , Paris , France.

The benefit associated with chemotherapy in older patients with acute myeloid leukemia (AML) is debated. The prognostic impact of molecular mutations in these patients is unknown. We identified 79 patients with AML aged 75 years or over. Forty-two received chemotherapy and 37 supportive care only. In intensively treated patients, overall survival was longer (p < 0.001). Achieving complete remission was associated with longer survival (p < 0.001). NPM1 mutations tended to be associated with a higher complete remission rate (p = 0.12). In multivariate analysis, FLT3-ITD was associated with poorer survival (p = 0.049). Patients harboring FLT3-ITD and no NPM1 mutation had a poorer prognosis than others (p = 0.02). Intensive treatments can benefit a portion of elderly patients. FLT3-ITD and NPM1 mutational status might be useful for prognosis stratification.
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http://dx.doi.org/10.3109/10428194.2014.913288DOI Listing
January 2015

Long-term imatinib maintenance therapy for adult Philadelphia positive acute lymphoblastic leukemia.

Leuk Lymphoma 2014 Nov 10;55(11):2646-8. Epub 2014 Mar 10.

Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint-Antoine, Assistance Publique - Hôpitaux de Paris , Paris , France.

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http://dx.doi.org/10.3109/10428194.2014.889828DOI Listing
November 2014

High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial.

J Clin Oncol 2014 Jan 2;32(3):219-28. Epub 2013 Dec 2.

Roelof Willemze, Constantijn J.M. Halkes, and Erik W.A. Marijt, Leiden University Medical Center, Leiden; Petra Muus, Joop Jansen, and Theo de Witte, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; Stefan Suciu and Liv Meert, European Organisation for Research and Treatment of Cancer Headquarters; Dominique Bron, Hôpital Universitaire, Bordet-Erasme, Brussels; Dominik L.D. Selleslag, Algemeen Ziekenhuis Sint-Jan, Brugge; Zwi Berneman, Universitair Ziekenhuis, Antwerpen; Georges Fillet, Centre Hospitalier Universitaire du Sart-Tilman, Liège; Anne Hagemeijer, Center for Human Genetics, University of Leuven, Leuven, Belgium; Giovanna Meloni, Marco Mancini, Silvia Maria Trisolini, and Franco Mandelli, "Sapienza" University; Sergio Amadori and Adriano Venditti, Tor Vergata University Hospital; Simona Sica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli; Paola Fazi and Marco Vignetti, Gruppo Italiano Malattie Ematologiche dell' Adulto Foundation, Central Office, Rome; Giorgina Specchia, Università degli Studi di Bari, Bari; Francesco Fabbiano, Ospedali Riuniti "Villa Sofia-Cervello"; Maria Enza Mitra, Policlinico "Paolo Giaccone," Palermo; Francesco Nobile, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria; Marco Sborgia, Azienda Unitá Sanitaria Locale di Pescara, Pescara; Andrea Camera, L'A.O. Universitaria-Università degli Studi di Napoli "Federico II," Napoli; Domenico Magro, A.O. Pugliese Ciaccio, Catanzaro; Nicola Cantore, A.O. San Giuseppe Moscati, Avellino; Lorella Melillo, Istituto Di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo; Pietro Leoni, A.O. Nuovo Ospedale Torrette, Ancona; Mario Luppi, A.O. Universitaria di Modena, Modena; Daniela Cilloni, University of Torino, Torino, Italy; Boris Labar, University Hospital Center-Rebro, Zagreb, Croatia; Jean-Pierre Marie, Saint-Antoine Hospital, Assistance Publique-Hopitaux de Paris and University Paris 6; Francois Lef

Purpose: Cytarabine plays a pivotal role in the treatment of patients with acute myeloid leukemia (AML). Most centers use 7 to 10 days of cytarabine at a daily dose of 100 to 200 mg/m(2) for remission induction. Consensus has not been reached on the benefit of higher dosages of cytarabine.

