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2.
Haematologica ; 2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-30076173

RESUMO

The randomized, phase 3 ALFA-0701 trial showed that a reduced and fractionated dose of gemtuzumab ozogamicin added to standard front-line chemotherapy significantly improves event-free survival in adults with de novo acute myeloid leukemia. Here we report an independent review of event-free survival, final overall survival, and additional safety results from ALFA-0701. Patients (N=271) aged 50-70 years with de novo acute myeloid leukemia were randomized to receive conventional front-line induction chemotherapy (3+7 daunorubicin+cytarabine) with/without gemtuzumab ozogamicin 3 mg/m2 on days 1, 4, and 7 during induction. Patients in remission following induction therapy received 2 courses of consolidation therapy (daunorubicin+cytarabine) with/without gemtuzumab ozogamicin (3 mg/2;/day on day 1) according to their initial randomization. The primary endpoint was investigator-assessed event-free survival. Secondary endpoints included overall survival and safety. A blinded independent review confirmed the investigator-assessed event-free survival results (August 1, 2011; hazard ratio, 0.66 [95% CI, 0.49-0.89]; 2-sided p=0.006), corresponding to a 34% reduction in risk of events in the gemtuzumab ozogamicin versus control arm. Final overall survival (April 30, 2013) favored gemtuzumab ozogamicin but was not significant. No differences were observed between arms in early death rate. The main toxicity associated with gemtuzumab ozogamicin was prolonged thrombocytopenia. Veno-occlusive disease (including after transplant) was observed in 6 patients in the gemtuzumab ozogamicin arm and 2 in the control arm. In conclusion, gemtuzumab ozogamicin added to standard intensive chemotherapy has a favorable benefit/risk ratio. These results expand front-line treatment options for adult patients with previously untreated acute myeloid leukemia. (ClinicalTrials.gov identifier: NCT00927498).

3.
Haematologica ; 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30026341

RESUMO

In standard risk acute promyelocytic leukemia, recent results have shown that ATRA + Arsenic trioxide combinations were at least as effective as classical ATRA + anthracycline based chemotherapy while being less myelosuppressive. However, the role of frontline arsenic trioxide is less clear in higher risk acute promyelocytic leukemia, and access to arsenic remains limited for frontline treatment of standard risk acute promyelocytic leukemia in many countries. In this randomized trial, we compared for consolidation treatment (after ATRA-Chemotherapy induction treatment) arsenic, ATRA and the classical AraC in standard risk acute promyelocytic leukemia, and evaluated the addition of arsenic during consolidation in higher risk APL. Newly diagnosed acute promyelocytic leukemia patients with white blood cells < 10 G/L, after an induction treatment consisting of ATRA plus Idarubicin-AraC, received consolidation chemotherapy with Idarubicin and AraC, arsenic or ATRA. Patients with white blood cells >10G received consolidation chemotherapy with arsenic or without arsenic.795 acute promyelocytic leukemia patients were enrolled in this trial. In Standard risk APL (n= 581), 5-year EFS from randomization was 88.7%, 95.7% and 85.4% in the AraC, arsenic and ATRA consolidation groups, respectively (p=0.0067) and 5 year cumulative incidence of relapse (CIR) was 5.5%, 0% and 8.2%. (p=0.001). In higher risk APL (n=214), 5-year EFS was 85.5% vs 92.1% (p=0.38) in the chemotherapy and chemotherapy+ arsenic groups, respectively and 5-year CIR of 4.6% and 3.5% (p= 0.99) in the chemotherapy and chemotherapy+ arsenic groups. Due to prolonged myelosuppression in the chemotherapy+ arsenic arm, an amendment excluded AraC during consolidation cycles in the chemotherapy+ arsenic group, resulting in no increase in relapse. Our results therefore advocate systematic introduction of arsenic in the first line treatment of acute promyelocytic leukemia, but probably not concomitantly with intensive chemotherapy, a situation where we found myelosuppression to be significant. (ClinicalTrials.gov Identifier: NCT00378365).

