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Biomedical subjects

P Fenaux

Publications and source records attributed to P Fenaux.

At least 19 recordsLinked to original sources
PubMed2005

Outcome of acute promyelocytic leukemia treated with all trans retinoic acid and chemotherapy in elderly patients: the European group experience.

We analyzed the outcome of patients aged more than 60 included in a multicenter trial in newly diagnosed acute promyelocytic leukemia (APL93 trial), which tested the role of early addition of chemotherapy to all trans retinoic acid (ATRA) and of maintenance with ATRA and/or low-dose chemotherapy. In total, 129/533 (24.2%) patients included in this trial were older than 60. The CR rate was 86% in patients older than 60 as compared to 94.5% in younger patients (P=0.0014), due to a higher incidence of early deaths in elderly patients. The 4-year incidence of relapse was 15.6% in adults older than 60 and 23.2% in younger adults although most elderly patients received less intensive consolidation chemotherapy. However, 18.6% of the patients older than 60 years who achieved CR died in CR, mainly from sepsis during consolidation course or maintenance treatment, as compared to 5.7% of younger adults (P<0.001). Thus, overall 4-year survival of elderly patients was 57.8% as compared to 78% in younger adults (P<0.0001). APL in elderly patients appears as sensitive to ATRA-Chemotherapy based regimen as in younger adults. Less favorable outcome is mainly due to an increase of early deaths and to toxicity of consolidation treatment, strongly suggesting a beneficial role for less intensive consolidation chemotherapy and possibly introduction of arsenic derivates in the treatment of APL in the elderly.

Adolescent↗
PubMed2004

Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group.

PURPOSE: To retrospectively determine the outcome of acute promyelocytic leukemia (APL) patients who underwent autologous or allogeneic stem-cell transplantation (SCT) during second complete remission. PATIENTS AND METHODS: Of 122 relapsing patients included in two successive multicenter APL trials who achieved hematological second complete remission (generally after a salvage regimen of all-trans-retinoic acid [ATRA] combined with chemotherapy), 73 (60%) received allogeneic (n = 23) or autologous (n = 50) SCT. RESULTS: Seven-year relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) in the autologous SCT group were 79.4%, 60.6%, and 59.8%, respectively, with a transplant-related mortality (TRM) of 6%. Of the 28 and two patients autografted with negative and positive, respectively, reverse transcriptase-polymerase chain reaction before auto SCT, three (11%) and one relapsed, respectively. In the allogeneic SCT group, 7-year RFS, EFS, and OS were 92.3%, 52.2%, and 51.8%, respectively, with 39% TRM. OS was significantly better in the autologous SCT group than in the allogeneic SCT group (P = .04), whereas RFS and EFS did not differ significantly (P = .19 and P = .11, respectively). In patients not receiving transplantation, 7-year RFS, EFS, and OS were 38%, 30.4%, and 39.5%, respectively. CONCLUSION: These retrospective data suggest that autologous SCT is very effective in APL relapsing after treatment with ATRA if performed in molecular remission. Allogeneic SCT yields few relapses, but it is associated with high TRM when performed after salvage with very intensive chemotherapy. Salvage with arsenic trioxyde, which has lower toxicity, should further improve the outcome of relapsing APL, especially before allogeneic SCT.

Adult↗
PubMed2004

Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy.

PURPOSE: To determine the results of treatment combining all-trans-retinoic acid (ATRA) and chemotherapy (CT) in childhood acute promyelocytic leukemia (APL). PATIENTS AND METHODS: Children (< 18 years) with newly diagnosed APL were included in the APL93 trial, treated by ATRA followed or combined with daunorubicin-cytarabine, and then randomly assigned between no maintenance, intermittent ATRA, continuous CT, or both. RESULTS: Of the 576 patients included in APL93 trial, 31 (5%) were children, including 22 girls (71%) and nine boys (29%). Thirty of the children (97%) obtained complete remission (CR). ATRA syndrome occurred in four children (13%), who all achieved CR, and headaches occurred in 12 children (39%), with signs of pseudotumor cerebri in five children (16%). Seven patients (23%) relapsed. None of the eight patients who received both ATRA and CT for maintenance relapsed. All relapsing patients achieved a second CR. Twenty-two patients remained in first CR after 43+ to 96+ months, six remained in second CR after 17+ to 66+ months, and three patients had died. The 5-year event-free survival (EFS), relapse, and overall survival rates were 71%, 27%, and 90%, respectively. No difference between adults and children included in the APL93 trial was seen for CR rate, 5-year relapse rate, EFS, and overall survival, but significantly better survival was seen in children after adjustment on WBC counts (P =.02) and incidence of microgranular M3 variant (P =.04). CONCLUSION: ATRA combined with CT for induction and also probably for maintenance provides as favorable results in children with APL as in adults and currently constitutes the reference first-line treatment in both age groups.

