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1.
Haematologica ; 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31004014

RESUMO

Acute myeloid leukemia with t(6;9)(p22;q34) is a distinct entity accounting for 1-2% of acute myeloid leukemia cases. A substantial proportion of these patients have a concomitant FLT3-ITD. While outcomes are dismal with intensive chemotherapy, limited evidence suggests allogeneic hematopoietic cell transplantation may improve survival if applied early during first complete remission. We report on a cohort of 178 patients with t(6;9)(p22;q34) within an international, multicenter collaboration. Median age was 46 (range: 16-76) years, acute myeloid leukemia was de novo in 88%, FLT3-ITD was present in 62%, and additional cytogenetic abnormalities in 21%. Complete remission was achieved in 81% (n=144), including 14 patients who received high-dose cytarabine after initial induction failure. With a median follow-up of 5.43 years, estimated overall survival at 5 years was 38% (95%-CI, 31-47%). Allogeneic hematopoietic cell transplantation was performed in 117 (66%) patients, including 89 in first complete remission. Allogeneic hematopoietic cell transplantation in first complete remission was associated with higher 5-year relapse-free and overall survival as compared to consolidation chemotherapy (45% [95%-CI, 35-59%] and 53% [95%-CI, 42-66%], vs. 7% [95%-CI, 3-19%] and 23% [95%-CI, 13-38%]. For patients undergoing allogeneic hematopoietic cell transplantation, overall survival rates at 5 years did not differ whether performed in first (53% [95%-CI, 42-66%]), or second complete remission (58% [95%-CI, 31-100%]; n=10) or with active disease/relapse (54% [95%-CI, 34-84%]; n=18) (P=0.67). Neither FLT3-ITD nor additional chromosomal abnormalities impacted survival. In conclusion, outcomes of t(6;9)(p22;q34) acute myeloid leukemias are poor with chemotherapy, and can be substantially improved with allogeneic hematopoietic cell transplantation.

2.
Leukemia ; 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30967620

RESUMO

Older adults with acute myeloid leukemia (AML) who are not fit for standard chemotherapy historically have poor outcomes. Approximately 12-15% of older patients with AML harbor isocitrate dehydrogenase 2 (IDH2) gene mutations. Enasidenib is an oral inhibitor of mutant IDH2 proteins. Among 39 patients with newly diagnosed mutant-IDH2 AML who received enasidenib monotherapy in this phase I/II trial, median age was 77 years (range 58-87) and 23 patients (59%) had had an antecedent hematologic disorder. The median number of enasidenib treatment cycles was 6.0 (range 1-35). The most common treatment-related adverse events were indirect hyperbilirubinemia (31%), nausea (23%), and fatigue, decreased appetite, and rash (18% each). Treatment-related grade 3-4 cytopenias were reported for eight patients (21%); there was no treatment-related grade 3-4 infections. Twelve patients achieved a response (overall response rate 30.8% [95% CI 17.0%, 47.6%]), including seven patients (18%) who attained complete remission. At a median follow-up of 8.4 months, the median duration of any response was not reached (NR). Median overall survival for all patients was 11.3 months (95% CI 5.7, 15.1), and was NR for responders. Oral, outpatient targeted treatment with enasidenib may benefit older adults with newly diagnosed mutant-IDH2 AML who are not candidates for cytotoxic regimens.

