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Biomedical subjects

Philippe Moreau

Publications and source records attributed to Philippe Moreau.

At least 19 recordsLinked to original sources
PubMed2007

Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome.

Acquired genomic aberrations have been shown to significantly impact survival in several hematologic malignancies. We analyzed the prognostic value of the most frequent chromosomal changes in a large series of patients with newly diagnosed symptomatic myeloma prospectively enrolled in homogeneous therapeutic trials. All the 1064 patients enrolled in the IFM99 trials conducted by the Intergroupe Francophone du Myélome benefited from an interphase fluorescence in situ hybridization analysis performed on purified bone marrow plasma cells. They were systematically screened for the following genomic aberrations: del(13), t(11;14), t(4;14), hyperdiploidy, MYC translocations, and del(17p). Chromosomal changes were observed in 90% of the patients. The del(13), t(11;14), t(4;14), hyperdiploidy, MYC translocations, and del(17p) were present in 48%, 21%, 14%, 39%, 13%, and 11% of the patients, respectively. After a median follow-up of 41 months, univariate statistical analyses revealed that del(13), t(4;14), nonhyperdiploidy, and del(17p) negatively impacted both the event-free survival and the overall survival, whereas t(11;14) and MYC translocations did not influence the prognosis. Multivariate analyses on 513 patients annotated for all the parameters showed that only t(4;14) and del(17p) retained prognostic value for both the event-free and overall survivals. When compared with the currently used International Staging System, this prognostic model compares favorably. In myeloma, the genomic aberrations t(4;14) and del(17p), together with beta2-microglobulin level, are important independent predictors of survival. These findings have implications for the design of risk-adapted treatment strategies.

Adolescent↗
PubMed2006

Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study.

BACKGROUND AND OBJECTIVES: Induction regimens prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma patients usually result in complete remission (CR) rates of <10%. The use of novel agents may increase the CR rate before ASCT, which may improve post-transplantation response and survival. DESIGN AND METHODS: This was a phase II, open-label trial of bortezomib (1.3 mg/m(2), days 1,4,8,11) and dexamethasone (40 mg,days 1-4 and 9-12 for cycles 1-2,days 1-4 for cycles 3-4) administered for four 21-day cycles as induction therapy in chemotherapy-naïve myeloma patients. RESULTS: Of 52 recruited patients, 48 were eligible for the study. The overall response rate was 66% including 21% CR and 10% very good partial remission (>90% reduction of the M-component). Four patients had a minimal response, six had stable disease and five had progression. One patient died after salvage therapy with VAD. The most common side effects were gastrointestinal symptoms, peripheral neuropathy, and fatigue. These were usually mild. Peripheral neuropathy was observed in 15 cases but was grade 2-3 in only seven cases (14%). There was no deep vein thrombosis and no hematologic toxicity greater than grade 2. Grade 3 infections were recorded in five patients including three who had herpes zoster infections. Stem cell collection was programmed in 44 cases and all patients had sufficient CD34+ cells to perform one ASCT (> 2 x 10(6)/kg). INTERPRETATION AND CONCLUSION: This regimen of bortezomib plus dexamethasone appears effective and well tolerated in newly diagnosed myeloma patients.

Adult↗
PubMed2006

Maintenance therapy with thalidomide improves survival in patients with multiple myeloma.

Newer chemotherapeutic protocols as well as high-dose chemotherapy have increased the response rate in myeloma. However, these treatments are not curative. Effective maintenance strategies are now required to prolong the duration of response. We conducted a randomized trial of maintenance treatment with thalidomide and pamidronate. Two months after high-dose therapy, 597 patients younger than age 65 years were randomly assigned to receive no maintenance (arm A), pamidronate (arm B), or pamidronate plus thalidomide (arm C). A complete or very good partial response was achieved by 55% of patients in arm A, 57% in arm B, and 67% in arm C (P = .03). The 3-year postrandomization probability of event-free survival was 36% in arm A, 37% in arm B, and 52% in arm C (P < .009). The 4-year postdiagnosis probability of survival was 77% in arm A, 74% in arm B, and 87% in arm C (P < .04). The proportion of patients who had skeletal events was 24% in arm A, 21% in arm B, and 18% in arm C (P = .4). Thalidomide is an effective maintenance therapy in patients with multiple myeloma. Maintenance treatment with pamidronate does not decrease the incidence of bone events.