Patients And Methods: The European Organisation for Research and Treatment of Cancer (EORTC) and Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Leukemia Groups conducted a randomized trial (AML-12; Combination Chemotherapy, Stem Cell Transplant and Interleukin-2 in Treating Patients With Acute Myeloid Leukemia) in 1,942 newly diagnosed patients with AML, age 15 to 60 years, comparing remission induction treatment containing daunorubicin, etoposide, and either standard-dose (SD) cytarabine (100 mg/m(2) per day by continuous infusion for 10 days) or high-dose (HD) cytarabine (3,000 mg/m(2) every 12 hours by 3-hour infusion on days 1, 3, 5, and 7). Patients in complete remission (CR) received a single consolidation cycle containing daunorubicin and intermediate-dose cytarabine (500 mg/m(2) every 12 hours for 6 days). Subsequently, a stem-cell transplantation was planned. The primary end point was survival.

Results: At a median follow-up of 6 years, overall survival was 38.7% for patients randomly assigned to SD cytarabine and 42.5% for those randomly assigned to HD cytarabine (log-rank test P = .06; multivariable analysis P = .009). For patients younger than age 46 years, survival was 43.3% and 51.9%, respectively (P = .009; multivariable analysis P = .003), and for patients age 46 to 60 years, survival was 33.9% and 32.9%, respectively (P = .91). CR rates were 72.0% and 78.7%, respectively (P < .001) and were 75.6% and 82.4% for patients younger than age 46 years (P = .01) and 68.3% and 74.8% for patients age 46 years and older (P = .03). Patients of all ages with very-bad-risk cytogenetic abnormalities and/or FLT3-ITD (internal tandem duplication) mutation, or with secondary AML benefitted from HD cytarabine.

Conclusion: HD cytarabine produces higher remission and survival rates than SD cytarabine, especially in patients younger than age 46 years.
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http://dx.doi.org/10.1200/JCO.2013.51.8571DOI Listing
January 2014

Sequential combination of gemtuzumab ozogamicin and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia: results of a randomized phase III trial by the EORTC and GIMEMA consortium (AML-17).

J Clin Oncol 2013 Dec 14;31(35):4424-30. Epub 2013 Oct 14.

Sergio Amadori and Adriano Venditti, Tor Vergata University Hospital; Paolo De Fabritiis, St Eugenio Hospital; Roberto Latagliata, University Sapienza; Paola Fazi and Marco Vignetti, Gruppo Italiano Malattie Ematologiche dell'Adulto, Roma; Franca Falzetti, University Hospital, Perugia; Domenico Magro, Pugliese Hospital, Catanzaro; Giorgina Specchia, University Hospital, Bari, Italy; Stefan Suciu and Matthias Karrasch, European Organisation for Research and Treatment of Cancer, Brussels; Dominik Selleslag, Algemeen Ziekenhuis St Jan, Brugge; Zwi Berneman, University Hospital, Antwerp, Belgium; Roberto Stasi, St George's Hospital, London, United Kingdom; Helmut R. Salih, University Hospital, Tubingen; Anthony D. Ho, University Hospital, Heidelberg; Michael Lübbert, Albert Ludwigs University, Freiburg, Germany; Petra Muus and Theo de Witte, Radboud University Medical Centre, Nijmegen; Constantijn J.M. Halkes and Roel Willemze, University Medical Center, Leiden, the Netherlands; Xavier Thomas, Edouard Herriot Hospital, Lyon; Jean-Pierre Marie, St. Antoine Hospital, Paris, France; and José E. Guimaraes, University Hospital, Porto, Portugal.

Purpose: This randomized trial evaluated the efficacy and toxicity of sequential gemtuzumab ozogamicin (GO) and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia (AML).

