RESUMEN
Venetoclax-azacitidine is the standard of treatment for unfit acute myeloid leukemia patients. In the VIALE-A study, treatment was given until progression but there are no data on its optimal duration for responding patients who do not tolerate indefinite therapy. We retrospectively analyzed the outcome of patients who discontinued venetoclax or venetoclax-azacitidine due to poor tolerance. Sixty-two newly diagnosed (ND) AML patients and 22 patients with morphological relapse or refractory AML were included. In the ND cohort (n = 62), 28 patients stopped venetoclax and azacitidine and 34 patients continued azacitidine monotherapy. With a median follow-up of 23 months (IQR, 20-32), median overall survival and treatment-free survival were 44 (IQR, 16-NR) and 16 (IQR, 8-27) months, respectively. Patients who stopped both treatments and those who continued azacitidine monotherapy had the same outcomes. Negative minimal residual disease was associated with a 2-year treatment-free survival of 80%. In the RR cohort (n = 22), median overall survival and treatment-free survival were 19 (IQR, 17-31) and 10 (IQR, 5-NR) months, respectively. Prior number of venetoclax-azacitidine cycles and IDH mutations were associated with increased overall survival. The only factor significantly impacting treatment-free survival was the number of prior cycles. This study suggests that patients who discontinued treatment in remission have favorable outcomes supporting the rationale for prospective controlled trials.
RESUMEN
The real-world efficacy and safety of gilteritinib was assessed in an ambispective study that included 167 R/R FLT3-mutated AML patients. Among them, 140 received gilteritinib as single agent (cohort B), including 67 previously treated by intensive chemotherapy and midostaurin (cohort C). The main differences in patient characteristics in this study compared to the ADMIRAL trial were ECOG ≥ 2 (83.6% vs. 16.6%), FLT3-TKD mutation (21.0% vs. 8.5%), primary induction failure (15.0% vs. 40.0%) and line of treatment (beyond 2nd in 37.1% vs. 0.0%). The rates of composite complete remission, excluding those that occurred after hematopoietic stem cell transplantation (HSCT), were similar at respectively 25.4% and 27.5% in cohorts B and C. Median overall survival (OS) for these two groups was also similar at respectively 6.4 and 7.8 months. Multivariate analyses for prognostic factors associated with OS identified female gender (HR 1.61), adverse cytogenetic risk (HR 2.52), and allogenic HSCT after gilteritinib (HR 0.13). Although these patients were more heavily pretreated, these real-world data reproduce the results of ADMIRAL and provide new insights into the course of patients previously treated by intensive chemotherapy and midostaurin and beyond the 2nd line of treatment who can benefit from treatment in an outpatient setting.
Asunto(s)
Leucemia Mieloide Aguda , Humanos , Femenino , Mutación , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Estaurosporina/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/uso terapéuticoAsunto(s)
Leucemia Mielomonocítica Crónica , Síndromes Mielodisplásicos , Humanos , Azacitidina/uso terapéutico , Estudios Prospectivos , Leucemia Mielomonocítica Crónica/complicaciones , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/tratamiento farmacológico , EsteroidesRESUMEN
Reduced intensity conditionings (RIC) before after allogeneic hematopoietic stem cell transplantation (HSCT) allow older or unfit patients of being transplanted, but survival expectancy and burden of late complications are poorly described in this setting. All patients (N = 456) who were alive and relapse-free 2 years after HSCT following RIC were included. Cumulative incidences (CI), standardized incidence, or mortality, ratio (SIR or SMR), and competing risk models were used. The 10-year CIs of relapse and non-relapse mortality incidences were 13.9 and 13.4%, respectively. Seventy-eight patients died, late relapse being the most frequent cause of death leading to a SMR of 6.38 (95% CI, 5.1-8.0; p < 0.001). Among non-relapsing patients (n = 412), 30 died (SMR 4.38; 95% CI, 3.3-5.8: p < 0.001). A total of 37 patients developed 41 SM leading to a 10-year cumulative incidence of 12.9%, and a significant SIR relative to the general population (1.4). Finally, we found high CI of cardiovascular (CVC) and venous thromboembolic complications (VTE) (10-year CI; 15.1% and 11.7%, respectively). Older age was the only significant risk factor for CVC and VTE in multivariable analysis. In conclusion, with life expectancy rate of 70%, late survivors after RIC warrants long-term follow-up and active intervention on averting cardiovascular disease and screening cancers.