Aged↗
PubMed2006

Mcl-1L cleavage is involved in TRAIL-R1- and TRAIL-R2-mediated apoptosis induced by HGS-ETR1 and HGS-ETR2 human mAbs in myeloma cells.

We evaluated the ability of 2 human mAbs directed against TRAILR1 (HGS-ETR1) and TRAILR2 (HGS-ETR2) to kill human myeloma cells. HGS-ETR1 and HGS-ETR2 mAbs killed 15 and 9 human myeloma cell lines (HMCLs; n = 22), respectively. IL-6, the major survival and growth factor for these HMCLs, did not prevent their killing. Killing induced by either HGS-ETR1 or HGS-ETR2 was correlated with the cleavage of Mcl-1L, a major molecule for myeloma survival. Mcl-1L cleavage and anti-TRAILR HMCL killing were dependent on caspase activation. Kinetic studies showed that Mcl-1L cleavage occurred very early (less than 1 hour) and became drastic once caspase 3 was activated. Our data showed that both the extrinsic (caspase 8, Bid) and the intrinsic (caspase 9) pathways are activated by anti-TRAIL mAb. Finally, we showed that the HGS-ETR1 and, to a lesser extent, the HGS-ETR2 mAbs were able to induce the killing of primary myeloma cells. Of note, HGS-ETR1 mAb was able to induce the death of medullary and extramedullary myeloma cells collected from patients at relapse. Taken together, our data clearly encourage clinical trials of anti-TRAILR1 mAb in multiple myeloma, especially for patients whose disease is in relapse, at the time of drug resistance.

Antibodies, Monoclonal↗
PubMed2006

Trough serum concentrations of beta-lactam antibiotics in cancer patients: inappropriateness of conventional schedules to pharmacokinetic/pharmacodynamic properties of beta-lactams.

Serum concentrations of beta-lactams that continuously exceed the minimum inhibitory concentration may improve therapeutic outcomes for immunosuppressed patients. The trough serum levels of ceftazidime (CAZ), cefepime (FEP) or imipenem (IMP) were prospectively determined on days 1 and 3 of treatment in cancer patients. Seventy-eight episodes of suspected infection were analysed. Trough serum levels were higher than 4 mg/L in 62%, 24% and 0% of cases in the CAZ, FEP and IMP groups, respectively, and were higher than 20 mg/L in 24% of cases in the CAZ group compared with 0% both in the FEP and IMP groups. For suspected infectious episodes in cancer patients, the traditional intermittent regimen of beta-lactams does not appear to be appropriate for the pharmacokinetic/pharmacodynamic properties of these antibiotics.

Adult↗
PubMed2006

Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma.

The Intergroupe Francophone du Myélome (IFM) initiated 2 trials in 1999 to study patients with high-risk (beta2-microglobulin level greater than 3 mg/L and chromosome 13 deletion at diagnosis) de novo multiple myeloma. In both protocols, the induction regimen consisted of vincristine, doxorubicin, and dexamethasone (VAD) followed by first autologous stem cell transplantation (ASCT) prepared by melphalan 200 mg/m(2). Patients with an HLA-identical sibling donor were subsequently treated with dose-reduced allogeneic stem cell transplantation (IFM99-03 trial), and patients without an HLA-identical sibling donor were randomly assigned to undergo second ASCT prepared by melphalan 220 mg/m(2) and 160 mg dexamethasone with or without anti-IL-6 monoclonal antibody (IFM99-04 protocol). Two hundred eighty-four patients-65 in the IFM99-03 trial and 219 in the IFM99-04 trial-were prospectively treated and received at least one course of VAD. On an intent-to-treat basis, overall survival (OS) and event-free survival (EFS) did not differ significantly in the studies (medians 35 and 25 months in the IFM99-03 trial vs 41 and 30 months in the IFM99-04 trial, respectively). With a median follow-up time of 24 months, the EFS of the 166 patients randomly assigned in the tandem ASCT protocol was similar to the EFS of the 46 patients who underwent the entire IFM99-03 program (median, 35 vs 31.7 months), with a trend for a better OS in patients treated with tandem ASCT (median, 47.2 vs 35 months; P = .07). In patients with high-risk de novo MM, the combination of ASCT followed by dose-reduced allogeneic transplantation was not superior to tandem dose-intensified, melphalan-based ASCT.