Patients And Methods: Patients (n = 472) age 61 to 75 years were randomly assigned to induction chemotherapy with mitoxantrone, cytarabine, and etoposide preceded, or not, by a course of GO (6 mg/m(2) on days 1 and 15). In remission, patients received two consolidation courses with or without GO (3 mg/m(2) on day 0). The primary end point was overall survival (OS).

Results: The overall response rate was comparable between the two arms (GO, 45%; no GO, 49%), but induction and 60-day mortality rates were higher in the GO arm (17% v 12% and 22% v 18%, respectively). With median follow-up of 5.2 years, median OS was 7.1 months in the GO arm and 10 months in the no-GO arm (hazard ratio, 1.20; 95% CI, 0.99 to 1.45; P = .07). Other survival end points were similar in both arms. Grade 3 to 4 hematologic and liver toxicities were greater in the GO arm. Treatment with GO provided no benefit in any prognostic subgroup, with the possible exception of patients age < 70 years with secondary AML, but outcomes were significantly worse in the oldest age subgroup because of a higher risk of early mortality.

Conclusion: As used in this trial, the sequential combination of GO and standard chemotherapy provides no benefit for older patients with AML and is too toxic for those age ≥ 70 years.
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http://dx.doi.org/10.1200/JCO.2013.49.0771DOI Listing
December 2013

Applying ecological and evolutionary theory to cancer: a long and winding road.

Evol Appl 2013 Jan 16;6(1):1-10. Epub 2012 Nov 16.

MIVEGEC (UMR CNRS/IRD/UM1) 5290 Montpellier Cedex 5, France ; CREEC Montpellier Cedex 5, France.

Since the mid 1970s, cancer has been described as a process of Darwinian evolution, with somatic cellular selection and evolution being the fundamental processes leading to malignancy and its many manifestations (neoangiogenesis, evasion of the immune system, metastasis, and resistance to therapies). Historically, little attention has been placed on applications of evolutionary biology to understanding and controlling neoplastic progression and to prevent therapeutic failures. This is now beginning to change, and there is a growing international interest in the interface between cancer and evolutionary biology. The objective of this introduction is first to describe the basic ideas and concepts linking evolutionary biology to cancer. We then present four major fronts where the evolutionary perspective is most developed, namely laboratory and clinical models, mathematical models, databases, and techniques and assays. Finally, we discuss several of the most promising challenges and future prospects in this interdisciplinary research direction in the war against cancer.
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http://dx.doi.org/10.1111/eva.12021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567465PMC
January 2013

Soluble endothelial protein C receptor (sEPCR) is likely a biomarker of cancer-associated hypercoagulability in human hematologic malignancies.

Cancer Med 2012 Oct 23;1(2):261-7. Epub 2012 Jul 23.

INSERM, UMRS 872, CRC, Université Pierre et Marie Curie-Paris 6, Université Paris Descartes, Paris, France.

Elevated plasma level of soluble endothelial protein C receptor (sEPCR) may be an indicator of thrombotic risk. The present study aims to correlate leukemia-associated hypercoagulability to high level plasma sEPCR and proposes its measurement in routine clinical practice. EPCR expressions in leukemic cell lines were determined by flow cytometry, immunocytochemistry, and reverse transcription polymerase chain reaction (RT-PCR). EPCR gene sequence of a candidate cell line HL-60 was also determined. Plasma samples (n = 76) and bone marrow aspirates (n = 72) from 148 patients with hematologic malignancies and 101 healthy volunteers were analyzed by enzyme-linked immunosorbent assay (ELISA) via a retrospective study for sEPCR and D-dimer. All leukemic cell lines were found to express EPCR. Also, HL-60 EPCR gene sequence showed extensive similarities with the endothelial reference gene. All single nucleotide polymorphisms (SNPs) originally described and some new SNPs were revealed in the promoter and intronic regions. Among these patients 67% had plasma sEPCR level higher than the controls (100 ± 28 ng/mL), wherein 16.3% patients had experienced a previous thrombotic event. These patients were divided into: group-1 (n = 45) with amount of plasmatic sEPCR below 100 ng/mL, group-2 (n = 45) where the concentration of sEPCR was between 100 and 200, and group-3 (n = 20) higher than 200 ng/mL. The numbers of thrombotic incidence recorded in each group were four, six, and eight, respectively. These results reveal that EPCR is expressed not only by a wide range of human malignant hematological cells but also the detection of plasma sEPCR levels provides a powerful insight into thrombotic risk assessment in cancer patients, especially when it surpasses 200 ng/mL.
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http://dx.doi.org/10.1002/cam4.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3544449PMC
October 2012