4.
Leuk Lymphoma ; 59(5): 1113-1120, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28838276

RESUMO

Azacitidine (AZA) prolonged overall survival (OS) in the AZA-AML-001 trial. However, few subjects were randomized to AZA or intensive chemotherapy (IC). The Medical Research Council (MRC) and the Leukemia Research Foundation (LRF) developed a score for older AML patients receiving IC or non-intensive regimens, whereas the E-ALMA study validated a score for survival and response in elderly patients receiving AZA in daily practice. Both identified three groups with different risk estimates. This analysis evaluates the efficacy of frontline AZA in older AML patients (N = 710) unfit for IC from different national registries (E-ALMA + series) stratified by the MRC/LRF risk score. Median OS of patients categorized as good, standard and poor-risk groups by the MRC/LRF score was 13.4 (95% CI, 10.8-16), 12.4 (95% CI, 9.9-14.8), and 8.1 months (95% CI, 7-9.1), respectively (p = .0001). In conclusion, this is the largest retrospective cohort of older AML patients treated with AZA.

5.
Expert Opin Investig Drugs ; 26(7): 803-811, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28541716

RESUMO

INTRODUCTION: Acute myelogenous leukemia (AML) is a heterogeneous group of malignancies driven by genetic mutations and deregulated epigenetic control. Relapse/refractory disease remains frequent in younger patients and even more so in older patients, including treatment with epigenetic drugs in this age group, mainly with hypomethylating agents. New treatment strategies are urgently needed. The recent discovery that epigenetic readers of the bromodomain (BRD) and extraterminal (BET) protein family, are crucial for AML maintenance by transcription of oncogenic c-MYC lead to rapid development of BET inhibitors entering clinical trials. Areas covered: We provide a critical overview using main sources for the use of BET inhibitors in AML treatment. Limits of this treatment approach including resistance mechanisms and future directions including development of new generation BET inhibitors and combination strategies with other drugs are detailed. Expert opinion: BET inhibitors were expected to overcome limits of conventional treatment in patients as impressive in vitro data emerged recently in well-characterized AML subsets, including those associated with poor risk characteristics in the clinic. Nevertheless single activity of BET inhibitors appears to be modest and resistance mechanisms were already identified. BET inhibitors with alternative mechanisms of action and/or combination strategies with epigenetic drugs should be tested.


Assuntos
Antineoplásicos/farmacologia , Drogas em Investigação/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Desenho de Drogas , Resistencia a Medicamentos Antineoplásicos , Epigênese Genética , Humanos , Leucemia Mieloide Aguda/patologia , Proteínas Nucleares/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas de Ligação a RNA/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores
6.
Curr Hematol Malig Rep ; 12(1): 1-10, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28286907

RESUMO

Acute myeloid leukemia (AML) is predominantly a disease of older adults associated with poor long-term outcomes with available therapies. Used as single agents, hypomethylating agents (HMAs) induce only 15 to 25% complete remissions, but current data suggest that median OS observed after HMAs is comparable to that observed after more intensive therapies. Whether long-term cure may be obtained in some patients treated with HMAs is unknown. Combinations of HMAs to novel agents are now extensively investigated and attractive response rates have been reported when combining HMAs to different drug classes. The absence of reliable predictive biomarkers of efficacy of HMAs in AML and the uncertainties regarding their most relevant mechanisms of action hinder the rational design of the combinations to be tested in priority, usually in untreated older AML patients.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Metilação de DNA , Decitabina , Quimioterapia Combinada , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Leucemia Mieloide Aguda/genética
7.
Haematologica ; 102(4): 728-735, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28034993