4.
Blood ; 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30510081

RESUMO

Approximately 8-19% of patients with acute myeloid leukemia (AML) have isocitrate dehydrogenase-2 (IDH2) mutations, which occur at active site arginine residues, R140 and R172. IDH2 mutations produce an oncometabolite, 2-hydroxyglutarate (2-HG), that leads to DNA and histone hypermethylation and impaired hematopoietic differentiation. Enasidenib is an oral inhibitor of mutant-IDH2 proteins. This first-in-human phase I/II study evaluated enasidenib doses of 50-650 mg/day, administered in continuous 28-day cycles, in patients with mutant-IDH2 hematologic malignancies (ClinicalTrials.gov, NCT01915498). Overall, 214/345 patients (62%) with relapsed/refractory AML received enasidenib 100 mg/day. Median age was 68 years. Forty-two patients (19.6%) attained complete remission (CR), 19 patients (10.3%) proceeded to an allogeneic bone marrow transplant, and overall response rate was 38.8% (95%CI 32.2-45.7). Median overall survival was 8.8 months (95%CI 7.7-9.6). Response and survival were comparable among patients with IDH2-R140 or IDH2-R172 mutations. Response rates were similar among patients who, at study entry, were in relapse (37.7%), or were refractory to intensive (37.5%) or non-intensive (43.2%) therapies. Sixty-six RBC transfusion-dependent (43.1%) and 53 platelet transfusion-dependent (40.2%) patients achieved transfusion independence. The magnitude of 2-HG reduction on-study was associated with CR in IDH2-R172 patients. Clearance of mutant-IDH2 clones was also associated with achievement of CR. Among all 345 patients, the most common grade 3-4 treatment-related adverse events were hyperbilirubinemia (10%), thrombocytopenia (7%), and IDH differentiation syndrome (6%). Enasidenib was well-tolerated and induced molecular remissions and hematologic responses in patients with AML for whom prior treatments had failed. The study is registered to https://clinicaltrials.gov as NCT01915498.

5.
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).

6.
Nat Med ; 24(8): 1167-1177, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30013198

RESUMO

Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clonal structure in cell populations at different stages of differentiation can reveal the response and evolution of clones during treatment response and relapse.

7.
N Engl J Med ; 378(25): 2386-2398, 2018 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-29860938

RESUMO

BACKGROUND: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS: Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS: In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).


Assuntos
Inibidores Enzimáticos/administração & dosagem , Glicina/análogos & derivados , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Piridinas/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Seguimentos , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Hemoglobinas/análise , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Piridinas/efeitos adversos , Piridinas/farmacocinética , Recidiva , Indução de Remissão , Taxa de Sobrevida , Adulto Jovem
8.
ACS Med Chem Lett ; 9(4): 300-305, 2018 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-29670690

RESUMO

Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.

9.
Br J Haematol ; 181(3): 350-359, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29611196

RESUMO

Treatment with azacitidine (AZA) has been suggested to be of benefit for higher-risk myelodysplastic syndrome (HR-MDS) patients with chromosome 7 abnormalities (Abn 7). This retrospective study of 235 HR-MDS patients with Abn 7 treated with AZA (n = 115) versus best supportive care (BSC; n = 120), assessed AZA treatment as a time-varying variable in multivariable analysis. A Cox Regression model with time-interaction terms of overall survival (OS) at different time points confirmed that, while chromosome 7 cytogenetic categories (complex karyotype [CK] versus non-CK) and International Prognostic Scoring System risk (high versus intermediate-2) retained poor prognosis over time, AZA treatment had a favourable impact on OS during the first 3 years of treatment compared to BSC (Hazard ratio [HR] 0·5 P < 0·001 at 1 year, 0·7 P = 0·019 at 2 years; 0·73 P = 0·029 at 3 years). This benefit was present in all chromosome 7 categories, but tended to be greater in patients with CK (risk reduction of 82%, 68% and 53% at 1, 3 and 6 months in CK patients; 79% at 1 month in non-CK patients, P < 0·05 for all). AZA also significantly improved progression-free survival (P < 0·01). This study confirms a time-dependent benefit of AZA on outcome in patients with HR-MDS and cytogenetic abnormalities involving chromosome 7, especially for those with CK.