Intensive consolidation therapy compared with standard consolidation and maintenance therapy for adults with acute myeloid leukaemia aged between 46 and 60 years: final results of the randomized phase III study (AML 8B) of the European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups.

Ann Hematol 2012 Jun 31;91(6):825-35. Epub 2012 Mar 31.

Radboud University Nijmegen Medical Center, The Netherlands.

The most effective post-remission treatment to maintain complete remission (CR) in adults aged between 46 and 60 years with acute myeloid leukaemia (AML) is uncertain. Previously untreated patients with AML in CR after induction chemotherapy with daunorubicin and cytarabine were randomized between two intensive courses of consolidation therapy containing high-dose cytarabine, combined with amsacrine or daunorubicin and a standard consolidation and maintenance therapy containing standard dose cytarabine and daunorubicin. One hundred fifty-eight CR patients were assigned to the intensive group and 157 patients to the standard group. After a median follow-up of 7.5 years, the 4-year survival rate was 32 % in the intensive group versus 34 % in the standard group (P = 0.29). In the intensive group, the 4-year relapse incidence was lower than in the standard group: 55 and 75 %, respectively (P = 0.0003), whereas treatment-related mortality incidence was higher: 22 versus 3 % (P < 0.0001). Two intensive consolidation courses containing high-dose cytarabine as post-remission treatment in patients with AML aged between 46 and 60 years old did not translate in better long-term outcome despite a 20 % lower relapse incidence. Better supportive care and prevention of treatment-related complications may improve the overall survival after intensified post-remission therapy in this age group.
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http://dx.doi.org/10.1007/s00277-012-1436-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345117PMC
June 2012

Double-delayed intensification paediatric protocol without radiotherapy is an efficient treatment in adult lymphoblastic lymphoma.

Hematol Oncol 2012 Dec 23;30(4):206-9. Epub 2012 Jan 23.

Département d'Hématologie, Hôpital Saint-Antoine, APHP and Université Pierre et Marie Curie, Paris, France.

Lymphoblastic lymphoma (LBL) is a rare disease associated with favourable prognosis in childhood but with poor prognosis in adults when treated with conventional non-Hodgkin lymphoma regimens. Improvements in long-term outcome have been made since the use of acute lymphoblastic leukaemia (ALL) regimens. We report here the feasibility of a double-delayed intensification paediatric protocol in 12 adult LBL patients. There were no relapses and no deaths, with a median follow-up of 4.7 years. Using the same protocol, overall survival was significantly longer in LBL patients versus ALL patients (100% vs 75%, p = 0.05). Overall tolerance was acceptable and better in ALL patients. We have shown the feasibility and the good results of using this paediatric protocol in LBL.
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http://dx.doi.org/10.1002/hon.2007DOI Listing
December 2012

Incidence rates of leukemia in French Polynesia.

Int J Cancer 2012 Sep 27;131(6):1486-7. Epub 2012 Jan 27.

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http://dx.doi.org/10.1002/ijc.27364DOI Listing
September 2012

Prognostic impact of high ABC transporter activity in 111 adult acute myeloid leukemia patients with normal cytogenetics when compared to FLT3, NPM1, CEBPA and BAALC.

Haematologica 2012 Feb 4;97(2):241-5. Epub 2011 Nov 4.