RESUMO

Patients with acute myeloblastic leukemia or higher risk myelodysplastic syndromes with 5q deletion (generally within a complex karyotype) respond poorly to intensive chemotherapy and have very poor survival. In this population, we evaluated escalating doses of lenalidomide combined with intensive chemotherapy in a phase II study. Treatment consisted of daunorubicin (45 mg/m2/day, days 1-3 in cohort 1, escalated to 60 mg/m2/day, days 1-3 in cohorts 2 and 3) combined with cytosine arabinoside (200 mg/m2/day, days 1-7) and lenalidomide (10 mg/day, days 1-21 in cohorts 1 and 2, escalated to 25 mg/day, days 1-21 in cohort 3). Eighty-two patients with 5q deletion were enrolled, including 62 with acute myeloblastic leukemia, 62/79 (78%) of whom had a complex karyotype (median 7 cytogenetic abnormalities, all but 2 of them monosomal) and three had unknown karyotypes. Thirty-eight patients (46%) achieved complete remission and the overall response rate was 58.5%. Among the 62 patients with a complex karyotype, 27 achieved complete remission (44%) and 21 had cytogenetic responses. A lower response rate was observed in patients with acute myeloblastic leukemia but other pretreatment factors, including cytogenetic complexity and treatment cohort, did not significantly influence response. Fifteen patients underwent allogeneic stem cell transplantation, including 11 patients in first remission. The 1-year cumulative incidence of relapse was 64.6% and the median overall survival was 8.2 months. By comparison with conventional intensive chemotherapy, the treatment protocol we used appeared to produce higher hematologic and cytogenetic complete remission rates in patients with very poor cytogenetics, but response duration was short in this very poor risk population, highlighting the need for better post-induction strategies. Clinical trial registry number: NCT00885508.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Deleção Cromossômica , Cromossomos Humanos Par 5 , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Lenalidomida , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Prognóstico , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Resultado do Tratamento
8.
J Clin Pathol ; 69(10): 933-7, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27484914

RESUMO

The reaction of Hector Battifora mesothelial epitope-1 (HBME-1) antibody with scattered pronormoblasts in normal bone marrow core biopsy specimens has been reported. This study evaluated the immunohistochemical profile of HBME-1 in a panel of 52 normal, dyserythropoietic and neoplastic marrow samples. We compared the staining property of HBME-1 with that of the commonly used erythroid marker, glycophorin A (CD235a) and in each case, we semi-quantitatively evaluated the HBME-1/CD235a-positive cells ratio. In normal samples, HBME-1 labelled scattered immature erythroid precursors. In dyserythropoietic specimens, HBME-1 stained nucleated erythroid precursors in varying degrees, from pronormoblast through normoblast stages, with the highest intensity in immature forms. Overall, the cellular background of non-erythroid progenitors, erythrocytes and neoplastic cells did not react with HBME-1, except in leukaemia cases with myelodysplasia-related changes. Our study shows that HBME-1 is a useful marker to identify immature erythroid precursors and that an HBME-1/CD235a-positive cells ratio ≥10% is associated with dyserythropoiesis.


Assuntos
Biomarcadores Tumorais/metabolismo , Medula Óssea/patologia , Células Precursoras Eritroides/metabolismo , Síndromes Mielodisplásicas/metabolismo , Anticorpos Monoclonais/imunologia , Biomarcadores Tumorais/imunologia , Biópsia com Agulha de Grande Calibre , Células Precursoras Eritroides/imunologia , Células Precursoras Eritroides/patologia , Glicoforina/metabolismo , Humanos , Síndromes Mielodisplásicas/diagnóstico , Estudos Retrospectivos
9.
Leuk Res ; 47: 136-41, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27337291

RESUMO

We wanted to describe the characteristics, treatment and outcome of autoimmune and inflammatory diseases (SAIDs) associated with chronic myelomonocytic leukemia (CMML), and conducted a French multicenter retrospective study and a literature review. We included 26 cases of CMML (median age 75 years, 54% female), 80% with CMML-1. CPSS score was low (0 or 1) in 75% of cases. SAIDS was systemic vasculitis in 54%. Diagnosis of the 2 diseases was concomitant in 31% cases, and CMML was diagnosed before SAIDs in 12 cases (46%). First line treatment for SAIDs consisted mostly of steroid, with 85% of response. Second-line treatment was needed in 40% cases. Six patients received hypomethylating agents, with 66% response on SAIDs. A literature review found 49 cases of CMML-associated SAIDs, in whom SAIDs was systemic vasculitis in 29% cases. Hence, vasculitis is the most frequent SAIDs associated with CMML. After initial response to steroids, recurrence and steroid-dependence were frequent. Hypomethylating agents may be interesting in this context.


