RESUMEN
AKT activation is associated with many malignancies, where AKT acts, in part, by inhibiting FOXO tumor suppressors. We show a converse role for AKT/FOXOs in acute myeloid leukemia (AML). Rather than decreased FOXO activity, we observed that FOXOs are active in â¼40% of AML patient samples regardless of genetic subtype. We also observe this activity in human MLL-AF9 leukemia allele-induced AML in mice, where either activation of Akt or compound deletion of FoxO1/3/4 reduced leukemic cell growth, with the latter markedly diminishing leukemia-initiating cell (LIC) function in vivo and improving animal survival. FOXO inhibition resulted in myeloid maturation and subsequent AML cell death. FOXO activation inversely correlated with JNK/c-JUN signaling, and leukemic cells resistant to FOXO inhibition responded to JNK inhibition. These data reveal a molecular role for AKT/FOXO and JNK/c-JUN in maintaining a differentiation blockade that can be targeted to inhibit leukemias with a range of genetic lesions.
Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Animales , Antígenos CD34/metabolismo , Apoptosis , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Células Cultivadas , Modelos Animales de Enfermedad , Proteína Forkhead Box O3 , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/metabolismoRESUMEN
Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.
Asunto(s)
Glicina/análogos & derivados , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Mutación/genética , Piridinas/uso terapéutico , Anciano , Anciano de 80 o más Años , Transfusión Sanguínea , Femenino , Glicina/efectos adversos , Glicina/uso terapéutico , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Piridinas/efectos adversos , Inducción de Remisión , Análisis de Supervivencia , Investigación Biomédica Traslacional , Resultado del TratamientoRESUMEN
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 .).
Asunto(s)
Inhibidores Enzimáticos/administración & dosificación , Glicina/análogos & derivados , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Piridinas/administración & dosificación , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Recuento de Células , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Estudios de Seguimiento , Glicina/administración & dosificación , Glicina/efectos adversos , Glicina/farmacocinética , Hemoglobinas/análisis , Humanos , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Piridinas/efectos adversos , Piridinas/farmacocinética , Recurrencia , Inducción de Remisión , Tasa de Supervivencia , Adulto JovenRESUMEN
Approximately 8% to 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), which leads to DNA and histone hypermethylation and impaired hematopoietic differentiation. Enasidenib is an oral inhibitor of mutant-IDH2 proteins. This first-in-human phase 1/2 study evaluated enasidenib doses of 50 to 650 mg/d, administered in continuous 28-day cycles, in patients with mutant-IDH2 hematologic malignancies. Overall, 214 of 345 patients (62%) with relapsed or refractory (R/R) AML received enasidenib, 100 mg/d. 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 the overall response rate was 38.8% (95% confidence interval [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 nonintensive (43.2%) therapies. Sixty-six (43.1%) red blood cell transfusion-dependent and 53 (40.2%) platelet transfusion-dependent 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 or 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 at www.clinicaltrials.gov as #NCT01915498.
Asunto(s)
Aminopiridinas/uso terapéutico , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas Mutantes/antagonistas & inhibidores , Mutación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Triazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Femenino , Estudios de Seguimiento , Humanos , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Proteínas Mutantes/genética , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Pronóstico , Inducción de Remisión , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) remain poor. Novel therapies specifically targeting AML are of high interest. Brentuximab vedotin (BV) is an antibody-drug conjugate that is specific for human CD30. In this phase 1 dose escalation study, the authors evaluated the safety of BV combined with mitoxantrone, etoposide, and cytarabine (MEC) re-induction chemotherapy for patients with CD30-expressing R/R AML. METHODS: Using a standard dose escalation design, the authors evaluated 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7. RESULTS: There were no dose-limiting toxicities noted and the maximum tolerated dose was not reached. The recommended phase 2 dose of BV was determined to be 1.8 mg/kg when combined with MEC. The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade ≥3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Among the 22 patients enrolled on the trial, the composite response rate was 36%, with a composite response rate of 42% noted among those who received the highest dose of BV. The median overall survival was 9.5 months, with a median disease-free survival of 6.8 months observed among responders. Approximately 55% of patients were able to proceed with either allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion. CONCLUSIONS: The combination of BV with MEC was found to be safe in patients with CD30-expressing R/R AML and warrants further study comparing this combination with the use of MEC alone in this population (ClinicalTrials.gov identifier NCT01830777). LAY SUMMARY: The outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are exceptionally poor. New and emerging treatment combinations are actively being studied in an effort to improve outcomes. The authors examined the combination of brentuximab vedotin, an antibody product that recognizes a marker called CD30, with mitoxantrone, etoposide, and cytarabine (MEC), a common chemotherapy regimen, in patients with R/R AML that expressed the CD30 marker. The authors found that the combination was safe and well tolerated. Future studies comparing this new combination with the use of MEC alone can help to inform its effectiveness for this patient population.
