Search PubMed⌕ Search

Biomedical subjects

Pierre Fenaux

Publications and source records attributed to Pierre Fenaux.

53 records · Page 3Linked to original sources
PubMed2003

Treatment of older adults with acute promyelocytic leukaemia.

Only 15 to 20% of acute promyelocytic leukaemia (APL) patients are older than 60 years, and the characteristics and outcome of APL in that age range are not well known. Published studies show that APL in elderly patients has haematological features similar to those of APL in younger patients. However, using the current combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy, the outcome for these patients, although it has much improved, remains less favourable than that for younger patients. This is due to a higher incidence of early deaths and deaths in complete remission (CR), during consolidation chemotherapy courses, whereas the relapse rate appears similar in older and younger adults. Treatment approaches with more limited myelosuppression, especially consolidation chemotherapy with an anthracycline alone (without Ara-C), low-dose maintenance treatment with 6-mercaptopurine, methotrexate and ATRA, and consolidation with arsenic trioxide, should be tested especially in elderly patients in order to replace more toxic 'classical' anthracycline-Ara-C consolidation treatment, after achieving CR with ATRA.

Age Factors↗
PubMed2003

Long-term follow-up of chronic autoimmune thrombocytopenic purpura refractory to splenectomy: a prospective analysis.

Splenectomy remains the most effective treatment of chronic autoimmune idiopathic thrombocytopenia (ITP) (i.e. of > 6 months duration). Treatment of patients refractory to splenectomy (with absence of response or relapse after initial response) is difficult, and their long-term outcome is not well known. Over a 10-year period, 183 patients with chronic ITP were splenectomized including 158 adults and 25 children (</= 15 years). Forty-seven of them, who were refractory to this treatment, were prospectively followed up for 5-15 years (median 7.5 years). Twelve of them, with moderate thrombocytopenia, remained untreated, and 35 were treated by a median of two regimens (range 1--6), to which 27 responded. Thirty-six (77%) of the refractory cases reached platelet counts durably > 100 x 10(9)/l, nine of them without treatment and 27 of them with low-dose steroids or azathioprine; six (13%) remained moderately thrombocytopenic (35 x 10(9)/l to 100 x 10(9)/l platelets); the last five patients, without response to any treatment (up to six regimens), remained severely thrombocytopenic (platelets < 20 x 10(9)/l), and three of them died from bleeding. Twenty-seven (57%) of the 47 refractory cases required at least one hospitalization, in the majority of cases for intravenous immunoglobulin (IVIg) infusions. Seven of the refractory cases occurred in children. Six of them subsequently reached platelet counts > 100 x 10(9)/l, but one died from bleeding. Our findings confirm the overall favourable long-term prognosis of chronic ITP refractory to splenectomy.

Adult↗
PubMed2002

Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA).

The transcription factor C/EBPalpha is crucial for differentiation of mature granulocytes. Recently, different CEBPA gene mutations likely to induce differentiation arrest have been described in nearly 10% of patients with acute myeloid leukemia (AML). In the present study, we retrospectively analyzed the prognostic significance of CEBPA mutations in 135 AML patients (French-American-British [FAB]-M3 excluded). All patients were prospectively enrolled between 1990 and 1996 in a multicenter trial of the ALFA (Acute Leukemia French Association) Group (median age 45 years, median follow-up 5.7 years). Mutations were assessed using direct sequencing of the CEBPA gene. Twenty-two mutations were found in 15 (11%) of 135 patients tested. Twelve patients had at least one mutation located in the N-terminal part of the protein leading to the lack of expression of the full-length C/EBPalpha protein. CEBPA mutations were present only in patients belonging to the intermediate cytogenetic risk subgroup and associated with the FAB-M1 subtype (P =.02). FLT3 internal tandem duplication (ITD) was found in 5 of 15 CEBPA-mutated as compared with 30 of 119 CEBPA-nonmutated cases tested (P =.54). Presence of CEBPA mutations was identified as an independent good prognosis factor for outcome even after adjustment on cytogenetics and FLT3 status (estimated 5-year overall survival 53% vs 25%, P =.04). FLT3-ITD appeared to act as a major bad prognosis factor in patients with CEBPA-mutated AML. We thus propose a risk classification that includes in the favorable subgroup all patients from the intermediate subgroup displaying CEBPA mutations when not associated with FLT3-ITD.