11.
JAMA Oncol ; 4(8): 1106-1110, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29346478

RESUMO

Importance: Enasidenib mesylate, a mutant isocitrate dehydrogenase 2 (IDH2) protein inhibitor that promotes differentiation of leukemic myeloblasts, was recently approved by the US Food and Drug Administration for use in relapsed/refractory (R/R) mutant IDH2 acute myeloid leukemia (AML). During the first study of enasidenib in humans, a minority of patients with advanced myeloid neoplasms experienced unexpected signs/symptoms of a differentiation syndrome (DS), a potentially lethal entity. Objective: To characterize IDH-inhibitor-associated DS (IDH-DS) and its effective management. Design, Setting, and Participants: Using data obtained from a multicenter, open-label, pivotal phase 1/2 study of enasidenib, a differentiation syndrome review committee retrospectively evaluated potential cases of IDH-DS in enasidenib-treated patients with R/R AML. Data were collected between August 27, 2013, and October 14, 2016. The committee identified and agreed on signs and symptoms characteristic of IDH-DS and developed an algorithm for identification and treatment. Among 281 patients with R/R AML enrolled in the trial, the committee identified 72 patients for review based on investigator-reported cases of DS (n = 33) or reported adverse events or signs and symptoms characteristic of IDH-DS. Interventions: Treatment with enasidenib at a dosage of 50 to 650 mg/d was evaluated during the dose-escalation phase, and a dosage of 100 mg/d was used in the phase 1 expansion and phase 2, all in continual 28-day cycles. Main Outcomes and Measures: Unexpected adverse events of IDH-DS during the phase 1/2 study. Results: Thirty-three of the 281 patients (11.7%) were identified as having possible or probable IDH-DS. Median age of those 33 patients was 70 years (range, 38-80 years); 20 (60.6%) were male. The most frequent manifestations were dyspnea, fever, pulmonary infiltrates, and hypoxia. Median time to onset was 30 days (range, 7-129 days). Patients who experienced IDH-DS were less likely to have less than 20% bone marrow blasts (6% vs 22%, P = .04) and more likely to have undergone fewer previous anticancer regimens (median, 1.0 [range, 1-4] vs 2.0 [range, 1-14], P = .05) at study entry than those who did not. Thirteen patients (39.4%) had concomitant leukocytosis. Isocitrate dehydrogenase differentiation syndrome was effectively managed with systemic corticosteroids. The enasidenib regimen was interrupted for 15 patients (45.5%), but permanent discontinuation of treatment was not required. Conclusions and Relevance: Isocitrate dehydrogenase differentiation syndrome is a recognizable and potentially lethal clinical entity, occurring in approximately 12% of enasidenib-treated patients with mutant-IDH2 R/R AML. It requires prompt recognition and management. As use of mutant IDH inhibitors increases, these findings and recommendations are increasingly germane to care of patients with mutant-IDH neoplasms. Trial Registration: clinicaltrials.gov Identifier: NCT01915498.

13.
Leuk Lymphoma ; 59(7): 1659-1665, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29179634

RESUMO

Although the tyrosine kinase inhibitor (TKI) era has brought great improvement in outcome in chronic myelogenous leukemia (CML), prognosis of accelerated phase or myeloid blast crisis patients or of de novo Philadelphia chromosome-positive acute myeloid leukemia remains poor. We conducted a retrospective study on patients with advanced phase disease treated with a TKI and azacytidine. Sixteen patients were eligible. Median age was 64.9 years, the median number of previous therapies was 2.5 lines, and median follow-up was 23.1 months. Hematologic response (HR) rate was 81.3%. Median overall survival (OS), event free survival and relapse-free survival (RFS) were 31.5, 23.3, and 32.2 months, respectively. All except one patient were treated as out-patients after the first cycle. Five patients were bridged to allogenic hematopoietic stem cells transplant. The combination of a TKI and azacytidine is a safe and efficient regiment for patients with CML patients in advanced phases.

14.
Sci Rep ; 7(1): 7305, 2017 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-28779088

RESUMO

The chemokine receptor CXCR4 mediates cell anchorage in the bone marrow (BM) microenvironment and is overexpressed in 25-30% of patients with acute myeloid leukemia (AML). Here we have shown that a new CXCR4 receptor antagonist IgG1 antibody (PF-06747143) binds strongly to AML cell lines and to AML primary cells inhibiting their chemotaxis in response to CXCL12. PF-06747143 also induced cytotoxicity in AML cells via Fc-effector function. To characterize the effects of PF-06747143 on leukemia progression, we used two different patient-derived xenograft (PDX) models: Patient 17CXCR4-low and P15CXCR4-high models, characterized by relatively low and high CXCR4 expression, respectively. Weekly administration of PF-06747143 to leukemic mice significantly reduced leukemia development in both models. Secondary transplantation of BM cells from PF-06747143-treated or IgG1 control-treated animals showed that leukemic progenitors were also targeted by PF-06747143. Administration of a single dose of PF-06747143 to PDX models induced rapid malignant cell mobilization into the peripheral blood (PB). These findings support evaluation of this antibody in AML therapy, with particular appeal to patients resistant to chemotherapy and to unfit patients, unable to tolerate intensive chemotherapy.