Asunto(s)
Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Brentuximab Vedotina/administración & dosificación , Inmunoconjugados/administración & dosificación , Quimioterapia de Inducción/métodos , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Inmunológicos/efectos adversos , Brentuximab Vedotina/efectos adversos , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Esquema de Medicación , Resistencia a Antineoplásicos , Etopósido/administración & dosificación , Femenino , Humanos , Inmunoconjugados/efectos adversos , Antígeno Ki-1/metabolismo , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/mortalidad , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Recurrencia , Adulto JovenRESUMEN
BACKGROUND: Acute myeloid leukemia (AML) cells harboring mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) produce the oncometabolite 2-hydroxyglutarate (2HG). This study prospectively evaluated the 2HG levels, IDH1/2 mutational status, and outcomes of patients receiving standard chemotherapy for newly diagnosed AML. METHODS: Serial samples of serum, urine, and bone marrow aspirates were collected from patients newly diagnosed with AML, and 2HG levels were measured with mass spectrometry. Patients with baseline serum 2HG levels greater than 1000 ng/mL or marrow pellet 2HG levels greater than 1000 ng/2 × 106 cells, which suggested the presence of an IDH1/2 mutation, underwent serial testing. IDH1/2 mutations and estimated variant allele frequencies were identified. AML characteristics were compared with the Wilcoxon test and Fisher's exact test. Disease-free survival and overall survival (OS) were evaluated with log-rank tests and Cox regression. RESULTS: Two hundred and two patients were treated for AML; 51 harbored IDH1/2 mutations. IDH1/2-mutated patients had significantly higher 2HG levels in serum, urine, bone marrow aspirates, and aspirate cell pellets than wild-type patients. A serum 2HG level greater than 534.5 ng/mL was 98.8% specific for the presence of an IDH1/2 mutation. Patients with IDH1/2-mutated AML treated with 7+3-based induction had a 2-year event-free survival (EFS) rate of 44% and a 2-year OS rate of 57%. There was no difference in complete remission rates, EFS, or OS between IDH1/2-mutated and wild-type patients. Decreased serum 2HG levels on day 14 as a proportion of the baseline were significantly associated with improvements in EFS (P = .047) and OS (P = .019) in a multivariate analysis. CONCLUSIONS: Among patients with IDH1/2-mutated AML, 2HG levels are highly specific for the mutational status at diagnosis, and they have prognostic relevance in patients receiving standard chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Glutaratos/sangre , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/mortalidad , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
Patients with relapsed AML have a poor prognosis and limited responses to standard chemotherapy. Lenalidomide is an immunomodulatory drug that may modulate anti-tumor immunity. We performed a study to evaluate the safety and tolerability of lenalidomide with mitoxantrone, etoposide and cytarabine (MEC) in relapsed/refractory AML. Adult patients with relapsed/refractory AML were eligible for this phase I dose-escalation study. We enrolled 35 patients using a "3 + 3" design, with a 10 patient expansion cohort at the maximum tolerated dose (MTD). Lenalidomide was initially given days 1-14 and MEC days 4-8; due to delayed count recovery, the protocol was amended to administer lenalidomide days 1-10. The dose of lenalidomide was then escalated starting at 5 mg/d (5-10-25-50). The primary objective was tolerability and MTD determination, with secondary outcomes including overall survival (OS). The MTD of lenalidomide combined with MEC was 50 mg/d days 1-10. Among the 35 enrolled patients, 12 achieved complete remission (CR) (34%, 90%CI 21-50%); 30-day mortality was 6% and 60-day mortality 13%. The median OS for all patients was 11.5 months. Among 17 patients treated at the MTD, 7 attained CR (41%); the median OS was not reached while 12-month OS was 61%. Following therapy with MEC and lenalidomide, patient CD4+ and CD8+ T-cells demonstrated increased inflammatory responses to autologous tumor lysate. The combination of MEC and lenalidomide is tolerable with an RP2D of lenalidomide 50 mg/d days 1-10, yielding encouraging response rates. Further studies are planned to explore the potential immunomodulatory effect of lenalidomide and MEC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Inhibidores de la Angiogénesis/uso terapéutico , Citarabina/administración & dosificación , Etopósido/administración & dosificación , Humanos , Lenalidomida/administración & dosificación , Leucemia Mieloide Aguda/mortalidad , Dosis Máxima Tolerada , Mitoxantrona/administración & dosificación , Inducción de Remisión/métodos , Terapia Recuperativa/métodos , Análisis de SupervivenciaRESUMEN
Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring "5+2" reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68-96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33-81%) and 42% (90% CI 17-65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. (clinicaltrials.gov Identifier:01779843).