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Tromboembolia Venosa , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Esperanza de Vida , Recurrencia , Estudios Retrospectivos , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Homólogo/efectos adversos , Tromboembolia Venosa/complicacionesRESUMEN
In this randomized phase 3 study, the FILO group tested whether the addition of 6 mg/m2 of gemtuzumab ozogamycin (GO) to standard chemotherapy could improve outcome of younger patients with de novo acute myeloid leukemia (AML) and intermediate-risk cytogenetics. GO arm was prematurely closed after 254 inclusions because of toxicity. A similar complete remission rate was observed in both arms. Neither event-free survival nor overall survival were improved by GO in younger AML patients (<60 years) ineligible for allogeneic stem-cell transplantation. (P = .086; P = .149, respectively). Using unsupervised hierarchical clustering based on mutational analysis of seven genes (NPM1, FLT3-ITD, CEBPA, DNMT3A, IDH1, IDH2, and ASXL1), six clusters of patients with significant different outcome were identified. Five clusters were based on FLT3-ITD, NPM1, and CEBPA mutations as well as epigenetic modifiers (DNMT3A, IDH1/2, ASXL1), whereas the last cluster, representing 25% of patients, had no mutation and intermediate risk. One cluster isolated FLT3-ITD mutations with higher allelic ratio and a very poor outcome. The addition of GO had no impact in these molecular clusters. Although not conclusive for GO impact in AML patients <60 years, this study provides a molecular classification that distinguishes six AML clusters influencing prognosis in younger AML patients with intermediate-risk cytogenetic.
Asunto(s)
Gemtuzumab/farmacología , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adolescente , Adulto , Análisis por Conglomerados , Análisis Citogenético , Citogenética , Análisis Mutacional de ADN , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Trasplante de Células Madre Hematopoyéticas , Humanos , Cariotipificación , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Inducción de Remisión , Riesgo , Adulto JovenAsunto(s)
Antineoplásicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Reordenamiento Génico , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-abl/genética , Adulto JovenRESUMEN
High-dose chemotherapy before autologous transplantation is a therapeutic option as consolidation in primary or relapsed lymphoma. Even if BEAM conditioning is generally used, alternative conditioning regimens have been published. The purpose of this study was to assess the outcome of 177 adult patients with lymphoma whose conditioning treatment included a BAM (busulfan, aracytine, and melphalan) regimen. With a median follow-up of 17.4 months, 2-year estimates of overall survival and progression-free survival for the entire group were 87% and 70.5%, respectively. Mucositis was the main reported complications and infectious episodes were described in 80.2% of patients. According to multivariate analysis, high performance status and age at diagnosis were adverse factors for survival and increased the risk of disease relapse and death. Despite its limitations, this retrospective study suggests that BAM combination is a valid conditioning regimen in lymphoma patients, with an acceptable rate of toxicity.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Médula Ósea , Linfoma/diagnóstico , Linfoma/terapia , Mucositis/diagnóstico , Acondicionamiento Pretrasplante/métodos , Adulto , Factores de Edad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Busulfano/administración & dosificación , Busulfano/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Femenino , Francia , Humanos , Linfoma/clasificación , Linfoma/mortalidad , Masculino , Melfalán/administración & dosificación , Melfalán/efectos adversos , Persona de Mediana Edad , Mucositis/inducido químicamente , Mucositis/patología , Análisis Multivariante , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Trasplante AutólogoRESUMEN
