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1.
Leukemia ; 31(6): 1391-1397, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28111463

RESUMEN

While therapy-related (t)-myelodysplastic syndromes (MDS) have worse outcomes than de novo MDS (d-MDS), some t-MDS patients have an indolent course. Most MDS prognostic models excluded t-MDS patients during development. The performances of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Global Prognostic System (MPSS), WHO Prognostic Scoring System (WPSS) and t-MDS Prognostic System (TPSS) were compared among patients with t-MDS. Akaike information criteria (AIC) assessed the relative goodness of fit of the models. We identified 370 t-MDS patients (19%) among 1950 MDS patients. Prior therapy included chemotherapy alone (48%), chemoradiation (31%), and radiation alone in 21%. Median survival for t-MDS patients was significantly shorter than for d-MDS (19 vs 46 months, P<0.005). All models discriminated survival in t-MDS (P<0.005 for each model). Patients with t-MDS had a significantly higher hazard of death relative to d-MDS in every risk model, and had inferior survival compared to patients with d-MDS within all risk group categories. AIC Scores (lower is better) were 2316 (MPSS), 2343 (TPSS), 2343 (IPSS-R), 2361 (WPSS) and 2364 (IPSS). In conclusion, subsets of t-MDS patients with varying clinical outcomes can be identified using conventional risk stratification models. The MPSS, TPSS and IPSS-R provide the best predictive power.


Asunto(s)
Investigación Biomédica , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/mortalidad , Medición de Riesgo/métodos , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapia , Estadificación de Neoplasias , Pronóstico , Factores de Riesgo , Tasa de Supervivencia
2.
Leuk Res ; 36(10): 1283-9, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22840315

RESUMEN

Forty-eight patients received CPX-351 (liposome-encapsulated cytarabine:daunorubicin at a 5:1 molar ratio) every other day for 3 doses at 10 dose levels. Pharmacokinetic parameters were dose-independent and exhibited low inter-patient variability. CPX-351 showed a negligible distribution phase and prolonged mono-exponential first-order plasma elimination (t(1/2)∼24 h). The plasma ratio of 5:1 was maintained at all dose levels. Nearly all of the detectable cytarabine and daunorubicin in circulation following CPX-351 administration was in the form of liposome encapsulated drug. Dose-dependent hematopoietic effects had early onset with cytopenias at 12 units/m(2), and a gradual increase in frequency and severity, until single induction complete response was achieved at 43 units/m(2). Non-hematologic effects had onset by 24 units/m(2) with shallow dose-response until maximum frequency and severity were observed at the 101-134 units/m(2) dose levels. Single induction response occurred over a 2.3-fold range of doses indicating that CPX-351 may be useful at high doses for patients suitable for intensive chemotherapy and at reduced doses for patients at increased risk of treatment-related mortality. The unique pharmacologic features of CPX-351 contribute to its promising antileukemic efficacy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Femenino , Humanos , Leucemia/sangre , Liposomas , Masculino , Persona de Mediana Edad , Nanotecnología , Pronóstico
3.
Leukemia ; 25(12): 1808-14, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21760592

RESUMEN

This study of vosaroxin evaluated dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics (PK), clinical activity and pharmacodynamics in relapsed/refractory leukemia. Dosing was weekly (days 1, 8 and 15) or twice weekly (days 1, 4, 8 and 11). Seventy-three treated patients had a median age of 65 years, 85% had acute myeloid leukemia and 78% had refractory disease. Weekly schedule: 42 patients received 18-90 mg/m(2); MTD was 72 mg/m(2). Twice-weekly schedule: 31 patients received 9-50 mg/m(2); MTD was 40 mg/m(2). DLT was stomatitis; primary non-hematologic toxicity was reversible gastrointestinal symptoms and febrile neutropenia. Thirty-day all-cause mortality was 11%. Five patients had complete or incomplete remissions; median duration was 3.1 months. A morphologic leukemia-free state (bone marrow blast reduction to <5%) occurred in 11 additional patients. Antileukemic activity was associated with total dose or weekly time above 1 µmol/l plasma vosaroxin concentration (P<0.05). Vosaroxin exposure was dose proportional over 9-90 mg/m(2). The average terminal half-life was ~25 h and clearance was non-renal. No induction or inhibition of vosaroxin metabolism was evident. Vosaroxin-induced DNA damage was detected as increased intracellular γH2AX. Vosaroxin had an acceptable safety profile, linear PK and encouraging clinical activity in relapsed/refractory leukemia.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Naftiridinas/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Terapia Recuperativa , Tiazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Resultado del Tratamiento , Adulto Joven
4.
Leukemia ; 24(4): 699-705, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20111068