Asunto(s)
Antineoplásicos/uso terapéutico , Azepinas/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Aurora Quinasa A/antagonistas & inhibidores , Azepinas/administración & dosificación , Azepinas/farmacocinética , Citarabina/administración & dosificación , Femenino , Humanos , Idarrubicina/administración & dosificación , Inmunohistoquímica , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Inducción de Remisión , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Outcomes among older patients with acute lymphoblastic leukemia remain poor. This study sought to determine the efficacy of an intensified, multi-agent approach derived from a Dana-Farber consortium trial in younger adults for patients older than 50 years (trial identifier NCT00973752). METHODS: The primary endpoint was overall survival (OS) at 1 year. Patients received induction chemotherapy with vincristine, prednisone, doxorubicin, and pegylated asparaginase. Imatinib was incorporated for Philadelphia chromosome-positive disease. After induction, the first consolidation incorporated clofarabine. Patients in remission could proceed to allogeneic hematopoietic cell transplantation (HCT) after induction and consolidation I. Those not receiving HCT went on to receive central nervous system, consolidation II, and continuation phases of treatment. RESULTS: Thirty patients were enrolled: 19 achieved a complete remission (CR) after induction and 1 achieved CR after consolidation I for a CR rate of 67%. Sixteen patients underwent HCT. The proportion surviving at 1 year was 63%, and this met the primary endpoint. The 2-year OS rate was 52% (n = 30), and the 2-year disease-free survival rate was 52% for patients achieving CR (n = 20). There was no survival advantage among those undergoing HCT. Therapy-related hyperbilirubinemia prompted adjustments and limitations to asparaginase dosing. CONCLUSIONS: Intensified chemotherapy can result in improved outcomes in comparison with historical data. Additional studies of similarly intensive regimens are warranted in this population. Cancer 2016;122:2379-2388. © 2016 American Cancer Society.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Factores de Edad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Inducción de Remisión , Análisis de Supervivencia , Trasplante HomólogoRESUMEN
BACKGROUND: Health care utilization in older adults (age ≥60 years) with acute myeloid leukemia (AML) has not been well studied. METHODS: We conducted a retrospective analysis of 330 consecutive older patients who were diagnosed with AML between May 1, 2005 and December 23, 2011, at 2 hospitals in Boston to examine their health care utilization and end-of-life care. Using multivariable logistic and linear regression models adjusting for covariates, we also compared health care utilization between patients who received intensive induction chemotherapy (n = 197; cytarabine/ anthracycline combination) versus nonintensive chemotherapy (n = 133; single-agent therapy). RESULTS: The median number of hospitalizations for the entire cohort was 4.2 (range, 1-18 hospitalizations). Patients who died spent a mean of 28.3% of their life after diagnosis in the hospital and 13.8% of their life attending outpatient clinic appointments. Although the majority of patients (87.9%) died during the 2-year follow-up period, a minority received palliative care (16.2%) or hospice (23.1%) services. Within 30 days of death, 84.5% of patients were hospitalized, and 61% died in the hospital. Among the patients who died, those who received intensive induction therapy (vs nonintensive therapy) spent 30% more of their life after diagnosis in the hospital (P < .0001) and were less likely to receive hospice services (odds ratio, 0.45; P = .05). CONCLUSIONS: The current findings highlight the intensity of health care utilization among older patients with AML, regardless of treatment modality. Despite the poor prognosis, palliative care and hospice services are rarely used. Future work should study novel health care delivery models to optimize care throughout the course of illness and at the end of life.