Département d’Hématologie, Hôpital Saint-Antoine, Assistance Publique - Hôpitaux de Paris, 184 Rue du Faubourg Saint-Antoine, Paris.

ATP-binding cassette transporter (and specially P-glycoprotein) activity is a well known prognostic factor in acute myeloid leukemia, but when compared to other molecular markers its prognostic value has not been well studied. Here we study relationships between this activity, fms-like tyro-sine kinase 3(FLT3/ITD), nucleophosmin(NPM1), CAAT-enhancer binding protein alpha(CEBPα), and brain and acute leukemia cytoplasmic protein (BAALC), in 111 patients with normal cytogenetics who underwent the same treatment, and evaluate its prognostic impact. Independent factors for survival were age (P=0.0126), ATP-binding cassette transporter activity (P=0.018) and duplications in the fms-like tyrosine kinase 3 (P=0.0273). In the 66 patients without fms-like tyrosine kinase 3 duplication and without nucleophosmin mutation, independent prognostic factors for complete remission achievement and survival were age and ATP-binding cassette transporter activity. In conclusion, ATP-binding cassette transporter activity remains an independent prognostic factor, and could assist treatment decisions in patients with no nucleophosmin mutation and no fms-like tyrosine kinase 3 duplication.
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http://dx.doi.org/10.3324/haematol.2010.034447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269484PMC
February 2012

The BH3-only protein Noxa is stimulated during apoptosis of chronic lymphocytic leukemia cells triggered by M2YN, a new plant-derived extract.

Int J Oncol 2011 Oct 12;39(4):965-72. Epub 2011 Jul 12.

Centre de Recherche des Cordeliers, INSERM U872, Equipe 18, Paris, France.

Deficiency of apoptosis is a hallmark of chronic lymphocytic leukemia (CLL) cells. M2Yn is a natural extract from plants of central Asia, identified for its antiangiogenic properties and its ability to block the migration of malignant cells. Here, we report that in vitro treatment of cells derived from CLL patients with M2Yn results in internucleosomal DNA fragmentation, phosphatidylserine externalization, mitochondrial membrane depolarization, caspase-3 activation and cleavage of the caspase substrate PARP-1. The extents of these effects depend on the patients and are mostly comparable to those of flavopiridol or hyperforin, two known plant-derived apoptosis inducers of CLL cells. M2Yn does not modulate Mcl-1 expression, while downregulation of this antiapoptotic protein is involved in the action of flavopiridol. By contrast, M2Yn, like hyperforin, upregulates the Noxa protein, possibly by inhibiting proteasomal activity. This BH3-only protein is known to trigger the activation of the pro-apoptotic protein Bak through displacement of the Mcl-1/Bak complex at the mitochondrial membrane, as actually observed here in M2Yn-treated cells. Our data, therefore, show that M2Yn can induce the caspase-dependent mitochondrial pathway of apoptosis in CLL cells via a mechanism resembling that of hyperforin. Our data also confirm that the BH3-only protein Noxa is a relevant target for CLL therapy.
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http://dx.doi.org/10.3892/ijo.2011.1121DOI Listing
October 2011

ATP Binding Cassette transporters associated with chemoresistance: transcriptional profiling in extreme cohorts and their prognostic impact in a cohort of 281 acute myeloid leukemia patients.

Haematologica 2011 Sep 23;96(9):1293-301. Epub 2011 May 23.

Université Pierre et Marie Curie, INSERM UMRs 872, Equipe 18, Centre de Recherche des Cordeliers, Paris, France.

Background: A major issue in the treatment of acute myeloid leukemia is resistance to chemotherapeutic drugs. An increasing number of ATP-Binding-Cassette transporters have been demonstrated to cause resistance to cancer drugs. The aim of this study was to highlight the putative role of other ATP-Binding-Cassette transporters in primary chemoresistant acute myeloid leukemia.