OBJECTIVES: Anthracyclines and cytarabine are cornerstones for intensive chemotherapy in acute myeloid leukemia (AML). The goals of this study were to comprehensively assess deviations from theoretical doses and the impact of body-surface area (BSA) on patients' characteristics, physicians' strategy, dose adjustment, and clinical outcome. METHODS: The GOELAMS 2001 phase III trial included 823 AML patients below 60 years of age. In the course of treatment, anthropomorphic parameters and chemotherapy doses were prospectively registered. RESULTS: Very high BSA (≥2.15 m2 ) was the factor most significantly associated with the physician's decision to reduce chemotherapy doses during induction and postremission therapy. Despite similar AML characteristics and therapeutic strategies, the very high BSA group exhibited a significantly worse survival (5-years OS of 27%) compared to the low (BSA≤1.5 m2 ), intermediate (1.5 m2 Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
, Superficie Corporal
, Leucemia Mieloide Aguda/tratamiento farmacológico
, Leucemia Mieloide Aguda/mortalidad
, Adulto
, Factores de Edad
, Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
, Pesos y Medidas Corporales
, Ensayos Clínicos Fase III como Asunto
, Femenino
, Humanos
, Leucemia Mieloide Aguda/diagnóstico
, Masculino
, Estudios Multicéntricos como Asunto
, Recurrencia
, Inducción de Remisión
, Análisis de Supervivencia
, Resultado del Tratamiento
, Adulto Joven
RESUMEN
Purpose Elderly patients with acute myeloid leukemia (AML) have a poor prognosis, and innovative maintenance therapy could improve their outcomes. Androgens, used in the treatment of aplastic anemia, have been reported to block proliferation of and initiate differentiation in AML cells. We report the results of a multicenter, phase III, randomized open-label trial exploring the benefit of adding androgens to maintenance therapy in patients 60 years of age or older. Patients and Methods A total of 330 patients with AML de novo or secondary to chemotherapy or radiotherapy were enrolled in the study. Induction therapy included idarubicin 8 mg/m2 on days 1 to 5, cytarabine 100 mg/m2 on days 1 to 7, and lomustine 200 mg/m2 on day 1. Patients in complete remission or partial remission received six reinduction courses, alternating idarubicin 8 mg/m2 on day 1, cytarabine 100 mg/m2 on days 1 to 5, and a regimen of methotrexate and mercaptopurine. Patients were randomly assigned to receive norethandrolone 10 or 20 mg/day, according to body weight, or no norethandrolone for a 2-year maintenance therapy regimen. The primary end point was disease-free survival by intention to treat. Secondary end points were event-free survival, overall survival, and safety. This trial was registered at www.ClinicalTrials.gov identifier NCT00700544. Results Random assignment allotted 165 patients to each arm; arm A received norethandrolone, and arm B did not receive norethandrolone. Complete remission or partial remission was achieved in 247 patients (76%). The Schoenfeld time-dependent model showed that norethandrolone significantly improved survival for patients still in remission at 1 year after induction. In arms A and B, respectively, 5-year disease-free survival was 31.2% and 16.2%, event-free survival was 21.5% and 12.9%, and overall survival was 26.3% and 17.2%. Norethandrolone improved outcomes irrelevant to all prognosis factors. Only patients with baseline leukocytes > 30 × 109/L did not benefit from norethandrolone. Conclusion This study demonstrates that maintenance therapy with norethandrolone significantly improves survival in elderly patients with AML without increasing toxicity.