Asunto(s)
Leucemia Mieloide Aguda/terapia , Aceptación de la Atención de Salud , Cuidado Terminal , Anciano , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Graft-versus-host disease (GVHD) is a donor T cell driven response against host tissue that can complicate allogeneic hematopoietic stem cell transplantation (HSCT). During acute GVHD, endogenous adjuvants such as uric acid are released by damaged host tissue, activating alloreactive donor T cells. A phase I study was conducted at the Massachusetts General Hospital between 2007 and 2010 to test the hypothesis that reduction of uric acid levels during allogeneic HSCT can modulate the development of acute GVHD. Twenty-one patients with hematologic malignancies in complete remission undergoing myeloablative peripheral blood HSCT received recombinant urate oxidase at .20 mg/kg for 5 consecutive days during conditioning. Results were compared with all patients who underwent allogeneic HSCT at our institution during the same time period who met the same inclusion and exclusion criteria but were not enrolled in the study. The only major adverse event was a case of hemolytic anemia in a patient who had glucose-6-phosphate dehydrogenase deficiency. Primary outcome was the cumulative incidence of grades II to IV acute GVHD, which was significantly decreased in the treatment group in the intention-to-treat analysis (57% [12/21] versus 24% [5/21], P = .036) and in the per-protocol analysis (P = .017). Patients who developed acute GVHD had a higher level of serum uric acid during the pretransplantation period compared with those who did not (P < .001). There was no difference in disease-free or overall survival. Our study suggests that urate oxidase can be safely administered during myeloablative conditioning and may reduce the incidence of acute GVHD.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Agonistas Mieloablativos/uso terapéutico , Acondicionamiento Pretrasplante , Urato Oxidasa/uso terapéutico , Enfermedad Aguda , Adulto , Esquema de Medicación , Femenino , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/patología , Neoplasias Hematológicas/sangre , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Humanos , Activación de Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéutico , Inducción de Remisión , Análisis de Supervivencia , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patología , Trasplante Homólogo , Ácido Úrico/sangreRESUMEN
Aa total of 105 patients (age ≥18 years) with newly diagnosed low or intermediate risk acute promyelocytic leukaemia (APL) were treated with a standard induction and consolidation regimen including arsenic trioxide (ATO). Sixty-eight patients who were polymerase chain reaction (PCR) negative for PML-RARA post-consolidation were randomized to either 1 year of maintenance with tretinoin, mercaptopurine and methotrexate, or observation. Enrollment in this non-inferiority trial was stopped prematurely due to slow accrual. With a median follow up of 36·1 months, the overall survival of the 105 patients was 93%, and there have been no relapses in the patients randomized to maintenance or observation. These results demonstrate that cures can be expected in >90% of patients with low and intermediate risk APL and suggest that maintenance therapy may not be needed if patients are treated with an intensive post-remission regimen including ATO. This trial was registered at clinicaltrials.gov as #NCT00492856.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de Consolidación , Leucemia Promielocítica Aguda/tratamiento farmacológico , Adulto , Anciano , Aminoglicósidos/administración & dosificación , Aminoglicósidos/efectos adversos , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trióxido de Arsénico , Arsenicales/administración & dosificación , Arsenicales/efectos adversos , Biomarcadores de Tumor , Citarabina/administración & dosificación , Citarabina/efectos adversos , Daunorrubicina/administración & dosificación , Daunorrubicina/efectos adversos , Supervivencia sin Enfermedad , Perros , Femenino , Gemtuzumab , Humanos , Quimioterapia de Mantención , Masculino , Mercaptopurina/administración & dosificación , Mercaptopurina/efectos adversos , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/sangre , Óxidos/administración & dosificación , Óxidos/efectos adversos , Recuento de Plaquetas , Inducción de Remisión , Riesgo , Resultado del Tratamiento , Tretinoina/administración & dosificación , Tretinoina/efectos adversos , Adulto JovenRESUMEN
Leaving the safety of home exposes our vulnerabilities. In this issue of Blood, Uy and coauthors explore the clinical benefit of interrupting the protective niches in which leukemia cells live in an effort to enhance the benefit of chemotherapy in treating patients with acute myeloid leukemia (AML).
