Biomedical subjects

E Wattel

Publications and source records attributed to E Wattel.

At least 19 recordsLinked to original sources

PubMed2005

Dental age in Dutch children.

Dental age was studied in a sample of 451 Dutch children (226 boys and 225 girls) according to the method of Demirjian. They were born between 1972 and 1993 and were between 3 and 17 years of age at the time a dental pantomogram (DPT) was obtained. All children were placed in the age group closest to their chronological age. All 451 DPTs were scored by one examiner. A subset of 52 DPTs was scored by a second examiner and the intra-class correlation coefficient (ICC) and Cohen's kappa were calculated. The ICC was 0.99 and Cohen's kappa 0.68. Boys and girls were analysed separately.A significant difference was found between chronological age and dental age. On average, the Dutch boys were 0.4 years and the girls 0.6 years ahead of the French-Canadian children analysed by Demirjian. Therefore, the French-Canadian standards were not considered suitable for Dutch children. New graphs for the Dutch population were constructed using a logistic curve with the equation Y = 100*{1/(1 + e(-alpha(x - x0)))} as a basis. The 90 per cent confidence interval was calculated. To determine whether the logistic curve was correct, a residual analysis was carried out and scatter plots of the differences were made. The explained variance was 93.9 per cent for the boys and 94.8 per cent for the girls. Both the residual analysis and the scatter plots indicated that the logistic curve was appropriate for use with Dutch children. In addition to the graphs, tables were produced which transfer the maturity scores calculated by the method of Demirjian into Dutch dental age.

Adolescent↗

PubMed2003

Molecular and cellular aspects of HTLV-1 associated leukemogenesis in vivo.

Most cancers and leukemias are preceded by a prolonged period of clinical latency during which cellular, chromosomal and molecular aberrations help move normal cell towards the malignant phenotype. The problem is that premalignant cells are usually indistinguishable from their normal counterparts, thereby ruling out the possibility to investigate the events that govern early leukemogenesis in vivo. Adult T cell leukemia/lymphoma (ATLL) is a T cell malignancy that occurs after a 40-60-year period of clinical latency in about 3-5% of HTLV-1-infected individuals. ATLL cells are monoclonally expanded and harbor an integrated provirus. A persistent oligo/polyclonal expansion of HTLV-1-bearing cells has been shown to precede ATLL, supporting the fact that in ATLL tumor cells arise from a clonally expanding non-malignant cell. It is possible to isolate infected, ie preleukemic, cells during the premalignant asymptomatic phase of the infection, thus providing an exceptional system to study the mechanisms underlying human cancers. Here we review some of the consequences of HTLV-1 on its host cell in vivo, at different stages of infection.

Base Sequence↗

PubMed2001

Somatic mutation in human T-cell leukemia virus type 1 provirus and flanking cellular sequences during clonal expansion in vivo.

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia/lymphoma, shows intrapatient genetic variability. Although HTLV-1 can replicate via the reverse transcription of virion RNA to a double-stranded DNA provirus (the conventional manner for retroviruses), its predominant mode of replication is via the clonal expansion (mitosis) of the infected cell. This expansion is achieved by the viral oncoprotein Tax, which keeps the infected CD4 T lymphocyte cycling. Because Tax also interferes with cellular DNA repair pathways, we investigated whether somatic mutations of the provirus that occur during the division of infected cells could account for HTLV-1 genetic variability. METHODS: An inverse polymerase chain reaction strategy was designed to distinguish somatic mutations from reverse transcription-associated substitutions. This strategy allows the proviral sequences to be isolated together with flanking cellular sequences. Using this method, we sequenced 208 HTLV-1 provirus 3' segments, together with their integration sites, belonging to 29 distinct circulating cellular clones from infected individuals. RESULTS: For 60% of the clones, 8%-80% of infected cells harbored a mutated HTLV-1 provirus, without evidence of reverse transcription-associated mutations. Mutations within flanking cellular sequences were also identified at a frequency of 2.8 x 10(-4) substitution per base pair. Some of these clones carried multiple discrete substitutions or deletions, indicating progressive accumulation of mutations during clonal expansion. The overall frequency of somatic mutations increased with the degree of proliferation of infected T cells. CONCLUSIONS: These data indicate that, in vivo, HTLV-1 variation results mainly from postintegration events that consist of somatic mutations of the proviral sequence occurring during clonal expansion. The finding of substitutions in flanking sequences suggests that somatic mutations occurring after integration, presumably coupled with selection, help move the cellular clones toward a transformed phenotype, of which adult T-cell leukemia/lymphoma is the end point.