Assuntos
Leucemia Mielomonocítica Crônica/complicações , Idoso , Doenças Autoimunes/tratamento farmacológico , Feminino , França , Humanos , Imunossupressores/uso terapêutico , Inflamação/tratamento farmacológico , Masculino , Estudos Retrospectivos , Esteroides/uso terapêutico , Inquéritos e Questionários , Vasculite
10.
Haematologica ; 101(8): 918-25, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27229713

RESUMO

The efficacy of azacitidine in patients with anemia and with lower-risk myelodysplastic syndromes, if relapsing after or resistant to erythropoietic stimulating agents, and the benefit of combining these agents to azacitidine in this setting are not well known. We prospectively compared the outcomes of patients, all of them having the characteristics of this subset of lower-risk myelodysplastic syndrome, if randomly treated with azacitidine alone or azacitidine combined with epoetin-ß. High-resolution cytogenetics and gene mutation analysis were performed at entry. The primary study endpoint was the achievement of red blood cell transfusion independence after six cycles. Ninety-eight patients were randomised (49 in each arm). Median age was 72 years. In an intention to treat analysis, transfusion independence was obtained after 6 cycles in 16.3% versus 14.3% of patients in the azacitidine and azacitidine plus epoetin-ß arms, respectively (P=1.00). Overall erythroid response rate (minor and major responses according to IWG 2000 criteria) was 34.7% vs. 24.5% in the azacitidine and azacitidine plus epoetin-ß arms, respectively (P=0.38). Mutations of the SF3B1 gene were the only ones associated with a significant erythroid response, 29/59 (49%) versus 6/27 (22%) in SF3B1 mutated and unmutated patients, respectively, P=0.02. Detection of at least one "epigenetic mutation" and of an abnormal single nucleotide polymorphism array profile were the only factors associated with significantly poorer overall survival by multivariate analysis. The transfusion independence rate observed with azacitidine in this lower-risk population, but resistant to erythropoietic stimulating agents, was lower than expected, with no observed benefit of added epoetin, (clinicaltrials.gov identifier: 01015352).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/uso terapêutico , Resistência a Medicamentos , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Azacitidina/administração & dosagem , Biomarcadores , Análise Citogenética , Análise Mutacional de DNA , Eritropoetina/administração & dosagem , Feminino , Hematínicos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Polimorfismo de Nucleotídeo Único , Proteínas Recombinantes/administração & dosagem , Análise de Sobrevida , Resultado do Tratamento
11.
Leuk Res ; 43: 13-7, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26922775

RESUMO

This retrospective study describes efficacy of Azacitidine on autoimmune disorders (AID) associated with MDS/CMML in 22 patients. Response of AID to Azacitidine was observed in 19 patients (86%). Reduction or discontinuation of steroids and/or immunosuppressive therapy (IST) was possible in 16 cases (73%). Hematologic response was seen in 55% of the patients. MDS/CMML and AID evolution was concordant in 13 cases (59%): both favorable (n=11), both unfavorable (n=2), but AID improved while MDS/CMML worsened (n=8) and vice versa (n=1). Azacitidine frequently seems effective in controlling steroid-dependent AID associated with MDS/CMML, but prospective studies are necessary to confirm those findings.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Azacitidina/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Azacitidina/efeitos adversos , Feminino , Humanos , Inflamação/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
12.
Clin Lymphoma Myeloma Leuk ; 16(3): 169-74, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26795084

RESUMO

BACKGROUND: Monitoring renal function is important in imatinib-treated patients with chronic myeloid leukemia because serum creatinine may increase during the course of therapy. The mechanism of this increase and its reversibility on treatment cessation have never been investigated. PATIENTS AND METHODS: We retrospectively analyzed data from imatinib-treated patients explored in our renal physiology unit with measurement of glomerular filtration rate (urinary clearance of (51)CrEDTA) and of urinary clearance and tubular secretion of creatinine. Results were compared with those of controls matched for measured glomerular filtration rate, age, gender, and ethnicity. We also analyzed variations of serum creatinine before and during imatinib cessation and after imatinib resumption in patients enrolled in imatinib discontinuation studies. RESULTS: In 4 imatinib-treated patients who underwent thorough renal exploration, the part of creatinine clearance due to tubular secretion was negligible (2.4, 3.1, -1.3, and 2.8 mL/min) and significantly lower than that measured in their respective controls (17.7 ± 5.6, 43.0 ± 18.0, 23.1 ± 6.7, and 18.6 ± 5.6 mL/min, P < .001). In 1 patient, exploration was repeated after imatinib discontinuation and evidenced a recovery of creatinine tubular secretion (20.3 vs. 17.9 ± 5.2 mL/min in the control population, P = .2). In 15 patients of imatinib discontinuation studies, a median decrease in serum creatinine of 17.9% was observed after imatinib cessation. Resumption of treatment in 6 patients led to a median increase in serum creatinine of 18.8%. CONCLUSIONS: Imatinib completely blunts tubular secretion of creatinine, a previously unreported pharmacologic property. This inhibition increases serum creatinine independently of any glomerular dysfunction and is fully reversible on imatinib cessation.