RESUMEN
Mutations of genes encoding isocitrate dehydrogenase (IDH1 and IDH2) have been recently described in acute myeloid leukemia (AML). Serum and myeloblast samples from patients with IDH-mutant AML contain high levels of the metabolite 2-hydroxyglutarate (2-HG), a product of the altered IDH protein. In this prospective study, we sought to determine whether 2-HG can potentially serve as a noninvasive biomarker of disease burden through serial measurements in patients receiving conventional therapy for newly diagnosed AML. Our data demonstrate that serum, urine, marrow aspirate, and myeloblast 2-HG levels are significantly higher in IDH-mutant patients, with a correlation between baseline serum and urine 2-HG levels. Serum and urine 2-HG, along with IDH1/2-mutant allele burden in marrow, decreased with response to treatment. 2-HG decrease was more rapid with induction chemotherapy compared with DNA-methyltransferase inhibitor therapy. Our data suggest that serum or urine 2-HG may serve as noninvasive biomarkers of disease activity for IDH-mutant AML.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Glutaratos/metabolismo , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/metabolismo , Enfermedad Aguda , Anciano , Azacitidina/administración & dosificación , Azacitidina/análogos & derivados , Citarabina/administración & dosificación , Análisis Mutacional de ADN , Decitabina , Femenino , Glutaratos/sangre , Glutaratos/orina , Células Precursoras de Granulocitos/metabolismo , Humanos , Idarrubicina/administración & dosificación , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Leucemia Mieloide/genética , Masculino , Persona de Mediana Edad , Mutación , Estudios Prospectivos , Factores de TiempoRESUMEN
We performed a retrospective study of the engraftment syndrome (ES) as defined by the Spitzer Criteria in adult patients undergoing allogeneic hematopoietic cell transplantation (HCT) for various hematological malignancies at a single institution, over a decade, and analyzed its relationship to acute GVHD; 217 patients underwent either myeloablative (38.7%) or reduced intensity (61.3%) HCT; 22.1% met the criteria for ES. Acute GVHD prophylaxis (P = 0.006) and transplants prior to 2006 (P < 0.0001) were significantly associated with a risk of ES in univariable analysis. Early aGVHD within 4 weeks of engraftment was significantly more common in the ES compared to the non ES cohort (21 vs. 8.3% respectively, P = 0.02). ES did not predict for future GVHD, as at day +180, the cumulative incidences of grades II-IV aGVHD (31 vs. 23%, P = 0.19) and of chronic GVHD at 2 years of engraftment (42 vs. 36%, P = 0.28) were not significantly different between the ES and non ES groups, respectively. No significant differences in NRM, overall survival and progression-free survival were observed between the two groups. Although predictive of early aGVHD, ES occurred independently of GVHD in 79% of the patients. Survival outcomes should be evaluated in a larger randomized study to investigate if there is a correlation with ES.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adulto , Anciano , Dermatitis Exfoliativa/etiología , Femenino , Fiebre/etiología , Supervivencia de Injerto/fisiología , Neoplasias Hematológicas/cirugía , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Edema Pulmonar/etiología , Estudios Retrospectivos , Factores de Riesgo , Síndrome , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo , Adulto JovenRESUMEN
Somatic chromosomal deletions in cancer are thought to indicate the location of tumour suppressor genes, by which a complete loss of gene function occurs through biallelic deletion, point mutation or epigenetic silencing, thus fulfilling Knudson's two-hit hypothesis. In many recurrent deletions, however, such biallelic inactivation has not been found. One prominent example is the 5q- syndrome, a subtype of myelodysplastic syndrome characterized by a defect in erythroid differentiation. Here we describe an RNA-mediated interference (RNAi)-based approach to discovery of the 5q- disease gene. We found that partial loss of function of the ribosomal subunit protein RPS14 phenocopies the disease in normal haematopoietic progenitor cells, and also that forced expression of RPS14 rescues the disease phenotype in patient-derived bone marrow cells. In addition, we identified a block in the processing of pre-ribosomal RNA in RPS14-deficient cells that is functionally equivalent to the defect in Diamond-Blackfan anaemia, linking the molecular pathophysiology of the 5q- syndrome to a congenital syndrome causing bone marrow failure. These results indicate that the 5q- syndrome is caused by a defect in ribosomal protein function and suggest that RNAi screening is an effective strategy for identifying causal haploinsufficiency disease genes.