Adult↗
PubMed2006

[New drugs for myeloma].

Thalidomide, administered orally, bortezomib (Velcade) intravenously and lenalidomide (Revlimid), also orally, are three agents that act on myeloma relapse. Thalidomide acts by a variety of mechanisms and is toxic to the peripheral nervous system as well as teratogenic. It acts in synergy with dexamethasone. Recent results prove that its use as first-line treatment combined with oral conventional "MP" chemotherapy improves survival in patients older than 65 years. Its use as first-line treatment with this chemotherapy appears likely. Bortezomib is the first drug in the proteasome inhibitor class. It too is toxic to the peripheral nervous system and synergistic with dexamethasone. Several studies show its efficacy as first-line 'induction treatment' with dexamethasone, in patients to receive a subsequent autologous stem cell transplantation. The combination of bortezomib and "MP" is also promising. Lenalidomide, a structural analog of thalidomide, is effective in relapsing patients. Its toxicity is essentially hematologic. It is also synergistic with dexamethasone and promising as first-line treatment. These different drugs can be used successively at relapse, making myeloma a chronic disease. They can also be used together for greater effectiveness. These combinations will replace conventional chemotherapies in the future.

Antineoplastic Agents↗
PubMed2006

Lack of CD27 in myeloma delineates different presentation and outcome.

CD27 expression was evaluated on normal plasma cells (PC), PC from patients with multiple myeloma (MM) at diagnosis or relapse and on human myeloma cell lines (HMCL). CD27 was expressed by normal PC but was lacking in PC from MM patients at diagnosis (36%) and relapse (47%), and in HMCL (92%). The prognostic impact of CD27 expression was evaluated in 42 patients with de novo MM. Overall survival was 92% at 3 years in CD27(+) vs. 50% in CD27(-) MM (P = 0.017). CD27 expression seems to delineate two important subsets of MM with different presenting features and clinical outcomes.

Aged↗
PubMed2006

The phenotype of normal, reactive and malignant plasma cells. Identification of "many and multiple myelomas" and of new targets for myeloma therapy.

The aim of this review is to integrate non-exhaustive relevant data on the phenotype of human plasma cells (PC), including normal, reactive and malignant (multiple myeloma, MM) PC. This review focuses on (i) a universal marker of both normal and malignant plasma cells, CD138; (ii) markers related to malignancy i.e., CD19, CD27, CD28, and CD56; (iii) markers associated with signaling and severity of MM (CD45, CD221). Finally, this review presents data from normal PC up to human myeloma cell lines in order to: (i) define different entities of MM based on expression of CD19, CD20, CD27 and CD117; and (ii) identify new therapeutic targets.

Antigens, CD↗
PubMed2005

HLA-G proteins in cancer: do they provide tumor cells with an escape mechanism?

Convincing clinical evidence indicates that the limited success of T-cell-based immunotherapy of malignant diseases is caused, at least in part, by the ability of malignant cells to escape from immune recognition and destruction. Among the multiple escape mechanisms identified, a major role is played by changes in the expression and/or function of HLA antigens expressed by tumor cells, because they may markedly affect tumor cell-host's immune system interactions. In this article, we review the data about the aberrant expression of the nonclassical HLA class I antigen HLA-G by tumor cells. Furthermore, we discuss the possible reasons for the conflicting information in the literature about HLA-G antigen expression by malignant cells. Lastly, in light of the well-documented immunotolerant function of HLA-G, we discuss the potential role of these antigens in the escape of tumor cells from immune recognition and destruction and in the clinical course of malignant diseases.