Assuntos
Antineoplásicos/uso terapêutico , Creatinina/sangue , Mesilato de Imatinib/uso terapêutico , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/farmacologia , Estudos de Casos e Controles , Substituição de Medicamentos , Feminino , Taxa de Filtração Glomerular , Humanos , Mesilato de Imatinib/farmacologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
13.
Blood ; 127(1): 53-61, 2016 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-26660429

RESUMO

Recent advances in acute myeloid leukemia (AML) biology and its genetic landscape should ultimately lead to more subset-specific AML therapies, ideally tailored to each patient's disease. Although a growing number of distinct AML subsets have been increasingly characterized, patient management has remained disappointingly uniform. If one excludes acute promyelocytic leukemia, current AML management still relies largely on intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), at least in younger patients who can tolerate such intensive treatments. Nevertheless, progress has been made, notably in terms of standard drug dose intensification and safer allogeneic HSCT procedures, allowing a larger proportion of patients to achieve durable remission. In addition, improved identification of patients at relatively low risk of relapse should limit their undue exposure to the risks of HSCT in first remission. The role of new effective agents, such as purine analogs or gemtuzumab ozogamicin, is still under investigation, whereas promising new targeted agents are under clinical development. In contrast, minimal advances have been made for patients unable to tolerate intensive treatment, mostly representing older patients. The availability of hypomethylating agents likely represents an encouraging first step for this latter population, and it is hoped will allow for more efficient combinations with novel agents.


Assuntos
Leucemia Mieloide Aguda/terapia , Terapia de Alvo Molecular , Adulto , Terapia Combinada , Humanos , Prognóstico
14.
Rheumatology (Oxford) ; 55(2): 291-300, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26350487

RESUMO

OBJECTIVE: We describe myelodysplastic syndrome (MDS)-associated systemic inflammatory and autoimmune diseases (SIADs), their treatments and outcomes and the impact of SIADs on overall survival in a French multicentre retrospective study. METHODS: In this study, 123 patients with MDS and SIADs were analysed. RESULTS: Mean age was 70 years (s.d. 13) and the male:female ratio was 2. The SIADs were systemic vasculitis in 39 (32%) cases, CTD in 31 (25%) cases, inflammatory arthritis in 28 (23%) cases, a neutrophilic disorder in 12 (10%) cases and unclassified in 13 cases (11%). The SIADs fulfilled the usual classification criteria in 75 (66%) cases, while complete criteria were not reached in 21 (19%) cases. A significant association was shown between chronic myelomonocytic leukaemia (CMML) and systemic vasculitis (P = 0.0024). One hundred and eighteen (96%) SIAD patients were treated (91% with steroids), with an 83% response to first-line treatment, including 80% for steroids alone. A second-line treatment for SIADs was required for steroid dependence or relapse in 48% of cases. The effect of MDS treatment on SIADs could be assessed in 11 patients treated with azacytidine and SIAD response was achieved in 9/11 (80%) and 6/11 (55%) patients at 3 and 6 months, respectively. Compared with 665 MDS/CMML patients without SIADs, MDS/CMML patients with SIADs were younger (P < 0.01), male (P = 0.03), less often had refractory anaemia with ring sideroblasts (P < 0.01), more often had a poor karyotype (16% vs 11%, P = 0.04) and less frequently belonged to low and intermediate-1 International Prognostic Scoring System categories, but no survival difference was seen between patients with MDS-associated SIADs and without SIADs (P = 0.5). CONCLUSION: The spectrum of SIADs associated to MDS is heterogeneous, steroid sensitive, but often steroid dependent.