Asunto(s)
Andrógenos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Factores de Edad , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: The GRASPALL/GRAALL-SA2-2008 Phase II trial evaluated the safety and efficacy of L-asparaginase encapsulated within erythrocytes (GRASPA®) in patients ≥ 55 years with Philadelphia chromosome-negative acute lymphoblastic leukemia. FINDINGS: Thirty patients received escalating doses of GRASPA® on Day 3 and 6 of induction Phases 1 and 2. The primary efficacy endpoint was asparagine depletion < 2 µmol/L for at least 7 days. This was reached in 85 and 71% of patients with 100 and 150 IU/kg respectively but not with 50 IU/kg. Grade 3/4 infection, hypertransaminasemia, hyperbilirubinemia and deep vein thrombosis occurred in 77, 20, 7, and 7% of patients, respectively. No allergic reaction or clinical pancreatitis was observed despite 17% of Grade 3/4 lipase elevation. Anti-asparaginase antibodies were detected in 50% of patients and related to a reduction in the duration of asparagine depletion during induction Phase 2 without decrease of encapsulated L-asparaginase activity. Complete remission rate was 70%. With a median follow-up of 42 months, median overall survival was 15.8 and 9.7 months, in the 100 and 150 IU/kg cohorts respectively. CONCLUSIONS: The addition of GRASPA®, especially at the 100 IU/kg dose level, is feasible in elderly patients without excessive toxicity and associated with durable asparagine depletion. (clinicaltrials.gov identifier NCT01523782).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Asparaginasa/uso terapéutico , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Micosis/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Anciano , Antibacterianos/uso terapéutico , Antifúngicos/uso terapéutico , Asparagina/metabolismo , Portadores de Fármacos , Composición de Medicamentos , Eritrocitos/química , Eritrocitos/citología , Femenino , Infecciones por Bacterias Gramnegativas/complicaciones , Infecciones por Bacterias Gramnegativas/mortalidad , Infecciones por Bacterias Gramnegativas/patología , Infecciones por Bacterias Grampositivas/complicaciones , Infecciones por Bacterias Grampositivas/mortalidad , Infecciones por Bacterias Grampositivas/patología , Humanos , Masculino , Persona de Mediana Edad , Micosis/complicaciones , Micosis/mortalidad , Micosis/patología , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Inducción de Remisión , Análisis de SupervivenciaRESUMEN
Core-binding factor acute myeloid leukemia is a favorable acute myeloid leukemia subset cytogenetically defined by t(8;21) or inv(16)/t(16;16) rearrangements, disrupting RUNX1 (previously CBFA/AML1) or CBFB transcription factor functions. The receptor tyrosine kinase KIT is expressed in the vast majority of these acute myeloid leukemias and frequent activating KIT gene mutations have been associated with a higher risk of relapse. This phase II study aimed to evaluate dasatinib as maintenance therapy in patients with core-binding factor acute myeloid leukemia in first hematologic complete remission, but at higher risk of relapse due to molecular disease persistence or recurrence. A total of 26 patients aged 18-60 years old previously included in the CBF-2006 trial were eligible to receive dasatinib 140 mg daily if they had a poor initial molecular response (n=18) or a molecular recurrence (n=8). The tolerance of dasatinib as maintenance therapy was satisfactory. The 2-year disease-free survival in this high-risk population of patients was 25.7%. All but one patient with molecular recurrence presented subsequent hematologic relapse. Patients with slow initial molecular response had a similar disease-free survival when treated with dasatinib (40.2% at 2 years) or without any maintenance (50.0% at 2 years). The disappearance of KIT gene mutations at relapse suggests that clonal devolution may in part explain the absence of efficacy observed with single-agent dasatinib in these patients (n. EudraCT: 2006-006555-12).
Asunto(s)
Antineoplásicos/uso terapéutico , Factores de Unión al Sitio Principal , Dasatinib/uso terapéutico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Francia/epidemiología , Humanos , Leucemia Mieloide Aguda/epidemiología , Masculino , Persona de Mediana Edad , Inducción de Remisión/métodos , Factores de Riesgo , Adulto JovenRESUMEN