RESUMEN

Heat shock protein 90 (Hsp90) is a molecular chaperone with many oncogenic client proteins. The small-molecule Hsp90 inhibitor alvespimycin, a geldanamycin derivative, is being developed for various malignancies. This phase 1 study examined the maximum-tolerated dose (MTD), safety and pharmacokinetic/pharmacodynamic profiles of alvespimycin in patients with advanced acute myeloid leukemia (AML). Patients with advanced AML received escalating doses of intravenous alvespimycin (8-32 mg/m(2)), twice weekly, for 2 of 3 weeks. Dose-limiting toxicities (DLTs) were assessed during cycle 1. A total of 24 enrolled patients were evaluable for toxicity. Alvespimycin was well tolerated; the MTD was 24 mg/m(2) twice weekly. Common toxicities included neutropenic fever, fatigue, nausea and diarrhea. Cardiac DLTs occurred at 32 mg/m(2) (elevated troponin and myocardial infarction). Pharmacokinetics revealed linear increases in C(max) and area under the curve (AUC) from 8 to 32 mg/m(2) and minor accumulation upon repeated doses. Pharmacodynamic analyses on day 15 revealed increased apoptosis and Hsp70 levels when compared with baseline within marrow blasts. Antileukemia activity occurred in 3 of 17 evaluable patients (complete remission with incomplete blood count recovery). The twice-weekly administered alvespimycin was well tolerated in patients with advanced AML, showing linear pharmacokinetics, target inhibition and signs of clinical activity. We determined a recommended phase 2 dose of 24 mg/m(2).


Asunto(s)
Antineoplásicos/uso terapéutico , Benzoquinonas/administración & dosificación , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Lactamas Macrocíclicas/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Apoptosis/efectos de los fármacos , Crisis Blástica , Femenino , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , Infusiones Intravenosas , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Tasa de Supervivencia , Resultado del Tratamiento , Células Tumorales Cultivadas
6.
Ann Hematol ; 83 Suppl 1: S87-8, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15124688

RESUMEN

Farnesyltransferase inhibitors (FTIs) are small-molecule inhibitors that selectively inhibit farnesylation of a number of intracellular substrate proteins such as Ras. Preclinical work has revealed their ability to effectively inhibit tumor growth in vitro and in vivo in animal models across a wide range of malignant phenotypes. Myeloid malignancies are appropriate disease targets, in that they express relevant biologic targets, such as Ras, Mitogen-Activated Protein Kinase (MAPK), AKT, and others that may depend upon farnesyl protein transferase (FTase) activity to promote proliferation and survival. Phase I trials in acute leukemias and myelodysplasia have demonstrated biologic and clinical activities as determined by target enzyme inhibition, low toxicity, and both complete and partial responses. As a result, phase II trials have been initiated in a variety of hematologic malignancies and disease settings, in order to further validate clinical activity and to identify downstream signal transduction targets that may be modified by these agents. It is anticipated that these studies will serve to define the optimal roles of FTIs in patients with hematologic malignancies and provide insight into effective methods by which to combine FTIs with other agents.


Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Leucemia Mieloide/tratamiento farmacológico , Ensayos Clínicos como Asunto , Farnesiltransferasa , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Trastornos Mieloproliferativos/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos
7.
Semin Oncol ; 31(6 Suppl 18): 59-61, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15726525

RESUMEN

We and others have previously shown that the use of amifostine (Ethyol; MedImmune Inc, Gaithersburg, MD) can ameliorate certain regimen-related toxicities of high-dose melphalan (HD-MEL) in the autologous hematopoietic stem cell transplant setting. Our recent experience indicated that the maximum tolerated dose of HD-MEL plus autologous hematopoietic stem cell transplant could be increased from approximately 200 mg/m2 to at least 280 mg/m2 with amifostine. Although a dose-limiting toxicity was not clearly identified, atrial fibrillation was noted in several patients. Phase II trials using this regimen have been reported in lymphoma and myeloma. Nonetheless, it is unlikely that single agent therapy, regardless of dose, will be highly curative in advanced hematologic malignancy. Thus, we used amifostine to permit dose escalation of HD-MEL within the BEAM (BCNU/etoposide/arabinosylcytosine/HD-MEL) combination chemotherapy regimen before autologous hematopoietic stem cell transplant in selected patients with lymphoma. Patient entry at the starting dose (ie, HD-MEL 140 mg/m2) has been completed without the development of severe regimen-related toxicities. This trial is ongoing.