Design And Methods: In the first part of this study, using taqman custom arrays, we analyzed the relative expression levels of 49 ATP-Binding-Cassette genes in 51 patients divided into two extreme cohorts, one very sensitive and one very resistant to chemotherapy. In the second part of this study, we evaluated the prognostic impact, in a cohort of 281 patients, of ATP-Binding-Cassette genes selected in the first part of the study.

Results: In the first part of the study, six genes (ATP-Binding-CassetteA2, ATP-Binding-CassetteB1, ATP-Binding-CassetteB6, ATP-Binding-CassettC13, ATP-Binding-CassetteG1, and ATP-Binding-CassetteG2) were significantly over-expressed in the resistant group compared with the sensitive group. In the second cohort, overexpression of 5 of these 6 ATP-Binding-Cassette genes was correlated with outcome in univariate analysis, and only the well-known ATP-Binding-CassetteB1 and G2, and the new ATP-Binding-CassetteG1 in multivariate analysis. Prognosis decreased remarkably with the number of these over-expressed ABC genes. Complete remission was achieved in 71%, 59%, 54%, and 0%, (P=0.0011) and resistance disease in 21%, 37%, 43%, and 100% (P<0.0001) of patients over-expressing 0, 1, 2, or 3, ABC genes, respectively. The number of ATP-Binding-Cassette genes expressed, among ATP-Binding-CassetteB1, G1, and G2, was the strongest prognostic factor correlated, in multivariate analysis, with achievement of complete remission (P=0.01), resistant disease (P=0.01), and overall survival (P=0.02).

Conclusions: Using expression profiling, we have emphasized the diversity of ATP-Binding-Cassette transporters that cooperate to promote chemoresistance rather than overexpression of single transporters and the putative role of new ATP-Binding-Cassette tranporters, such as ATP-Binding-CassetteG1. Modulation of these multiple transporters might be required to eradicate leukemic cells.
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http://dx.doi.org/10.3324/haematol.2010.031823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166099PMC
September 2011

Phase I studies of AVE9633, an anti-CD33 antibody-maytansinoid conjugate, in adult patients with relapsed/refractory acute myeloid leukemia.

Invest New Drugs 2012 Jun 26;30(3):1121-31. Epub 2011 Apr 26.

Hematology and Oncology Department, Saint-Antoine Hospital, AP-HP, Paris, France.

The efficacy of anti-CD33 immunoconjugates had been previously demonstrated for gemtuzumab-ozogamicin. AVE9633 is an anti-CD33-maytansine conjugate created by ImmunoGen Inc. Phase I trials of AVE9633 were performed in patients with AML to evaluate tolerability, pharmacokinetics and pharmacodynamics. Three phase I studies of AVE9633 were performed in 54 patients with refractory/relapsed AML, evaluating drug infusion on day 1 of a 21-day cycle (Day 1 study), day 1 and 8 (Day 1/8 study) and day 1, 4 and 7 (Day 1/4/7 study) of a 28-day cycle. Toxicity was mainly allergic reaction during infusion (3 grade 3 bronchospasms). DLT was reached for the D1-D7 schedule at 150 mg/sqm (1 keratitis, 1 liver toxicity), and the MTD was set at 130 mg/sqm for this schedule. In the two other phases I, the DLT was not reached. In the Day 1/8 study, CD33 on peripheral blasts was saturated and down-modulated for doses of 75 mg/m(2) × 2 or higher, which was correlated with WBC kinetics and plasma levels of AVE9633. Decrease of DM4/CD33 ratio on the blasts surface between day 1 and 8 was the rational for evaluating day 1/4/7 schedule. This induced relatively constant DM4/CD33 levels over the first 8 days, however no activity was noted. One CRp, one PR and biological activity in five other patients were observed in this study. The Day 1 and Day 1/4/7 studies were early discontinued because of drug inactivity at doses significantly higher than CD33 -saturating doses. No myelossuppression was observed at any trial of AVE9633. The pharmacokinetics/pharmacodynamics data obtained in these studies will provide very useful information for the design of the next generation of immunoconjugates.
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http://dx.doi.org/10.1007/s10637-011-9670-0DOI Listing
June 2012

Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia. Final results of a prospective randomized European Intergroup Trial.