15.
Blood ; 130(6): 732-741, 2017 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-28588019

RESUMO

Recurrent mutations at R140 and R172 in isocitrate dehydrogenase 2 (IDH2) occur in many cancers, including ∼12% of acute myeloid leukemia (AML). In preclinical models these mutations cause accumulation of the oncogenic metabolite R-2-hydroxyglutarate (2-HG) and induce hematopoietic differentiation block. Single-agent enasidenib (AG-221/CC-90007), a selective mutant IDH2 (mIDH2) inhibitor, produced an overall response rate of 40.3% in relapsed/refractory AML (rrAML) patients with mIDH2 in a phase 1 trial. However, its mechanism of action and biomarkers associated with response remain unclear. Here, we measured 2-HG, mIDH2 allele burden, and co-occurring somatic mutations in sequential patient samples from the clinical trial and correlated these with clinical response. Furthermore, we used flow cytometry to assess inhibition of mIDH2 on hematopoietic differentiation. We observed potent 2-HG suppression in both R140 and R172 mIDH2 AML subtypes, with different kinetics, which preceded clinical response. Suppression of 2-HG alone did not predict response, because most nonresponding patients also exhibited 2-HG suppression. Complete remission (CR) with persistence of mIDH2 and normalization of hematopoietic stem and progenitor compartments with emergence of functional mIDH2 neutrophils were observed. In a subset of CR patients, mIDH2 allele burden was reduced and remained undetectable with response. Co-occurring mutations in NRAS and other MAPK pathway effectors were enriched in nonresponding patients, consistent with RAS signaling contributing to primary therapeutic resistance. Together, these data support differentiation as the main mechanism of enasidenib efficacy in relapsed/refractory AML patients and provide insight into resistance mechanisms to inform future mechanism-based combination treatment studies.


Assuntos
Aminopiridinas/uso terapêutico , Antineoplásicos/uso terapêutico , Glutaratos/metabolismo , Hematopoese/efeitos dos fármacos , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Triazinas/uso terapêutico , Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Feminino , Frequência do Gene , Glutaratos/antagonistas & inibidores , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Triazinas/farmacologia
16.
Blood ; 130(6): 722-731, 2017 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-28588020

RESUMO

Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498.


Assuntos
Aminopiridinas/uso terapêutico , Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Triazinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Medula Óssea/patologia , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Triazinas/efeitos adversos , Triazinas/farmacocinética , Adulto Jovem
17.
J Clin Oncol ; 35(11): 1223-1230, 2017 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-28221862

RESUMO

Purpose To evaluate the efficacy and safety of a clofarabine-based combination (CLARA) versus conventional high-dose cytarabine (HDAC) as postremission chemotherapy in younger patients with acute myeloid leukemia (AML). Patients and Methods Patients age 18 to 59 years old with intermediate- or unfavorable-risk AML in first remission and no identified donor for allogeneic stem-cell transplantation (SCT) were eligible. Two hundred twenty-one patients were randomly assigned to receive three CLARA or three HDAC consolidation cycles. The primary end point was relapse-free survival (RFS). To handle the confounding effect of SCT that could occur in patients with late donor identification, hazard ratios (HRs) of events were adjusted on the time-dependent treatment × SCT interaction term. Results At 2 years, RFS was 58.5% (95% CI, 49% to 67%) in the CLARA arm and 46.5% (95% CI, 37% to 55%) in the HDAC arm. Overall, 110 patients (55 in each arm) received SCT in first remission. On the basis of a multivariable Cox-adjusted treatment × SCT interaction, the HR of CLARA over HDAC before or in absence of SCT was 0.65 (95% CI, 0.43 to 0.98; P = .041). In a sensitivity analysis, when patients who received SCT in first remission were censored at SCT time, 2-year RFS was 53.3% (95% CI, 39% to 66%) in the CLARA arm and 31.0% (95% CI, 19% to 43%) in the HDAC arm (HR, 0.63; 95% CI, 0.41 to 0.98; P = .043). Gain in RFS could be related to the lower cumulative incidence of relapse observed in the CLARA arm versus the HDAC arm (33.9% v 46.4% at 2 years, respectively; cause-specific HR, 0.61; 95% CI, 0.40 to 0.94; P = .025). CLARA cycles were associated with higher hematologic and nonhematologic toxicity than HDAC cycles. Conclusion These results suggest that CLARA might be considered as a new chemotherapy option in younger patients with AML in first remission.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/efeitos adversos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversos , Clofarabina , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
18.
Cancer Discov ; 7(5): 478-493, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28193778

RESUMO

Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation-positive advanced hematologic malignancies.Significance: Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478-93. ©2017 AACR.See related commentary by Thomas and Majeti, p. 459See related article by Shih et al., p. 494This article is highlighted in the In This Issue feature, p. 443.


Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/genética , Triazinas/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Isocitrato Desidrogenase/genética , Camundongos , Mutação , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Anticancer Drugs ; 28(5): 540-545, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28225458

RESUMO

Despite considerable progress in hematological malignancies (HM) biology during the last decades, translation into clinical benefit remains a major challenge. To improve patient selection and identify patients most likely to benefit from phase I trials, we designed and validated, in an independent cohort, a simple prognostic score. Treatment outcome, toxicity, and survival data from 82 consecutive patients enrolled in 14 phase I trials were reviewed (January 2008-February 2012). We validated these results on a prospectively collected cohort (17 phase I trials, February 2012-May 2014, 88 patients). Within a median follow-up of 19.1 months (range: 2.1-43.8 months), the median progression-free and overall survival (OS) were, respectively, 4.1 months [95% confidence interval (CI): 3.0-5.3] and 19.8 months (95% CI: 16.1-36.8). Best overall response and disease control rates were similar to HM salvage regimens (28 and 64%, respectively). Through multivariate analysis of independent prognostic factors, we designed and prospectively validated a simple prognostic score based on histological subtype, performance status, and albumin. Patients with a low-risk score experienced significantly better OS compared with patients with an intermediate or a high score (median OS: 37 vs. 17 vs. 5 months; hazard ratio=11.68, 95% CI: 4.09-33.3). Our data indicate the safety and efficacy of phase I trials in a significant number of relapsed/refractory HM patients, with clinical benefit achieved in more than half of patients. Our simple scoring system offers a valuable selection tool encouraging HM patient inclusions in phase I trials.


Assuntos
Ensaios Clínicos Fase I como Assunto/métodos , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
20.
J Clin Oncol ; 35(2): 185-193, 2017 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-28056203

RESUMO

Purpose This study assessed the prognostic impact of postinduction NPM1-mutated ( NPM1m) minimal residual disease (MRD) in young adult patients (age, 18 to 60 years) with acute myeloid leukemia, and addressed the question of whether NPM1m MRD may be used as a predictive factor of allogeneic stem cell transplantation (ASCT) benefit. Patients and Methods Among 229 patients with NPM1m who were treated in the Acute Leukemia French Association 0702 (ALFA-0702) trial, MRD evaluation was available in 152 patients in first remission. Patients with nonfavorable AML according to the European LeukemiaNet (ELN) classification were eligible for ASCT in first remission. Results After induction therapy, patients who did not achieve a 4-log reduction in NPM1m peripheral blood-MRD (PB-MRD) had a higher cumulative incidence of relapse (subhazard ratio [SHR], 5.83; P < .001) and a shorter overall survival (OS; hazard ratio [HR], 10.99; P < .001). In multivariable analysis, an abnormal karyotype, the presence of FLT3-internal tandem duplication (ITD), and a < 4-log reduction in PB-MRD were significantly associated with a higher relapse incidence and shorter OS. In the subset of patients with FLT3-ITD, only age, white blood cell count, and < 4-log reduction in PB-MRD, but not FLT3-ITD allelic ratio, remained of significant prognostic value. In these patients with nonfavorable AML according to European LeukemiaNet, disease-free survival and OS were significantly improved by ASCT in those with a < 4-log reduction in PB-MRD. This benefit was not observed in those with a > 4-log reduction in PB-MRD, with a significant interaction between ASCT effect and PB-MRD response ( P = .024 and .027 for disease-free survival and OS, respectively). Conclusion Our study supports the strong prognostic significance of early NPM1m PB-MRD, independent of the cytogenetic and molecular context. Moreover, NPM1m PB-MRD may be used as a predictive factor for ASCT indication.


Assuntos
Leucemia Mieloide Aguda/terapia , Mutação , Neoplasia Residual/terapia , Proteínas Nucleares/genética , Transplante de Células-Tronco , Adulto , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasia Residual/genética , Prognóstico , Indução de Remissão , Resultado do Tratamento
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