The choice of postremission therapy for acute myeloid leukemia (AML) patients is now based on the blasts' cytogenetic and molecular profile. However, the potential benefit of autologous hematopoietic stem cell transplantation (auto-HSCT) according to the NPM1/FLT3-ITD status has been poorly studied in AML patients with a normal karyotype (NK). Therefore, we evaluated the NPM1/FLT3-ITD molecular status in 135 NK-AML patients treated by allogeneic HSCT (allo-HSCT), auto-HSCT, or chemotherapy as consolidation therapy within the GOELAMS LAM-2001 trial. In univariate analyzes, 4-year leukemia-free survival (LFS) and overall survival (OS) were significantly higher for NPM1+/FLT3-ITD- patients compared with patients presenting another molecular profile (61 vs. 43% and 72 vs. 48%, P = 0.02 and P = 0.01, respectively). In the NPM1+/FLT3-ITD- subgroup, there was no benefit for allo-HSCT or auto-HSCT vs. chemotherapy (4-year LFS: 71, 56, and 60%; 4-year OS: 73, 71, and 60%, respectively; P = NS). For patients with other NPM1/FLT3-ITD molecular profiles, allo-HSCT was found to be the best consolidation therapy, whereas auto-HSCT was associated with a better outcome when compared with chemotherapy (allo-HSCT-, auto-HSCT-, and chemotherapy-related 4-year LFS: 68, 44, and 36%, P = 0.004; 4-year OS: 68, 52, and 29%, respectively, P = 0.02). Our study indicates that allo-HSCT and auto-HSCT provide similar outcomes compared with chemotherapy as consolidation for NPM1+/FLT3-ITD- NK-AML patients. For NK-AML patients with an adverse molecular profile, auto-HSCT could represent an alternative therapeutic approach when no human leukocyte antigen-matched allogeneic donor is available.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/cirugía , Proteínas Nucleares/genética , Tirosina Quinasa 3 Similar a fms/genética , Adolescente , Adulto , Estudios de Cohortes , Citogenética , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Mutación , Proteínas Nucleares/metabolismo , Nucleofosmina , Estudios Retrospectivos , Trasplante Autólogo , Resultado del Tratamiento , Adulto Joven , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
Therapy-related acute myeloid leukemia (t-AML) is a clinical syndrome occurring as a complication after cytotoxic and/or radiation therapy. The incidence of t-AML after acute promyelocytic leukemia (APL), all-transretinoic acid (ATRA), and anthracycline-based therapy is rather low. However, because of the high remission rates and long-term overall survival achieved with current APL treatments, late complications related to antileukemic therapy should be taken into account, giving priority to efficacy agents with the lowest potential of leukemogenesis, despite individual genetic susceptibilities that are not well known. Here, we report two cases of t-AML observed in two young women who achieved a rapid, complete molecular remission (CMR) of APL and who were still in CMR when t-AML was diagnosed. These t-AMLs shared some clinical and biological features such as poor-risk cytogenetics and a rapidly progressing, unfavorable outcome. Retrospective RT-PCR WT1 expression from the onset of APL to t-AML diagnosis did not prove to be a good marker for t-AML development.
Asunto(s)
Leucemia Mieloide Aguda/etiología , Leucemia Promielocítica Aguda/terapia , Adulto , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Promielocítica Aguda/complicaciones , Inducción de RemisiónRESUMEN
The prognosis of acute myeloid leukemia (AML) is very poor in elderly patients, especially in those classically defined as having unfavorable cytogenetics. The recent monosomal karyotype (MK) entity, defined as 2 or more autosomal monosomies or combination of 1 monosomy with structural abnormalities, has been reported to be associated with a worse outcome than the traditional complex karyotype (CK). In this retrospective study of 186 AML patients older than 60 years, the prognostic influence of MK was used to further stratify elderly patients with unfavorable cytogenetics. CK was observed in 129 patients (69%), and 110 exhibited abnormalities according to the definition of MK (59%). MK(+) patients had a complete response rate significantly lower than MK(-) patients: 37% vs 64% (P = .0008), and their 2-year overall survival was also decreased at 7% vs 22% (P < .0001). In multivariate analysis, MK appeared as the major independent prognostic factor related to complete remission achievement (odds ratio = 2.3; 95% confidence interval, 1-5.4, P = .05) and survival (hazard ratio = 1.7; 95% confidence interval, 1.1-2.5, P = .008). In the subgroup of 129 CK(+) patients, survival was dramatically decreased for MK(+) patients (8% vs 28% at P = .03). These results demonstrate that MK is a major independent factor of very poor prognosis in elderly AML.