Adult↗

PubMed2001

Two-step nature of human T-cell leukemia virus type 1 replication in experimentally infected squirrel monkeys (Saimiri sciureus).

After experimental infection of squirrel monkeys (Saimiri sciureus) with human T-cell leukemia virus type 1 (HTLV-1)-infected cells, the virus is transcribed only transiently in circulating blood, spleen, and lymph nodes. Stable disappearance of viral expression occurs at 2 to 3 weeks after inoculation. This coincides with the development of the anti-HTLV-1 immune response and persistent detection of the provirus in peripheral blood mononuclear cells (PBMCs). In this study, the HTLV-1 replication pattern was analyzed over time in PBMCs and various organs from two HTLV-1-infected squirrel monkeys. Real-time quantitative PCR confirmed that PBMCs and lymphoid organs constitute the major reservoirs for HTLV-1. The PCR amplification of HTLV-1 flanking sequences from PBMCs evidenced a pattern of clonal expansion of infected cells identical to that observed in humans. Dissemination of the virus in body compartments appeared to result from cellular transport of the integrated provirus. The circulating proviral burden increased as a function of time in one animal studied over a period of 4 years. The high proviral loads observed in the last samples resulted from the accumulation of infected cells via the extensive proliferation of a restricted number of persistent clones on a background of polyclonally expanded HTLV-1-positive cells. Therefore, HTLV-1 primary infection in squirrel monkeys is a two-step process involving a transient phase of reverse transcription followed by persistent multiplication of infected cells. This suggests that the choice of the target for blocking HTLV-1 replication might depend on the stage of infection.

Animals↗

PubMed2000

Basis of HTLV type 1 target site selection.

Sequencing integration sites from >/=200 proviruses isolated from infected individuals revealed that HTLV-1 integration is not random at the level of the nucleotide sequence. The virus was found to integrate in A/T-rich regions with a weak consensus sequence at positions within and without the hexameric repeat generated during integration. These features were not associated with a preference for integration near active regions or repeat elements of the host chromosomes. However, about 6% of HTLV-1 proviruses were found to be integrated into transcription units, suggesting that in some cells, HTLV-1 integration may alter gene expression in vivo. Therefore, the target choice in vivo seems to be determined by local features rather than by the accessibility of specific regions. This led us subsequently to analyze the role of the DNA structure in HTLV-1 integration in vitro. Double-strand HTLV-1 or HIV-1 3' LTR extremities were used as substrates for in vitro strand transfer reactions using highly purified HTLV-1 and HIV-1 integrases (INs) expressed in Escherichia coli, and two synthetic naked 50-bp double-strand DNA molecules harboring different structures were used as targets. A fluorometric quantitative analysis of integration products was designed to assess the reaction efficiency for both target sequences. As suggested for HTLV-1 in vivo (present results), and, as previously described for other retroviruses in vitro, the structure of the target was found to greatly influence the site and the efficiency of integration. Both HIV-1 and HTLV-1 INs underwent the same target structural constraint, i.e., a strong preference for curved DNA. Altogether these results indicate that if most or all the regions of the genome appear to be accessible to HTLV-1 integration, local DNA curvature seems to confer a kinetic advantage for both in vitro and in vivo HTLV-1 integration.

Base Sequence↗

PubMed2000

High circulating proviral load with oligoclonal expansion of HTLV-1 bearing T cells in HTLV-1 carriers with strongyloidiasis.

Adult T cell leukemia (ATLL) develops in 3 - 5% of HTLV-1 carriers after a long period of latency during which a persistent polyclonal expansion of HTLV-1 infected lymphocytes is observed in all individuals. This incubation period is significantly shortened in HTLV-1 carrier with Strongyloides stercoralis (Ss) infection, suggesting that Ss could be a cofactor of ATLL. As an increased T cell proliferation at the asymptomatic stage of HTLV-1 infection could increase the risk of malignant transformation, the effect of Ss infection on infected T lymphocytes was assessed in vivo in HTLV-1 asymptomatic carriers. After real-time quantitative PCR, the mean circulating HTLV-1 proviral load was more than five times higher in HTLV-1 carriers with strongyloidiasis than in HTLV-1+ individuals without Ss infection (P<0.009). This increased proviral load was found to result from the extensive proliferation of a restricted number of infected clones, i.e. from oligoclonal expansion, as evidenced by the semiquantitative amplification of HTLV-1 flanking sequences. The positive effect of Ss on clonal expansion was reversible under effective treatment of strongyloidiasis in one patient with parasitological cure whereas no significant modification of the HTLV-1 replication pattern was observed in an additional case with strongyloidiasis treatment failure. Therefore, Ss stimulates the oligoclonal proliferation of HTLV-1 infected cells in HTLV-1 asymptomatic carriers in vivo. This is thought to account for the shortened period of latency observed in ATLL patients with strongyloidiasis. Oncogene (2000) 19, 4954 - 4960