Asunto(s)
Cromosomas Humanos Par 5/genética , Ligamiento Genético/genética , Predisposición Genética a la Enfermedad/genética , Interferencia de ARN , Proteínas Ribosómicas/genética , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/fisiopatología , Diferenciación Celular , Células Cultivadas , Deleción Cromosómica , Células Eritroides/citología , Células Eritroides/metabolismo , Células Madre Hematopoyéticas/metabolismo , Humanos , Fenotipo , Precursores del ARN/genética , Precursores del ARN/metabolismo , ARN Ribosómico/genética , ARN Ribosómico/metabolismo , ARN Ribosómico 18S/genética , Proteínas Ribosómicas/deficiencia , Proteínas Ribosómicas/metabolismo , Ribosomas/química , Ribosomas/genética , Ribosomas/metabolismo , SíndromeRESUMEN
Invasive fungal disease (IFD) is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HCT). We performed a retrospective review of 271 adults with a hematologic malignancy undergoing allogeneic HCT to determine the incidence of and risk factors for IFD and to examine the impact of IFD on nonrelapse mortality and overall survival. We defined IFD using standard criteria and selected proven and probable cases for analysis. Diagnoses in the study group included acute leukemia (42%), non-Hodgkin lymphoma (24%), myelodysplastic syndrome (15%), chronic lymphocytic leukemia (5%), and other hematologic disorders (14%). Conditioning included reduced-intensity (64%) and myeloablative (36%) regimens. Donor sources were HLA-matched sibling (60%), matched unrelated (20%), haploidentical (12%), and cord blood (8%). A total of 51 episodes of IFD were observed in 42 subjects (15%). Aspergillus spp (47%) was the most frequent causative organism, followed by Candida spp (43%). The majority of IFD cases (67%) were reported after day +100 post-HCT. In multivariate analysis, haploidentical donor transplantation (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.49-9.77; P = .005) and grade II-IV acute graft-versus-host disease (HR, 2.55; 95% CI, 1.07-6.10; P = .03) were risk factors for the development of IFD. Conversely, higher infused CD34(+) cell dose was associated with a lower risk of IFD (HR, 0.80; 95% CI, 0.68-0.94; P = .006, per 1 × 10(6) cells/kg increase in CD34(+) cell infusion). IFD-related mortality was 33.3%. Nonrelapse mortality was significantly higher in patients who developed IFD compared with those without IFD (P < .001, log-rank test). Patients with IFD had lower overall survival (5.8 months versus 76.1 months; P < .001, log-rank test). Further studies exploring strategies to increase the infused cell dose and determine adequate prophylaxis, especially against aspergillus, beyond day +100 are needed.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Micosis/sangre , Micosis/etiología , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Micosis/prevención & control , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Adulto JovenRESUMEN
Comparisons of myeloablative conditioning versus reduced-intensity conditioning (RIC) have demonstrated a tradeoff between relapse and toxicity. Dose intensity across RIC regimens vary and may affect treatment outcomes. In this retrospective analysis, we investigated the effect of i.v. busulfan dosing (total dose 3.2 mg/kg versus 6.4 mg/kg) in RIC regimens that combined fludarabine and busulfan on outcomes in patients who were undergoing hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). A total of 217 consecutive patients with MDS or AML underwent first busulfan and fludarabine RIC peripheral blood stem cell transplantation from well-matched related or unrelated donors at our institutions between 2004 and 2009. Of the 217 patients, 135 patients received Bu1 (3.2 mg/kg of busulfan) and 82 patients received Bu2 (6.4 mg/kg of busulfan), both with daily fludarabine (30 mg/m(2)/day for 4 days). The choice of RIC regimen was based on temporal institutional standard, enrollment on protocols, and physician choice. Patients had similar characteristics with a few notable differences: Patients who received Bu1 were younger (median age 61 versus 64 years, P < . 001), received more single-antigen mismatched unrelated grafts (14.1% versus 1.2%, P < . 