Adolescent↗
PubMed2004

[Orbital granulocytic sarcoma revealing acute myeloblastic syndrome: a case study].

Granulocytic sarcoma is a rare orbital complication of acute leukemia. It concerns primarily children under 10 years of age suffering from primitive acute myeloid leukemia. As this type of symptom can sometimes affect the elderly during the acute phase of myelodysplastic syndrome, it raises a problem with diagnosis and consequently with therapeutic treatments. We report the case of a 77-year-old female patient who had acute inflammatory proptosis during regressive right ethmoiditis. The diagnosis was reached by computed tomography showing an extraconical intraorbital tumor sprouting from the sinus, and by clinical examination and confirmed by the hematological investigation. Acute proptosis developing in an acute myeloblastic leukemia context heavily swayed diagnosis towards orbital granulocytic sarcoma. Chemotherapy by cytarabine and hydroxycarbamide associated with intravenous corticoid therapy resulted in complete disappearance of the proptosis within 10 days. This case report is a reminder of this peculiar sign of tumoral syndrome in acute myeloid leukemia. We also discuss different diagnostic methods and various therapeutic approaches, and analyze the disease course and patient follow-up.

Acute Disease↗
PubMed2003

Therapy-related acute promyelocytic leukemia.

PURPOSE: To analyze patient cases of therapy-related acute promyelocytic leukemia (tAPL), occurring after chemotherapy (CT), radiotherapy (RT) or both for a prior disorder, diagnosed during the last 20 years in three European countries. PATIENTS AND METHODS: The primary disorder and its treatment, interval from primary disorder to tAPL, characteristics of tAPL, and its outcome were analyzed in 106 patients. RESULTS: Eighty of the 106 cases of tAPL were diagnosed during the last 10 years, indicating an increasing incidence of tAPL. Primary disorders were predominantly breast carcinoma (60 patients), non-Hodgkin's lymphoma (15 patients), and other solid tumors (25 patients). Thirty patients had received CT alone, 27 patients had received RT alone, and 49 patients had received both. CT included at least one alkylating agent in 68 patients and at least one topoisomerase II inhibitor in 61 patients, including anthracyclines (30 patients), mitoxantrone (28 patients), and epipodophyllotoxins (19 patients). Median interval from primary disorder to tAPL diagnosis was 25 months (range, 4 to 276 months). Characteristics of tAPL were generally similar to those of de novo APL. With treatment using anthracycline-cytarabine-based CT or all-trans-retinoic acid combined with CT, actuarial survival was 59% at 8 years. CONCLUSION: tAPL is not exceptional, and develops usually less than 3 years after a primary neoplasm (especially breast carcinoma) treated in particular with topoisomerase II-targeted drugs (anthracyclines or mitoxantrone and less often etoposide). Characteristics and outcome of tAPL seem similar to those of de novo APL.

Adult↗
PubMed2003

Gamma-irradiation enhances transgene expression in leukemic cells.

The majority of immunotherapy-based gene therapy protocols consist of ex vivo gene transfer in tumor cells. To prevent further in vivo growth, modified cells must be irradiated before reinjection into patients. The present study examines the effects of gamma-irradiation on transgene expression in transduced leukemic cells. Human and murine leukemic cells were transfected with retroviral vectors or plasmids carrying beta-galactosidase, GM-CSF or CD80 genes. Fresh leukemic cells from patients with acute myeloid leukemia (AML) were transfected with AdZ.F(pK7) adenoviral vector. gamma-irradiation at various lethal doses enhanced transgene expression in leukemic cell lines and fresh AML cells when the gene of interest was under CMV promoter but not when SV40 promoter was used. Oxidative stress also enhanced transgene expression and both irradiation and oxidative stress effects were inhibited by addition of N-acetyl-L-cysteine, a thiol anti-oxidant, indicating the involvement of reactive oxygen species. Transgene expression was also enhanced in vivo 48 and 120 h after subcutaneous injection of irradiated leukemic cells in syngeneic mice. These results show that a cell vaccine protocol using ex vivo gene transfer of transduced cells might be feasible in acute leukemia even if leukemic cells must be irradiated at lethal doses prior to reinjection to patients.