Adult↗

PubMed2000

Common human T cell leukemia virus type 1 (HTLV-1) integration sites in cerebrospinal fluid and blood lymphocytes of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis indicate that HTLV-1 crosses the blood-brain barrier via clonal HTLV-1-infected cells.

In the spinal cord of patients with human T cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), infiltrating CD4(+) lymphocytes seem to be the major reservoir for the virus. Little, however, is known about the mechanisms by which HTLV-1 crosses the blood-brain barrier. An oligoclonal proliferation of HTLV-1-infected CD4 lymphoid T cells is present in the peripheral blood of all HTLV-1-infected individuals. Here, such oligoclonal distribution of HTLV-1-infected cells is evidenced in the cerebrospinal fluid (CSF) derived from 5 patients with HAM/TSP. Furthermore, clonal populations of HTLV-1-infected lymphocytes sharing the same HTLV-1 proviral flanking sequences (i.e. , integration sites in the cellular DNA), and thus derived from a single HTLV-1-infected progenitor, were found, for a given patient, in both the CSF and the peripheral blood. These data demonstrate that HTLV-1 crosses the blood-brain barrier by migration of HTLV-1-infected lymphocytes in vivo.

Adult↗

PubMed2000

patients with the description of a new scoring system and its validation on 253 other patients.

Using Cox models, we established a new prognostic system based on simple clinical parameters in a training series of 232 patients whose diagnoses were made before 1989. Adverse prognostic factors for survival (P <.01) were age 65 years or older, male gender, albumin level lower than 40 g/L, hemoglobin level lower than 12 g/dL, platelet count less than 150 x 10(9)/L, white blood cell count less than 4 x 10(9)/L, high number of cytopenias, and hepatomegaly. Taking age (age 65 years or older, 1 point; younger than 65 years, 0 points), albumin (less than 40 g/L, 1 point; 40 g/L or more, 0 points), and total number of cytopenias (no cytopenia, 0 points; 1 cytopenia, 1 point; 2 or 3 cytopenias, 2 points) into account, we separated the 232 patients into 3 groups with low (score 0 or 1), intermediate (score 2), or high (score 3 or 4) risk, associated with 5-year survival rates at 87%, 62%, and 25%, respectively (P <.0001). Only the presence of 2 or 3 cytopenias was an independent prognostic factor among patients younger than 65 years (P <.0001). Albumin level lower than 40 g/L and the presence of 1 or more cytopenia defined a prognostic system for patients 65 years and older. Patients at low risk, intermediate risk, and high risk had 5-year survival rates at 92%, 63%, and 27%, respectively (P <.0001). The 3 prognostic systems separated the 167 patients of a test series in groups with significantly different survival rates. The overall scoring system retained a significant prognostic value in 86 additional patients treated between 1990 and 1996. We conclude that the combination of age, albumin level, and blood cell counts might help to select patients with Waldenström macroglobulinemia for treatment and to evaluate therapeutic results.

Adult↗

PubMed2000

Expression of the multidrug resistance-associated protein in myelodysplastic syndromes.