Assuntos
Autoimunidade/imunologia , Azacitidina/uso terapêutico , Glucocorticoides/uso terapêutico , Inflamação/imunologia , Leucemia Mielomonocítica Crônica/imunologia , Síndromes Mielodisplásicas/imunologia , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Quimioterapia Combinada , Feminino , Seguimentos , França , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Leucemia Mielomonocítica Crônica/complicações , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Masculino , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Prognóstico , Estudos Retrospectivos
15.
Oncotarget ; 6(39): 42345-53, 2015 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-26486081

RESUMO

Acute myeloid leukemia (AML) is a heterogeneous disease. Even within the same NPM1-mutated genetic subgroup, some patients harbor additional mutations in FLT3, IDH1/2, DNMT3A or TET2. Recent studies have shown the prognostic significance of minimal residual disease (MRD) in AML but it remains to be determined which molecular markers are the most suitable for MRD monitoring. Recent advances in next-generation sequencing (NGS) have provided the opportunity to use multiple molecular markers. In this study, we used NGS technology to assess MRD in 31 AML patients enrolled in the ALFA-0701 trial and harboring NPM1 mutations associated to IDH1/2 or DNMT3A mutations. NPM1 mutation-based MRD monitoring was performed by RTqPCR. IDH1/2 and DNMT3A mutations were quantified by NGS using an Ion Torrent Proton instrument with high coverage (2 million reads per sample). The monitoringof IDH1/2 mutations showed that these mutations were reliable MRD markers that allowed the prediction of relapse in the majority of patients. Moreover, IDH1/2 mutation status predicted relapse or disease evolution in 100% of cases if we included the patient who developed myelodysplastic syndrome. In contrast, DNMT3A mutations were not correlated to the disease status, as we found that a preleukemic clone with DNMT3A mutation persisted in 40% of the patients who were in complete remission, reflecting the persistence of clonal hematopoiesis.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Isocitrato Desidrogenase/genética , Leucemia Mieloide/genética , Mutação , Neoplasia Residual/genética , Doença Aguda , Adulto , Idoso , Biomarcadores Tumorais/genética , França , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Leucemia Mieloide/diagnóstico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasia Residual/diagnóstico , Proteínas Nucleares/genética , Prognóstico , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Adulto Jovem
16.
Am J Hematol ; 90(8): 737-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26017030

RESUMO

Acquired α-thalassemia myelodysplastic syndrome (MDS) (ATMDS) is an acquired syndrome characterized by a somatic point mutation or splicing defect in the ATRX gene in patients with myeloid disorders, primarily MDS. In a large MDS patient series, the incidence of ATMDS was below 0.5%. But no large series has yet assessed the incidence of ATMDS in microcytic MDS. In this study, we focused on patients with MDS and unexplained microcytosis, which was defined as absence of iron deficiency, inflammatory disease, or history of inherited hemoglobinopathy. Our data confirm the low frequency of ATRX mutations in MDS: 0% in an unselected clinical trial cohort of 80 low risk MDS, 0.2-0.8% in a multicenter registry of 2,980 MDS and 43% of MDS with unexplained microcytosis in this same registry. In addition, we reported four novel mutations of the ATRX gene in ATMDS. This study further determines the frequency of ATRX mutations and highlights the importance of microcytosis to detect ATRX mutations within MDS patients.


Assuntos
DNA Helicases/genética , Células-Tronco Hematopoéticas/patologia , Taxa de Mutação , Síndromes Mielodisplásicas/genética , Proteínas Nucleares/genética , Talassemia alfa/genética , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Humanos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Análise de Sobrevida , Proteína Nuclear Ligada ao X , Talassemia alfa/metabolismo , Talassemia alfa/mortalidade , Talassemia alfa/patologia
17.
Oncotarget ; 6(19): 17698-712, 2015 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-25989842

RESUMO

The bromodomain (BRD) and extraterminal (BET) proteins including BRD2, BRD3 and BRD4 have been identified as key targets for leukemia maintenance. A novel oral inhibitor of BRD2/3/4, the thienotriazolodiazepine compound OTX015, suitable for human use, is available. Here we report its biological effects in AML and ALL cell lines and leukemic samples. Exposure to OTX015 lead to cell growth inhibition, cell cycle arrest and apoptosis at submicromolar concentrations in acute leukemia cell lines and patient-derived leukemic cells, as described with the canonical JQ1 BET inhibitor. Treatment with JQ1 and OTX15 induces similar gene expression profiles in sensitive cell lines, including a c-MYC decrease and an HEXIM1 increase. OTX015 exposure also induced a strong decrease of BRD2, BRD4 and c-MYC and increase of HEXIM1 proteins, while BRD3 expression was unchanged. c-MYC, BRD2, BRD3, BRD4 and HEXIM1 mRNA levels did not correlate however with viability following exposure to OTX015. Sequential combinations of OTX015 with other epigenetic modifying drugs, panobinostat and azacitidine have a synergic effect on growth of the KASUMI cell line. Our results indicate that OTX015 and JQ1 have similar biological effects in leukemic cells, supporting OTX015 evaluation in a Phase Ib trial in relapsed/refractory leukemia patients.