Acute Disease↗
PubMed2003

Phase II trial of CPT-11 in myelodysplastic syndromes with excess of marrow blasts.

CPT-11 is an antineoplastic agent which acts as a specific inhibitor of DNA topisomerase 1 and has a broad spectrum of activity in solid tumors. Very few studies have evaluated the activity of CPT-11 in hematological malignancies. We conducted a phase II trial of CPT-11 in 26 patients with high-risk MDS (RAEB 1: n = 4; RAEB 2: n = 9; MDS having progressed to AML: n = 10; CMML: n = 3) who could not receive anthracycline/cytarabine intensive chemotherapy. Induction therapy consisted of four courses of CPT-11 given intravenously at 200 mg/m(2) every 2 weeks. Patient characteristics were: median age, 71 (range 51-77); sex, (M/F), 21/5, median % marrow blasts cells, 13.5 (range 7-52). Cytogenetics according to IPSS were: low-risk n = 13, intermediate-risk n = 6, high-risk n = 3, failure or not done n = 4. Six patients stopped treatment after only one or two courses of CPT-11 due to severe infection (n = 2), progressive disease (n = 3), acute lysis syndrome with renal failure (n = 1). In the 20 patients who received at least three cycles of CPT-11, complete remission was achieved in one case, partial remission in four cases, and hematological improvement in three cases with an overall response rate of 33% in the 26 patients. Duration of response was short (median 4 months, range 1-6 months) and median survival was 8 months (range 1-23 months). Digestive toxicity (diarrhea) occurred in 26/89 (29%) courses, but was mild (grade 1, 20% courses; grade 2 or 3, 9% courses). Hematological toxicity was difficult to assess in non-responders because of initial pancytopenia, but all the patients who responded had grade 3/4 hematological toxicity associated with grade >/=2 infection requiring hospitalization in 18% of the courses. No other major toxicity was observed. Thus CPT-11 has an interesting activity in MDS with excess of blasts; toxicity is easily managed and most patients can be treated in the out-clinic setting. These results suggest that further evaluation of CPT-11 in MDS is warranted.

Aged↗
PubMed2003

New mechanisms of AML1 gene alteration in hematological malignancies.

The human AML1 gene (also named CBFA2 or RUNX1), located in the 21q22 chromosomal band, encodes for one of the two subunits forming a heterodimeric transcription factor, the human core binding factor (CBF). AML1 protein contains a highly evolutionary conserved domain of 128 amino acids called runt domain, responsible for both heterodimerization with the beta subunit of CBF and for DNA binding. AML1 is normally expressed in all hematopoietic lineages and acts to regulate the expression of various genes specific to hematopoiesis playing a pivotal role in myeloid differentiation. AML1 is one of the genes most frequently deregulated in leukemia through different mechanisms including translocation, mutation and amplification. Translocations lead to the formation of fusion genes encoding for chimerical proteins such as AML1-ETO which induces leukemogenesis. Recently, new mechanisms of AML1 deregulation by point mutations or amplification have been reported. To our knowledge, 51 patients (among 805 studied) with AML1 point mutations have been described. Forty of them have acute myeloid leukemia (AML) most often M0 AML. In this subtype of AML, the frequency of AML1 mutation is significantly higher; 21.5% of patients mutated (34/158). Mutations have also been found with lower frequency in other FAB subtype AML (6 cases), in myeloproliferative disorders (6 cases), in myelodysplastic syndrome (3 cases) and rarely in acute lymphoblastic leukemia (1 case). AML1 gene amplification has been found essentially in childhood ALL (12 cases) and more rarely in myeloid malignancies (4 cases). Here, we reviewed all these cases of AML1 point mutations and amplification and focused on the mechanisms of AML1 deregulation induced by these alterations.

Acute Disease↗
PubMed2003

Early onset of chemotherapy can reduce the incidence of ATRA syndrome in newly diagnosed acute promyelocytic leukemia (APL) with low white blood cell counts: results from APL 93 trial.

Treatment combining ATRA and chemotherapy (CT) has improved the outcome of APL patients, by comparison with CT alone. ATRA syndrome is a life-threatening complication of ATRA treatment whose prophylaxis remains somewhat controversial. In APL93 trial, newly diagnosed APL patients </=65 years and with initial WBC counts below 5000/mm(3) were randomized between ATRA until CR achievement followed by CT (ATRA --> CT) and ATRA with early addition of CT, on day 3 of ATRA treatment (ATRA + CT). The incidence of ATRA syndrome in the ATRA --> CT arm was 18% (22/122) as compared to 9.2% (17/184) in the ATRA + CT arm (P = 0.035). In the ATRA --> CT arm, three (2.5%) patients died from ATRA syndrome, as compared to one (0.5%) in the ATRA + CT group. Early addition of chemotherapy to ATRA in newly diagnosed APL with low WBC counts significantly reduced the incidence of ATRA syndrome.