Adolescent↗
PubMed2002

M0 AML, clinical and biologic features of the disease, including AML1 gene mutations: a report of 59 cases by the Groupe Français d'Hématologie Cellulaire (GFHC) and the Groupe Français de Cytogénétique Hématologique (GFCH).

Mutations of the AML1 gene are frequent molecular abnormalities in minimally differentiated acute myeloblastic leukemia (M0 AML), a rare type of AML. In this retrospective multicenter study, morphologic, immunophenotypical, cytogenetic, and molecular features of 59 de novo M0 AML cases were analyzed and correlated to AML1 mutations. Point mutations of AML1 gene were observed in 16 cases (27%). They were correlated with higher white blood cell (WBC) count (P =.001), greater marrow blast involvement (P =.03), higher incidence of immunoglobulin H/T-cell receptor (IgH/TCR) gene rearrangement (P <.0001), and with a borderline significant lower incidence of complex karyotypes. In the 59 patients, FLT3 mutations were the only significant prognostic factors associated with short survival.

Adult↗
PubMed2002

Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia--results of the prospective multicenter LALA-94 trial.

From 1994 to 2000, 154 adults with Philadelphia chromosome-positive (Ph(+)) and/or BCR-ABL(+) acute lymphoblastic leukemia (ALL) were treated according to a prospective trial (median follow-up, 4.5 years) with the aim to study the prognostic value of early response to therapy and the role of stem cell transplantation (SCT) in first complete remission (CR). All patients received a standard induction course followed by a course of mitoxantrone and intermediate-dose cytarabine (HAM). After each course, minimal residual disease was tested by specific reverse transcriptase-polymerase chain reaction (RT-PCR) (median sensitivity, 10(-5)). Allogeneic SCT (if a donor) or autologous SCT (if not) was planned at 3 months in all patients in CR after HAM. CR rates after induction, after HAM, and at 3 months were 53%, 67%, and 62%, respectively. High leukocyte count and m-bcr subtype were the 2 identified bad-prognosis factors for CR at 3 months, both superseded by a poor early response assessed at day 8 of the induction course. HAM-associated salvage rate was higher in patients with M-bcr than in those with m-bcr ALL (55% vs 30%; P =.05). In the 103 patients eligible for SCT, the existence of a donor and the negative BCR-ABL status after HAM were independently predictive of remission duration (P <.001 and.01, respectively) and survival (P =.02 and.01, respectively). Relapse was the most common cause of treatment failure in all patient groups. Allogeneic SCT in first CR is the current best treatment option in adults with the disease. New strategies must be tested during early phases of therapy to increase the rate of BCR-ABL(-) remissions.

Adolescent↗
PubMed2002

Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment.

Targeting the tyrosine kinase activity of BCR-ABL represents a very promising therapeutic strategy in chronic myeloid leukemia (CML). Despite strong efficacy of the tyrosine kinase inhibitor STI571, resistance has been observed in a significant proportion of patients in advanced CML stage or in Ph-positive acute lymphoid leukemia (ALL). We investigated in this study the mechanism of resistance to STI571 through point mutations in the tyrosine kinase domain and/or BCR-ABL gene amplification in 24 patients (16 in chronic phase and 8 in accelerated phase of the disease) who obtained no cytogenetic response to STI571 treatment. Screening for the already-described Thr315Ile point mutation in the ABL domain using a reverse transcription polymerase chain reaction restriction fragment length polymorphism (RT-PCR-RFLP) technique, 3 patients showed a proportion of mutated transcript at the time of resistance. The same technique failed to detect mutation at diagnosis, but a specific allele-specific oligonucleotide (ASO)-PCR on DNA for the Thr315Ile mutation and, after sequencing, for 2 newly described Phe311Leu and Met351Thr substitutions, showed the presence of rare mutated cells prior to STI571 therapy. Furthermore, the increased proportion of mutated cells during treatment detected by ASO-PCR strongly suggested clonal selection by the functional inhibiting effect of these mutations. Finally, no BCR-ABL gene amplification was detected by fluorescent in situ hybridization (FISH) in the 24 STI571-resistant patients. Our data support that in CML patients treated with STI571, ABL mutations are not restricted to the accelerated phase of the disease and that, at least in some cases, mutations seem to occur prior to STI571 therapy, probably as second mutational events during the course of CML.