Assuntos
Acetanilidas/farmacologia , Antineoplásicos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Leucemia/patologia , Proteínas Nucleares/biossíntese , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Proto-Oncogênicas c-myc/biossíntese , Fatores de Transcrição/biossíntese , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Imunofluorescência , Humanos , Immunoblotting , Masculino , Proteínas Nucleares/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/efeitos dos fármacos , Proteínas de Ligação a RNA/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição/efeitos dos fármacos , Transcriptoma
18.
Leuk Res ; 39(5): 501-4, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25735917

RESUMO

Outcome of patients with high risk MDS and CMML who failed treatment with azacitidine remains poor with a median survival of 6 months, without established therapy available except allogeneic hematopoietic stem cell transplantation. The objective of our study was to evaluate efficacy of decitabine after azacitidine failure in a relatively large patient cohort based on conflicting results with 0-28% response rates (RR) in this setting in small patient series. Thirty-six consecutive high risk MDS and CMML patients who received decitabine after azacitidine failure were retrospectively reviewed. Response was based on IWG 2006 criteria for MDS and CMML with WBC<13G/l and also included for proliferative CMML the evolution of WBC, splenomegaly (SMG) and extramedullary disease (EMD). Patients received a median number of 3 (range 1-27) cycles of decitabine and 12 patients received at least 6 cycles. Seven (19.4%) patients were responders including 3 marrow CR (mCR), 2 stable disease (SD) with HI-E, 1 SD with HI-N and HI-P and 1 SD with HI-N. In a CMML patient with SD, specific skin lesions resolved with decitabine. Responses were generally short lived (2-5 months) except 1 responder currently ongoing with +11 months follow up. Two non-responders had prolonged SD (without HI) of 21 and 27 months duration respectively. Median OS from onset of decitabine was 7.3 months, without significant difference between responders and non-responders. Treatment with decitabine after azacitidine failure yielded modest ORR (19.4%) with short response duration and poor OS. Thus, use of decitabine in such patients who failed or progressed after azacitidine cannot be recommended, underscoring the need for novel strategies in this setting.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Decitabina , Progressão da Doença , Feminino , Humanos , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/epidemiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/epidemiologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Falha de Tratamento , Resultado do Tratamento
20.
Leuk Res ; 39(2): 124-30, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25524177

RESUMO

The prognosis of patients older than 50 with relapsed or refractory AML is dismal. Azacitidine has been investigated in older AML patients. Here we report the outcome of 130 patients older than 50 years included in a multicenter patient named program of azacitidine after relapse (n=67) or induction failure (n=63) of intensive chemotherapy. Median age was 67 years, cytogenetic risk was high in 28% and performance status ≥2 in 15% of cases. Most (72%) patients received azacitidine at the standard schedule (75mg/m(2)/d, 7 days/month) for a median of 4 courses. The overall response rate was 17% (CR: 10%, CRi: 7%). Median overall survival was 8.4 months. Achievement of CR/CRi was associated with prolonged survival (P=0.0001), whereas hematological improvement according to MDS criteria, achieved in 36% of patients with resistant disease, did not improve survival. In multivariate analysis, high risk cytogenetics (P=0.022) and peripheral blasts >10% (P<0.0001) at onset of azacitidine were independently predictive of poor prognosis. Combining these two factors, we identified a subgroup of 48% of patients with intermediate risk cytogenetics and peripheral blasts ≤10% and a median OS of 11.3 months. These results warrant further investigation of azacitidine-based regimens in this subgroup of patients.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Azacitidina/administração & dosagem , Crise Blástica/tratamento farmacológico , Crise Blástica/mortalidade , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
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