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Navitoclax (ABT-263) is an oral BCL2 homology-3 mimetic that binds with high affinity to pro-survival BCL2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor also promotes apoptosis and inhibits tumor angiogenesis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. In this phase 1 study, we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). Maximum tolerated dose (MTD) was determined using the continual reassessment method. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. Ten patients were enrolled in the dose escalation cohort and 15 HCC patients were enrolled in the expansion cohort. Two dose levels were tested, and the MTD was navitoclax 150 mg daily plus sorafenib 400 mg twice daily. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities. Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, and there were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Navitoclax plus sorafenib is tolerable but showed limited efficacy in the HCC expansion cohort. These findings do not support further development of this combination for the treatment of advanced HCC. This phase I trial was conducted under ClinicalTrials.gov registry number NCT01364051.
Assuntos
Compostos de Anilina , Carcinoma Hepatocelular , Neoplasias Hepáticas , Sorafenibe , Humanos , Compostos de Anilina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Sulfonamidas/uso terapêuticoRESUMO
The day 14 bone marrow aspirate and biopsy (D14BM) is regularly used to predict achievement of complete remission (CR) with induction chemotherapy in acute myeloid leukemia (AML), however its utility has been questioned. Clearance of peripheral blood blasts (PBB) may serve as an early measure of chemosensitivity. PBB rate of clearance (PBB-RC) was calculated for treatment-naive AML patients (n = 164) undergoing induction with an anthracycline and cytarabine (7+3) and with detectable PBB at diagnosis. PBB-RC was defined as the percentage of the absolute PBB count on the day of diagnosis that was cleared with each day of therapy, on average, until D14 or day of PBB clearance. Each 5% increase in PBB-RC approximately doubled the likelihood of D14BM clearance (OR = 1·81; 95% CI: 1·24-2·64, P < 0·005). PBB-RC was also associated with improved CR rates (OR per 5% = 1·97; 95% CI: 1·27-3·01, P < 0·005) and overall survival (OS) [hazard ratio (HR) per 5% = 0·67; 95% CI: 0·52-0·87]. African American patients had poorer OS adjusted for PBB-RC (HR = 2·18; 95% CI: 1·13-4·23), while race was not associated with D14BM or CR rate. PBB-RC during induction chemotherapy is predictive of D14BM clearance, CR, and OS, and can therefore serve as a prognostic marker for clinical outcomes in AML.
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Crise Blástica/fisiopatologia , Leucemia Mieloide Aguda/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mieloide Aguda/complicações , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
The incorporation of L-asparaginase and pegylated asparaginase into pediatric-inspired regimens has conferred a survival advantage in treatment of adults with acute lymphoblastic leukemia. Use of asparaginase products requires careful prevention, monitoring, and management of adverse effects including hypersensitivity, hepatotoxicity, pancreatitis, coagulopathy, and thrombosis. Currently, there is limited published literature to offer guidance on management of these toxicities. At the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, a standard of practice guideline was created to prevent and manage asparaginase-related adverse events. By sharing our long-term experience with asparaginase products and clinical management of asparaginase-induced toxicities, this article aims to improve patient safety and optimize treatment outcomes.
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Antineoplásicos/administração & dosagem , Asparaginase/administração & dosagem , Institutos de Câncer/normas , Gerenciamento Clínico , Monitoramento de Medicamentos/normas , Polietilenoglicóis/administração & dosagem , Guias de Prática Clínica como Assunto/normas , Adulto , Antineoplásicos/efeitos adversos , Asparaginase/efeitos adversos , Pré-Escolar , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Humanos , Polietilenoglicóis/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Trombose/induzido quimicamente , Trombose/epidemiologia , Trombose/prevenção & controle , Resultado do TratamentoRESUMO
Adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with conventional chemotherapy have dismal outcomes. Novel immunotherapies targeting CD19, including the bispecific T-cell engager blinatumomab and chimeric antigen-receptor T (CAR-T) cells, have revolutionized the treatment of R/R B-ALL. Robust response rates to CAR-T cell therapy after blinatumomab have recently been reported, but it is unknown whether blinatumomab can be effective following failure of anti-CD19 CAR-T cell therapy. Herein, we describe a patient with Philadelphia chromosome-positive B-ALL who relapsed after CD19-directed CAR-T therapy, but subsequently responded to the combination of blinatumomab and the tyrosine kinase inhibitor ponatinib, with the achievement of a complete remission lasting 12 months.
Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos CD19/metabolismo , Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Piridazinas/uso terapêutico , Adulto , Terapia Baseada em Transplante de Células e Tecidos , Quimioterapia Combinada , Humanos , Masculino , Cromossomo Filadélfia , Receptores de Antígenos de Linfócitos T/uso terapêutico , RecidivaAssuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos CD19/análise , Antineoplásicos Imunológicos/uso terapêutico , Leucemia Aguda Bifenotípica/tratamento farmacológico , Terapia de Alvo Molecular , Adulto , Antígenos CD19/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem da Célula , Terapia Combinada , Citarabina/administração & dosagem , Dasatinibe/administração & dosagem , Daunorrubicina/administração & dosagem , Substituição de Medicamentos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunofenotipagem , Leucemia Aguda Bifenotípica/patologia , Leucemia Aguda Bifenotípica/terapia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Células-Tronco Neoplásicas/química , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Indução de RemissãoRESUMO
Depletion of glutamine (Gln) has emerged as a potential therapeutic approach in the treatment of acute myeloid leukemia (AML), as neoplastic cells require Gln for synthesis of cellular components essential for survival. Asparaginases deplete Gln, and asparaginase derived from Erwinia chrysanthemi (Erwinaze) appears to have the greatest glutaminase activity of the available asparaginases. In this Phase I study, we sought to determine the dose of Erwinaze that safely and effectively depletes plasma Gln levels to ≤ 120 µmol/L in patients with relapsed or refractory (R/R) AML. Five patients were enrolled before the study was halted due to issues with Erwinaze manufacturing supply. All patients received Erwinaze at a dose of 25,000 IU/m2 intravenously three times weekly for 2 weeks. Median trough plasma Gln level at 48 h after initial Erwinaze administration was 27.6 µmol/L, and 80% (lower limit of 1-sided 95% CI 34%) of patients achieved at least one undetectable plasma Gln value (< 12.5 µmol/L), with the fold reduction (FR) in Gln level at 3 days, relative to baseline, being 0.16 (p < 0.001 for rejecting FR = 1). No dose-limiting toxicities were identified. Two patients responded, one achieved partial remission and one achieved hematologic improvement after six doses of Erwinaze monotherapy. These data suggest asparaginase-induced Gln depletion may have an important role in the management of patients with AML, and support more pharmacologic and clinical studies on the mechanistically designed asparaginase combinations in AML.
Assuntos
Antineoplásicos/administração & dosagem , Asparaginase/administração & dosagem , Dickeya chrysanthemi/enzimologia , Glutamina/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Adulto JovemRESUMO
BACKGROUND: ABL1 gene translocations can be seen in precursor T-acute lymphoblastic leukemia (T-ALL). The typical translocation partner is the NUP214 gene. BCR-ABL translocations are relatively rare in this entity. Furthermore, while there have been unique patterns of amplification noted among the NUP214-ABL fusion genes, there have been few such reports among cases with BCR-ABL fusion genes. CASE PRESENTATION: Here we report a unique case of a 44-year old patient with T-ALL in which the blasts demonstrated a derivative chromosome 9 involving a 9;22 translocation and a dicentric Philadelphia chromosome 22 with a homogeneously staining region at the interface of the 9;22 translocation, leading to BCR-ABL1 gene amplification. Fluorescence in-situ hybridization (FISH) showed abnormal BCR/ABL1 fusions with the BCR-ABL1 gene amplification in 48% of the interphase cells analyzed. The translocation was confirmed by SNP array. CONCLUSIONS: We present a novel derivative chromosome 9 that shows BCR-ABL gene fusion along with a dicentric Philadelphia chromosome 22 with BCR-ABL1 gene amplification. This is a unique pattern of BCR-ABL fusion which has never been described in T-ALL. It is significant that the patient responded to standard treatment with the CALGB 10403 protocol and supplementation with a tyrosine kinase inhibitor. Identification of additional patients with this pattern of BCR-ABL fusion will allow for enhanced risk assessment and prognostication.