In the myelodysplastic syndromes (MDS), P-glycoprotein (P-gp) expression is clinically associated with drug resistance, whereas the clinical significance of multidrug resistance-associated protein (MRP1) is uncertain. Bone marrow from 56 patients with MDS, including six with refractory anaemia (RA)/RA with ringed sideroblasts (RARS), 23 cases of RA with excess blasts/in transformation (RAEB/T), four patients with chronic myelomonocytic leukaemia (CMML) and 23 cases of MDS having progressed to acute myeloid leukaemia (MDS-AML), were studied. MRP1 expression was investigated by immunocytochemistry (ICC) and by flow cytometry using MRPm6 monoclonal antibody. The efflux test using calcein-AM (CAM) +/- probenecid to evaluate MRP1 activity was performed in ten of the 56 patients. Twenty-eight of the 56 cases (50%) expressed MRP1. MRP1 expression was more frequent in MDS-AML than in MDS (70% vs. 36%). The efflux test using CAM was positive in three out of the ten patients tested. The results were in agreement with expression of MRP1 in six cases, and were discordant in four cases (1 MRP-/CAM+, 3 MRP+/CAM-). No correlation was observed between MRP1 expression and P-gp, lung resistance-associated protein (LRP) or CD34 expression, although there was a trend for more frequent MRP1 expression in P-gp-positive cases in MDS-AML (P = 0.08). Ten of the 26 patients treated with intensive chemotherapy achieved complete remission including six out of 16 MRP1+ and four out of ten MRP1- cases (P = NS). In conclusion, MRP1 expression was correlated with disease stage in MDS in our study. As for P-gp, discordant expression/function of MRP1 could be found in some cases, suggesting the existence of non-functional transport proteins in MDS. MRP1 expression did not seem to be a prognostic factor in MDS in our experience.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

Host sequences flanking the human T-cell leukemia virus type 1 provirus in vivo.

Human pathogenic retroviruses do not have common loci of integration. However, many factors, such as chromatin structure, transcriptional activity, DNA-protein interaction, CpG methylation, and nucleotide composition of the target sequence, may influence integration site selection. These features have been investigated by in vitro integration reactions or by infection of cell lines with recombinant retroviruses. Less is known about target choice for integration in vivo. The present study was conducted in order to assess the characteristics of cellular sequences targeted for human T-cell leukemia virus type 1 (HTLV-1) integration in vivo. Sequencing integration sites from >/=200 proviruses (19 kb of sequence) isolated from 29 infected individuals revealed that HTLV-1 integration is not random at the level of the nucleotide sequence. The virus was found to integrate in A/T-rich regions with a weak consensus sequence at positions within and without of the hexameric repeat generated during integration. These features were not associated with a preference for integration near active regions or repeat elements of the host chromosomes. Most or all of the regions of the genome appear to be accessible to HTLV-1 integration. As with integration in vitro, integration specificity in vivo seems to be determined by local features rather than by the accessibility of specific regions.

AT Rich Sequence↗

PubMed2000

Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia: a long-term study of 70 patients-report of the French society of bone marrow transplantation.

PURPOSE: To identify predictive factors of survival, relapse, and transplantation-related mortality (TRM) among patients with therapy-related myelodysplastic syndrome (t-MDS) or acute leukemia (t-AML) who underwent allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: From 1980 to 1998, 70 patients underwent allogeneic BMT for t-MDS (n = 31) or t-AML (n = 39) after prior cytotoxic exposure. Thirty-three patients had received induction-type chemotherapy before BMT. At the time of transplantation, there were 24 patients in complete remission (CR) and 46 with active disease. RESULTS: With a median follow-up of 7.9 years (range, 1.1 to 18.8 years) after BMT, 16 patients are alive, whereas 19 died of relapse, 34 of TRM, and one of relapse of the primary disease. The estimated 2-year overall survival, event-free survival, relapse, and TRM rates were 30% (95% confidence interval [CI], 19% to 40%), 28% (95% CI, 18% to 39%), 42% (95% CI, 26% to 57%), and 49% (95% CI, 36% to 62%), respectively. In multivariable analysis, age greater than 37 years, male sex, positive recipient cytomegalovirus (CMV) serology, absence of CR at BMT, and intensive schedules used for conditioning were associated with poor outcome. CONCLUSION: BMT is an effective treatment for patients with t-MDS or t-AML who have responsive disease and, in particular, who have no poor-risk cytogenetic features. The poor results of the other patients, especially those with active disease at BMT, emphasize the need to delineate indications and perform prospective protocols.

Adolescent↗

PubMed1999

Implication of HTLV-I infection, strongyloidiasis, and P53 overexpression in the development, response to treatment, and evolution of non-Hodgkin's lymphomas in an endemic area (Martinique, French West Indies).

