RESUMEN
The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49-8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9-8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1-7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.
Asunto(s)
Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Bencimidazoles/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Terapia Molecular Dirigida , Mutación , Adulto , Anciano , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/efectos adversos , Compuestos de Anilina/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Médula Ósea/patología , Análisis Mutacional de ADN , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Isocitrato Deshidrogenasa/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Acute myeloid leukemia (AML) characterized by Feline McDonough Sarcoma-like tyrosine kinase-3 (FLT-3) internal tandem duplication (ITD) mutations have poor outcomes. Treatment options are limited, because these mutations confer resistance to conventional chemotherapy. FLT-3 inhibitors such as sorafenib have been studied as a single agent and in combination with conventional chemotherapy or azacytidine with fair responses. PATIENTS AND METHODS: Here we describe our preclinical and clinical experience with the combination of the DNA hypomethylating agent, decitabine and sorafenib for the treatment of FLT-3 ITD-mutant AML. RESULTS: In vitro treatment of the human FLT-3 ITD-mutant AML cell line, MV4-11, with both drugs significantly improved growth inhibition over single-agent therapy and resulted in synergistic antitumor effects (combination index < 1). A case series of 6 patients treated with off protocol combination of decitabine and sorafenib demonstrated overall responses in 5 patients (83%) with a median survival of 155 days. Four of the 5 patients (80%) with relapsed/refractory AML achieved complete responses with incomplete count recovery. The combination was also well tolerated. CONCLUSION: Further investigation is warranted to confirm these responses.
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Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Azacitidina/administración & dosificación , Azacitidina/uso terapéutico , Línea Celular Tumoral , Decitabina , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Persona de Mediana Edad , Mutación , Niacinamida/administración & dosificación , Niacinamida/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Sorafenib , Análisis de SupervivenciaRESUMEN
INTRODUCTION: Homoharringtonine (HHT) and other alkaloid esters were originally isolated from the Cephalotaxus evergreen tree and have been used in traditional Chinese medicine since the 1970s to treat a variety of malignancies. Although HHT was investigated for the treatment of chronic myeloid leukemia (CML) in the 1990s with good results, the advent of BCR-ABL1 tyrosine kinase inhibitors (TKIs) at that time rapidly established a new standard of care for CML. Omacetaxine mepesuccinate is a semisynthetic derivative of HHT with known clinical activity in relapsed or refractory CML following TKI therapy. AREAS COVERED: In this review, we summarize the biologic effects of HHT and its derivative, omacetaxine, in CML. Additionally, we analyze the concepts learned from the early trials using these drugs. Data from clinical trials resulting in drug approval are also reviewed. EXPERT OPINION: Omacetaxine has a clear role in the CML armamentarium for patients in chronic and accelerated phase who have failed or were intolerant to two or more TKIs.
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Antineoplásicos/uso terapéutico , Harringtoninas/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Animales , Antineoplásicos/farmacocinética , Ensayos Clínicos como Asunto , Harringtoninas/farmacocinética , Homoharringtonina , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patologíaRESUMEN
Dual differentiation therapy with arsenic trioxide and tretinoin (all-trans-retinoic acid; ATRA) for the management of low and intermediate risk acute promyelocytic leukemia has recently been recommended by the National Comprehensive Cancer Network. Some less common toxicities of the combination may have yet to be fully realized. Of ten patients we have treated thus far, five (50%) have developed pseudotumor cerebri. In one patient, temporary discontinuation of ATRA and initiation of acetazolamide controlled symptoms. In four patients, topiramate was substituted for acetazolamide to relieve symptoms and allow ATRA dose re-escalation. We conclude that providers should monitor for pseudotumor cerebri and consider topiramate if acetazolamide fails.
RESUMEN
BACKGROUND: Several studies have suggested that low 25(OH) vitamin D3 levels may be prognostic in some malignancies, but no studies have evaluated their impact on treatment outcome in patients with acute myeloid leukemia (AML). METHODS: Vitamin D levels were evaluated in 97 consecutive, newly diagnosed, intensively treated patients with AML. MicroRNA expression profiles and single nucleotide polymorphisms (SNPs) in the 25(OH) vitamin D3 pathway genes were evaluated and correlated with 25(OH) vitamin D3 levels and treatment outcome. RESULTS: Thirty-four patients (35%) had normal 25(OH) vitamin D3 levels (32-100 ng/mL), 34 patients (35%) had insufficient levels (20-31.9 ng/mL), and 29 patients (30%) had deficient levels (<20 ng/mL). Insufficient/deficient 25(OH) vitamin D3 levels were associated with worse relapse-free survival (RFS) compared with normal vitamin D3 levels. In multivariate analyses, deficient 25(OH) vitamin D3 , smoking, European Leukemia Network genetic group, and white blood cell count retained their statistical significance for RFS. Several microRNAs and SNPs were associated with 25(OH) vitamin D3 levels, although none remained significant after multiple test corrections; one 25(OH) vitamin D3 receptor SNP, rs10783219, was associated with a lower complete remission rate (P = .0442) and with shorter RFS (P = .0058) and overall survival (P = .0011). CONCLUSIONS: It remains to be determined what role microRNA and SNP profiles play in contributing to low 25(OH) vitamin D3 level and/or outcome and whether supplementation will improve outcomes for patients with AML.
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Calcifediol/sangre , Colecalciferol/sangre , Regulación Neoplásica de la Expresión Génica , Leucemia Mieloide Aguda/sangre , MicroARNs/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Polimorfismo de Nucleótido Simple/genética , Pronóstico , Receptores de Calcitriol/genética , Transcriptoma , Resultado del TratamientoRESUMEN
Timing of the anti-angiogenic agent with respect to the chemotherapeutic agent may be crucial in determining the success of combination therapy in cancer. We investigated the effects of sequential therapy with the potent VEGF inhibitor, aflibercept, and doxorubicin (DOX) in preclinical acute myeloid leukemia (AML) models. Mice were engrafted with human HL-60 and HEL-luciferase leukemia cells via S.C. and/or I.V. injection and treated with two to three doses of aflibercept (5-25 mg/kg) up to 3-7 days prior to doxorubicin (30 mg/kg) administration. Leukemia growth was determined by local tumor measurements (days 0-16) and systemic bioluminescent imaging (days 0-28) in animals receiving DOX (3 mg/kg) with or without aflibercept. A PK/PD model was developed to characterize how prior administration of aflibercept altered intratumoral DOX uptake. DOX concentration-time profiles were described using a four-compartment PK model with linear elimination. We determined that intratumoral DOX concentrations were 6-fold higher in the aflibercept plus DOX treatment group versus DOX alone in association with increased drug uptake rates (from 0.125 to 0.471 ml/h/kg) into tumor without affecting drug efflux. PD modeling demonstrated that the observed growth retardation was mainly due to the combination of DOX plus TRAP group; 0.00794 vs. 0.0043 h(-1). This PK/PD modeling approach in leukemia enabled us to predict the effects of dosing frequency and sequence for the combination of anti-VEGF and cytotoxic agents on AML growth in both xenograft and marrow, and may be useful in the design of future rational combinatorial dosing regimens in hematological malignancies.