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Isocitrate dehydrogenase (IDH) mutations have been recognized in a few neoplasms including glioma, acute myeloid leukemia, chondrosarcoma, cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma. The direct methods to detect IDH mutations include DNA sequencing, immunohistochemistry (IHC), or by measuring its byproduct, 2-hydroxyglutarate (2-HG), in the blood or urine. Moreover, conventional magnetic resonance imaging can be modified to magnetic resonance spectroscopy (MRS) to measure 2-HG in tumor. By conducting a search in Medline/PubMed and ISI/Web of Science for the published articles in English related to the methods for detection of IDH mutations and its byproduct 2-HG, we compared different methodologies to detect these mutations and discuss advantages and limitations of each method. Studies in which a methodology of detection was compared with another modality were included. Multiple studies have shown that both DNA sequencing and IHC are reliable methods for detecting IDH mutations in glioma and other solid neoplasms. IHC appeared to be less costly, easier to perform, and may be slightly more accurate than DNA sequencing. 2-HG has also been measured in bone marrow aspirate, serum and urine of patients with mutant IDH acute myeloid leukemia, and correlated very well with sequencing and IHC. Lastly, in some glioma patients, MRS detected IDH mutations noninvasively and reliably with excellent correlations with other modalities such as IHC and sequencing. In conclusion, IHC, MRS, and 2-HG detection all are clinically useful and comparable with DNA sequencing in identifying IDH mutations in different neoplasms. 2-HG and MRS can be utilized for monitoring treatment response in a variety of neoplasms.
Assuntos
Glutaratos/análise , Isocitrato Desidrogenase/genética , Neoplasias/enzimologia , Neoplasias/fisiopatologia , Glutaratos/metabolismo , Humanos , Imuno-Histoquímica/normas , Espectrometria de Massas/normas , Mutação/genética , Neoplasias/genética , Análise de Sequência de DNA/normasRESUMO
The synthesis, characterization and antileukemic activity of rationally designed amino dimeric naphthoquinone (BiQ) possessing aziridine as alkylating moiety is described. Bis-aziridinyl BiQ decreased proliferation of acute myeloid leukemia (AML) cell lines and primary cells from patients, and exhibited potent (nanomolar) inhibition of colony formation and overall cell survival in AML cells. Effective production of reactive oxygen species (ROS) and double stranded DNA breaks (DSB) induced by bis-aziridinyl BiQ is reported. Bis-dimethylamine BiQ, as the isostere of bis-aziridinyl BiQ but without the alkylating moiety did not show as potent anti-AML activity. Systemic administration of bis-aziridinyl BiQ was well tolerated in NSG mice.
Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Naftoquinonas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos NOD , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Numerous solid tumors overexpress or have excessively activated insulin-like growth factor receptor-1 (IGF-1R). We summarize preclinical studies and the first-in-human study of KW-2450, an oral tyrosine kinase inhibitor with IGF-1R and insulin receptor (IR) inhibitory activity. Preclinical activity of KW-2450 was evaluated in various in vitro and in vivo models. It was then evaluated in a phase I clinical trial in 13 patients with advanced solid tumors (NCT00921336). In vitro, KW-2450 inhibited human IGF-1R and IR kinases (IC50 7.39 and 5.64 nmol/L, respectively) and the growth of various human malignant cell lines. KW-2450 40 mg/kg showed modest growth inhibitory activity and inhibited IGF-1-induced signal transduction in the murine HT-29/GFP colon carcinoma xenograft model. The maximum tolerated dose of KW-2450 was 37.5 mg once daily continuously; dose-limiting toxicity occurred in two of six patients at 50 mg/day (both grade 3 hyperglycemia) and in one of seven patients at 37.5 mg/day (grade 3 rash). Four of 10 evaluable patients showed stable disease. Single-agent KW-2450 was associated with modest antitumor activity in heavily pretreated patients with solid tumors and is being further investigated in combination therapy with lapatinib/letrozole in patients with human epidermal growth factor receptor 2-postive metastatic breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Receptor ErbB-2/genética , Receptor IGF Tipo 1/genética , Receptor de Insulina/genética , Adulto , Idoso , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Feminino , Humanos , Dose Máxima Tolerável , Camundongos , Receptor IGF Tipo 1/biossíntese , Receptor de Insulina/biossíntese , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: PARP is essential for recognition and repair of DNA damage. In preclinical models, PARP inhibitors modulate topoisomerase I inhibitor-mediated DNA damage. This phase I study determined the MTD, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib, an orally bioavailable PARP1/2 inhibitor, in combination with irinotecan. EXPERIMENTAL DESIGN: Patients with advanced solid tumors were treated with 100 mg/m(2) irinotecan on days 1 and 8 of a 21-day cycle. Twice-daily oral dosing of veliparib (10-50 mg) occurred on days 3 to 14 (cycle 1) and days -1 to 14 (subsequent cycles) followed by a 6-day rest. PK studies were conducted with both agents alone and in combination. Paired tumor biopsies were obtained after irinotecan alone and veliparib/irinotecan to evaluate PARP1/2 inhibition and explore DNA damage signals (nuclear γ-H2AX and pNBS1). RESULTS: Thirty-five patients were treated. DLTs included fatigue, diarrhea, febrile neutropenia, and neutropenia. The MTD was 100 mg/m(2) irinotecan (days 1 and 8) combined with veliparib 40 mg twice daily (days -1-14) on a 21-day cycle. Of 31 response-evaluable patients, there were six (19%) partial responses. Veliparib exhibited linear PK, and there were no apparent PK interactions between veliparib and irinotecan. At all dose levels, veliparib reduced tumor poly(ADP-ribose) (PAR) content in the presence of irinotecan. Several samples showed increases in γ-H2AX and pNBS1 after veliparib/irinotecan compared with irinotecan alone. CONCLUSIONS: Veliparib can be safely combined with irinotecan at doses that inhibit PARP catalytic activity. Preliminary antitumor activity justifies further evaluation of the combination. Clin Cancer Res; 22(13); 3227-37. ©2016 AACR.
Assuntos
Benzimidazóis/farmacocinética , Benzimidazóis/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/efeitos adversos , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Proteínas de Ciclo Celular/metabolismo , Reparo do DNA/genética , Feminino , Histonas/metabolismo , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Poli(ADP-Ribose) Polimerases/efeitos dos fármacosRESUMO
Selective targeting of the oxidative state, which is a tightly balanced fundamental cellular property, is an attractive strategy for developing novel anti-leukemic chemotherapeutics with potential applications in the treatment of acute myeloid leukemia (AML), a molecularly heterogeneous disease. Dimeric naphthoquinones (BiQs) with the ability to undergo redox cycling and to generate reactive oxygen species (ROS) in cancer cells are a novel class of compounds with unique characteristics that make them excellent candidates to be tested against AML cells. We evaluated the effect of two BiQ analogues and one monomeric naphthoquinone in AML cell lines and primary cells from patients. All compounds possess one halogen and one hydroxyl group on the quinone cores. Dimeric, but not monomeric, naphthoquinones demonstrated significant anti-AML activity in the cell lines and primary cells from patients with favorable therapeutic index compared to normal hematopoietic cells. BiQ-1 effectively inhibited clonogenicity and induced apoptosis as measured by Western blotting and Annexin V staining and mitochondrial membrane depolarization by flow cytometry. BiQ-1 significantly enhances intracellular ROS levels in AML cells and upregulates expression of key anti-oxidant protein, Nrf2. Notably, systemic exposure to BiQ-1 was well tolerated in mice. In conclusion, we propose that BiQ-induced therapeutic augmentation of ROS in AML cells with dysregulation of antioxidants kill leukemic cells while normal cells remain relatively intact. Further studies are warranted to better understand this class of potential chemotherapeutics.