Asunto(s)
Aberraciones Cromosómicas/estadística & datos numéricos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Monosomía/genética , Anciano , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
PURPOSE: No significant improvement in treatment outcome has been seen in elderly patients with acute myeloid leukemia (AML) over the past 20 years. This retrospective analysis investigated the prognostic factors for complete remission (CR) and survival in older patients with AML. PATIENTS AND METHODS: The study involved 847 patients older than 60 years enrolled onto three trials carried out in France between 1995 and 2005. Induction therapy consisted of idarubicin (8 mg/m(2), days 1 through 5) and cytarabine (100 mg/m(2), days 1 through 7; group I, 339 patients) or the same drugs plus lomustine (200 mg/m(2) orally on day 1; group II, 508 patients). Consolidation therapy consisted of anthracycline and cytarabine courses at lower doses, preceded or not by a first course of intermediate-dose cytarabine. RESULTS: The rate of CR was significantly higher in patients in group II compared with group I (68% v 58%; P = .002). The rate of toxic death was similar in the two groups. In multivariate analysis, two prognostic factors were linked to CR: nonadverse cytogenetic (P < .003) and addition of lomustine to induction chemotherapy (P = .002). Median overall survival was significantly improved in patients treated with lomustine (median and SE, 12.7 +/- 2.2 months v 8.7 +/- 2.7 months; P = .004). In multivariate analysis, five prognostic factors positively affected overall survival: addition of lomustine (P = .002), age < or = 69 years (P < .001), Eastern Cooperative Oncology Group performance status lower than 2 (P = .002), French-American-British subgroup 1/2 (P = .02), and nonadverse cytogenetic (P < .001). CONCLUSION: Lomustine improves the rate of CR and survival in elderly patients with de novo AML when added to standard induction therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Citarabina/administración & dosificación , Femenino , Humanos , Idarrubicina/administración & dosificación , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Lomustina/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
10-20% of APL patients relapse and the challenge remains to early identify these patients to improve survival rate. We report PML-RARalpha transcript detection by RQ-PCR in 260 consecutive APL patients (n = 970 samples). 223 patients with samples of sufficient RNA quality to demonstrate they reached molecular remission were monitored for MRD. During follow-up, 38 of these patients were tested positive for PML-RARalpha mRNA. 13 out of the 38 patients (34%) effectively developed hematological relapse. In the first positive sample, specific PML-RARalpha NCN thresholds over which, or under which, patients could effectively be predicted to relapse or not, were identified and subsequently validated in a second cohort.
Asunto(s)
Leucemia Promielocítica Aguda/patología , Proteínas de Fusión Oncogénica/genética , Humanos , Leucemia Promielocítica Aguda/genética , Recurrencia , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND AND OBJECTIVES: T-lymphoblastic lymphoma is an infrequent disease usually treated as T-acute lymphoblastic leukemia with an induction chemotherapy course and sequential reinduction and maintenance chemotherapy. The T-LBL/ALL-GOELAL02 study evaluated the impact of randomized reinduction chemotherapy against intensified conditioning followed by autologous stem cell transplantation (ASCT), after an induction regimen of the type used for acute lymphoblastic leukemia (ALL). DESIGN AND METHODS: Patients with favorable characteristics were randomized to receive chemotherapy or ASCT. Patients with unfavorable characteristics (bone marrow involvement and age over 35 years old or leukocytosis >30 x 10(9)/L or failure to achieve medullar complete remission [CR] after one induction course) received a second induction course and ASCT. RESULTS: Among 45 patients, the CR rate was 71% after induction and 87% after a second induction course. Within the group of 27 patients with favorable characteristics, ten received ASCT and 17 chemotherapy. Ten patients in the group with unfavorable characteristics received ASCT. The 7-year overall survival and progression-free survival rates were 64 and 65%, respectively. Surprisingly, CR obtained after only two induction courses was associated with improved overall survival (p=0.04). None of the known prognostic factors significantly affected survival. INTERPRETATION AND CONCLUSIONS: Randomized maintenance or high-dose therapy (HDT) and ASCT or intensified HDT according to initial presentation gave similar overall and relapse-free survival rates. However, HDT allowed sparing of mediastinal irradiation and shortened treatment duration.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Trasplante de Células Madre , Adolescente , Adulto , Supervivencia sin Enfermedad , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Inducción de Remisión , Tasa de Supervivencia , Trasplante AutólogoRESUMEN