Adult↗
PubMed2003

Prognostic value of GST-pi expression in diffuse large B-cell lymphomas.

Among mechanisms potentially involved in resistance to alkylating agents and anthracyclines, the glutathione system has been extensively studied in vitro. We analyzed by immunohistochemistry the relation between glutathione s-transferase pi (GST-pi) expression in tumor cells and outcome in 69 cases of diffuse large B-cell NHL (DLBCL). GST-pi expression was considered as low when <50% of tumor cells were stained and high when >/=50% tumor cells were stained. Median follow-up was 58 months. GST-pi expression was correlated with the probability of achieving complete remission (CR). Patients with high GST-pi expression had a worse 5-year freedom from progression (FFP). High GST-pi expression was associated with a trend for lower survival. In the group of patients with International Prognostic Index (IPI) 0-1, low GST-pi expression was associated with a CR rate of 88%, a 5-year FFP of 76+/-20% and a 5-year survival of 78+/-16% compared to 36, 14+/-16 and 40+/-32%, respectively, in patients with a high GST-pi expression (P=0.002, P&<10(-5) and P=0.01, respectively). No correlation was found between GST-pi expression and lactico deshydrogenase serum level, age, Ann Arbor stage, performance status, and IPI index. Both GST-pi expression and the IPI index correlated with FFP. After incorporating IPI and GST-pi expression in a multivariate analysis for FFP, GST-p expression remained the only prognostic factor (P=0.003). Our findings suggest that GST-pi expression had strong prognostic significance in DLBCL, which appears to be independent of other prognostic parameters in those disorders.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Myelodysplastic syndrome after acute promyelocytic leukemia: the European APL group experience.

With improved treatment of acute promyelocytic leukemia (APL) by all trans retinoic acid (ATRA) combined to anthracycline-aracytin chemotherapy (CT), a larger number of those patients may be at risk of late complications. Recently, the Rome group reported five cases of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML, non-APL) occurring during the course of 77 APL patients (6.5%) in complete remission (CR). From 1991 to 1998, we treated 677 newly diagnosed cases of APL, and 617 of them achieved CR with ATRA combined to CT (n=579) or CT alone (n=38); 246 of them received subsequent maintenance CT with 6 mercaptopurine and methotrexate. With a median follow-up of 51 months, 6 patients (0.97%) developed MDS, 13-74 months after the diagnosis of APL. In all six cases, t(15;17) and PML-RARalpha rearrangement were absent at the time of MDS diagnosis, and karyotype mainly showed complex cytogenetic abnormalities involving chromosomes 5 and/or 7, typical of MDS observed after treatment with alkylating agents, although none of the six patients had received such agents for the treatment of APL. Our findings suggest that MDS can indeed be a long-term complication in APL, although probably at lower incidence than that previously reported.

Adolescent↗
PubMed2002

Allogeneic bone marrow transplantation in patients with follicular lymphoma: a single center study.

The role of allogeneic BMT for follicular lymphoma remains to be established. From 1995 to 2000, 16 patients with follicular lymphoma underwent allogeneic BMT at our center. At the time of transplantation, two patients were in complete remission, 11 in partial remission and three had refractory disease. Fourteen patients were transplanted using a standard myeloablative conditioning regimen and two a nonmyeloablative conditioning regimen. With a median follow-up of 1184 days (range 403-1999 days) after BMT, 11 patients were alive, whereas five died of transplant-related mortality. Eight patients remained in CR 284+ to 1022+ days (median 560+ days) after BMT. Two patients relapsed 63 and 1073 days after BMT. They achieved a further complete remission after salvage treatment and remained alive 403 and 1224 days after BMT, respectively. One patient with autologous reconstitution had never been in CR after BMT. He was retreated with salvage chemotherapy but only achieved CR with subsequent rituximab treatment and was still alive, 1999 days after transplantation. The estimated 2-year overall survival and event-free survival rates were 68% and 55%, respectively. Age greater than 37 years at diagnosis, positive recipient CMV serology and ECOG performance status > or =1 at diagnosis were associated with shorter overall survival (P = 0.05, P = 0.009 and P = 0.03, respectively). Ann Arbor III-IV stage at diagnosis was associated with shorter event-free survival (P < 0.04). Allogeneic BMT seems to be effective for patients with follicular lymphoma. However, the relatively high rate of early transplant-related mortality emphasizes the need to define indications and use prospective protocols involving a less toxic transplant procedure.