RESUMO
BACKGROUND: Multimeric naphthoquinones are redox-active compounds that exhibit antineoplastic, antiprotozoal, and antiviral activities. Due to their multimodal effect on perturbation of cellular oxidative state, these compounds hold great potential as therapeutic agents against highly proliferative neoplastic cells. In our previous work, we developed a series of novel dimeric naphthoquinones and showed that they were selectively cytotoxic to human acute myeloid leukemia (AML), breast and prostate cancer cell lines. We subsequently identified the oxidoreductase NAD(P)H dehydrogenase, quinone 1 (NQO1) as the major target of dimeric naphthoquinones and proposed a mechanism of action that entailed induction of a futile redox cycling. RESULTS: Here, for the first time, we describe a direct physical interaction between the bromohydroxy dimeric naphthoquinone E6a and NQO1. Moreover, our studies reveal an extensive binding interface between E6a and the isoalloxazine ring of the flavin adenine dinucleotide (FAD) cofactor of NQO1 in addition to interactions with protein side chains in the active site. We also present biochemical evidence that dimeric naphthoquinones affect the redox state of the FAD cofactor of NQO1. Comparison of the mode of binding of E6a with those of other chemotherapeutics reveals unique characteristics of the interaction that can be leveraged in future drug optimization efforts. CONCLUSION: The first structure of a dimeric naphthoquinone-NQO1 complex was reported, which can be used for design and synthesis of more potent next generation dimeric naphthoquinones to target NQO1 with higher affinity and specificity.
Assuntos
Antineoplásicos/farmacologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Naftoquinonas/farmacologia , Antineoplásicos/química , Cristalografia por Raios X , NAD(P)H Desidrogenase (Quinona)/química , Naftoquinonas/química , Oxirredução , Ligação Proteica , Conformação ProteicaRESUMO
The incidence of acute myeloid leukemia (AML) is rising and the outcome of current therapy, which has not changed significantly in the last 40 years, is suboptimal. Cellular oxidative state is a credible target to selectively eradicate AML cells, because it is a fundamental property of each cell that is sufficiently different between leukemic and normal cells, yet its aberrancy shared among different AML cells. To this end, we tested whether a short-time treatment of AML cells, including cells with FLT3-ITD mutation, with sub-lethal dose of dichloroacetate (DCA) (priming) followed by pharmacologic dose of arsenic trioxide (ATO) in presence of low-dose DCA could produce insurmountable level of oxidative damage that kill AML cells. Using cellular cytotoxicity, apoptotic and metabolic assays with both established AML cell lines and primary AML cells, we found that priming with DCA significantly potentiated the cytotoxicity of ATO in AML cells in a synergistic manner. The combination decreased the mitochondrial membrane potential as well as expression of Mcl-1 and GPx in primary AML cells more than either drug alone. One patient with AML whose disease was refractory to several lines of prior treatments was treated with this combination, and tolerated it well. These data suggest that targeting cellular redox balance in leukemia may provide a therapeutic option for AML patients with relapsed/refractory disease.