Animals↗
PubMed2005

Switch of HLA-G alternative splicing in a melanoma cell line causes loss of HLA-G1 expression and sensitivity to NK lysis.

Considerable information has been accumulated on HLA-G expression in tumor lesions in which HLA-G is viewed as a way to turn off anti-tumoral immunity. Nevertheless, there is little data concerning the mechanisms by which expression and function of HLA-G are regulated in malignant cells. Here, we have addressed these points by studying a melanoma cell line derived from a surgically-removed HLA-G-positive melanoma lesion. We show that HLA-G expression in melanoma cells can be regulated at the mRNA splicing level. Indeed, melanoma cells rapidly switched from cell-surface HLA-G1 to intra-cellular HLA-G2 expression. This mechanism restored tumor sensitivity to NK lysis. Moreover, switch from HLA-G1 to HLA-G2 was strong enough to prevent re-expression of immunoprotective HLA-G1 even following treatments with cytokines and DNA demethylating agent. Modulating HLA-G at the mRNA splicing level would be an efficient way of lifting in vivo HLA-G-mediated tumor immune escape.

Alternative Splicing↗
PubMed2005

Tandem autologous stem cell transplantation in high-risk de novo multiple myeloma: final results of the prospective and randomized IFM 99-04 protocol.

The combination of high levels of beta2-microglobulin (beta2-m) and chromosome 13 deletion allows identification of a high-risk subgroup of patients with de novo multiple myeloma (MM). In this population of patients, we have evaluated the impact of a murine anti-interleukin 6 (anti-IL-6) monoclonal antibody (BE-8) as part of the second conditioning regimen in a multicenter prospective randomized trial of tandem autologous stem cell transplantation (ASCT). Conditioning for the first ASCT was accomplished with melphalan 200 mg/m2 and for the second one with melphalan 220 mg/m2 plus dexamethasone with or without BE-8 infusion. This trial included 219 patients, of whom 166 were randomized, 85 without BE-8 (arm A) and 81 with BE-8 (arm B). The median overall survival (OS) and event-free survival (EFS) times of the whole group of patients were 41 and 30 months, respectively. Response rates, OS, and EFS were not different between the 2 arms of the trial. OS at 54 months was 46% in arm A and 51% in arm B (P = .90); median EFS was 35 months in arm A and 31 in arm B (P = .39). In high-risk patients the dose intensity of melphalan at 420 mg/m2 led to encouraging results, but the addition of anti-IL-6 monoclonal antibody to the second conditioning regimen did not improve either OS nor EFS.

Adult↗
PubMed2005

Linking two immuno-suppressive molecules: indoleamine 2,3 dioxygenase can modify HLA-G cell-surface expression.

Nonclassical human leukocyte antigen (HLA) class I molecule HLA-G and indoleamine 2,3 dioxygenase (INDO) in humans and mice, respectively, have been shown to play crucial immunosuppressive roles in fetal-maternal tolerance. HLA-G inhibits natural killer and T cell function by high-affinity interaction with inhibitory receptors, and INDO acts by depleting the surrounding microenvironment of the essential amino acid tryptophan, thus inhibiting T cell proliferation. We investigated whether HLA-G expression and INDO function were linked. Working with antigen-presenting cell (APC) lines and monocytes, we found that functional inhibition of INDO by 1-methyl-tryptophan induced cell surface expression of HLA-G1 by HLA-G1-negative APCs that were originally cell-surface negative, and that in reverse, the functional boost of INDO by high concentrations of tryptophan induced a complete loss of HLA-G1 cell surface expression by APCs that were originally cell-surface HLA-G1-positive. This mechanism was shown to be posttranslational because HLA-G protein cell contents remained unaffected by the treatments used. Furthermore, HLA-G cell surface expression regulation by INDO seems to relate to INDO function, but not to tryptophan catabolism itself. Potential implications in fetal-maternal tolerance are discussed.