001), received more sirolimus-based graft-versus-host disease (GVHD) prophylaxis regimens (63% versus 45%, P < .0001), received less antithymocyte globulin for GVHD prophylaxis (0% versus 22%, P < .001), and had less enrollment on a clinical trial that used prophylactic rituximab for the prevention of chronic GVHD (2.2% versus 11.0%, P = .011). Clinical disease status was similar between the groups. Median follow-up for survivors was 4.4 years for Bu1 and 3.2 years for Bu2. Because of the differences in characteristics, the 2 groups were compared with the adjustment of a propensity score that predicted Bu2 to account for measured differences. The day +200 cumulative incidence rates of grades II to IV acute GVHD (Bu1, 17%, versus Bu2, 8.5%; hazard ratio [HR], .56; 95% confidence interval [CI], .22 to 1.41; P = .22) or grades III to IV acute GVHD (Bu1, 6.7%, versus Bu2, 4.9%) were not different. The 2-year cumulative incidence of chronic GVHD was not significantly different between Bu1 and Bu2 (41.5% versus 28%, respectively; HR, .70; CI, .42 to 1.17; P = .09). Two-year nonrelapse mortality rates were similar for Bu1 and Bu2 (8.9% versus 9.8%, respectively; HR, .80; CI, .29 to 2.21; P = .67). Two-year progression-free survival and overall survival were also similar between Bu1 and Bu2 (progression-free survival: 40.6% versus 39.3%, respectively; HR, .82; CI, .57 to 1.30; P = .33; and overall survival: 47.4% versus 48.8%, respectively; HR, .96; CI, .64 to 1.44; P = .85). Subset analysis defined by clinical disease and cytogenetic risk with the propensity risk score applied suggest that in patients with high clinical disease risk and nonadverse cytogenetics, the higher dose busulfan RIC regimen may be of marginal benefit (2-year progression-free survival: HR, .54; CI, .29 to 1.03; P = .062). For the majority of patients with MDS or AML undergoing busulfan and fludarabine RIC peripheral blood stem cell transplantation, however, the dose of busulfan (3.2 mg/kg versus 6.4 mg/kg) is not associated with significant differences in overall outcomes.
Asunto(s)
Busulfano/uso terapéutico , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/uso terapéutico , Síndromes Mielodisplásicos/terapia , Trasplante de Células Madre de Sangre Periférica , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Anciano , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Donante no Emparentado , Vidarabina/uso terapéuticoRESUMEN
Large chromosomal deletions are among the most common molecular abnormalities in cancer, yet the identification of relevant genes has proven difficult. The 5q- syndrome, a subtype of myelodysplastic syndrome (MDS), is a chromosomal deletion syndrome characterized by anemia and thrombocytosis. Although we have previously shown that hemizygous loss of RPS14 recapitulates the failed erythroid differentiation seen in 5q- syndrome, it does not affect thrombocytosis. Here we show that a microRNA located in the common deletion region of 5q- syndrome, miR-145, affects megakaryocyte and erythroid differentiation. We find that miR-145 functions through repression of Fli-1, a megakaryocyte and erythroid regulatory transcription factor. Patients with del(5q) MDS have decreased expression of miR-145 and increased expression of Fli-1. Overexpression of miR-145 or inhibition of Fli-1 decreases the production of megakaryocytic cells relative to erythroid cells, whereas inhibition of miR-145 or overexpression of Fli-1 has a reciprocal effect. Moreover, combined loss of miR-145 and RPS14 cooperates to alter erythroid-megakaryocytic differentiation in a manner similar to the 5q- syndrome. Taken together, these findings demonstrate that coordinate deletion of a miRNA and a protein-coding gene contributes to the phenotype of a human malignancy, the 5q- syndrome.
Asunto(s)
Anemia Macrocítica/genética , MicroARNs/genética , Sistemas de Lectura Abierta/genética , Anemia Macrocítica/etiología , Animales , Estudios de Casos y Controles , Diferenciación Celular/genética , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Células Eritroides/metabolismo , Eritropoyesis/genética , Eritropoyesis/fisiología , Humanos , Pérdida de Heterocigocidad , Megacariocitos/metabolismo , Megacariocitos/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , MicroARNs/metabolismo , MicroARNs/fisiología , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Proteína Proto-Oncogénica c-fli-1/genética , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína Proto-Oncogénica c-fli-1/fisiología , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/fisiología , Células Tumorales CultivadasRESUMEN
The myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic disorders characterized by cytopenias, dysplasia in one or more myeloid lineages, and the potential for development of acute myeloid leukemia. These disorders primarily affect older adults. The NCCN Clinical Practice Guidelines in Oncology for MDS provide recommendations on the diagnostic evaluation and classification of MDS, risk evaluation according to established prognostic assessment tools (including the new revised International Prognostic Scoring System), treatment options according to risk categories, and management of related anemia.