Haematologica 2010 Oct 21;95(10):1754-61. Epub 2010 May 21.

Department of Tumorimmunology, Radboud University Medical Centre Nijmegen, Nijmegen, the Netherlands.

Background: Allogeneic stem cell transplantation is usually considered the only curative treatment option for patients with advanced or transformed myelodysplastic syndromes in complete remission, but post-remission chemotherapy and autologous stem cell transplantation are potential alternatives, especially in patients over 45 years old.

Design And Methods: We evaluated, after intensive anti-leukemic remission-induction chemotherapy, the impact of the availability of an HLA-identical sibling donor on an intention-to treat basis. Additionally, all patients without a sibling donor in complete remission after the first consolidation course were randomized to either autologous peripheral blood stem cell transplantation or a second consolidation course consisting of high-dose cytarabine.

Results: The 4-year survival of the 341 evaluable patients was 28%. After achieving complete remission, the 4-year survival rates of patients under 55 years old with or without a donor were 54% and 41%, respectively, with an adjusted hazard ratio of 0.81 (95% confidence interval [95% CI], 0.49-1.35) for survival and of 0.67 (95% CI, 0.42-1.06) for disease-free survival. In patients with intermediate/high risk cytogenetic abnormalities the hazard ratio in multivariate analysis was 0.58 (99% CI, 0.22-1.50) (P=0.14) for survival and 0.46 (99% CI, 0.22-1.50) for disease-free survival (P=0.03). In contrast, in patients with low risk cytogenetic characteristics the hazard ratio for survival was 1.17 (99% CI, 0.40-3.42) and that for disease-free survival was 1.02 (99% CI, 0.40-2.56). The 4-year survival of the 65 patients randomized to autologous peripheral blood stem cell transplantation or a second consolidation course of high-dose cytarabine was 37% and 27%, respectively. The hazard ratio in multivariate analysis was 1.22 (95% CI, 0.65-2.27) for survival and 1.02 (95% CI, 0.56-1.85) for disease-free survival.

Conclusions: Patients with a donor and candidates for allogeneic stem cell transplantation in first complete remission may have a better disease-free survival than those without a donor in case of myelodysplastic syndromes with intermediate/high-risk cytogenetics. Autologous peripheral blood stem cell transplantation does not provide longer survival than intensive chemotherapy.
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http://dx.doi.org/10.3324/haematol.2009.019182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948102PMC
October 2010

Outcome of 40 adults aged from 18 to 55 years with acute lymphoblastic leukemia treated with double-delayed intensification pediatric protocol.

Leuk Res 2011 Jan;35(1):66-72

Département d'Hématologie Hôpital Hôtel Dieu, AP-HP and Université Pierre et Marie Curie, Paris, France.

Adolescents ALL have a better outcome when treated with pediatric protocol compared to adult protocol. We have tested the feasibility of pediatric protocol to treat 40 consecutive adults ALL. DFS and OS were 73±7%, and 72±7%, and were significantly longer in patients under 40 yo (81±9% vs 51±15%, p=0.05 [DFS] and 83±7.8% vs 45±15%, p=0.003 [OS], respectively) or cortico/chemo-sensitive (86±9% vs 36±16%, p=0.001 [DFS] and 95±4.4% vs 28±13%, p<0.0001 [OS]) than in other patients. Overall tolerance was acceptable. We have shown the feasibility of using this unmodified pediatric protocol to treat adult with ALL up to 40 years.
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http://dx.doi.org/10.1016/j.leukres.2010.04.002DOI Listing
January 2011