Cell Line↗
PubMed2005

Administration of mylotarg 4 days after beginning of a chemotherapy including intermediate-dose aracytin and mitoxantrone (MIDAM regimen) produces a high rate of complete hematologic remission in patients with CD33+ primary resistant or relapsed acute myeloid leukemia.

We have used the dose of 9 mg/m(2) of mylotarg 4 days after the beginning of a chemotherapy including intermediate-dose aracytin and mitoxantrone (MIDAM) in 17 patients with refractory (n=4) or relapsed (n=13) AML. Thirteen patients (76%) achieved CR (n=12) or partial CR (n=1). All four refractory patients and all four patients with poor risk cytogenetic achieved CR or CRp. Although the dose of mylotarg given in combination with chemotherapy was not reduced, the toxicity profile was acceptable (1VOD/17 patients). The MIDAM protocol appears to be highly effective especially in patients with poor risk cytogenetic and/or refractory disease.

Acute Disease↗
PubMed2005

HLA-G*0105N null allele encodes functional HLA-G isoforms.

Expression of the nonclassical HLA class I antigen, HLA-G, is associated with immune tolerance in view of its role in maintaining the fetus in utero, allowing tumor escape, and favoring graft acceptance. Expressed on invasive trophoblast cells, HLA-G molecules bind inhibitory receptors on maternal T lymphocytes and NK cells, thereby blocking their cytolytic activities and protecting the fetus from maternal immune system attack. The HLA-G gene consists of 15 alleles, including a null allele, HLA-G*0105N. HLA-G*0105N presents a single base deletion, preventing translation of both membrane-bound (HLA-G1) and full-length soluble isoforms (HLA-G5) as well as of the spliced HLA-G4 isoform. The identification of healthy subjects homozygous for this HLA-G null allele suggests that the HLA-G*0105N allele may generate other HLA-G isoforms, such as membrane-bound HLA-G2 and -G3 and the soluble HLA-G6 and -G7 proteins, which may substitute for HLA-G1 and -G5, thus assuming the immune tolerogeneic function of HLA-G. To investigate this point, we cloned genomic HLA-G*0105N DNA and transfected it into an HLA-class I-positive human cell line. The results obtained indicated that HLA-G proteins were indeed present in HLA-G*0105N-transfected cells and were able to protect against NK cell lysis. These findings emphasize the role of the other HLA-G isoforms as immune tolerogeneic molecules that may also contribute to maternal tolerance of the semiallogenic fetus as well as tumor escape and other types of allogeneic tissue acceptance.

Alleles↗
PubMed2005

HLA-G gene activation in tumor cells involves cis-acting epigenetic changes.

The tissue distribution of HLA-G molecules is broader than originally reported in trophoblastic cells. On the basis of numerous studies, HLA-G is also expressed in malignant tumors and involved in tumor immune escape. The mechanisms of HLA-G gene regulation differ from those of classical HLA class I genes and involve epigenetic processes. Here, we provide additional evidence on the influence of DNA demethylation on HLA-G activation. We also analyze the 5' regulatory region of HLA-G in 2 cellular models, melanoma (FON, M8) and choriocarcinoma (JEG-3, JAR), either expressing HLA-G transcripts or not. The data strongly suggest that HLA-G is silenced as a result of CpG site hypermethylation within a 5' regulatory region encompassing 450 bp upstream of the start codon, whereas it is activated upon demethylation. This result correlates with the acetylation status of histones within this region and the putative locus control region located at -1.2 kb. cis-acting epigenetic changes and the fact that demethylating agents activate HLA-G expression at least 5 days following treatment should be taken into account in epigenetic cancer therapies.

Burkitt Lymphoma↗