Asunto(s)
Amifostina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carmustina/uso terapéutico , Citarabina/uso terapéutico , Etopósido/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Linfoma/terapia , Melfalán/uso terapéutico , Adulto , Amifostina/toxicidad , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Carmustina/toxicidad , Terapia Combinada , Citarabina/toxicidad , Citoprotección , Etopósido/toxicidad , Humanos , Melfalán/toxicidad , Persona de Mediana Edad , Protectores contra Radiación/efectos adversos , Protectores contra Radiación/uso terapéutico , Trasplante Autólogo
8.
Leukemia ; 17(9): 1806-12, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12970780

RESUMEN

Patients with acute myelogenous leukemia or myelodysplastic syndrome may respond to farnesyl transferase inhibitors (FTIs) with partial or complete response rates noted in about 30% of such patients. FTIs prevent the attachment of a lipid farnesyl moiety to dependent proteins prior to their insertion into the plasma membrane and thereby prevent activity of these prenylation-dependent proteins, but their mechanism of tumor suppression remains unknown. Many patients receiving FTIs do experience myelosuppression. In this work, the in vitro effects of the FTI, R115777 on normal and leukemic hematopoiesis have been examined as have its effects on apoptosis induction and cell cycle profile in both leukemic blasts and normal CD34+ cells. R115777 was inhibitory to normal CD34+ cell proliferation and to leukemic blast cells, but did not affect long-term culture initiating cell frequency nor NOD-SCID reconstituting capacity. No induction of apoptosis or cell cycle changes were noted in AML blasts. These data suggest that myelosuppression with R115777 occurs largely at the intermediate to late progenitor stage of hematopoiesis and that cyclic use might avoid long-term marrow suppression.


Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Hematopoyesis/efectos de los fármacos , Leucemia/tratamiento farmacológico , Quinolonas/farmacología , Animales , Antígenos CD34/metabolismo , Apoptosis/efectos de los fármacos , Caspasa 3 , Caspasas/metabolismo , Adhesión Celular/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Ensayo de Unidades Formadoras de Colonias , Farnesiltransferasa , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Poli(ADP-Ribosa) Polimerasas/metabolismo , Factores de Tiempo , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/trasplante
9.
Curr Opin Oncol ; 13(6): 470-6, 2001 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11673687

RESUMEN

Farnesyltransferase inhibitors represent a new class of agents that target signal transduction pathways responsible for the proliferation and survival of diverse malignant cell types. Although these agents were developed to prevent a processing step necessary for membrane attachment and maturation of Ras proteins, recent studies suggest that farnesyltransferase inhibitors block the farnesylation of additional cellular polypeptides, thereby exerting antitumor effects independent of the presence of activating ras gene mutations. Clinical trials of two farnesyltransferase inhibitors--the tricyclic SCH66336 and the methylquinolone R115777--as single agents have demonstrated disease stabilization or objective responses in 10 to 15% of patients with refractory malignancies. Combinations of farnesyltransferase inhibitors with cytotoxic chemotherapies are yielding complete and partial responses in patients with advanced solid tumors. A phase I trial of R115777 in refractory and relapsed acute leukemias induced responses in 8 (32%) of 25 patients with acute myelogenous leukemia (including two complete remissions) and in two of three with chronic myelogenous leukemia in blast crisis. In patients with solid tumors, accessible normal tissues such as peripheral blood lymphocytes or, perhaps more germane to epithelial malignancies, buccal mucosa have provided surrogate tissues that allow confirmation that farnesyltransferase is inhibited in vivo at clinically achievable drug doses. In conjunction with the R115777 acute leukemia trial, serial measurements provided evidence of farnesyltransferase enzyme inhibition, interference with farnesyltransferase function ( ie, protein processing), and blockade of signal transduction pathways in leukemic bone marrow cells. Preclinical studies of farnesyltransferase inhibitor resistance and clinical trials of farnesyltransferase inhibitors in combination with other agents currently are in progress.


Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Piperidinas/farmacología , Piridinas/farmacología , Quinolonas/farmacología , Transferasas Alquil y Aril/metabolismo , Ensayos Clínicos como Asunto , Farnesiltransferasa , Humanos , Leucemia/tratamiento farmacológico , Leucemia/fisiopatología , Neoplasias/tratamiento farmacológico , Transducción de Señal
10.
Blood ; 97(11): 3361-9, 2001 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-11369625

RESUMEN

R115777 is a nonpeptidomimetic enzyme-specific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria. Non-dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression. R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (activated) form in 8 (36.4%) of 22 pretreatment marrows and became undetectable in 4 of those 8 after one cycle of treatment. Pharmacokinetics revealed a linear relationship between dose and maximum plasma concentration or area under the curve over 12 hours at all dose levels. Weekly marrow samples demonstrated that R115777 accumulated in bone marrow in a dose-dependent fashion, with large increases in marrow drug levels beginning at 600 mg bid and with sustained levels throughout drug administration. Clinical responses occurred in 10 (29%) of the 34 evaluable patients, including 2 complete remissions. Genomic analyses failed to detect N-ras gene mutations in any of the 35 leukemias. The results of this first clinical trial of a signal transduction inhibitor in patients with acute leukemias suggest that inhibitors of FT may have important clinical antileukemic activity. (Blood. 2001;97:3361-3369)


Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Quinolonas/uso terapéutico , Adulto , Anciano , Médula Ósea/metabolismo , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Farnesiltransferasa , Femenino , Genes ras , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mutación , Fosforilación , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Prenilación de Proteína , Quinolonas/efectos adversos , Quinolonas/farmacocinética , Recurrencia , Inducción de Remisión , Resultado del Tratamiento
11.
Hematol Oncol Clin North Am ; 14(1): 251-67, 2000 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-10680081

RESUMEN

Effective treatment of the elderly patient with AML remains a challenging task. Acute myelogenous leukemia is clearly a different disease in the elderly than in the young, for many reasons, both clinical and biologic, which contribute to the worse prognosis in the elderly. The elderly, as a group, have been underrepresented in clinical trials. Several important prognostic variables have been identified and described, however, that can help the physician select the appropriate treatment for any individual patient. Age itself should not preclude an attempt at therapy, especially for AML, which progresses very rapidly in the absence of treatment. After careful analysis of prognostic factors, in any individual patient, however, the outlook may be so poor that it may be desirable to withhold treatment. With a better understanding of the pathophysiology of AML in the elderly, more targeted and less toxic treatment regimens will become available. At present, however, clinicians must use an improved understanding of the disease to predict its behavior in an individual patient, so that the currently available treatment modalities are used most prudently.


Asunto(s)
Envejecimiento , Leucemia Mieloide Aguda , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Persona de Mediana Edad , Pronóstico
12.
Bone Marrow Transplant ; 22(3): 265-71, 1998 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-9720740

RESUMEN

Seventy consecutive patients with refractory or relapsed Hodgkin's disease who received high-dose chemotherapy followed by autologous stem cell rescue were analyzed to identify clinically relevant predictors of long-term event-free survival. High-dose therapy consisted primarily of carmustine (BCNU), etoposide, cytarabine and cyclophosphamide (BEAC). The 5-year Kaplan-Meier event-free survival (EFS) for the entire cohort was 32% (95% confidence interval; 18-45%) with a median follow-up of 3.6 years (range 7 months-7.6 years). The most significant predictor of improved survival was the presence of minimal disease (defined as all areas < or =2 cm) at the time of transplant: the 5 years EFS was 46 vs 10% for patients with bulky disease (P = 0.0002). Other independent predictors identified by step-wise regression analysis included the presence of non-refractory disease and the administration of post-transplant involved-field radiotherapy (XRT). Treatment-related mortality occurred in 13 of 70 patients: nine patients (13%) died within the first 100 days, mainly from cardiopulmonary toxicity. However, only one of 24 patients (4%) transplanted during the last 4.5 years died from early treatment-related complications. While high-dose therapy followed by autotransplantation led to long-term EFS of 50% for patients with favorable prognostic factors, a substantial proportion of patients relapsed, indicating that new therapeutic strategies are needed.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carmustina/efectos adversos , Carmustina/uso terapéutico , Terapia Combinada , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Citarabina/efectos adversos , Citarabina/uso terapéutico , Supervivencia sin Enfermedad , Etopósido/efectos adversos , Etopósido/uso terapéutico , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/radioterapia , Humanos , Masculino , Pronóstico , Radioterapia Adyuvante , Recurrencia , Trasplante Autólogo
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