Alleles↗
PubMed2002

A white blood cell index as the main prognostic factor in t(8;21) acute myeloid leukemia (AML): a survey of 161 cases from the French AML Intergroup.

While the t(8;21) translocation is one of the most recurrent chromosomal abnormalities in acute myeloid leukemia, prognostic studies have been hampered by the relatively few number of patients reported. We thus performed a large retrospective study in 161 adults and children with t(8;21) acute myeloid leukemia, all prospectively enrolled in 6 different trials conducted in France between 1987 and 1998 (median follow-up 4.9 years). Prognostic studies were performed in the 154 patients who achieved a complete remission. Individual data were registered, including sex, age, blood and marrow counts, extramedullary disease, and cytogenetics. The value of allogeneic stem cell transplantation versus chemotherapy as postremission therapy was evaluated according to the intent-to-treat principle. Estimated 5-year disease-free survival (DFS) and overall survival were 52% and 59%, respectively. Outcome was not significantly better in patients from the stem cell transplantation group (estimated 5-year DFS and survival, 56% vs 52% and 67% vs 57%; P =.55 and.64, respectively). White blood cell count (WBC) was the only identified prognostic factor. To further take into account the spontaneous differentiation potential of the leukemic clone, a WBC index was derived as the product of WBC by the ratio of marrow blast. This WBC index was a more powerful factor than the original WBC, allowing us to distinguish 3 subgroups of patients with different outcomes (low index, < 2.5; intermediate index, 2.5-20; high index, 20 or more). In multivariate analysis, the WBC index was the only prognostic factor for DFS (P =.003), complete remission duration (P =.002), and overall survival (P =.04).

Acute Disease↗
PubMed2002

Unlike AML1, CBFbeta gene is not deregulated by point mutations in acute myeloid leukemia and in myelodysplastic syndromes.

The core-binding factor (CBF) complex is a heterodimeric transcription factor composed of 2 subunits, CBFalpha and CBFbeta, that play a major role in hematopoiesis. Both members of the CBF complex are frequently altered in acute myeloid leukemia (AML) by translocation, most commonly t(8;21), t(12;21), and t(3;21) for CBFalpha, located in 21q22, and inv(16)(p13;q22) for CBFbeta, located on 16q22. Recently, a new mechanism of alteration of CBFalpha, by point mutation, has been reported in myeloid malignancies, particularly in M0 AML. In the present study, we found no point mutation of the CBFbeta gene in 30 myelodysplastic syndromes and 100 AMLs, suggesting a limited role, if any, of CBFbeta point mutations in those disorders.

Acute Disease↗
PubMed2002

p16(INK4a) immunocytochemical analysis is an independent prognostic factor in childhood acute lymphoblastic leukemia.

We investigated the prognostic value of p16(INK4a) immunocytochemistry (ICC) analysis in 126 cases of newly diagnosed childhood acute lymphoblastic leukemia (ALL). The incidence of negative p16(INK4a) ICC was 38.1% and was more frequent in T-lineage ALL. Overall survival (OS) and event-free survival (EFS) were significantly higher in patients with positive p16(INK4a) ICC than in patients with negative ICC (6 years OS, 90% versus 63%, P =.0014; 6 years EFS, 77.8% versus 55%, P =.0033). The p16(INK4a) ICC remained a significant prognostic factor within the subgroup of B-precursor ALL. Multivariate analysis showed that negative p16(INK4a) ICC was an independent prognostic factor for OS (relative risk [RR], 3.38; P =.02) and EFS (RR, 2.49; P =.018). Sequential study showed that p16(INK4a) expression remained stable during first relapse in most patients. These findings indicate that p16(INK4a) ICC is an independent factor of outcome in childhood ALL.

Adolescent↗
PubMed2002

[Prognostic factors in myelodysplasia syndromes].

Large studies have shown that, in MDS, main prognostic factors for survival and progression to AML were the percentage of bone marrow blasts, the number and importance of cytopenias, and the presence of cytogenetic abnormalities. The combination of those 3 factors has yielded an International Prognostic Scoring System (IPSS), with very strong prognostic value for survival and progression to AML, which can therefore be used as a guideline for therapeutic choices. Other important prognostic factors can be derived from molecular studies. They include ras genes mutations, p53 mutations and p15 hypermethylation, but their independent prognostic value remains uncertain.