BACKGROUND AND OBJECTIVES: In non-randomized studies, thalidomide appeared to be effective in myeloid metaplasia with myelofibrosis (MMM). We compared thalidomide to placebo for treatment of anemia in MMM. DESIGN AND METHODS: A prospective phase II B, randomized double-blind multicenter trial comparing thalidomide 400 mg/d with placebo for 180 days was conducted in 52 anemic patients (hemoglobin pounds Sterling 9 g/dL or transfused). The main outcome measure was a 2 g/L increase in hemoglobin or 20% reduction in transfusions. RESULTS: In the thalidomide group only 10 patients completed 6 months of treatment. At 180 days, in an intention-to-treat analysis, no difference was observed between the thalidomide and placebo groups as regards improvement of hemoglobin levels (one patient in each group) or reduction of red blood cell transfusions (three vs five patients, respectively). The spleen size, determined by ultrasonography, increased significantly less in the thalidomide group than in the placebo group (p < 0.05). Thalidomide had no apparent benefit on the Dupriez score, the severity score, survival, death, or any other clinical or biological parameter. Somnolence, gastro-intestinal signs, weight gain, and edema were significantly more frequent in the thalidomide group. Outpatient discontinuation of thalidomide was significantly correlated with a high severity score > 4 (odds ratio, OR = 16; p < 0.01), and g-glutamyl transferase levels > 40 IU/L (OR = 12; p < 0.05). INTERPRETATION AND CONCLUSIONS: Thalidomide (200-400 mg/d) does not demonstrate substantial efficacy in anemic MMM patients. The natural history of disease in the placebo group revealed spontaneous periods of remission of anemia. Tolerance of thalidomide was significantly correlated wih the severity and liver involvement of the disease.
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Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/tratamiento farmacológico , Talidomida/uso terapéutico , Inhibidores de la Angiogénesis/uso terapéutico , Método Doble Ciego , Francia , Humanos , Placebos , Reproducibilidad de los Resultados , Proyectos de Investigación , Talidomida/toxicidadRESUMEN
AIM OF THE STUDY: To evaluate the short and long-term effects of anthracycline chemotherapy in adults using conventional echocardiography and pulsed tissue Doppler imaging (TDI). METHODS AND RESULTS: Twenty patients were included of which 16 had a complete follow up. They underwent an echocardiography before chemotherapy, 1-3 months and 3.5+/-0.6 years after the treatment. We recorded pulsed TDI at the mitral annulus, the basal segments of the left ventricular (LV) lateral and posterior walls; peak velocities in systole (Sm), early (Em) and late diastole and the isovolumic relaxation time (IVRT) were measured. The cumulative dose of doxorubicin was 211+/-82 g/m2. Early after anthracycline therapy, we observed changes in the diastolic LV function with a decrease of the mitral E peak velocity and TDI Em. At the late control, diastolic changes were more pronounced and associated with an alteration of the systolic function (LV ejection fraction and Sm). Four patients had a LV ejection fraction <50%; in these patients we observed a mitral annulus IVRT <80 ms at the early control; this could be of interest to predict later impairment of the LV ejection fraction. CONCLUSION: We found early changes in LV diastolic function and observed that late impairment of the LV ejection fraction occurred frequently after anthracycline therapy, despite normal systolic LV function during the first months of follow-up.
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Antraciclinas/efectos adversos , Ecocardiografía/métodos , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/diagnóstico por imagen , Adulto , Análisis de Varianza , Neoplasias de la Mama/tratamiento farmacológico , Ecocardiografía Doppler , Femenino , Humanos , Leucemia/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Masculino , Estudios Prospectivos , Estadísticas no ParamétricasRESUMEN
The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway has been shown to be frequently activated in blast cells from patients with acute myeloid leukemia (AML) and to contribute to survival and proliferation of these cells. Of the 8 distinct mammalian isoforms of PI3K, it is the class I PI3Ks (p110alpha, p110beta, p110gamma, and p110delta) that are responsible for Akt activation. It is not known which PI3K isoform is critical in AML. Here we show that the p110delta isoform of PI3K is consistently expressed at a high level in blast cells from AML, in contrast to the other class I isoforms, the expression of which was very variable among patients. IC87114, a p110delta-selective inhibitor, suppressed both constitutive and Flt-3-stimulated Akt activation in blasts to the same extent as Ly294002, an inhibitor of all PI3K isoforms. Moreover, IC87114 inhibited AML cell proliferation without affecting the proliferation of normal hematopoietic progenitor cells. These observations identify p110delta as a potential therapeutic target in AML.