A clinicopathologic study was conducted to assess the implication of HTLV-I infection, Strongyloides stercoralis (Ss) infection, and P53 overexpression in the development, response to treatment, and evolution of non-Hodgkin's lymphoma (NHL) in Martinique, French West Indies. Two groups of patients, with 22 and 41 participants with B-cell and T-cell lymphoma, respectively, were analyzed. HTLV-I antibodies were detected in 24 (59%) patients with T-cell lymphoma of whom 19 (46%) fulfilled diagnostic criteria of adult T-cell leukemia/lymphoma (ATLL). By comparison with other T-cell lymphomas, patients with ATLL were significantly younger (52 versus 63 years; p = .03), had a significantly higher incidence of hypercalcemia (60% versus 0%; p = .0001), a trend for higher incidence of digestive tract localization (21% versus 4%; p = .1) and significantly shorter median survival (6 versus 17 months; p = .03). Similar results were observed when all 24 HTLV-I-infected patients with T-cell lymphoma were compared with the 17 seronegative patients. Strongyloidiasis was diagnosed in 11 of 34 patients tested for Ss infection. All 4 Ss-infected (Ss-positive) ATLL patients treated with combination chemotherapy achieved complete remission (CR) versus only 2 of 7 Ss-negative ATLL patients (p = .04). In addition, survival of Ss-positive patients with ATLL was better than that of the uninfected patients: 27 versus 5 months, p = .04, respectively). P53 expression was assessed by immunohistochemistry on lymph node biopsies from 37 patients including 18 B-cell lymphomas, 14 ATLL, and 5 other T-cell lymphomas. P53 overexpression (P53-positive) was observed in 6 samples that corresponded in all 6 patients with ATLL. All P53-positive ATLL patients had stage IV disease with elevated lactate dehydrogenase (LDH) levels. By comparison with other ATLL patients studied for p53 expression, P53-positive ATLL were characterized by a lower response rate to combination chemotherapy (CR: 0 of 6 versus 4 of 6; p = .04) and a shorter survival (2 versus 9 months, p = .04). Our results suggest that ATLL represents almost 50% of T-cell lymphomas in Martinique; Ss infection during ATLL seems to be linked with a high response rate to chemotherapy and prolonged survival; and P53 overexpression is observed in almost 50% of aggressive ATLL from Martinique and, even in advanced clinical subtypes, is associated with resistance to chemotherapy and short-term survival.

Adolescent↗

PubMed1999

Quinine improves results of intensive chemotherapy (IC) in myelodysplastic syndromes (MDS) expressing P-glycoprotein (PGP). Updated results of a randomized study. Groupe Français des Myélodysplasies (GFM) and Groupe GOELAMS.

We designed a randomized trial of IC with or without quinine, an agent capable of reverting the multidrug resistance (mdr) phenotype, in patients aged < or = 65 years with high risk MDS. Patients were randomized to receive Mitoxantrone 12 mg/m2/d d2-5 + AraC 1 g/m2/12 h d1-5, with (Q+) or without (Q-) quinine (30 mg/kg/day). 131 patients were included. PGP expression analysis was successfully made in 91 patients and 42 patients (46%) had positive PGP expression. In PGP positive cases, 13 of the 25 (52%) patients who received quinine achieved CR, as compared to 3 of the 17 (18%) patients treated with chemotherapy alone (p = 0.02). In PGP negative cases, the CR rate was 35% and 49%, respectively in patients who received quinine or chemotherapy alone (difference not significant). In the 42 PGP positive patients, median Kaplan-Meier (KM) survival was 13 months in patients allocated to the quinine group, and 8 months in patients treated with chemotherapy alone (p = 0.01). In PGP negative patients, median KM survival was 14 months in patients allocated to the quinine group, and 14 months in patients treated with chemotherapy alone. Side effects of quinine mainly included vertigo and tinnitus that generally disappeared with dose reduction. Mucositis was significantly more frequently observed in the quinine group. No life threatening cardiac toxicity was observed. In conclusion, results of this randomized study show that quinine increases the CR rate and survival in PGP positive MDS cases treated with IC. The fact that quinine had no effect on the response rate and survival of PGP negative MDS suggests a specific effect on PGP mediated drug resistance rather than, for instance, a simple effect on the metabolism of Mitoxantrone and/or AraC.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

Assessment of P-glycoprotein expression by immunocytochemistry and flow cytometry using two different monoclonal antibodies coupled with functional efflux analysis in 34 patients with acute myeloid leukemia.