Assuntos
Arsenicais/uso terapêutico , Ácido Dicloroacético/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Estresse Oxidativo , Óxidos/uso terapêutico , Trióxido de Arsênio , Linhagem Celular Tumoral , Humanos , Leucemia Mieloide Aguda/patologiaRESUMO
Purpose Filanesib (ARRY-520) is a highly selective, targeted inhibitor of kinesin spindle protein (KSP) inhibitor that induces mitotic arrest and subsequent tumor cell death. This first-in-human Phase 1 study evaluated dose-limiting toxicities (DLTs) and determined a maximum tolerated dose (MTD) for filanesib administered as a 1-h intravenous infusion on 2 treatment schedules in patients with advanced solid tumors. The pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of filanesib were also evaluated. Methods Filanesib was administered on Day 1 of each 3-week cycle (Initial Schedule) or Days 1 and 2 of each 2-week cycle (Alternate Schedule). A standard 3 + 3 dose-escalation design was employed. An expansion cohort was conducted at the MTD of the Initial Schedule. Filanesib PK was evaluated in plasma (both schedules) and urine (Initial Schedule only). Monopolar spindle formation was evaluated in biopsies taken from patients in the expansion cohort. Results Forty-one patients received filanesib. The MTD was equivalent for both the Initial and Alternate Schedules (2.50 mg/m(2)/cycle). The prevalence of neutropenia as a DLT for both schedules necessitated adding prophylactic filgrastim to another dose escalation on the Alternate Schedule (highest tolerated dose 3.20 mg/m(2)/cycle). Neurotoxicity related to filanesib was not observed. Dose-proportional increases in filanesib exposure were observed. The half-life for filanesib was ~70 h. Monopolar spindles in patient biopsy samples indicated KSP inhibition. Stable disease was the best tumor response observed in 18 % (7/39) of evaluable patients. Conclusion Filanesib provided exposures with acceptable tolerability and evidence of target-specific pharmacodynamic effects.
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Antineoplásicos/farmacologia , Cinesinas/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Tiadiazóis/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Meia-Vida , Humanos , Masculino , Dose Máxima Tolerável , Proteínas de Membrana , Pessoa de Meia-Idade , Tiadiazóis/administração & dosagem , Tiadiazóis/efeitos adversos , Tiadiazóis/farmacocinéticaRESUMO
Patients with acute leukemia develop venous thrombosis (VT) related to central venous catheters (CVCs). Anticoagulation (AC) in these patients who are thrombocytopenic and often coagulopathic is challenging. To evaluate the safety and efficacy of AC in treating CVC-related VT, we retrospectively compared outcomes of patients with acute leukemia who were treated or not with AC during induction chemotherapy and post-discharge. Twenty-one patients with CVC-related VT received AC, 14 did not. VT resolved in 80% of patients in the AC group (similarly with low-dose and high-dose enoxaparin) and 45% in the non-AC group (p = 0.11). Fourteen (67%) patients in the AC group are alive (median survival not reached), compared to four patients (29%) in the non-AC group (median survival 9 months) (p = 0.015) with a hazard ratio (HR) of 0.32 (95% confidence interval: 0.12-0.85) in favor of AC. HR remained < 1 after adjustments for leukemia type and cytogenetics. Bleeding (< grade 4) occurred in five and one patients in the AC vs. non-AC groups, respectively (p = 0.37).
Assuntos
Anticoagulantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cateterismo Venoso Central/efeitos adversos , Hemorragia/tratamento farmacológico , Leucemia/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Trombose Venosa/tratamento farmacológico , Doença Aguda , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Seguimentos , Hemorragia/etiologia , Humanos , Leucemia/complicações , Leucemia/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/complicações , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Trombose Venosa/etiologiaRESUMO
BACKGROUND: Racial disparity in the incidence of multiple myeloma is well established; however, to the authors' knowledge, little is known regarding the impact of racial differences on disease characteristics, response to therapy, and clinical outcome. METHODS: The authors studied 453 patients (174 of whom were black and 279 of whom were white) who underwent transplant between 2000 and 2013. The median follow-up was 4.4 years. RESULTS: Black patients were significantly younger than white patients (median age, 54 years vs 59 years; P<.0001), more frequently presented with anemia (P = .04), had more of the immunoglobulin G isotype (P<.001), and had a borderline favorable cytogenetic risk (P = .06). Overall response to induction was similar, but deeper responses were observed in more white patients compared with black patients receiving immunomodulatory drug-based induction (P = .02). Referral for transplant was significantly delayed in black individuals (median, 1.3 years vs 0.9 years; P = .003). Overall survival from the time of transplant was similar for black and white patients, with medians of 6.2 years and 5.7 years, respectively, but survival from the time of diagnosis was significantly longer among black individuals (median, 7.7 years vs 6.1 years; P = .03). Maintenance therapy was found to positively impact progression-free survival but not overall survival, irrespective of race. CONCLUSIONS: The results of the current study confirm ethnic differences in age, referral patterns, response to therapy, and overall survival. Future validation of these disparities is urgently needed.
Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Mieloma Múltiplo/etnologia , População Branca/estatística & dados numéricos , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/etnologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Transplante AutólogoRESUMO
PURPOSE: To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospholipid modulator of signal transduction, using different oral loading and maintenance regimens in an effort to avoid gastrointestinal toxicity while seeking maximal sustained plasma concentrations. METHODS: Thirty-one patients with advanced neoplasms were treated with monthly cycles of perifosine loading doses of 300, 600, 900, 1,200 and 1,500 mg (dose levels 1 through 5, respectively) on days 1-2 depending on the actual dose of the initial cycle. For subsequent cycles, perifosine loading doses were reduced to 100, 200, 300, 400 and 1,000 mg at the respective corresponding dose levels. Daily perifosine "maintenance" doses of 50, 100, 150, 200 and 250 mg for levels 1 through 5, respectively, commenced on days 2 or 3 and continued for a total of 21 days. No treatment was given for days 22-27. The pharmacokinetics of perifosine with these schedules was characterized. RESULTS: Dose-limiting diarrhea developed at or above dose level 4. The MTD and recommended phase II dose was dose level 3B, with a loading dose of 900 mg on day 1 divided into two doses of 450 mg administered 6 h apart and a maintenance dose of 150 mg on day 2 through 21. On subsequent cycles, the loading dose was reduced to 300 mg. Non-gastrointestinal toxicities included three episodes of gout or gout-like syndromes observed at doses above the MTD. The median peak plasma concentration of perifosine achieved at the MTD was approximately 8.3 µg/mL. Four patients had stable disease ranging from 167 to 735 days. CONCLUSIONS: Perifosine given according to a loading and maintenance schedule can safely sustain concentrations of drug, approaching concentrations achieved in preclinical models with evidence of anti-tumor effect.
Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fosforilcolina/análogos & derivados , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anorexia/induzido quimicamente , Área Sob a Curva , Diarreia/induzido quimicamente , Progressão da Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Fadiga/induzido quimicamente , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias/patologia , Fosforilcolina/efeitos adversos , Fosforilcolina/farmacocinética , Resultado do Tratamento , Adulto JovemRESUMO
Asparaginases are among the most effective agents against acute lymphoblastic leukemia (ALL) and are Food and Drug Administration-approved for the treatment of pediatric and adult ALL. However, the efficacy of these drugs for the treatment of other hematologic malignancies particularly acute myeloid leukemia is not well established. The mechanism of action of asparaginases has thought to be related to a swift and sustained reduction in serum L-asparagine, which is required for rapid proliferation of metabolically demanding leukemic cells. However, asparagine depletion alone appears not to be sufficient for effective cytotoxic activity of asparaginase against leukemia cells, because glutamine can rescue asparagine-deprived cells by regeneration of asparagine via a transamidation chemical reaction. For this reason, glutamine reduction is also necessary for full anti-leukemic activity of asparaginase. Indeed, both Escherichia coli and Erwinia chrysanthemi asparaginases possess glutaminase enzymatic activity, and their administrations have shown to reduce serum glutamine level by deamidating glutamine to glutamate and ammonia. Emerging data have provided evidence that several types of neoplastic cells require glutamine for the synthesis of proteins, nucleic acids, and lipids. This fundamental role of glutamine and its metabolic pathways for growth and proliferation of individual malignant cells may identify a special group of patients whose solid or hematologic neoplasms may benefit significantly from interruption of glutamine metabolism. To this end, asparaginase products deserve a second look particularly in non-ALL malignant blood disorders. Here, we review mechanisms of anti-tumor activity of asparaginase focusing on importance of glutamine reduction, pharmacology of asparaginase products, in vitro activities as well as clinical experience of incorporating asparaginase in therapeutic regimens for non-ALL hematologic malignancies.