Humans↗
PubMed2002

Acquired trisomy 21 and distinct clonal evolution in acute megakaryoblastic leukaemia in young monozygotic twins.

An intrauterine origin of childhood acute lymphoblastic leukaemia (ALL) was proven by the identical clonotypic gene rearrangement in the concordant leukaemias of monozygotic twins, arising from a single clonogenic progeny. The monozygotic twins, presented at the age of 22 months with acute megakaryoblastic leukaemia (AML-M7) in one and myelodysplasia transformed to AML-M7 in the other. Leukaemic cells in both twins carried trisomy 21 and additional different clonal evolution changes of del(20q) in the first twin and trisomy 8 in the second. AML-M7 of late infancy with trisomy 21 may be included in the leukaemias of intrauterine origin, possibly a result of genotoxic insult.

Cytogenetic Analysis↗
PubMed2002

Established practice in the treatment of patients with acute promyleocytic leukemia and the introduction of arsenic trioxide as a novel therapy.

First-line therapy for patients with newly diagnosed acute promyelocytic leukemia (APL) has been established in a series of randomized clinical trials. Remission induction and consolidation are based on the differentiation agent, all-trans retinoic acid (ATRA), and anthracycline-based chemotherapy. Maintenance therapy is also based on ATRA and may involve additional chemotherapy. Established protocols are associated with a high rate of complete responses (CRs) (87% to 97%), and long-term follow-up has indicated a 4-year disease-free survival of greater than 60%. Therapy for patients who relapse or are refractory to ATRA-based regimens is not standardized and there is a need for new approaches. Arsenic trioxide (ATO) has recently been licensed for use in patients with relapsed/refractory APL. Controlled clinical trials have indicated that ATO is associated with a CR rate of 87% in this population. This agent has a manageable toxicity profile and presents a welcome option for patients with relapsed disease for whom other, more debilitating therapies are unsuitable. Several prognostic factors have been defined in patients with APL, and it is possible that novel treatments such as ATO should be differentially applied to specific prognostic groups.

Antineoplastic Agents↗
PubMed2002

Primary central nervous system lymphoma in immunocompetent adults: poor results mainly associated with high treatment related toxicities.

Treatment of primary central nervous system lymphoma (PCNSL) occurring in immunocompetent patients remains controversial but long-term survival has been reported in patients treated by chemotherapy regimens containing non-lipophilic drugs. We report 34 consecutive PCNSL patients treated at our institution by a chemotherapy regimen that combined drugs crossing and not crossing the blood-brain barrier. Early toxicity was high as 10 of 17 deaths that occurred within the first year of diagnosis were treatment related. Infections and thromboembolism were the main causes of toxicity. We concluded that the use of drugs of uncertain efficacy in these particularly fragile patients is questionable.

Aged↗
PubMed2001

Chromosome and molecular abnormalities in myelodysplastic syndromes.

Cytogenetic abnormalities are seen in approximately 50% of cases of myelodysplastic syndrome (MDS) and 80% of cases of secondary MDS (following chemotherapy or radiotherapy). These abnormalities generally consist of partial or complete chromosome deletion or addition (del5q, -7, +8, -Y, del20q), whereas balanced or unbalanced translocations are rarely found in MDS. Fluorescence hybridization techniques (fluorescence in situ hybridization [FISH], multiplex FISH, and spectral karyotyping) are useful in detecting chromosomal anomalies in cases in which few mitoses are obtained or rearrangements are complex. Ras mutations are the molecular abnormalities most frequently found in MDS, followed by p15 gene hypermethylation, FLT3 duplications, and p53 mutations, but none of these abnormalities are specific for MDS. The rare cases of balanced translocations in MDS have allowed the identification of genes whose rearrangements appear to play a role in the pathogenesis of some cases of MDS. These genes include MDS1-EVI1 in t(3;3) or t(3;21) translocations, TEL in t(5;12), HIP1 in t(5;7), MLF1 in t(3;5), and MEL1 in t(1;3). Genes more frequently implicated in the pathogenesis of MDS cases, such as those involving del5q, remain unknown, although some candidate genes are currently being studied. Cytogenetic and known molecular abnormalities generally carry a poor prognosis in MDS and can be incorporated into prognostic scoring systems such as the International Prognostic Scoring System.

Chromosome Aberrations↗