Drug resistance often results in failure of anticancer chemotherapy in leukemias. A large number of studies have been published on the effect of P-glycoprotein (Pgp) expression on prognosis in AML. However, a consensus has been difficult to reach, due to the variable results obtained by different laboratories. Pgp expression was investigated here in bone marrow samples from 34 patients with AML including 19 newly diagnosed cases and 15 relapsing patients. Pgp expression was performed by immunocytochemistry (ICC) using the aviding-biotin-peroxydase technique with JSB1 and UIC2 MoAbs. Flow cytometry (FCM) analysis of Pgp expression was performed using UCI2 MoAbs in an indirect immunofluorescent assay without cell permeabilization. Rhodamine 123 (Rh 123) uptake was measured in the presence or absence of verapamil. Result was discordant in only 1/20 samples studied with both JSB1 and UIC2 by ICC. Results of Pgp expression were consistent on FCM and ICC in 23 of the 28 (82%) samples tested. Overall, Pgp expression was observed by ICC or FCM in 23 (67%) patients, including 11 (58%) newly diagnosed patients and 12 (80%) patients in relapse. Functional Rh123 efflux (Rh123+) was observed in 20 cases (59%): 10 de novo AML (53%) vs 10 AML in relapse (67%). The functional efflux was correlated with Pgp expression in 25 of the 34 cases analyzed (p = 0.013). 3 (9%) and 6 (18%) samples were Pgp-/Rh123+ and Pgp+/Rh123- respectively. Nine of the 14 pts (64%) treated with intensive anthracyclin-Ara C chemotherapy achieved complete remission, including 5/5 (100%) Pgp- cases vs 4/9 (44%) Pgp+ cases (p = 0.04) and 4/6 (67%) Rh 123- vs 4/7 (57%) Rh123+ cases (p = 0.5). In conclusion, assessment of Pgp expression by ICC and FMC using 2 different MoAbs coupled with functional efflux analysis confirms that Pgp expression is correlated with disease stage and response to treatment in AML. Discordant Pgp/Rh123 cases suggest a non functional Pgp or another alteration of drug transport.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

Combined anti-fungal therapy and surgical resection as treatment of pulmonary zygomycosis in allogeneic bone marrow transplantation.

Opportunistic fungal infection is a rare but severe complication in allogeneic bone marrow transplant (BMT) recipients. We report a 49-year-old patient who developed pneumonitis after BMT, due to a Mucorales fungus (class Zygomycetes), Absidia corymbifera. Infections due to mucormycosis are likely to become increasingly recognized even though the occurrence after BMT has only been described sporadically. We postulate that the patient was contaminated before BMT despite no intensive drug treatment or other iatrogenic features, related to his poor living conditions and developed the infection during aplasia. He immediately received i.v. liposomal amphotericin B (AmBisome) and GM-CSF. Because there was no response, the infected area and necrotic tissue were resected. Despite initial clinical and biological improvement and the absence of Mucor on mycological examination post-surgery, the patient died 3 weeks later from bilateral pulmonary infection and multiorgan failure.

Absidia↗

PubMed1999

A prospective study of autologous bone marrow or peripheral blood stem cell transplantation after intensive chemotherapy in myelodysplastic syndromes. Groupe Français des Myélodysplasies. Group Ouest-Est d'étude des Leucémies aiguës myéloïdes.

We prospectively assessed autologous stem cell transplantation for consolidation treatment in a trial of intensive chemotherapy in high risk myelodysplastic syndromes (MDS). In this trial, patients aged 55 years or less with no HLA-identical sibling and achieving CR were scheduled to receive unmanipulated autologous bone marrow transplantation (ABMT) preceded by a consolidation chemotherapy course. Forty-two of the 83 patients aged 55 years or less included in the trial (51%) achieved CR. Three were allografted in CR. Twenty-four of the remaining 39 patients who achieved CR (62%) received ABMT (16 patients) or autologous peripheral blood stem cell transplantation (APSCT) (eight patients). Indeed, as bone marrow harvest was often insufficient, APSCT was subsequently proposed after mobilization by consolidation chemotherapy followed by G-CSF. The conditioning regimen combined cyclophosphamide and busulfan. ABMT and APSCT were performed 1-7 months (median 3) after CR achievement. Hematological reconstitution occurred in all patients and tended to be faster after APSCT than ABMT although not significantly. Three patients died from the procedure, nine relapsed after 2-26 months and 12 (50%) were still in CR after 8-55 months. In autografted patients, median Kaplan-Meier disease-free survival and survival were 29 and 33 months from the autograft, respectively. Thus, ABMT or APSCT can be performed in almost two-thirds of MDS patients who achieve CR with intensive chemotherapy. PBSC collection may yield higher numbers of stem cells than marrow collection in some cases, and could improve the percentage of MDS patients autografted in CR. Longer follow-up is required to determine if autograft will prolong CR duration in at least some patients.