Adult↗
PubMed2002

Gene transfer of CD154 and IL12 cDNA induces an anti-leukemic immunity in a murine model of acute leukemia.

IL12 is an essential cytokine for the generation of T helper 1 response, natural killer (NK) cells and cytotoxic T lymphocyte (CTL) stimulation. CD154 triggers CD40 on antigen-presenting cells, thus inducing antigen presentation to the immune system and production of IL12. As IL12 and CD154 share several pathways mediating immune response, we investigated in an aggressive murine model of acute leukemia the relative antileukemic efficiency of IL12, CD154 and IL12 + CD154 gene transfer. Live leukemic cells transduced by IL12, CD154, and IL12 + CD154 showed reduced leukemogenicity but CD154 protective effect was reduced when 10(6) leukemic cells were injected. Vaccines with lethally irradiated IL12-transduced cells were able to cure mice previously injected with 10(4) leukemic cells and adoptive transfer of IL12-induced antileukemic immunity protected recipient mice. NK cytotoxicity was enhanced in mice vaccinated with leukemic cells transduced by IL12, CD154, and CD154 + IL12. IL12 transduced cells induced IFN-gamma mRNA in CD4(+) and CD8(+) T cells isolated from the spleen of vaccinated animals, however, in vivo depletion experiments showed that IL12 vaccine effect was CD4(+) but not CD8(+) T cell dependent. We conclude that IL12 gene is a more potent candidate than CD154 for gene therapy of acute leukemia.

Acute Disease↗
PubMed2002

Prognostic significance of FLT3 internal tandem repeat in patients with de novo acute myeloid leukemia treated with reinforced courses of chemotherapy.

FLT3 internal tandem duplications (FLT3-ITDs) are present in nearly 25% of patients with AML and have been associated with poor response to conventional therapy and poor outcome. We retrospectively evaluated the effect of reinforced courses of chemotherapy on the prognostic value of FLT3-ITDs in 159 AML patients prospectively enrolled in the ALFA-9000 trial, which randomly compared three reinforced induction regimens (standard 3+7 including high-dose daunorubicin, double induction, and timed-sequential therapy). FLT3-ITD was present in 40/159 (25%) blast samples and associated with high WBC (P = 0.002) and cytogenetics (P < 0.001) with a higher incidence (35%) in patients with a normal karyotype. There was no difference in CR rate between FLT3-wt and FLT3-ITD patients (80% vs 78%). Relapse-free survival (RFS) was similar in both groups (5-year RFS, 33% vs 32%; P = 0.41), even after adjustment for age, sex, WBC, cytogenetics, and treatment arm. A trend to a worse survival was observed in the FLT3-ITD group (estimated 5-year OS, 23% vs 37%; P = 0.09), mainly in patients with a normal karyotype. This was associated with a dramatic outcome in relapsing FLT3-ITD patients (estimated 3-year post-relapse survival, 0% vs 27%; P = 0.04). These results suggest that the bad prognosis associated with FLT3-ITDs in AML might be partly overcome using reinforced chemotherapy. Early detection of FLT3 mutations might thus be useful to intensify induction as well as post-remission therapy in FLT3-ITD patients.

Acute Disease↗
PubMed2001

In vitro all-trans retinoic acid sensitivity of acute promyelocytic leukemia blasts: a novel indicator of poor patient outcome.

Acute promyelocytic leukemia (APL) blasts possess a unique sensitivity to the differentiating effects of all-trans retinoic acid (ATRA). Multicenter trials confirm that the combination of differentiation and cytotoxic therapy prolongs survival in APL patients. However relapses still occur, and exquisite adaptation of therapy to prognostic factors is essential to aim at a possible cure of the disease. A heterogeneity was previously reported in the differentiation rate of patients' APL blasts, and it was postulated that this may reflect the in vivo heterogeneous outcome. In this study, it is demonstrated that patients of the APL93 trial whose leukemic cells achieved optimal differentiation with ATRA in vitro at diagnosis had a significantly improved event-free survival (P =.01) and lower relapse rate (P =.04). This analysis highlights the importance of the differentiation step in APL therapy and justifies ongoing studies aimed at identifying novel RA-differentiation enhancers.

Adult↗