Adolescent↗

PubMed1999

Semiquantitative analysis of residual disease in patients treated for adult T-cell leukaemia/lymphoma (ATLL).

Many adult T-cell leukaemia/lymphoma (ATLL) patients who respond to induction treatment, then relapse. Knowing the clonality pattern of residual tumourous clones during treatment could help understand disease evolution and aid therapeutic decisions. We developed a sensitive and semi-quantitative molecular analysis of these clones in ATLL patients. DNA samples from PBMCs derived from eight ATLL patients were studied over time by quadruplicate linker mediated PCR (LMPCR) amplification of HTLV-1 integration sites. Patients were treated with combination chemotherapy, zidovudine-interferon-alpha and/or by peripheral stem cell transplantation or allogeneic bone marrow transplantation. Persistence of tumourous clones at a high frequency (>1/300 PBMCs) was frequently observed, even in complete responders, and was invariably correlated with relapse and/or poor outcome. Fluctuation in the frequency of some tumourous clones was observed with evidence for clonal change under treatment in one patient, indicating that treatment of ATLL can result in the selection of resistant clones. Finally, allogeneic bone marrow transplantation (BMT) using an HTLV-1 infected sibling as donor was found to be associated with long-lasting disappearance of tumourous clones and a possible cure of the disease. Long-term persistent clonal expansion of circulating HTLV-1 bearing T cells which derived from the donor bone marrow was evidenced in this patient. In conclusion, variable success in treatment of ATLL is probably due to the clonal heterogeneity which results in the selection of resistant clones. Semi-quantitative assessment of residual disease (RD) through LMPCR may predict treatment failure. Accordingly, additional therapy may be tailored to the clonality pattern observed after first-line therapy.

Adult↗

PubMed1999

Continuous-infusion carboplatin in combination with idarubicin or mitoxantrone for high-risk acute myeloid leukemia: a randomised phase II study.

Fifty-three patients of median age 66 years (39 patients > 60 yrs), including 5 with FAB unclassified or secondary acute myeloid leukemia (AML) at diagnosis, 14 with resistant AML, 19 in first and 15 in subsequent relapse, were treated with carboplatin (CBP), 200 mg/m2/day, as a continuous infusion, (days 3 to 7) with mitoxantrone (MIT) or idarubicin (IDA), (12 mg/m2/day) as an i.v. bolus, on days 1 to 3. Results were evaluated after one induction course. Overall, 15 patients (28% [95% confidence interval (CI), 17-42%], 8/28 with IDA and 7/25 with MIT) achieved complete remission (CR). There was no statistical difference between IDA and MIT arms. Fourty-nine percent (95% CI, 35-63%) had resistant disease (53% IDA versus 44% MIT respectively) and 23% (95% CI, 12-36%) died from toxicity (18% IDA versus 28% MIT). Median durations of neutrophils less than 0.5 x 10(9)/l and platelet counts less than 20 x 10(9)/l were 32 and 32 days respectively in the IDA arm and 31 and 26 days respectively in the MIT arm. Severe toxicity included infections (45%), diarrhea (21%), bleeding (9%), vomiting (7%), hyperbilirubinemia (6%), mucositis (4%) (no statistical difference was seen between both arms). Nephrotoxicity was observed in only one case in the IDA arm. Cardiac toxicity included reversible pulmonary oedema in one patient in the IDA arm. No severe ototoxicity was noted. CR patients received maintenance courses with 3 days of CBP and one day of IDA or MIT. Median survival was 2 months (range, 1-30+ months) and 2.5 months (range, 0.5-19.5 months), and median disease-free survival (DFS) 2 months (range, 1-30+ months) and 2.5 months (range, 1-14 months) in the IDA and MIT arms respectively. We conclude that CBP at a cumulative dosage of 1 g/m2 together with intercalating agents (IDA/MIT) has antileukemic efficacy in elderly patients.

Adult↗